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WO2008016095A1 - REMÈDE PRÉVENTIF OU CURATIF POUR LES KÉRATOCONJONCTIVITES CONTENANT UN ACTIVATEUR DE Nrf2 EN TANT QUE MATIÈRE ACTIVE - Google Patents

REMÈDE PRÉVENTIF OU CURATIF POUR LES KÉRATOCONJONCTIVITES CONTENANT UN ACTIVATEUR DE Nrf2 EN TANT QUE MATIÈRE ACTIVE Download PDF

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WO2008016095A1
WO2008016095A1 PCT/JP2007/065126 JP2007065126W WO2008016095A1 WO 2008016095 A1 WO2008016095 A1 WO 2008016095A1 JP 2007065126 W JP2007065126 W JP 2007065126W WO 2008016095 A1 WO2008016095 A1 WO 2008016095A1
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group
corneal
acid
methyl
nrf2
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Japanese (ja)
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Masatsugu Nakamura
Shin-Ichiro Hirai
Atsushi Yoshida
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Santen Pharmaceutical Co Ltd
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Santen Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • 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
    • A61K31/095—Sulfur, selenium, or tellurium compounds, e.g. thiols
    • A61K31/10—Sulfides; Sulfoxides; Sulfones
    • 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
    • A61K31/12—Ketones
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • 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
    • 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

Definitions

  • Nrf 2 activator an agent for the prophylaxis or treatment of keratoconjunctival disorders comprising Nrf 2 activator as an active ingredient
  • the present invention relates to dry eye comprising puncta activating substance as an active ingredient, punctate surface keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis dry, upper ring keratoconjunctivitis, filamentous
  • the present invention relates to an agent for the prophylaxis or treatment of keratoconjunctival disorders such as keratoconjunctivitis, infectious keratitis, noninfectious keratitis, infectious conjunctivitis, noninfectious conjunctivitis and the like.
  • a living body regulates the balance between oxidation and antioxidation, and functions by maintaining the intracellular redox state constant.
  • the state in which the balance between oxidation and antioxidation is inclined in the direction of oxidation is called oxidation stress.
  • Oxidative stress modifies and damages biopolymers such as lipids, DNA and proteins, causing cell dysfunction and cell death, causing carcinogenesis, hypertension, arteriosclerosis, cranial nerve disease, inflammation, asthma, skin disease, It is known to be deeply involved in the onset and progression of age-related chronic diseases such as age-related macular degeneration and cataract.
  • the defense mechanism that maintains a constant level of oxidation-antioxidation is a vital defense system for the living body, and enhancing the ability to protect against oxidative stress is useful for the prevention and treatment of these diseases. It is thought! /, Ru (nonpatent literature 1).
  • Nrf2 NF-E2 related factor 2
  • NF-E2 related factor 2 is a glutathion S transferase that directly detoxifies electrophilic substances, quinone oxidoreductase and ⁇ , ⁇ ⁇ ⁇ ⁇ Phase 2 enzyme and hemoxigenase, and peroxidase ⁇ ⁇ ⁇ ! It is a transcription factor that induces / regulates the expression of genes such as oxidases.
  • Nrf2 In steady state (unstimulated state), Nrf2 forms a complex with Keapl (Kelch-like ECH associated protein 1) in the cytoplasm and is in the inactive state to oxidative stress such as electrophilic substance or reactive oxygen species. When exposed, the interaction with Keapl is diminished (the dissociation is promoted) and it shifts to the nucleus. Nrf 2 transferred to the nucleus forms a heterodimer with a small Maf (Musculo pauro otic Fibrosarcoma) group factor, and the target sequence is the antioxidant response. It binds to a promoter called antioxidant responsive element (ARE) and induces gene expression of the above-mentioned enzymes.
  • ARE antioxidant responsive element
  • Nrf2 gene-deficient mice mice in which the Keapl-Nrf 2 system is disrupted (Nrf2 gene-deficient mice), the balance of oxidation-antioxidation in the cells is lost, and the oncogenic potential (progesteral carcinogenesis due to benzpyrene, 2) Torosamine causes bladder cancer etc.), foreign body / sensitivity to oxidative stress (hepatotoxicity caused by acetoaminophen, lung injury caused by exposure to high oxygen etc.), inflammation 'immune system abnormality (glomerulonephritis, systemic self It has been reported to show immune diseases, cigarette-induced emphysema etc.).
  • functional loss of Nrf 2 causes oxidative stress and induces cancer, hypertension, brain neurodegenerative diseases, inflammation and inflammation, and / or other diseases (Non-patent Document 3).
  • Nrf 2 activation of Nrf 2 is considered to be very effective in the prevention and amelioration of diseases associated with oxidative stress.
  • Orchibrazo or sulforaphan known as a substance that activates Nrf 2 suppresses foresite carcinogenesis caused by benzpyrene
  • Orchibraz a substance that activates Nrf 2 suppresses bladder carcinogenesis caused by nitrosamine. Is reported! /, (Non-patent document 3).
  • Non-Patent Documents 4 to 5 and Patent Documents 3 to 4 show the usefulness of Nrf 2 activators for age-related macular degeneration and cataract, which are ophthalmic diseases associated with oxidative stress.
  • Age-related macular degeneration is a degeneration accompanied by age-related changes in the macula, and it is known that retinaldehyde (all-trans- retinaldehyde) accumulated by exposure to ultraviolet light and oxidative stress damage retinal pigment cells.
  • Non-Patent Document 4 and Patent Document 1 report that Nrf 2 activators such as sulforaphan and bis 2-hydroxybenzylideneacetone suppress this cell damage.
  • Non-Patent Document 5 reports that curcumin, an Nrf2 activator, suppresses galactose-induced cataract.
  • Patent Documents 2 and 3 describe a method for treating drusen formation of age-related macular degeneration, Nb 2 activator, retinopathy associated with diabetic retinopathy and glaucoma, and optic neuropathy.
  • Nrf2 activating substances on corneal and conjunctival disorders such as dry eye, corneal ulcer, keratitis and conjunctivitis.
  • Nrf2 activity There are no reports to examine the preventive and ameliorating effects of chemical substances on dry eye.
  • Patent Document 1 International Publication 03/51313 brochure
  • Patent Document 2 International Publication 2005/063249 Pamphlet
  • Patent Document 3 International Publication No. 2005/063295 brochure
  • Non-patent literature l Biomed. Pharmacother. 57, 251-60 (2003)
  • Non-patent literature 2 J. Biol. Chem., 278, 14, 12029-38 (2003)
  • Nonpatent literature 3 A separate volume “medical history of medicine” medicine of redox stress defense, 46-9 (2005)
  • Nonpatent literature 4 Proc. Natl. Acad. Sci., 101, 10446-51 (2004)
  • Non-patent literature 5 Mol. Vis., 9, 223-30 (2003)
  • Nrf2 activators searching for new medical applications is an interesting task.
  • Nrf2 activators have conducted intensive studies to search for new pharmaceutical uses of Nrf2 activators, and it has been reported that compounds having the ability to activate Nrf2 S, human corneal epithelium We also found that in cells, we control the gene expression of foreign phase 2 enzymes and antioxidative enzymes. Furthermore, the present inventors have found that the Nrf2 activating substance exerts an excellent preventive and ameliorating effect on corneal disorders in a corneal disorder healing efficacy test using a corneal disorder model, and has led to the present invention.
  • dry eye punctate superficial keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, upper ring keratoconjunctivitis containing Nrf2 activator as an active ingredient.
  • It is an agent for the prophylaxis or treatment of keratoconjunctival disorders such as filamentous keratoconjunctivitis, infectious keratitis, noninfectious keratitis, infectious conjunctivitis, non-infectious conjunctivitis and the like.
  • the Nrf2 activating substance of the present invention is a compound having an action of activating the transcription factor Nrf2, and the activation of Nrf2 forms a complex with Nrf2 to form a cytoplasm. Dissociating from the trapped Keapl. In addition, as a result of this dissociation, Nrf2 is transferred to the nucleus to induce gene expression of foreign-phase metabolizing system phase 2 enzymes, antioxidative enzymes, etc. 2 Activators also have the effect of promoting the transfer of Nrf2 to the nucleus.
  • the Nrf2 activating substance of the present invention is, for example, (1) Michael reaction acceptor, (2) diphenols, quinones, butylated hydroxysoles, butylated hydroxytoluenes, (3) (4) hydroperoxides, (5) mercaptans, in particular vicinal dithiols in which two thiol groups are adjacent, (6) 1,2 dithiolthiones, (7) thiocarbamates (8) Arsenic compounds, (9) Heavy metals, (10) Diaryl sulfide, Indole-3-indole rubinol, Epigallocatechin gallate, Ellagic acid, Ethoxyquin, Carotenoids, Conjugated polyenes, 4, 4 Dimethyl- 3 , 4-dihydro-2H-1, 2-benzoselenadines, isohumulonic acid, isomerized hop extract (WO2006 / 043671), salts thereof, etc.
  • Examples of the Michael reaction acceptor include compounds having a carbon-carbon double bond linked to an electron withdrawing group such as a carbonyl group, a tolyl group or a nitro group ( ⁇ , 13 unsaturated carbonyl compound etc.) Specifically, maleic acid derivatives (Jechiru maleic acid, maleic phosphate dimethyl like), fumaric acid derivatives, 1 twelve Torrox 1 cyclohexene Shikuro, 2- Mechiren 4-butyrolactone, 15 Dokishi eighteen 12 '14 — Prostaglandin J, 7 (E) — [6—
  • R R R R R R and R are the same or different and are a hydrogen atom or an alkyl group
  • X represents a hydrogen atom, a halogen atom, a nitro group, a cyano group, an aldehyde group or a carboxyl group,
  • Y represents a cyano group or CO-Z
  • Z represents a hydrogen atom, a halogen atom, a hydroxyl group, an alkoxy group, an amino group or an imidazole ring
  • aromatic heterocyclic ring selected from the group consisting of triazole ring and benzoimidazole ring.
  • the aromatic heterocycle defined above may be substituted by a halogen atom, an alkyl group or a phenyl group.
  • diphenols, quinones, butylated hydroxysoles and butylated hydroxylones are exemplified by catechol, taercetin, carnosol, rosmanol, epirosmanol, carnozic acid, etc.
  • tert butyl hydroxytoluene etc. are mentioned.
  • isothiocyanates 1-isothiocyanato-4 (methylsulfier) butane (hereinafter, also referred to as “sulforaphane”), 6 And the like, and also include duccosinolate which is a precursor of isothiocyanates, dulcolaphanin (precursor of sulforaphan), and the like.
  • hydroperoxides include tammen hydroperoxide, tert butyl hydroperoxide and the like.
  • Examples of mercaptans include 2,3 dimercaptopropanol, 1,2 ethanedithiol and the like! /, And two thiol groups adjacent to each other! /, Vicinal dithiols and the like.
  • 1, 2 dithiol thiones 4-methyl-5 pyrazine 3H-1, 2-dithiol 3-thione (hereinafter, also referred to as "oltipraz"), 1, 2-dithiol thione, acetonetol trithion etc. It can be mentioned.
  • Examples of thiocarbamates include pyrrolidine thiocarbamate and the like.
  • As an example of the arsenic compound trivalent arsenous acid (NaAsO) etc.
  • Examples include compounds having the property of binding to two adjacent thiol groups with an arsenic compound of two.
  • heavy metals such as HgCl (Hg 2+ ), CdCl (Cd 2+ ), ZnCl (Zn 2+ ), etc.
  • CDD 0 As preferable examples of the compound represented by the general formula [I], 2 Shenau 3, 12 dioxooreana 1, 9 (11) Gen 28 Oic Acid (hereinafter referred to as “CDD 0” represented by the following Formula [II] (Also referred to as “CD”), a 2-cyano 3, 12 dioxooreana one represented by the following formula [III] 1, 9 (11) Gen 28 acid acid methyl ester (hereinafter also referred to as “CDDO-Me”), or 1 [2 SHANO 3, 12 dioxooreana 1, 9 (11)-GEN-28 oil] imidazole (hereinafter also referred to as "CDDO-Im”) represented by [IV] can be mentioned.
  • CDDO-Me 2-cyano 3, 12 dioxooreana one represented by the following formula [III] 1, 9 (11) Gen 28 acid acid methyl ester
  • CDDO-Im 1 [2 SHANO 3, 12 dioxooreana 1, 9 (1
  • the Nrf 2 activators of the present invention include those of various chemical structures, and no common point is found in the chemical structures.
  • SH (thiol) group is reactive as a property which is almost common to various substances having different structures.
  • the fact is that the activation power S of Nrf2, S, and the three-dimensional three-dimensional structure of chemical substances In recognition of its reactivity (electrophilicity), it suggests that it is!
  • Nrf2 is trapped in the cytoplasm by interacting with Keapl's Kelch domain and is in an inactive state.
  • Keapl has a region called IVR, and the action of the electrophilic substance in this region promotes the conformational change of the Kelch domain and attenuates the interaction with Nrf 2, thereby dissociating Nrf 2. It is believed to be More specifically, it is believed that IVR has a highly reactive cysteine residue and promotes the change in the conformation of Kelch domain by the covalent bond between this cysteine residue and an electrophilic substance. (Biology, 76 (4), P. 339- 48 (2004)).
  • Nrf2 activating substance of the present invention broadly refers to a electrophilic compound having reactivity with SH group.
  • Nrf 2 activating substance can also be examined by using the amount of Nrf 2 in the nucleus as an indicator, as in the test method described later (Example 1).
  • the compounds represented by the general formula [I] can be prepared according to the usual methods in the field of synthetic organic chemistry, and the methods described in JP 2002-530272 and ⁇ ⁇ 2004/064723 have been described. Based on! /, You can even manufacture S power.
  • alkyl refers to linear or branched alkyl having 1 to 8 carbon atoms, preferably linear to branched alkyl having from 6 to 6 carbon atoms. Specific examples thereof include methyl, ethyl, ⁇ -propyl, ⁇ -butyl, ⁇ -pentyl, ⁇ -hexyl, isopropyl, isobutyl, isopentyl, isohexyl, sec-butyl, t-butyl and the like.
  • Alkoxy represents a linear or branched alkoxy having 1 to 8 carbon atoms, and preferably represents a linear or branched alkoxy having from 6 to 6 carbon atoms. Specific examples thereof include methoxy, ethoxy, n-propoxy, ⁇ -butoxide, ⁇ -pentoxy, n-hexenoryloxy, isopropoxy, isobutoxy, isopentoxy, isohexyloxy, sec-butoxy, t-butoxy and the like.
  • the halogen atom is fluorine, chlorine, bromine or iodine.
  • the salts of the present compound are not particularly limited as long as they are pharmaceutically acceptable salts, and sodium salts, potassium salts, lithium salts, calcium salts, magnesium salts, zinc salts, iron salts, manga And salts with inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid, salts with organic acids such as acetic acid, fumaric acid, maleic acid, oxalic acid and tartaric acid, etc., and quaternary ammonium salts Included in the salts in the invention.
  • the compounds may be in the form of hydrates and solvates.
  • optical isomers, geometric isomers, tautomers, polymorphs and the like of the present compound are included in the scope of the present invention.
  • the keratoconjunctival disorder refers to a condition in which the cornea or the conjunctiva is damaged due to various factors such as tear abnormality, metabolic abnormality, external injury, etc.
  • tear abnormality for example, dry eye, point Superficial keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis sicca, upper limb keratoconjunctivitis, filamentous keratoconjunctivitis, infective keratitis, noninfectious keratitis, infective conjunctivitis, noninfection Sexual conjunctivitis etc. are mentioned.
  • dry eye refers to tear reduction, xerostomia, oryalgia, Shiedaren syndrome, keratoconjunctivitis sicca, Stevens Johnson syndrome, lacrimal gland dysfunction, meibomian gland dysfunction, blepharitis, VDT (Visual Display Terminal) Check the keratoconjunctival disorder associated with work, surgery, medicine, trauma, contact lens wearing, etc. or a symptom associated with the keratoconjunctival disorder.
  • the agent for preventing or treating corneal and conjunctival disorders of the present invention can be administered orally or parenterally (such as eye drops and percutaneous administration).
  • Dosage forms include eye drops, eye ointments, gels, skin ointments, injections, tablets, capsules, granules, fine granules, powders and the like. These can be formulated using widely used techniques.
  • tonicity agents such as sodium chloride and concentrated glycerin
  • buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monohydrate, polyoxyl stearate, polyoxyethylene hydrogenated castor Surfactants such as oils, stabilizers such as sodium citrate and sodium edetate, preservatives such as benzalkonium chloride and benzene, etc.
  • the pH may be within the range acceptable for the ophthalmic preparation, but a range of 4 to 8 is preferred.
  • An eye ointment can be prepared using a commonly used base such as white petrolatum, liquid paraffin, etc.
  • a commonly used base such as white petrolatum, liquid paraffin, etc.
  • extenders such as lactose, crystalline cellulose, starch and vegetable oil, lubricants such as magnesium stearate and talc, hydroxypropyl cellulose Binder such as Polyvinyl pyrrolidone
  • a disintegrating agent such as calcium hydroxide, a coating agent such as hydroxypropyl methyl cellulose, macrogol, silicone resin or the like, a gelatin film or the like may be added.
  • the present invention also relates to a method for preventing or treating keratoconjunctival disorder, comprising administering to a patient an effective amount of Nrf2 activator.
  • the dosage of the Nrf2 activating substance of the present invention may generally be changed in the case of an oral preparation, depending on the dosage form, the severity of the condition of the patient to be administered, the age, the body weight, and the judgment of the physician. It is possible to administer 0. 0;! To 5000 mg, preferably ⁇ 0.1 to 2500 mg, more preferably ⁇ 0.5 to 5 per adult; per single or several divided doses of OO mg per adult. . Also, in the case of eye drops or penetrants, it is possible that: 0. 000001; 10% (w / v), preferably 0. 00001-1% (w / v), more preferably 0 ⁇ 0001-0. 1 % (w / v) of the active ingredient concentration can be administered once or several times a day.
  • Nrf2 tert-Butyl hydroquinone which has been reported to have Nrf2 activating ability, Oltipras', sulforafuan, carnozic acid, carnosone acid, carnosolole, canorectin, CDDO, CDDO- Me and CDDO- Im
  • tert-Butyl hydroquinone which has been reported to have Nrf2 activating ability
  • Oltipras' sulforafuan
  • carnozic acid carnosone acid
  • carnosolole canorectin
  • CDDO CDDO- Me
  • CDDO- Im tert-Butyl hydroquinone
  • Target gene glutamate cysteine ligase regulation sub-unit Glutamate-cysteine ligase, modifier subunit: hereinafter also referred to as “GCLM”
  • GCLM Target gene glutamate cysteine ligase regulation sub-unit
  • TRxR thioredoxin reductase
  • Heme oxygenase 1 Heme oxidogenase 1: hereinafter also referred to as “H01”
  • NAD P
  • H quinone oxidoreductase NAD
  • P H quinone oxidoreductase 1:
  • NQ 01 NAD
  • Nrf2 activating substance induces and controls gene expression of foreign substance metabolism system phase 2 enzymes (for example, NQOl) and antioxidant enzymes (for example, HO 1) also in human corneal epithelial cells.
  • foreign substance metabolism system phase 2 enzymes for example, NQOl
  • antioxidant enzymes for example, HO 1
  • target genes GCLM, TRxR, HOI and NQOl whose expression is regulated by Nrf2, in human corneal epithelial cells in 4,4 Dimethyl-3,4 Dihydro-2H-1,2-Benzo selenazine Indicated.
  • 4,4 Dimethyl-3, 4-Dihydro-2H-1, 2-Benzo selenazine has the ability to activate Nrf2, and it is a foreign phase metabolising phase 2 enzyme in human corneal epithelial cells and Inducible control of gene expression of antioxidant enzymes.
  • Nrf2-activating substances tert-butylhydroquinone, ortiplusa ', sulforaphane, carnosonere, curcumin, 4, 4-dimethynole-3, 4-dihydro-2H-1, 2-benzoserenadine , CDDO, CDDO-Me and CDDO-Im showed superior improvement in the corneal injury model.
  • the Nrf2 activator is dry eye, punctate surface keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, dry keratitis, upper ring keratoconjunctivitis, filamentous keratoconjunctivitis, infectious keratitis, It is useful as a preventive or therapeutic agent for keratoconjunctival disorders such as noninfectious keratitis, infectious conjunctivitis and noninfectious conjunctivitis.
  • the amount of nuclear Nrf2 can be used as an indicator to determine whether it has Nrf2 activation ability.
  • Hepatic cancer cells can be used to evaluate whether a compound has the ability to activate Nrf2.
  • monolayer HepG2 cells are cultured in alpha MEM medium containing 10% fetal bovine serum, and when reaching subconfluent, medium is replaced with the medium containing the test compound. After 24 hours of culture, the nuclear extract is collected as described in the method of Abhinav. Jain et al. (J. Biol. Chem., 280, 32, 29158-29168 (2005)), and immunoblotted. Determine the amount of Nrf2. If the amount of Nrf2 in the nuclear extract of cells treated with the test compound is increased as compared to control cells without the test compound, it can be judged that the compound has Nrf2 activating ability.
  • Xenobiotic metabolism system in human corneal epithelial cells of compounds reported to have Nrf2 activating ability and 4,4 dimethyl-3,4-dihydro-2H 1, 2-benzoserenadine.
  • HCE-T SV40 immortalized human corneal epithelial cells obtained from RIKEN BioResource Center. 6 Ueno plates were seeded with 1 ⁇ 10 5 HCE-T and cultured for 3 days at 37 ° C., 5% CO. Culture 40 ⁇ 15% fetal bovine serum (ICN)
  • DMEM / Ham's F12 (Nacalai Tester) containing / mL gentamycin (Gibco) was used.
  • the culture broth was removed, tert-butyl hydroquinone (100 M), ortibraz (100%), 4, 4-dimethyl-3, 4-dihydro-2-, 1-, 2-benzoselenadine (15%), sulforaphane Change to a culture medium containing (15%), carnozic acid (15%), carnosol (15%), curcumin (15 ⁇ ), CDDO (IOONM), CDDO-Me ( ⁇ ) or CDDO-Im ( ⁇ ) And cultured at 37 ° C., 5% CO 2 for 12 hours.
  • the compound was dissolved in DMSO and adjusted to the above concentration by diluting 1000 times with culture solution.
  • a culture solution containing only DMSO was used as a base culture solution.
  • RNA is extracted from the cells using RNeasy Mini Kit (manufactured by Qiagen), and Oligo (dT) primer (manufactured by Invitrogen) and M-MLV Reverse Transcriptase dnvitrogen) are used.
  • cDNA was synthesized.
  • primers of the following sequence and the QuantiTectTM SYBR Green PCR Kit manufactured by Qiagen
  • various types can be used with the ABI PrismTM 7000 Sequence Detection System (manufactured by Applied Systems Inc.)
  • the gene expression level was measured.
  • the gene expression level was corrected using Glyceraldehyde 3-phosphate dehydrogenase (hereinafter referred to as “GAPDH”), which is a housekeeping key gene, as an internal standard.
  • GPDH Glyceraldehyde 3-phosphate dehydrogenase
  • Nrf2 As apparent from Table 3, in all the compounds used in this test, an increase in the expression level of the target gene GCLM, TRxR, NQOl and HOI induced and controlled by Nrf2 was observed.
  • Compounds such as tBHQ, oltipraz, sulforafuan, carnozic acid, carnosol, clorectin, CDDO, CDDO-Me and CDDO-Im have been reported to activate Nrf 2 in various cells. These Nrf 2) It has been shown that the activator also regulates and regulates the gene expression of foreign phase 2 enzymes and anti-oxidant enzymes in human corneal epithelial cells.
  • BXT-51072 induces and regulates gene expression of foreign-type metabolic system phase 2 enzymes and antioxidant enzymes in human corneal epithelial cells, as in the case of the above-mentioned Nrf2-activating substance. Therefore, it was suggested that BXT-51072 has Nrf 2 activation ability.
  • Michael reaction acepter represented by curcumin, CDDO, CDDO-Me and CDDO-Im, diphenols represented by carnozic acid and carnosol, quinones represented by tBHQ, and isothi represented by sulforaphane Nrf2 activators such as ionates, 1,2-dithiolethione represented by Orchibraz, and BXT-51072 Gene expression of foreign phase 2 phase enzyme and antioxidant enzyme also in human corneal epithelial cells Induction control It was shown to do.
  • a corneal injury model was prepared according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1) 96-100 (2001)). Miyata et al.'S method (Ophthalmology Clinic, 48 (2), 183-188 (1994)) after modification of the corneal injury model (Modified Ophthalmology, 21 (1), 87-90 (2004)) The rate of improvement of corneal disorder was determined.
  • Nrf2 activators tBHQ, altipraz, BXT-51072, sulforaphane, carnosol and curcumin were administered as follows.
  • Physiological saline containing alchibraz 500 M was instilled in both eyes 6 times a day for 14 days (group of 4 animals: 8 eyes).
  • a saline solution containing BXT-51072 (25 M) was instilled in both eyes six times a day for 14 days (group of 4 animals: 8 eyes).
  • a saline solution containing sulfoorophane (25 M) was instilled in both eyes 6 times a day for 14 days (group of 4 animals: 8 eyes).
  • CDDO Me Eye Drop Group
  • the degree of staining with fluorescein was scored according to the following criteria, and the improvement rate of the corneal disorder was calculated from the average value of the total score in each portion. Also for normal eyes, the average value of the total score of each part was calculated.
  • Staining is moderate, and a part of spot-like stained parts are adjacent.
  • Improvement rate (%) ⁇ (control)-(test compound) ⁇ / degree of failure X 100
  • Mykenore reaction oxidators represented by Talcmin, CDDO, CDDO-Me and CDDO-Im, Diphenols represented by Carnosol, Quinones represented by tBHQ, Isothiocyanates represented by Sulforaphane It has been shown that it has an improving effect on Nrf2 activator power S such as 1,2-dithiolthiones represented by ortho-blaz and BXT-51072 and corneal disorder.
  • the concentrations were 0.10% (w / v), 0. 03% (w / v), 0.1% (w / v), 0. 3% (w) / v), 1% (w / v) eye drops can be prepared.
  • the concentration is 0 ⁇ 05% (w / v), 0.3% (w / v) by changing the amount of addition of orchibraz
  • An eye drop of 0.5% (w / v) and 1% (w / v) can be prepared.
  • the concentration becomes 0.05% (w / v), 0.1% (w
  • Curcumin and lactose are mixed in a mixer, and carboxymethyl cellulose and hydroxypropyl cellulose are added to the mixture to granulate, and the resulting granules are dried and sized, and the sized granules are stearic acid. Add magnesium, mix and tablet with a tablet press. In addition, by changing the amount of curcumin added, tablets having a content of 0.1 mg, 10 mg and 50 mg in 100 mg can be prepared.
  • the present invention provides dry eye containing puncta Nrf2 activator as an active ingredient, punctate surface keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, keratoconjunctivitis dry, upper ring keratoconjunctivitis, filamentous It is possible to provide an agent for preventing or treating keratoconjunctival disorders such as keratoconjunctivitis, infectious keratitis, noninfectious keratitis, infectious conjunctivitis, noninfectious conjunctivitis and the like.

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Abstract

La présente invention concerne un remède préventif ou curatif innovant des kératoconjonctivites. L'invention concerne un activateur de Nrf2 qui régule l'induction de l'expression des gènes d'une enzyme métabolisante xénobiotique de phase II, d'une enzyme antioxydante, etc., dans des cellules épithéliales cornéennes et qui exerce donc un excellent effet d'amélioration dans un modèle d'affection cornéenne. Par conséquent, il est utilisable en tant que remède préventif ou curatif des kératoconjonctivites telles que l'œil sec, la kératopathie ponctuée, le défaut épithélial cornéen, l'érosion de la cornée, l'ulcère cornéen, le défaut épithélial conjonctival, la kératoconjonctivite sèche, la kératoconjonctivite limbique supérieure, la kératoconjonctivite filamenteuse, la kératite infectieuse, la kératite non infectieuse, la conjonctivite infectieuse, la conjonctivite non infectieuse, etc.
PCT/JP2007/065126 2006-08-02 2007-08-02 REMÈDE PRÉVENTIF OU CURATIF POUR LES KÉRATOCONJONCTIVITES CONTENANT UN ACTIVATEUR DE Nrf2 EN TANT QUE MATIÈRE ACTIVE Ceased WO2008016095A1 (fr)

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US8124799B2 (en) 2008-04-18 2012-02-28 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: oleanolic acid derivatives with amino and other modifications at C-17
US8129429B2 (en) 2008-01-11 2012-03-06 Reata Pharmaceuticals, Inc. Synthetic triterpenoids and methods of use in the treatment of disease
WO2012009171A3 (fr) * 2010-07-15 2012-04-19 The Schepens Eye Research Institute, Inc. Compositions et méthodes de traitement de troubles de l'endothélium cornéen
US8258329B2 (en) 2008-04-18 2012-09-04 Reata Pharmaceuticals, Inc. Dehydroandrosterone analogs including an anti-inflammatory pharmacore and methods of use
US8394967B2 (en) 2008-04-18 2013-03-12 Reata Pharmaceuticals, Inc. Antioxidant inflammation modulators: C-17 homologated oleanolic acid derivatives
WO2013164512A3 (fr) * 2012-05-04 2014-03-20 Universidad De Valladolid Composition utilisée dans le traitement et/ou la prévention d'inflammation, de stress oxydant et de néovascularisation oculaire
US8993640B2 (en) 2012-04-27 2015-03-31 Reata Pharmaceuticals, Inc. 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
US9000188B2 (en) 2008-07-22 2015-04-07 Trustees Of Dartmouth College Monocyclic cyanoenones and methods of use thereof
US9174941B2 (en) 2010-12-17 2015-11-03 Reata Pharmaceuticals, Inc. Pyrazolyl and pyrimidinyl tricyclic enones as antioxidant inflammation modulators
US20160000809A1 (en) * 2011-12-29 2016-01-07 Industry-Academic Cooperation Foundation, Yonsei University Pharmaceutical composition for treatment of eye pain, containing pge2 synthesis inhibitor
US9278912B2 (en) 2012-09-10 2016-03-08 Reata Pharmaceuticals, Inc. C13-hydroxy derivatives of oleanolic acid and methods of use thereof
WO2016037971A1 (fr) * 2014-09-08 2016-03-17 Bios Line S.P.A. Compositions comportant des précurseurs de glucosinolates de sulforaphane en combinaison avec des extraits de romarin
US9290536B2 (en) 2011-03-11 2016-03-22 Reata Pharmaceuticals, Inc. C4 monomethyl triterpenoid derivatives and methods of use thereof
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