WO2021075585A1 - Agent thérapeutique pour dysfonctionnement rénal - Google Patents

Agent thérapeutique pour dysfonctionnement rénal Download PDF

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WO2021075585A1
WO2021075585A1 PCT/JP2020/039805 JP2020039805W WO2021075585A1 WO 2021075585 A1 WO2021075585 A1 WO 2021075585A1 JP 2020039805 W JP2020039805 W JP 2020039805W WO 2021075585 A1 WO2021075585 A1 WO 2021075585A1
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group
hydrogen atom
amino
renal dysfunction
present
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PCT/JP2020/039805
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English (en)
Japanese (ja)
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裕之 櫻井
木村　徹
妙織 西尾
紗夜 武田
仁 遠藤
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学校法人 杏林学園
国立大学法人北海道大学
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Publication of WO2021075585A1 publication Critical patent/WO2021075585A1/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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a therapeutic agent for renal dysfunction, for example, polycystic kidney disease.
  • kidney disease CKD
  • Chronic kidney disease has become the biggest challenge to be overcome in the field of nephrology, and its prevention, that is, prevention and treatment of renal dysfunction, has always been a challenge.
  • polycystic kidney disease is a hereditary disease in which many cysts (bags of water) are formed in the kidneys, the kidneys grow larger, and the function of the kidneys gradually declines. ..
  • cysts bags of water
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive polycystic kidney disease
  • PKD1, PKD2 Patients with polycystic kidney disease have congenital abnormalities in genes (PKD1, PKD2).
  • the PKD1 gene is located on p13.3 of the short arm of chromosome 16, and the PKD2 gene is located on the long arm q21-23 of chromosome 4.
  • Abnormalities in the proteins (PC1, PC2) produced by these genes cause polycystic kidney disease. It is known that there is a difference in the pathological condition depending on which gene is abnormal, PKD1 or PKD2.
  • PC1 and PC2 play a role in the kidney, liver, blood vessels and the like.
  • the kidney senses the flow of fluid through the tubules
  • the liver senses the flow of bile in the tubules, causing the tubules and gallbladder cells to line up in an orderly manner.
  • the tubules work to play their original role.
  • renal tubules and biliary tubule cells do not line up regularly in a tubular shape, the number of cells increases in a planar shape, and cysts are formed.
  • ADPKD the vasopressin receptor inhibitor tolvaptan
  • this drug has side effects such as liver dysfunction, polyuria, and electrolyte imbalance (hypernatremia), and it has been reported that more than 20% of patients cannot continue treatment, which lowers the QOL of patients.
  • Non-Patent Document 1 See, for example, Non-Patent Document 1). Therefore, there is a need for an ADPKD therapeutic agent that has fewer side effects and is more effective.
  • amino acids are essential nutrients for living organisms, but some amino acids have a role as signal molecules and are involved in various biological reactions such as nerve excitement and promotion of cell proliferation.
  • leucine which is one of the essential amino acids, is known to activate the mammarian target of rapamycin (mTOR) system and increase cell proliferation.
  • the L-type amino acid transporter 1 (LAT1) is an amino acid transporter that transports large neutral amino acids including leucine. LAT1 is expressed in the placenta, testis, and blood-brain barrier in the living body, and is considered to be important for crossing the amino acid barrier.
  • LAT1 is highly expressed in fast-growing cells such as early-stage development and cancer cells (see, for example, Non-Patent Document 2), and considering the cell growth-promoting action of its substrate, leucine. , This transporter is likely to play an important role in cell proliferation.
  • ADPKD cysts If the proliferation of cells forming ADPKD cysts can be suppressed, it is expected to be an ADPKD therapeutic agent that replaces the vasopressin receptor inhibitor.
  • the present invention has been made in consideration of the above circumstances, and provides the following therapeutic agents for renal dysfunction, therapeutic pharmaceutical compositions, and the like.
  • a therapeutic agent for renal dysfunction which comprises, as an active ingredient, a compound represented by, or a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
  • the compound has the following formula (II): [In the formula, R 5 is an amino group or a dimethyl amino group, R 6 is a hydrogen atom, a chlorine atom or a dimethyl amino group, and X is CH or N. ]
  • the compound represented by the formula (II) is O- (5-amino-2-phenylbenzoxazole-7-yl) methyl-3,5-dichloro-L-tyrosine, as described in (2) above.
  • the therapeutic agent described described.
  • the therapeutic agent according to any one of (1) to (3) above, wherein the renal dysfunction is polycystic kidney disease (for example, autosomal dominant polycystic kidney disease).
  • Pharmaceutical composition for the treatment of renal dysfunction, which comprises the compound represented by the formula (I), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
  • the subject is administered with the compound represented by the formula (I), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
  • a treatment method for renal dysfunction which comprises the compound represented by the formula (I), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
  • kit for the treatment of renal dysfunction, which comprises the compound represented by the formula (I), a prodrug thereof, a pharmacologically acceptable salt thereof, or a hydrate or solvate thereof.
  • the compound represented by the formula (I) is, for example, for example.
  • Examples of renal dysfunction include polycystic kidney disease (for example, autosomal dominant polycystic kidney disease). Effect of the invention
  • a pharmaceutical preparation / composition useful for treating renal dysfunction especially polycystic kidney disease, particularly autosomal dominant polycystic kidney disease (ADPKD), and a method useful for treating the renal dysfunction.
  • a kit for treating the renal dysfunction and the like can be provided.
  • therapeutic agent for renal dysfunction therapeutic pharmaceutical composition, etc.
  • the therapeutic agent for renal dysfunction of the present invention (hereinafter, may be referred to as “therapeutic agent of the present invention”), and the pharmaceutical composition for the treatment of renal dysfunction. (Hereinafter, it may be referred to as "the pharmaceutical composition of the present invention”.)
  • R 4 is a hydrogen atom, a chlorine atom or a dimethylamino group, and X is CH or N.
  • Compounds represented by hereinafter, may be referred to as “compounds of the present invention”
  • prodrugs thereof or pharmacologically acceptable salts thereof, or hydrates or solvates thereof (hereinafter, solvates).
  • solvates "The compound of the present invention, etc." is contained as an active ingredient.
  • the compound of the present invention or the like is used, specifically, for example, an effective amount of the compound or the like of the present invention is tested as a test subject (patient with renal dysfunction or a patient at risk thereof, or a patient thereof).
  • Methods for treating renal dysfunction including administration to non-human mammals such as, (ii) use of the compounds of the present invention, etc. for producing agents for the treatment of renal dysfunction, (iii) renal function. It also includes the use of the compounds of the present invention for the treatment of disorders, and (iv) the compounds of the present invention for the treatment of renal dysfunction.
  • the treatment of renal dysfunction specifically includes, for example, suppression of progression of renal dysfunction, improvement of prognosis, treatment leading to remission, and further, general treatment. Not limited to the meaning, it also includes prevention of renal dysfunction and prevention of recurrence.
  • the renal dysfunction to be treated includes any of those that may lead to the development of chronic kidney disease (CKD), and is not particularly limited, but for example, polycystic kidney disease and non-polycystic kidney disease. Renal cysts, a decrease in the number of nephrons in CKD, and the like can be mentioned, and polycystic kidney disease is particularly preferable.
  • the polycystic kidney disease is not limited, but examples thereof include autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD), and ADPKD is preferable.
  • ADPKD autosomal dominant polycystic kidney disease
  • ARPKD autosomal recessive polycystic kidney disease
  • the amino protecting group of R 1 may be any group that can generally protect the amino group.
  • an acyl group for example, a lower alkanoyl which may be substituted with an alkoxycarbonyl, a halogen atom or the like, a cyclolower alkyloxy, a lower alkanoyl, a carboxy lower alkanoyl, a lower alkylcarbamoyl, an aloyl, an allenesulfonyl group and the like are preferably mentioned.
  • More preferred amino protecting groups include t-butoxycarbonyl, trifluoroacetyl, acetyl and the like.
  • low grade as used herein means one having 1 to 6 carbon atoms, unless otherwise specified.
  • alkyl group of R 2 a lower alkyl group is preferable, and specific examples thereof include methyl, ethyl and propyl.
  • examples of the aralkyl group include benzyl, phenethyl and the like.
  • Examples of the aryl group include phenyl, trill, xsilyl, cumenyl, mesyl, naphthyl, biphenyl and the like.
  • R 1 and R 2 in the compound of the formula (I) are preferably hydrogen atoms.
  • R 4 or X when the 1-position of the binding site of the benzoxazole ring, it is preferably present in the 4-position.
  • R 4 is a hydrogen atom
  • X is preferably present at the 4th position
  • R 4 is other than a hydrogen atom and X is N
  • R 4 is present at the 4th position (para position).
  • X preferably exists at the third position.
  • R 5 is an amino group or a dimethyl amino group
  • R 6 is a hydrogen atom, a chlorine atom or a dimethyl amino group
  • X is CH or N.
  • the compound represented by is preferably mentioned.
  • R 6 or X when the 1-position of the binding site of the benzoxazole ring, it is preferably present in the 4-position.
  • R 6 is a hydrogen atom
  • X is preferably present at the 4th position
  • R 6 is other than a hydrogen atom and X is N
  • R 6 is present at the 4th position (para position).
  • X preferably exists at the third position.
  • the compound represented by, that is, O- (5-amino-2-phenylbenzoxazole-7-yl) methyl-3,5-dichloro-L-tyrosine is preferably mentioned.
  • a commercially available compound known as the product name “JPH203” can be used, but the compound is not limited, and a compound that has been independently synthesized, extracted, purified, or the like may be used.
  • a derivative of the compound of the present invention can be used together with the compound of the present invention or in place of the compound of the present invention.
  • the derivative may be any derivative that is considered to be the derivative based on the common technical knowledge of those skilled in the art, such as having a chemical structure derived from the compound of the present invention, and is not limited, but for polycystic kidney disease (particularly ADPKD). It is preferable that the therapeutic effect is comparable to that of the compound of the present invention.
  • the compounds of the present invention and derivatives thereof include, for example, those that undergo metabolism such as oxidation, reduction, hydrolysis, or conjugation in vivo, and also undergo metabolism such as oxidation, reduction, or hydrolysis in vivo. Also included are compounds that produce the compounds of the present invention and their derivatives (so-called prodrugs).
  • the prodrug refers to a pharmacologically acceptable compound obtained by modifying the parent compound with a group usually used in a prodrug, and is endowed with properties such as improvement in stability and persistence.
  • the prodrug of the compound of the present invention can be a prodrugizable group (eg, a hydroxyl group, an amino group, or the like) in the compound by a conventional method using a corresponding prodrugizing reagent such as a halide. It can be produced by appropriately introducing a group constituting a prodrug into one or more arbitrary groups selected from (groups) according to a conventional method, and then isolating and purifying as necessary.
  • the group constituting the above prodrug is not limited, but for example, lower alkyl-CO-, lower alkyl-O-lower alkylene-CO-, lower alkyl-OCO-lower alkylene-CO-, lower alkyl. -OCO-, lower alkyl-O-lower alkylene-OCO- and the like are preferably mentioned.
  • the active ingredients of the therapeutic agents and pharmaceutical compositions of the present invention include the compounds of the present invention and their derivatives and their prodrugs, or in place of the compounds of the present invention and their derivatives and their prodrugs, their pharmacology. It is also possible to use an acceptable salt.
  • the pharmacologically acceptable salt of the compound of the present invention and a derivative thereof is not limited, and includes, for example, a hydride halide (eg, a hydrochloride salt, a hydride bromide, and a hydride iodide).
  • Inorganic acid salts eg, sulfates, nitrates, perchlorates, phosphates, carbonates, and bicarbonates
  • organic carboxylates eg, acetates, trifluoroacetates, maleates
  • organic sulfonates eg, methane sulfonate, trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate, toluene sulfonate
  • camphor Amino acid salts eg, aspartate and glutamate
  • quaternary amine salts alkali metal salts (eg, sodium and potassium salts, etc.), alkaline earth metal salts (eg, magnesium). (Salt, calcium salt, etc.) and the like are preferably mentioned.
  • the compounds of the present invention used in the present invention include all isomers (for example, geometric isomers, asymmetric carbon-based optical isomers, rotational isomers, stereoisomers, and tautomers) that may occur due to the structure of the compound. Etc.) and a mixture of two or more of these isomers are also included, and the description is not limited to the description of the structural formula for convenience.
  • the compound and the like of the present invention may be any of S-form, R-form and RS-form, and are not limited.
  • the compound of the present invention may exist in the form of a hydrate or a solvate depending on the type thereof, and in the present invention, the hydrate and the solvate are also included in the compound of the present invention. It can be used as an active ingredient of the therapeutic agent and pharmaceutical composition of the present invention.
  • the solvate is not limited, and examples thereof include a solvate with ethanol and isopropyl alcohol.
  • the content ratio of the compound of the present invention as an active ingredient is not limited and can be appropriately set, but for example, with respect to the entire therapeutic agent or pharmaceutical composition. , 0.01 to 99% by weight, preferably 0.01 to 30% by weight, more preferably 0.05 to 20% by weight, still more preferably 0.1 to 10% by weight. It may be within the range.
  • the therapeutic agent and the pharmaceutical composition of the present invention can sufficiently exert a therapeutic effect on renal dysfunction, for example, polycystic kidney disease (particularly ADPKD).
  • the therapeutic agent and the pharmaceutical composition of the present invention may contain other components in addition to the compound of the present invention and the like as long as the effects of the present invention are not significantly impaired.
  • examples of other components include known or under-developed drugs, and for example, one or more of tolvaptan, baldoxomethyl, metformin, bengrustat and the like can be used in combination.
  • the therapeutic agent and the pharmaceutical composition of the present invention may include, for example, those generally used in drug production described later.
  • the therapeutic agents and pharmaceutical compositions of the present invention can be administered to human or non-human mammals (eg, rats, rabbits, sheep, pigs, cows, cats, dogs, monkeys, etc.) as test subjects in various routes of administration. Specifically, it can be administered orally or parenterally (for example, intravenous injection (intravenous injection), intramuscular injection, intraperitoneal injection, subcutaneous injection, rectal administration, transdermal administration). Therefore, the compound of the present invention can be used alone, but it can be formulated into an appropriate dosage form using a pharmaceutically acceptable carrier by a method commonly used according to the route of administration. it can.
  • a pharmaceutically acceptable carrier for example, intravenous injection, intramuscular injection, intraperitoneal injection, subcutaneous injection, rectal administration, transdermal administration.
  • Dosage forms include, for example, tablets, powders, fine granules, granules, coated tablets, capsules, liquids for internal use, suspensions, emulsions, syrups, troches, etc.
  • oral preparations include injections (including infusions), inhalants, ointments, nasal drops, and liposomes.
  • the therapeutic agent and the pharmaceutical composition of the present invention can be used as a supplement (for example, corresponding to a functional food) in some cases.
  • Carriers that can be used to formulate these preparations include, for example, commonly used excipients, binders, disintegrants, lubricants, colorants, and flavoring agents, as well as stabilizers and emulsifiers, if necessary. , Absorption enhancers, surfactants, pH adjusters, preservatives, antioxidants, bulking agents, wetting agents, surface activators, dispersants, buffers, preservatives, solubilizers, soothing agents, etc. It is possible to formulate a drug by a conventional method by blending a known component that can be used as a raw material for a pharmaceutical preparation.
  • Non-toxic substances that can be used as the component include, for example, animal and vegetable oils such as soybean oil, beef fat, and synthetic glyceride; hydrocarbons such as liquid paraffin, squalane, and solid paraffin; octyldodecyl myristate, and isopropyl myristate.
  • Etc . higher alcohols such as cetostearyl alcohol and behenyl alcohol; silicon resin; silicon oil; polyoxyethylene fatty acid ester, sorbitan fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene hydrogenated castor oil, and Surfactants such as polyoxyethylene-polyoxypropylene block copolymers; water-soluble polymers such as hydroxyethyl cellulose, polyacrylic acid, carboxyvinyl polymers, polyethylene glycol, polyvinylpyrrolidone, and methylcellulose; lower alcohols such as ethanol and isopropanol; Polyhydric alcohols (polyol) such as glycerin, propylene glycol, dipropylene glycol, sorbitol, and polyethylene glycol; sugars such as glucose and sucrose; inorganic powders such as silicic anhydride, aluminum magnesium silicate, and aluminum silicate. Inorganic salts such as sodium chloride and
  • Excipients include, for example, lactose, fructose, corn starch, sucrose, glucose, mannitol, sorbit, crystalline cellulose, silicon dioxide and the like
  • binders include, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose and gum arabic.
  • Calcium carbonate, sodium hydrogen carbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose / calcium and the like are used as lubricants, and for example, magnesium stearate, talc, polyethylene glycol, silica and cured vegetable oil are colorants.
  • the flavoring and odorant for example, cocoa powder, syrup brain, aromatic powder, syrup oil, dragon brain, katsura powder, etc. are preferably mentioned, and all of them are permitted to be added to pharmaceuticals. It may be the salt or a hydrate thereof.
  • the pH adjuster is used when formulating as an injection.
  • the pH adjusting agent is not particularly limited as long as it is pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable, and specifically, sodium carbonate, potassium carbonate, sodium ethoxydo. , Potassium butoxide, sodium hydroxide, alkali metal hydroxides such as potassium hydroxide, sodium hydride, alkali metal hydrides such as potassium hydride, alkali metal or alkaline earth metal carbonates, alkali metal alkoxides, etc. Can be mentioned.
  • the pH adjuster to be blended may be used alone or in combination of two or more.
  • the pH is preferably 3 to 6, more preferably 3 to 5, further preferably 3 to 4.5, and preferably 3.5 to 4.5. Especially preferable.
  • cyclodextrins When formulated as an injection, cyclodextrins may be contained. Cyclodextrins are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutically) or physiologically acceptable. Examples of such cyclodextrins include unmodified cyclodextrin and modified cyclodextrin. Examples of the unmodified cyclodextrin include ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin and the like.
  • modified cyclodextrin for example, an alkylated cyclodextrin (for example, dimethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, dimethyl- ⁇ -cyclodextrin, etc.), a hydroxyalkylated cyclodextrin (for example, hydroxypropyl- ⁇ ) -Cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, hydroxypropyl- ⁇ -cyclodextrin, etc.), sulfoalkyl ether cyclodextrin (eg, sulfobutyl ether- ⁇ -cyclodextrin, sulfobutyl ether- ⁇ -cyclodextrin, sulfobutyl ether- ⁇ ) -Cyclodextrin), branched cyclodextrin (for example, maltosyl- ⁇ -cyclodextrin, mal
  • Cyclodextrins may be used alone or in any combination of two or more.
  • the cyclodextrins to be blended are preferably hydroxypropyl- ⁇ -cyclodextrin or sulfobutyl ether- ⁇ -cyclodextrin, and more preferably sulfobutyl ether- ⁇ -cyclodextrin.
  • the content of cyclodextrins is not particularly limited, and is appropriately set according to the type, use of the injection, method of use, and the like.
  • the content of cyclodextrins is, for example, preferably 5 to 50% by weight, more preferably 10 to 40% by weight, and 10 to 30% by weight based on the total amount of the injection. More preferred.
  • the dose of the therapeutic agent and the pharmaceutical composition of the present invention is generally determined by the age, weight, and illness of the subject (patient) to be administered, taking into consideration the blending ratio of the active ingredient (compound of the present invention, etc.) in the preparation. It can be set in a wide range as appropriate in consideration of the type / progress status, administration route, number of administrations (/ day), administration period, and the like.
  • the case where the therapeutic agent and the pharmaceutical composition of the present invention are used as a parenteral agent or an oral agent will be specifically described below.
  • parenteral agent When used as a parenteral agent, its form is generally not limited, but in the case of various injections, for example, the state of a unit dose ampoule or a high dose container, or the state of a lyophilized powder to be redissolved in a solution at the time of use. Can be provided at.
  • the parenteral preparation may contain various known shaping materials and additives according to various forms within a range in which the effect of the active ingredient is not impaired. it can.
  • water, glycerol, propylene glycol, aliphatic polyalcohols such as polyethylene glycol and the like can be mentioned.
  • the dose (per day) of the parenteral agent is not limited, but for example, in the case of various injections, the compound of the present invention, which is an active ingredient, is generally applied to the body weight of the subject (subject, patient, etc.).
  • the amount can be 0.01 to 1000 mg, 0.05 to 500 mg, or 0.1 to 50 mg per 1 kg, or 0.5 to 20 mg or 1 to 10 mg can be taken. it can.
  • the oral preparation When used as an oral preparation, its form is generally not limited, and it may be any of the above-mentioned dosage forms, or it may be a dried product to be redissolved at the time of use.
  • the oral preparation may contain various known shaping materials and additives according to various forms within a range in which the effect of the active ingredient is not impaired. ..
  • binders for example, binders (syrup, gum arabic, gelatin, sorbitol, tragacant, polyvinylpyrrolidone, etc.), fillers (lactose, sugar, cornstarch, potato starch, calcium phosphate, sorbitol, glycine, etc.), lubricants (magnesium stearate, talc, etc.) Examples thereof include polyethylene glycol, silica, etc.), disintegrants (various starches, etc.), and wetting agents (sodium lauryl sulfate, etc.).
  • the dose (per day) of the oral preparation is generally 0.05 to 5000 mg or 0.1 to 1000 mg per 1 kg of the body weight of the subject (subject, patient, etc.) to which the compound of the present invention, which is the active ingredient, is applied. , Or 0.1 to 100 mg, or 0.5 to 50 mg or 1 to 10 mg.
  • the blending ratio of the active ingredient in the oral preparation is not limited, and can be appropriately set in consideration of the number of administrations per day and the like.
  • Kit In treating renal dysfunction, for example, polycystic kidney disease (particularly ADPKD), a kit containing the compound of the present invention or the like (specifically, a kit containing the therapeutic agent or pharmaceutical composition of the present invention described above) is used. Can be used.
  • the form of the compound or the like of the present invention in the kit is not limited, but may be provided in a dissolved state in consideration of stability (preservability), ease of use, and the like.
  • the kit may contain other components as appropriate in addition to the compounds of the present invention and the like.
  • the kit may include at least the compound of the present invention as a component. Therefore, all of the components essential for the treatment of the renal dysfunction may be provided together with the compound of the present invention or may be provided separately, and are not limited. ..
  • Proximal tubule cells (Wei F, Karihalo A, Yu Z, et) conditionally immortalized from PKD1 flox mice (mice having a locus with the target PKD1 gene region sandwiched between Cre recombinase target sequences loxP). al. Neutrofil gelatinase-associated lipocalin suppresses cyst gloss by Pkd1 all cells in in vitro and in vivo. Kidney Int. 2008; 74: 1310- PKD ⁇ / ⁇ ) and cells not allowed to act on recombinase (PKD +/ ⁇ in FIG. 1) were cultured at 37 ° C.
  • Pkd1 flox / flox mice and Mx1-Cre mice were mated to generate pkd1 flex / flox / Mx1-Cre mice, which are drug-induced pkd1 conditional knockout mice.
  • 10 ⁇ g / g (body weight) of polyinocin / polycitidic acid was intraperitoneally administered to pkd1 flox / flox / Mx1-Cre mice for 5 to 6 consecutive days after birth to delete the pkd1 gene. Then, from 12 days after birth to 34 days after birth, 50 ⁇ g / g (body weight) of JPH203 (manufactured by Jay Pharma Co., Ltd.) was intraperitoneally administered every other day.
  • mice lacking the pkd1 gene by the same procedure were intraperitoneally administered cyclodextrin every other day from the 12th day after birth to the 34th day after birth. These mice were sacrificed 35 days after birth and the renal phenotype was compared.
  • the kidneys recirculated and fixed with 4% paraformaldehyde at the time of slaughter were embedded in paraffin to prepare sections, and hematoxylin and eosin staining (HE staining) was performed.
  • HE staining hematoxylin and eosin staining
  • Cystic Index was measured using WinROOF (Mitani Corporation, Tokyo, Japan) and was defined as the ratio of the cyst area to the cross-sectional area divided into two on the long axis of the kidney.
  • BUN renal function
  • serum urea nitrogen mg / dl
  • the present invention relates to a pharmaceutical preparation / composition useful for treating renal dysfunction, especially polycystic kidney disease, particularly autosomal dominant polycystic kidney disease (ADPKD), a method useful for treating the renal dysfunction, and a method useful for treating the renal dysfunction.
  • a kit for treating the renal dysfunction and the like can be provided.

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Abstract

La présente invention concerne un agent thérapeutique, etc., pour un dysfonctionnement rénal. La présente invention concerne un agent thérapeutique, une composition pharmaceutique thérapeutique, etc., pour un dysfonctionnement rénal (tel que la maladie polykystique des reins) qui comprend, en tant que substance active, un composé représenté par la formule (I), un promédicament de celui-ci, un sel pharmacologiquement acceptable de ceux-ci, ou un hydrate ou un solvate de ceux-ci.
PCT/JP2020/039805 2019-10-17 2020-10-16 Agent thérapeutique pour dysfonctionnement rénal WO2021075585A1 (fr)

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JP2019-190112 2019-10-17
JP2019190112A JP2022180668A (ja) 2019-10-17 2019-10-17 腎機能障害の治療剤

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