WO2020090967A1 - Inhibiteur d'expression de gène induisant une fibrose et son utilisation - Google Patents

Inhibiteur d'expression de gène induisant une fibrose et son utilisation Download PDF

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WO2020090967A1
WO2020090967A1 PCT/JP2019/042747 JP2019042747W WO2020090967A1 WO 2020090967 A1 WO2020090967 A1 WO 2020090967A1 JP 2019042747 W JP2019042747 W JP 2019042747W WO 2020090967 A1 WO2020090967 A1 WO 2020090967A1
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group
fibrosis
phenyl
present
lower alkyl
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PCT/JP2019/042747
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English (en)
Japanese (ja)
Inventor
初音 榎本
秀尚 立木
幹郎 中嶋
要 大山
洋志 曽木
敬天 宮元
達夫 稲嶺
崇二 寺井
顕也 上村
規裕 酒井
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東和薬品株式会社
国立大学法人 長崎大学
国立大学法人 新潟大学
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Priority to JP2020554030A priority Critical patent/JPWO2020090967A1/ja
Publication of WO2020090967A1 publication Critical patent/WO2020090967A1/fr

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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • 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

Definitions

  • the present invention relates to a fibrosis induction gene expression inhibitor and its use.
  • non-alcoholic fatty liver disease is known as a form of liver disease leading to cirrhosis.
  • NAFLD non-alcoholic fatty liver
  • NASH non-alcoholic steatohepatitis
  • there is no effective therapeutic drug at each stage of NAFLD Non-Patent Document 1).
  • the expression inhibitor of the fibrosis-inducing gene of the present invention is a compound represented by the following formula (I), a salt thereof, or a solvate thereof. Including: In the formula (I), R, R 0 and R 1, which may be the same or different, are independently hydrogen atoms; or R and R 0 are present on adjacent carbon atoms and are taken together to form a bond.
  • R 2 is a hydrogen atom, lower alkyl group, phenyl group, cyano-phenyl group, trifluoromethyl-phenyl group, halogenated phenyl group, lower alkoxy-phenyl group, hydroxy-phenyl group, lower alkyl-phenyl group, phenyl- A lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R 1 and R 2 together form a lower alkylidene group or di- [ (Lower alkoxy or hydroxy) -phenyl] -lower alkylidene group; or R 1 and R 2 together form a straight-chain alkylene group having 4 to 6 carbon atoms or ortho-phenylene bridged 2 carbon atom
  • the drug for fibrosis of the present invention contains the expression inhibitor of the fibrosis-inducing gene of the present invention.
  • the expression inhibitor of the fibrosis-inducing gene of the present invention is, as described above, a compound represented by the following formula (I), a salt thereof, or a solvate thereof (hereinafter, referred to as “the compound of the present invention or a salt thereof, etc. Also referred to as “”.
  • R, R 0 and R 1 which may be the same or different, are independently hydrogen atoms; or R and R 0 are present on adjacent carbon atoms and are taken together to form a bond.
  • the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene, as described above.
  • expression suppression may be, for example, suppression of transcription from a target gene, suppression of production amount of a transcript from the target gene, suppression of activity of the transcript, or of the target gene. It may be suppression of translation from mRNA, suppression of the amount of translation product produced from the target gene, or suppression of activity of the translation product.
  • the “expression suppression” may be, for example, suppression of transcription of a functional transcript or suppression of translation of a functional translation product.
  • the protein include a mature protein or a precursor protein before being subjected to processing or post-translational modification. The suppression of expression can be confirmed, for example, by measuring the production amount of the transcription product, the activity of the transcription product, the production amount of the translation product, or the activity of the translation product.
  • expression suppression means that the expression level of the fibrosis-inducing gene is (significantly) decreased as compared with the absence of the expression inhibitor of the present invention (non-administration condition). However, the expression level of the fibrosis-inducing gene may be higher than that at the start (at the start of administration). In this case, the “expression suppression” can also be referred to as, for example, “maintaining the expression amount”, “suppressing the increase in the expression amount”, or the like.
  • the fibrosis-inducing gene includes, for example, TGF- ⁇ (Transforming Growth Factor- ⁇ ), CTGF (Connective Tissue Growth Factor), ⁇ -SMA ( ⁇ -Smooth Muscle Actin) and YAP1 (Yes-associated Protein 1). ) Etc.
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • CTGF Connective Tissue Growth Factor
  • ⁇ -SMA ⁇ -Smooth Muscle Actin
  • YAP1 Yes-associated Protein 1).
  • Etc examples include TGF- ⁇ 1, TGF- ⁇ 2, TGF- ⁇ 3, TGF- ⁇ 4, TGF- ⁇ 5 and the like, and preferably TGF- ⁇ 1 or TGF- ⁇ 2.
  • the compound of the present invention has an asymmetric carbon atom.
  • the compounds of the present invention may, for example, exist as racemates, their R and S enantiomers, or mixtures of R and S in any proportion.
  • the compounds of the present invention may have more than one asymmetric center.
  • the compounds of the invention may include diastereomers and mixtures thereof.
  • the compound of the present invention may include geometrical isomer forms, for example, cis and trans isomers.
  • lower in an organic group or compound means, for example, one having 7 or less, 4 or less, or 1 or 2 carbon atoms (number of carbon atoms).
  • the lower alkyl group is, for example, an alkyl group containing 1 to 4 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a propyl group or a butyl group, and preferably a methyl group.
  • the modification position of the cyano group and the number of substitutions thereof are not particularly limited, and examples thereof include any one of 2-position, 3-position, 4-position, 5-position and 6-position of the phenyl ring, and 2-position. One, or three or more.
  • the modification position of the halogen group is, for example, any one, two, three, two, three, four, five and six positions of the phenyl ring. One, four, or five.
  • the modified position of the lower alkoxy group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position and 6-position of the phenyl ring. , Or five.
  • the lower alkoxy group is, for example, an alkoxy group containing 1 to 4 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, or a tert-butoxy group. , And preferably a methoxy group or an ethoxy group.
  • the modification position of the hydroxy group is, for example, any one of the 2-position, 3-position, 4-position, 5-position and 6-position of the phenyl ring, 2, 3, 4, or There are five.
  • the modification position of the lower alkyl group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position and 6-position of the phenyl ring. , Or five.
  • the modification position of the hydroxy group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position and 6-position of the phenyl ring. One or five.
  • the modification position of the cyano group is, for example, any one, two, three, four of the 2-position, 3-position, 4-position, 5-position and 6-position of the phenyl ring. , Or five.
  • the pyridyl group is a 2-, 3- or 4-pyridyl group, preferably a 3- or 4-pyridyl group, and more preferably a 3-pyridyl group.
  • the thienyl group is, for example, a 2- or 3-thienyl group, preferably a 2-thienyl group.
  • the lower alkylidene group is preferably a linear lower alkylidene group, more preferably a methylidene group or an ethylidene group.
  • the alkylene group having 4 to 6 carbon atoms is preferably a butylene group or a pentylene group.
  • the linear alkylene group having 2 to 4 carbon atoms which is crosslinked with ortho-phenylene is preferably CH 2 CH 2 which is crosslinked with ortho-phenylene.
  • R and R 0 are a hydrogen atom or a lower alkyl group; or R and R 0 are taken together, together with a benzene ring to which they are bound, naphthalene. You may form a ring.
  • the substituent-phenyl group (substituted phenyl group) in R 2 is a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, a trifluoromethyl group, or a cyano group. Substituted phenyl groups are preferred.
  • the compound represented by the formula (I) may be, for example, a compound in which W is a 1-imidazolyl (imidazole) group or a lower alkyl-substituted 1-imidazolyl (imidazole) group, and W is The compound may be a 1- (1,2,4 or 1,3,4) -triazolyl group, or W may be a 3-pyridyl group.
  • R and R 0 are independently a hydrogen atom; or R and R 0 are present on adjacent carbon atoms and are combined together, Forms a naphthalene ring with the benzene ring to which they are bonded;
  • R 1 is a hydrogen atom;
  • R 2 is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted A phenyl-lower alkyl group, a thienyl group, or a pyridyl group; or R 1 and R 2 together are a lower alkylidene group or an alkylene group having 4 to 6 carbon atoms;
  • W is 1- (1 , 2,4 or 1,3,4) -triazolyl group or 3-pyridyl group; the substituted phenyl group is a lower alkyl group, a lower alkoxy group, a hydroxy group, a
  • the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (II).
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group or a benzyl group
  • R 2 ′ is a phenyl group monosubstituted by a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, or a trifluoromethyl group on the phenyl ring, or a cyano group or a hydroxy group, respectively.
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is a hydrogen atom, a lower alkyl group or a pyridyl group; or R 2 ′ is unsubstituted or on a phenyl ring, A cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, or a phenyl group mono-substituted with a halogen group, or a benzyl group mono-substituted with a cyano group or a hydroxy group; and R 3 is a hydrogen atom. More preferably.
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group or a 3- or 4-pyridyl group
  • R 2 ′ Is, on its phenyl ring, a phenyl group mono-substituted with a cyano group, a halogen group, a lower alkoxy group, a lower alkyl group, or a trifluoromethyl group, or a benzyl group mono-substituted with a cyano group or a hydroxy group, respectively. More preferably, it is a group; R 3 is a hydrogen atom.
  • R 1 ′ and R 3 are hydrogen atoms; and R 2 ′ is 3-pyridyl group, p-cyanobenzyl group, or p-cyanophenyl group. ..
  • the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (III).
  • R 2 ′ is a 3-pyridyl group, a p-cyanobenzyl group or a p-cyanophenyl group.
  • R and R 0 are independently a hydrogen atom; or R and R 0 are present on adjacent carbon atoms and are combined together, Forms a naphthalene ring with the benzene ring to which they are bonded;
  • R 1 is a hydrogen atom;
  • R 2 is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted A phenyl-lower alkyl group, a thienyl group, or a pyridyl group; or R 1 and R 2 together are a lower alkylidene group or an alkylene group having 4 to 6 carbon atoms; and W is a 1-imidazolyl group.
  • the substituted phenyl group is a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, a trifluoromethyl group. And is preferably a phenyl group substituted with 1 substituent selected from cyano group.
  • the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (V).
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is mono-substituted with a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group, a benzyl group; a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group or a trifluoromethyl group.
  • a phenyl group; or a benzyl group monosubstituted with a cyano group or a hydroxy group on the phenyl ring (respectively, a cyano-phenyl-methyl group, a hydroxy-phenyl-methyl group); or R 1 ′ and R 2 ′ Represents a lower alkylidene group together; or R 1 ′ and R 2 ′ together represent a straight chain alkylene group having 4 to 6 carbon atoms; R 3 is a hydrogen atom or a lower alkyl group.
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group, a 3- or 4-pyridyl group
  • R 3 is in the 4-position or It is preferably a hydrogen atom at the 5-position or a lower alkyl group.
  • R 1 ′ and R 3 are hydrogen atoms;
  • R 2 ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group, a 3- or 4-pyridyl group.
  • the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (VI).
  • R 2 ′ is a 3-pyridyl group, a p-cyanobenzyl group or a p-cyanophenyl group.
  • the expression inhibitor of the present invention preferably contains, for example, a compound represented by the following formula (VII).
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group, or a benzyl group
  • R 2 ′ is a cyano group, a lower alkyl group, a lower alkoxy group on the phenyl ring.
  • R 1 ′ and R 3 are hydrogen atoms;
  • R 2 ′ is a hydrogen atom, a lower alkyl group, or a pyridyl group; or
  • R 2 ′ is a non-hydrogen atom.
  • R 1 ′ and R 3 are hydrogen atoms;
  • R 2 ′ is a hydrogen atom, a lower alkyl group, a benzyl group, a phenyl group, or 3- or 4-pyridyl a group; or, R 2 'is in its phenyl ring, respectively, a cyano group, a halogen group, a lower alkoxy group, a lower alkyl group or a trifluoromethyl group-substituted phenyl group, or a cyano group or a hydroxy, More preferably, it is a benzyl group mono-substituted with a group.
  • R 1 ′ and R 3 each represent a hydrogen atom;
  • R 2 ′ represents a 3- or 4-pyridyl group, a p-cyanobenzyl group, or a p-cyanophenyl group. Is most preferred.
  • the compound of the present invention may be, for example, an isomer.
  • the isomers include tautomers and stereoisomers.
  • Examples of the tautomers or stereoisomers include all theoretically possible tautomers or stereoisomers.
  • the configuration of each substituent is not particularly limited.
  • the compound of the present invention may be, for example, a solvate such as a hydrate of the compound represented by the above formula (I) or a salt thereof.
  • the compound of the present invention is represented by, for example, the above formulas (I) to (VII), and a specific example thereof is letrozole.
  • the compound of the present invention may be, for example, a solvate.
  • the description of the compound of the present invention can be applied to the description of the salt of the compound of the present invention or a solvate thereof.
  • the salt of the compound of the present invention is not particularly limited and is, for example, a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is not particularly limited, and examples thereof include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; ammonium salt; trimethylamine salt, triethylamine salt, Aliphatic amine salts such as dicyclohexylamine salt, ethanolamine salt, diethanolamine salt and triethanolamine salt; aralkylamine salts such as N, N-dibenzylethylenediamine; heterocycles such as pyridine salt, picoline salt, quinoline salt and isoquinoline salt Aromatic amine salts; quaternary ammonium salts such as tetramethylammonium salt, tetraethylammonium salt, benzyltrimethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, t
  • the expression inhibitor of the present invention may be used, for example, in vivo or in vitro .
  • the expression-suppressing agent of the present invention can be used, for example, as a research reagent or a pharmaceutical. In the latter case, the expression-suppressing agent of the present invention can also be referred to as a drug or pharmaceutical composition for suppressing the expression of the fibrosis-inducing gene.
  • the administration subject of the expression inhibitor of the present invention is not particularly limited.
  • the subject to be administered includes, for example, humans or non-human animals other than humans.
  • the non-human animals include mammals such as mice, rats, rabbits, dogs, sheep, horses, cats, goats, monkeys and guinea pigs, birds, fish and the like.
  • the administration target includes, for example, cells, tissues, organs, etc.
  • the cells include, for example, cells collected from a living body, cultured cells and the like.
  • the tissue or organ include a tissue (living tissue) or an organ collected from a living body.
  • the cells include hepatocytes, iPS cells (induced pluripotent stem cells), stem cells and the like.
  • the hepatocyte means, for example, a cell constituting the liver.
  • the use condition (administration condition) of the expression inhibitor of the present invention is not particularly limited, and for example, the administration form, administration timing, dose and the like can be appropriately set according to the type of administration subject.
  • the dose of the expression inhibitor of the present invention is not particularly limited.
  • the expression inhibitor of the present invention when used in vivo, it can be appropriately determined depending on, for example, the type of subject to be administered, symptoms, age, administration method and the like.
  • the total dose of the compound per day is, for example, 0.001 to 30 mg / kg, preferably 0.05 to 5 mg / kg.
  • the administration frequency is, for example, 1 to 5 times, 1 to 3 times, and preferably once.
  • the dose of the compound per day is, for example, 2.5 mg, and the number of administrations per day is, for example, once.
  • the content of the compound in the expression inhibitor is not particularly limited and can be appropriately set depending on, for example, the above-mentioned daily dose.
  • the administration form of the expression inhibitor of the present invention is not particularly limited.
  • the expression inhibitor of the present invention may be administered orally or parenterally.
  • the parenteral administration includes, for example, intravenous injection (intravenous administration), intramuscular injection (intramuscular administration), transdermal administration, subcutaneous administration, intradermal administration, enteral administration, rectal administration, vaginal administration, nasal administration, Examples include pulmonary administration, intraperitoneal administration, and local administration.
  • the dosage form of the expression-suppressing agent of the present invention is not particularly limited and can be appropriately determined depending on, for example, the above-mentioned administration form.
  • Examples of the dosage form include liquid form and solid form.
  • Specific examples of the dosage form include modified release preparations (enteric-coated preparations, sustained-release preparations, etc.), capsules, oral liquid preparations (elixir preparations, suspensions, emulsions, aromatic water preparations, limonade preparations, etc.), syrup preparations.
  • injection preparations such as injections (implanted injections, continuous injections, infusions (drip preparations), freeze-dried injections, powder injections, filled syringes, cartridges, etc.); dialysis agents (Peritoneal dialysis agents, hemodialysis agents) and other dialysis preparations; inhalants (inhalation agents) Aerosols, inhalation solutions, inhalation powders, etc.) preparations for bronchial and pulmonary applications; eye ointments, eye drops, etc.
  • ear drops, etc. ear administration preparations
  • nasal drops nasal drops (nasal drops, drops) Nasal powder preparations) and other nasal preparations
  • suppositories rectal semi-solid preparations, rectal preparations such as enema preparations
  • vaginal suppositories vaginal preparations such as vaginal tablets
  • external liquid preparations laiquor, liniment preparations
  • Lotions, etc. creams, gels, external solids (external powders, etc.), sprays (aerosols, pump sprays, etc.), patches (tapes, poultices, etc.), ointments, etc. Applicable agents; and the like.
  • the dosage forms include, for example, tablets, coated tablets, pills, fine granules, granules, powders, capsules, solutions, syrups, emulsions, suspensions, etc. Can be given.
  • examples of the dosage form include injection preparations and infusion preparations.
  • examples of the dosage form include external preparations such as patches, coatings, ointments, creams and lotions.
  • the expression inhibitor of the present invention may, for example, optionally contain an additive, and when the expression inhibitor of the present invention is used as a medicine or a pharmaceutical composition, the additive is pharmaceutically acceptable. It is preferable to include an additive or a pharmaceutically acceptable carrier.
  • the additive is not particularly limited, and examples thereof include base materials, excipients, colorants, lubricants, binders, disintegrants, stabilizers, coating agents, preservatives, and flavoring agents such as fragrances. Can be given.
  • the compounding amount of the additive is not particularly limited as long as it does not hinder the function of the compound.
  • excipient examples include sugar derivatives such as lactose, lactose hydrate, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch and dextrin; cellulose derivatives such as crystalline cellulose; Arabic. Rubber; Dextran; Organic excipients such as pullulan; Light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, silicate derivatives such as magnesium aluminometasilicate; Phosphates such as calcium hydrogen phosphate; Calcium carbonate, etc. Carbonates; inorganic excipients such as sulfates such as calcium sulfate. Examples of the colorant include yellow ferric oxide.
  • Examples of the lubricant include stearic acid, calcium stearate, magnesium stearate, and other stearic acid metal salts; talc; polyethylene glycol; silica; hydrogenated vegetable oil and the like.
  • Examples of the flavoring agents include cocoa powder, peppermint, aroma powder, peppermint oil, borneol, cinnamon powder and the like, sweeteners, acidulants and the like.
  • Examples of the binder include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol and the like.
  • disintegrant examples include cellulose derivatives such as carboxymethyl cellulose and carboxymethyl cellulose calcium; chemically modified starch such as carboxymethyl starch, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, and sodium starch glycolate, and chemically modified celluloses.
  • stabilizer examples include paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid. Sorbic acid and the like can be mentioned.
  • the coating agent examples include hypromellose, macrogol such as macrogol 6000, talc, and titanium oxide.
  • the compounds represented by the above formulas (I) to (VII) can be produced by a known method.
  • JP-A-62-212369 US Pat. No. 4,749,713
  • the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene, as described above.
  • the expression inhibitor of the present invention can also be used as a fibrosis inhibitor in fibrosis medicine, non-alcoholic steatohepatitis, non-alcoholic steatohepatitis, etc., for example, as described below.
  • the pharmaceutical for fibrosis of the present invention contains the expression inhibitor of the present invention as described above.
  • the medicament for fibrosis of the present invention is characterized by containing the expression inhibitor of the present invention, that is, containing the compound represented by the formula (I) or a salt thereof, and other constitution and conditions are , Not particularly limited.
  • the description of the expression inhibitor of the present invention can be used, for example.
  • the expression of the fibrosis-inducing gene can be suppressed, and thus fibrosis can be treated.
  • treatment may mean any of the treatment, prevention, amelioration of fibrosis, suppression of progression of symptoms, and / or termination of progression of symptoms. Therefore, the drug for fibrosis of the present invention can be referred to as, for example, a therapeutic drug, a preventive drug, an ameliorating drug, a progress inhibitor, and / or a progress stopping drug for fibrosis. Further, the fibrosis drug of the present invention is (figure) suppressed fibrosis of living tissues or cells as compared with the absence of the fibrosis drug of the present invention (non-administration condition). As long as it is sufficient, the fibrosis may be advanced as compared with the start time (start of administration).
  • the fibrosis is not particularly limited, and examples thereof include pulmonary fibrosis, myelofibrosis, skin sclerosis, arteriosclerosis and the like.
  • the fibrosis excludes liver fibrosis, for example.
  • the administration condition of the medicinal agent for fibrosis of the present invention is not particularly limited and, for example, the administration form, administration timing, dose and the like can be appropriately set according to the type of administration subject.
  • the administration subject and administration conditions of the fibrosis medicine of the present invention the explanation of the administration subject and administration conditions of the expression inhibitor of the present invention can be applied, for example.
  • the drug for non-alcoholic steatohepatitis (NASH) of the present invention contains the expression inhibitor of the present invention as described above.
  • the medicament for NASH of the present invention is characterized by containing the expression inhibitor of the present invention, that is, containing the compound represented by the formula (I), a salt thereof or a solvate thereof, and
  • the configuration and conditions are not particularly limited.
  • the description of the expression inhibitor of the present invention can be incorporated.
  • the drug for NASH of the present invention by suppressing the expression of the fibrosis-inducing gene, it is possible to suppress the fibrosis of the liver tissue that progresses in NASH, and thus it is possible to treat NASH.
  • treatment may mean any of treatment, prevention, amelioration of fibrosis, suppression of progression of symptoms, and / or termination of progression of symptoms. Therefore, the drug for NASH of the present invention can also be referred to as, for example, a therapeutic drug, a preventive drug, an improving drug, a progress inhibitor, and / or a progress stopping drug for NASH.
  • the suppression of progression of the above-mentioned symptoms means, for example, suppression of progression from non-alcoholic steatohepatitis to cirrhosis.
  • the drug for NASH of the present invention is the progress of NASH in living tissues (eg, liver) or cells (eg, hepatocytes) as compared with the absence of the above-mentioned NASH drug of the present invention (non-administration condition). May be (significantly) suppressed, and NASH may be advanced compared with the start time (start of administration).
  • the administration conditions of the drug for NASH of the present invention are not particularly limited, and for example, the administration form, administration timing, dose, etc. can be appropriately set according to the type of administration subject.
  • the administration subject and administration conditions of the NASH drug of the present invention for example, the explanation of the administration subject and administration conditions of the expression inhibitor of the present invention can be incorporated.
  • the fibrosis-suppressing agent of the present invention includes the expression-suppressing agent of the present invention, as described above.
  • the fibrosis-suppressing agent of the present invention is characterized by containing the expression suppressing agent of the present invention, that is, containing the compound represented by the formula (I), a salt thereof or a solvate thereof, and the like.
  • the configuration and conditions of are not particularly limited.
  • the fibrosis-suppressing agent of the present invention for example, the description of the expression-suppressing agent of the present invention can be incorporated.
  • the fibrosis-suppressing agent of the present invention can suppress the expression of the fibrosis-inducing gene, and thus suppress fibrosis.
  • the fibrosis-suppressing agent of the present invention can be used for suppressing fibrosis, more specifically for treating, preventing, improving fibrosis, suppressing the progress of fibrosis, and / or stopping the progress of fibrosis. Therefore, the fibrosis-suppressing agent of the present invention can also be referred to as, for example, a therapeutic agent, a prophylactic agent, an improving agent, a progress inhibitor, and / or a progress arresting agent for fibrosis. According to the fibrosis-suppressing agent of the present invention, as described above, by suppressing the expression of the fibrosis-inducing gene, it is possible to suppress the fibrosis of the liver tissue that progresses in NASH.
  • the fibrosis-suppressing agent of the present invention can also be referred to as, for example, a fibrosis-suppressing agent in non-alcoholic steatohepatitis or an agent for suppressing progression of non-alcoholic steatohepatitis to cirrhosis.
  • fibrosis inhibition means that fibrosis of biological tissue or cells is (significantly) suppressed as compared with the absence of the fibrosis inhibitor of the present invention (non-administration condition). As long as it is sufficient, fibrosis may be advanced as compared with the start time (start of administration). In this case, the “suppression of fibrosis” can also be referred to as “suppression of progression of fibrosis” or the like.
  • the fibrosis can be evaluated, for example, by directly or indirectly measuring the amount of collagen protein. Examples of the indirect measurement include measurement of hydroxyproline.
  • the administration conditions of the fibrosis-suppressing agent of the present invention are not particularly limited, and for example, the administration form, administration timing, dose and the like can be appropriately set according to the type of administration subject.
  • the administration subject and administration conditions of the fibrosis-suppressing agent of the present invention for example, the explanation of the administration subject and administration conditions of the expression-suppressing agent of the present invention can be incorporated.
  • the expression suppression method of the present invention includes, for example, an administration step of administering the expression inhibitor, and specifically includes an administration step of administering the expression inhibitor to an administration subject.
  • the expression inhibitor may be administered in vitro or may be administered in vivo .
  • the administration subject and administration condition of the expression inhibitor of the present invention for example, the explanation of the administration subject and administration condition in the expression inhibitor of the present invention can be incorporated.
  • the method for treating fibrosis of the present invention includes an administration step of administering the drug for fibrosis of the present invention to a subject.
  • the method for treating fibrosis of the present invention is characterized by administering the pharmaceutical agent for fibrosis of the present invention, and other steps and conditions are not particularly limited.
  • the description of the expression inhibitor, the fibrotic drug, and the expression suppression method of the present invention can be incorporated.
  • the fibrosis is not particularly limited, and examples thereof include pulmonary fibrosis, myelofibrosis, skin sclerosis, arteriosclerosis and the like.
  • the method for treating fibrosis of the present invention includes, for example, an administration step of administering the fibrosis medicine, and specifically includes an administration step of administering the fibrosis medicine to an administration subject.
  • the drug for fibrosis may be administered in vitro or in vivo .
  • the administration subject and administration conditions of the fibrosis drug of the present invention for example, the explanation of administration subjects and administration conditions in the expression-suppressing agent of the present invention can be incorporated.
  • the method for treating non-alcoholic steatohepatitis of the present invention includes an administration step of administering the drug for non-alcoholic steatohepatitis of the present invention to a subject.
  • the method for treating NASH of the present invention is characterized by administering the above-mentioned pharmaceutical agent for NASH of the present invention, and other steps and conditions are not particularly limited.
  • the description of the expression inhibitor, the NASH drug, and the expression suppression method of the present invention can be incorporated.
  • the method for treating NASH of the present invention includes, for example, an administration step of administering the NASH drug, and specifically includes an administration step of administering the NASH drug to an administration subject.
  • the above-mentioned pharmaceutical agent for NASH may be administered in vitro or may be administered in vivo .
  • the administration subject and administration conditions of the NASH drug of the present invention for example, the explanation of the administration subject and administration conditions in the expression inhibitor of the present invention can be incorporated.
  • the method for suppressing fibrosis of the present invention includes an administration step of administering the fibrosis inhibitor of the present invention to a subject.
  • the fibrosis-suppressing method of the present invention is characterized by administering the fibrosis-suppressing agent of the present invention, and other steps and conditions are not particularly limited.
  • the description of the expression-suppressing agent, the fibrosis-suppressing agent, and the expression-suppressing method of the present invention can be incorporated.
  • the method for suppressing fibrosis of the present invention can also be referred to as, for example, a method for suppressing fibrosis in non-alcoholic steatohepatitis or a method for suppressing progression from non-alcoholic steatohepatitis to cirrhosis.
  • the fibrosis-suppressing method of the present invention includes, for example, an administration step of administering the fibrosis-suppressing agent, and specifically includes an administration step of administering the fibrosis-suppressing agent to an administration subject.
  • the fibrosis-suppressing agent may be administered in vitro or in vivo .
  • the explanation of the administration subject and administration conditions in the expression-suppressing agent of the present invention can be incorporated.
  • the present invention is the use of the compound represented by the above formula (I), a salt thereof or a solvate thereof for producing an expression inhibitor of a fibrosis-inducing gene, which is a pharmaceutical for treating fibrosis.
  • the present invention can be incorporated by reference, for example, to the expression inhibitor, the fibrotic drug, the NASH drug, and the fibrosis inhibitor of the present invention.
  • Example 1 It was confirmed that the expression-suppressing agent of the present invention suppresses the expression of the fibrosis-inducing gene.
  • letrozole which is the expression inhibitor of the present invention, was added to half of the mice in the MCD group, in place of the MCD feed, in an amount equivalent to 0.1 mg / kg per daily food intake.
  • MCD feed (MCD + LET) added as described above was given, and the mice were bred for 5 weeks to give mice (MCD + LET) of the examples.
  • MCD feed (MCD) was continuously fed was used as a NASH model mouse (MCD) and used as a control.
  • mice in the negative control group which had been continuously fed with the control feed (CTL) were bred for 5 weeks in the same manner as the negative control mice (CTL).
  • CTL control feed
  • the general condition applying, breathing, and behavior
  • body weight and amount of residual feed are measured every two weeks, and blood is collected before the start of letrozole administration, 2 weeks after the start, and 5 weeks after the start.
  • aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin / total cholesterol (TC), and neutral fat (TG) were measured (the measurement was entrusted to Oriental Yeast Co., Ltd.).
  • RNA was extracted from the extracted liver tissue using an RNA preparation kit (RNeasy Mini kit, QIAGEN).
  • cDNA was synthesized using a cDNA preparation kit (QuantiTect (registered trademark) Reverse Transcription Kit, manufactured by QIAGEN).
  • an RT-PCR reagent QuantantiTect (registered trademark) SYBR (registered trademark) Green PCR kits (QIAGEN)
  • a PCR device Step One Plus (registered trademark) -01, manufactured by Applied Biosystems
  • TGF- ⁇ 1 Transforming Growth Factor- ⁇ 1
  • CTGF Connective Tissue Growth Factor
  • ⁇ -SMA ⁇ -Smooth Muscle Actin
  • YAP1 Yes-associated Protein 1
  • the expression level of GAPDH mRNA of the standard gene was measured, and the relative expression level to the expression level of GAPDH gene was calculated. Further, the relative expression level of each mRNA in the negative control mice sacrificed at 5 weeks was similarly measured, and the average value of the relative expression levels of mRNA of each gene was used as a calibrator to compare C t method ( ⁇ C t). Method) was used to calculate the relative value of the expression level of each gene.
  • FIG. 1 shows the results of TGF- ⁇ 1
  • FIG. 2 shows the results of CTGF
  • C shows the results of ⁇ -SMA
  • D shows the results of YAP1.
  • the vertical axis represents the relative value of the expression level of each gene
  • the horizontal axis represents the period after the start of letrozole administration.
  • the expression of the fibrosis-inducing gene is higher than that in the negative control mouse (CTL), and the fibrosis in NASH is caused. all right.
  • the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene.
  • Example 2 It was confirmed that the expression inhibitor of the present invention suppresses fibrosis of liver tissue in NASH, that is, can treat NASH.
  • FIG. 2 is a microscopic photograph of the stained liver tissue, (A) shows a HE-stained photograph, and (B) shows a Sirius red-stained photograph. 2 (A) and 2 (B), the photographs are the results of the negative control mouse (CTL), the control mouse (MCD), and the example mouse (MCD + LET) from the left.
  • CTL negative control mouse
  • MCD control mouse
  • MCD + LET example mouse
  • the control mouse in comparison with the negative control mouse (CTL), the control mouse (MCD) had a large number of fibrotic regions in the area surrounded by the arrow, and in particular, it was typical from the perivascular region. Fibrosis was occurring, and fibrosis of liver tissue was progressing. In contrast, in the mouse of the example (MCD + LET), the fibrosis around the blood vessel was suppressed, and the fibrosis of the liver tissue was significantly suppressed, as compared with the control mouse (MCD).
  • CTL negative control mouse
  • FIG. 3A is a graph showing the fibrosis index
  • FIG. 3B is a graph showing the amount of hydroxyproline.
  • the horizontal axis represents the period after the start of letrozole administration
  • the vertical axis represents the fibrosis index in (A)
  • the vertical axis in FIG. The amount of proline is shown.
  • the fibrosis of the liver tissue was advanced in the control mouse (MCD).
  • the fibrosis of the liver tissue was significantly suppressed as compared with the control mouse (MCD).
  • the control mouse (MCD) had a significantly increased amount of hydroxyproline and the amount of collagen in the liver tissue was higher than that of the negative control mouse (CTL). It was found that there was an increase, that is, fibrosis of liver tissue was progressing.
  • the mouse of the example (MCD + LET) has a significantly decreased amount of hydroxyproline and a decreased amount of collagen, as compared with the control mouse (MCD), that is, the liver tissue. It was found that the progression of fibrosis in S. was suppressed.
  • Example 2 Measurement of blood marker After each mouse of Example 1 (2) was bred for 5 weeks, blood was collected and the concentration of two types of fibrosis markers (Mac-2 Binding Protein (M2BP) and hyaluronic acid) in serum was collected. Was measured.
  • M2BP Mac-2 Binding Protein
  • the M2BP was measured using an M2BP measurement kit (mouse mac-2 BP assay kit, manufactured by Immuno-Biological Laboratories).
  • the hyaluronic acid was measured using a hyaluronic acid measurement kit (hyaluronan immunoassay kit, manufactured by R & D systems). The results are shown in FIG.
  • FIG. 4 shows the result of M2BP, and (B) shows the result of hyaluronic acid.
  • the vertical axis represents the concentration of each serum marker.
  • M2BP Mac-2 Binding Protein
  • M2BP + LET the concentration of two types of fibrosis markers in the serum was lower than that of the control (MCD) mouse. It was found that the expression inhibitor of the present invention can inhibit fibrosis of liver tissue.
  • the expression inhibitor of the present invention can suppress the fibrosis of liver tissue in NASH, that is, can treat NASH.
  • Example 3 It was confirmed that the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene in human hepatocytes in vivo .
  • the expression level of each gene in the control was set to 1, and the relative expression level was calculated.
  • the expression level of TGF- ⁇ 2 was 0.87
  • the expression level of CTGF was 0.16
  • ⁇ -SMA was 0.57
  • YAP-1 was 0.64. It was suppressed. From these results, it was found that the expression-suppressing agent of the present invention can suppress the expression of the fibrosis-inducing gene in human hepatocytes in vivo .
  • a fibrosis-inducing gene expression inhibitor comprising a compound represented by the following formula (I), a salt thereof or a solvate thereof:
  • R, R 0 and R 1 which may be the same or different, are independently hydrogen atoms; or R and R 0 are present on adjacent carbon atoms and are taken together to form a bond.
  • R 2 is a hydrogen atom, lower alkyl group, phenyl group, cyano-phenyl group, trifluoromethyl-phenyl group, halogenated phenyl group, lower alkoxy-phenyl group, hydroxy-phenyl group, lower alkyl-phenyl group, phenyl- A lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R 1 and R 2 together form a lower alkylidene group or di- [ (Lower alkoxy or hydroxy) -phenyl] -lower alkylidene group; or R 1 and R 2 together form a straight-chain alkylene group having 4 to 6 carbon atoms or ortho-phenylene bridged 2 carbon atom
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is a hydrogen atom, a lower alkyl group, a phenyl group, a pyridyl group, a thienyl group or a benzyl group
  • R 2 ′ is a phenyl group monosubstituted by a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, a halogen group, or a trifluoromethyl group on the phenyl ring, or a cyano group or a hydroxy group, respectively.
  • R 1 ′ is a hydrogen atom
  • R 2 ′ is a hydrogen atom, a lower alkyl group or a pyridyl group
  • R 2 ′ is a cyano group, a lower alkyl group, a lower alkoxy group, a hydroxy group, or a halogen group on an unsubstituted or phenyl ring, respectively.
  • the expression inhibitor according to Appendix 2 wherein R 3 is a hydrogen atom.
  • R 1 ′ and R 3 are hydrogen atoms;
  • Appendix 5 The expression inhibitor according to any one of appendices 1 to 4, comprising a compound represented by the following formula (III): In the formula (III), R 2 ′ is a 3-pyridyl group, a p-cyanobenzyl group, or a p-cyanophenyl group.
  • the fibrosis-inducing gene is selected from the group consisting of TGF- ⁇ (Transforming Growth Factor- ⁇ ), CTGF (Connective Tissue Growth Factor), ⁇ -SMA ( ⁇ -Smooth Muscle Actin) and YAP1 (Yes-associated Protein 1).
  • TGF- ⁇ Transforming Growth Factor- ⁇
  • CTGF Connective Tissue Growth Factor
  • ⁇ -SMA ⁇ -Smooth Muscle Actin
  • YAP1 Yes-associated Protein 1).
  • a medicament for fibrosis which comprises the expression inhibitor of the fibrosis-inducing gene according to any one of appendices 1 to 7.
  • (Appendix 9) The fibrosis medicine according to appendix 8, wherein the fibrosis is at least one selected from the group consisting of pulmonary fibrosis, myelofibrosis, skin sclerosis, and arteriosclerosis.
  • (Appendix 10) A medicament for nonalcoholic steatohepatitis, which comprises the expression inhibitor of the fibrosis-inducing gene according to any one of appendices 1 to 7.
  • (Appendix 11) A fibrosis-suppressing agent comprising the expression-suppressing agent for a fibrosis-inducing gene according to any one of Supplementary Notes 1 to 7.
  • Appendix 12 The fibrosis-suppressing agent according to Appendix 11, wherein the fibrosis-suppressing agent is an agent for suppressing progression of non-alcoholic steatohepatitis to cirrhosis.
  • Appendix 13 A method for suppressing the expression of a fibrosis-inducing gene, comprising the step of administering the fibrosis-inducing gene expression-suppressing agent according to any one of Supplementary Notes 1 to 7.
  • the fibrosis-inducing gene is selected from the group consisting of TGF- ⁇ (Transforming Growth Factor- ⁇ ), CTGF (Connective Tissue Growth Factor), ⁇ -SMA ( ⁇ -Smooth Muscle Actin) and YAP1 (Yes-associated Protein 1).
  • a method for treating fibrosis comprising the step of administering to the subject the pharmaceutical for fibrosis according to Supplementary Note 8 or 9.
  • Appendix 18 A method for treating non-alcoholic steatohepatitis, comprising the step of administering the drug for non-alcoholic steatohepatitis according to Supplementary Note 10 to a subject.
  • Appendix 19 A method for suppressing fibrosis, comprising the step of administering the fibrosis-suppressing agent according to appendix 11 or 12 to a subject.
  • the subject is a patient with non-alcoholic steatohepatitis, 20.
  • Appendix 21 The subject is a patient with non-alcoholic steatohepatitis, 21.
  • R 2 is a hydrogen atom, lower alkyl group, phenyl group, cyano-phenyl group, trifluoromethyl-phenyl group, halogenated phenyl group, lower alkoxy-phenyl group, hydroxy-phenyl group, lower alkyl-phenyl group, phenyl- A lower alkyl group, a hydroxy-phenyl-lower alkyl group, a cyano-phenyl-lower alkyl group, a pyridyl group or a thienyl group; or R 1 and R 2 together form a lower alkylidene group or di- [ (Lower alkoxy or hydroxy) -phenyl] -lower alkylidene group; or R 1 and R 2 together form a straight-chain alkylene group having 4 to 6 carbon atoms or ortho-phenylene bridged 2 carbon atom
  • (Appendix 23) A compound represented by the above formula (I), a salt thereof, or a solvate thereof for use in the treatment of fibrosis.
  • (Appendix 24) A compound represented by the above formula (I), a salt thereof or a solvate thereof for use in the treatment of non-alcoholic steatohepatitis.
  • (Appendix 25) A compound represented by the above formula (I), a salt thereof, or a solvate thereof for use in suppressing fibrosis.
  • the expression inhibitor of the present invention can suppress the expression of the fibrosis-inducing gene by including the compound of the formula (I), a salt thereof, or a solvate thereof. That is, according to the present invention, since the expression of the fibrosis-inducing gene can be suppressed, the fibrosis of living tissue such as liver tissue can be suppressed and can be used for the treatment of fibrosis. Further, in NASH, fibrosis progresses. Therefore, according to the present invention, a drug for NASH can be provided. Therefore, the present invention can be said to be extremely useful in the fields of medicine and the like.

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Abstract

L'invention concerne un inhibiteur d'expression capable d'inhiber l'expression d'un gène induisant une fibrose. La présente invention concerne un inhibiteur d'expression comprenant un composé représenté par la formule (I) ou un sel de celui-ci.
PCT/JP2019/042747 2018-10-31 2019-10-31 Inhibiteur d'expression de gène induisant une fibrose et son utilisation WO2020090967A1 (fr)

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Citations (2)

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JP2010505783A (ja) * 2006-10-04 2010-02-25 アレス トレーディング ソシエテ アノニム 非アルコール性脂肪肝炎の治療
CN103157110A (zh) * 2011-12-14 2013-06-19 上海市肿瘤研究所 芳香化酶抑制剂在制备抗肝硬化或抗肝纤维化的药物中的应用

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JP2010505783A (ja) * 2006-10-04 2010-02-25 アレス トレーディング ソシエテ アノニム 非アルコール性脂肪肝炎の治療
CN103157110A (zh) * 2011-12-14 2013-06-19 上海市肿瘤研究所 芳香化酶抑制剂在制备抗肝硬化或抗肝纤维化的药物中的应用

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