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WO2025192605A1 - Médicament thérapeutique pour maladie rénale chronique, et procédé de criblage de médicament thérapeutique pour maladie rénale chronique - Google Patents

Médicament thérapeutique pour maladie rénale chronique, et procédé de criblage de médicament thérapeutique pour maladie rénale chronique

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Publication number
WO2025192605A1
WO2025192605A1 PCT/JP2025/009121 JP2025009121W WO2025192605A1 WO 2025192605 A1 WO2025192605 A1 WO 2025192605A1 JP 2025009121 W JP2025009121 W JP 2025009121W WO 2025192605 A1 WO2025192605 A1 WO 2025192605A1
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Prior art keywords
group
optionally substituted
independently selected
substituents independently
group optionally
Prior art date
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PCT/JP2025/009121
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English (en)
Japanese (ja)
Inventor
広文 甲斐
剛 首藤
メリーアン スイコ
将大 加世田
潤 堀園
和弘 大沼
洋彦 吹屋
秀利 砂本
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galts Pharma
Galts Pharma Co Ltd
Ube Corp
Original Assignee
Galts Pharma
Galts Pharma Co Ltd
Ube Corp
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Publication of WO2025192605A1 publication Critical patent/WO2025192605A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing

Definitions

  • the present invention relates to a therapeutic agent for chronic kidney disease (hereinafter also referred to simply as "CKD") that is suitable for improving renal function and/or renal pathology, and a method for screening therapeutic agents for chronic kidney disease.
  • CKD chronic kidney disease
  • Nrf2 Nuclear factor-erythroid 2-related factor 2 is a transcription factor that plays a central role in the body's defense mechanism against oxidative stress.
  • Nrf2 is captured in the cytoplasm by Keap1 (Kelch-like ECH-associated protein 1), an adaptor protein for Cullin3-type ubiquitin ligase, and is degraded by the 26S proteasome, maintaining its transcriptional activity at a low level.
  • Keap1 Kerch-like ECH-associated protein 1
  • highly reactive cysteine residues in Keap1 are modified, causing a structural change in the Nrf2-capturing site of Keap1. This allows Nrf2, which is spared from degradation, to translocate into the nucleus and promote the transcription of target genes.
  • Recent research findings have shown that oxidative stress is associated with many diseases, including chronic kidney disease, and therefore drug development targeting the Nrf2 pathway is attracting attention (Non-Patent Document 1).
  • the present invention was made in consideration of the above-mentioned problems with the conventional technology, and aims to provide a therapeutic agent for chronic kidney disease that can significantly improve renal function and/or renal pathology in chronic kidney disease, as well as a method for screening therapeutic agents for chronic kidney disease.
  • renin-angiotensin system (RAS) inhibitor can significantly improve renal function and/or renal pathology in chronic kidney disease (e.g., significantly extending survival rates and the transition period to renal failure, which have not been achieved before).
  • RAS renin-angiotensin system
  • the present invention has been completed based on the above findings. That is, the present invention is as follows.
  • a therapeutic agent for chronic kidney disease comprising an Nrf2 activator, for use in combination with a renin-angiotensin inhibitor.
  • a therapeutic agent for chronic kidney disease including a renin-angiotensin inhibitor, for use in combination with an Nrf2 activator.
  • Therapeutic agents for chronic kidney disease including renin-angiotensin inhibitors and Nrf2 activators.
  • Nrf2 activator comprises a compound represented by the following general formula (I) (hereinafter also referred to as compound (I)) or a pharmaceutically acceptable salt thereof:
  • R is a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E;
  • R 1 and R 2 are each independently a hydrogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group optionally substituted with 1 to 5 substituents independently selected from Group E; or
  • R 1 and R 2 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E;
  • R 3 , R 4 , and R 6 are each independently a hydrogen atom,
  • a in the above formula (I) has a structure represented by the following formula (II-1-1):
  • R7 and R8 are each independently a hydrogen atom or an alkyl group; or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring;
  • X1 and X2 are each independently CR9 ; any one of Y 1 , Y 2 , Y 3 , and Y 4 is a nitrogen atom, and the other three are each independently CR 10 ;
  • R 9 is a hydrogen atom;
  • Each R 10 is independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group.
  • R is a hydrogen atom or an alkyl group
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a monocyclic carbocyclic ring
  • R 3 , R 4 , and R 6 are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group
  • R5 is (i) a hydrogen atom, or (ii) an alkyl group optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a phenyl group, and an alkoxy group
  • R7 and R8 are each independently a hydrogen atom or an alkyl group
  • the therapeutic agent according to ⁇ 4> wherein the compound represented by the general formula (I) includes a compound represented by the following formula or a pharmaceutically acceptable salt thereof: (In the above formula, * indicates an asymmetric center. The asymmetric center marked with * may be in the R-configuration or the S-configuration, and the compound as a whole may be a mixture of diastereomers.)
  • ⁇ 8> The therapeutic agent according to any one of ⁇ 1> to ⁇ 3>, wherein the renin-angiotensin inhibitor comprises a compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof: (In the above formula (A), ring BB represents an optionally substituted nitrogen-containing heterocycle, Ra represents a group capable of forming an anion or a group capable of converting into an anion, X represents a phenylene group and a phenyl group bonded directly or via a spacer having an atom chain of 2 or less, and n represents an integer of 1 or 2.)
  • ⁇ 10> A method for screening therapeutic agents for chronic kidney disease to be used in combination with a renin-angiotensin inhibitor, the method comprising a step of screening using at least one indicator selected from the group consisting of inhibition of albumin reabsorption from the renal tubules and inhibition of damage to renal tubular cells caused by modified albumin reabsorbed from the renal tubules.
  • the screening step further includes screening using suppression of excessive urine filtration function in glomeruli as an indicator.
  • ⁇ 12> A method for screening therapeutic agents for chronic kidney disease to be used in combination with an Nrf2 activator, the method comprising a step of screening using the suppression of excessive urine filtration function in the glomerulus as an indicator.
  • Nrf2 activator comprises a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof:
  • R is a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E;
  • R 1 and R 2 are each independently a hydrogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group optionally substituted with 1 to 5 substituents independently selected from Group E; or R 1 and R 2 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E;
  • R 3 , R 4 , and R 6 are each independently a hydrogen atom, a halogen atom, an alkyl group optionally substituted with 1 to 5 substituents
  • renin-angiotensin inhibitor comprises a compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof:
  • ring BB represents an optionally substituted nitrogen-containing heterocycle
  • Ra represents a group capable of forming an anion or a group capable of converting into an anion
  • X represents a phenylene group and a phenyl group bonded directly or via a spacer having an atom chain of 2 or less
  • n represents an integer of 1 or 2.
  • the renin-angiotensin inhibitor comprises losartan (2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-methanol) or a pharmaceutically acceptable salt thereof.
  • a method for treating chronic kidney disease comprising administering to a subject
  • the present invention it is possible to provide a therapeutic agent for chronic kidney disease that can significantly improve renal function and/or renal pathology in chronic kidney disease (preferably, can significantly increase survival rate, can significantly extend the transition period to renal failure, etc.), and a method for screening a therapeutic agent for chronic kidney disease.
  • the survival rate can be significantly (preferably significantly or synergistically) increased compared to the administration of an existing therapeutic drug alone, or the transition period to renal failure can be significantly extended, thereby making it possible to avoid medical procedures such as dialysis therapy and kidney transplantation, and reducing the number of patients requiring dialysis, kidney transplantation, etc.
  • FIG. 2 is a schematic diagram showing the administration schedule for the Nrf2 activator Compound 1 to CKD mice. The results shown in the following Figures 2 to 5 were obtained from the individuals used in this Reference Example.
  • FIG. 1 shows the results of Compound 1 improving glomerular damage, inflammation, and fibrotic pathology in CKD mice.
  • FIG. 1 shows the results of improving renal function in CKD mice by Compound 1.
  • FIG. 1 shows the results of transiently increasing proteinuria and albuminuria in CKD mice by Compound 1.
  • FIG. 1 shows the results of Compound 1 inhibiting albumin uptake in the proximal tubules of CKD mice and reducing the expression of the reabsorption transporter megalin.
  • FIG. 1 is a schematic diagram showing the administration schedule for Compound 1, losartan potassium, and a combination of Compound 1 and losartan potassium to CKD mice.
  • the main purpose of this example was to measure survival time, and the results shown in Figures 7 to 9 below were obtained from the individuals used in this example.
  • This figure shows the results that the combined use of losartan potassium and Compound 1 significantly extended the survival time of CKD mice compared with either losartan potassium or Compound 1 alone.
  • Figure 7A shows a summary of the results
  • Figures 7B, C, and D show the individual results for the groups administered 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day of the Nrf2 activator, respectively.
  • FIG. 1 shows that Compound 1 transiently increases proteinuria in CKD mice, Losartan potassium decreases it, and the combined use of Compound 1 and Losartan potassium shows intermediate values.
  • FIG. 1 shows that the combined use of losartan potassium and Compound 1 improves renal function parameters in CKD mice more than either losartan or Compound 1 alone.
  • 1 is a schematic diagram showing the administration schedule for Compound 1, losartan potassium, and a combination of Compound 1 and losartan potassium to CKD mice from the age of 6 weeks. The main purpose of this example was pathological evaluation, and the results shown in Figures 11, 12, and 15 below were obtained from the individuals used in this example.
  • FIG. 1 shows that Compound 1 transiently increases proteinuria in CKD mice, Losartan potassium decreases it, and the combined use of Compound 1 and Losartan potassium shows intermediate values.
  • FIG. 1 shows that the combined use of losartan potassium and Compound 1 improves renal function parameters in CKD mice more than either losartan or Compound 1 alone
  • alkynyl group refers to a straight-chain or branched-chain unsaturated hydrocarbon group having one carbon-carbon triple bond and 2 to 6 carbon atoms (C 2 to C 6 ), e.g., 2 to 4 carbon atoms (C 2 to C 4 ), such as an ethynyl group, a 1-propynyl group, a 2-butynyl group, a 4-pentynyl group, a 5-hexynyl group, and various branched-chain isomers thereof.
  • At least one action selected from the group consisting of inhibiting the reabsorption of albumin from the renal tubules and inhibiting damage to renal tubular cells caused by modified albumin reabsorbed from the renal tubules can inhibit the reabsorption of toxic modified albumin from the renal tubules, promote excretion of modified albumin, prevent proximal tubule (cell) damage caused by the reabsorption of modified albumin, and improve renal function. Furthermore, the inhibitory effect on excessive urine filtration function in pathological glomeruli can significantly improve renal function and/or renal pathology, similar to the renin-angiotensin inhibitors described below.
  • Renin-angiotensin inhibitors have the effect of suppressing excessive urinary filtration in pathological glomeruli, thereby normalizing the urinary filtration function in glomeruli and suppressing the excretion of proteinuria (particularly albumin (preferably reduced albumin)), thereby significantly improving renal function and/or renal pathology.
  • renal function refers to a function such as excretion of waste products (e.g., waste products in the blood), and examples thereof include a urine filtration function. More specifically, renal function includes an increase in GFR value, Reduction of blood and/or urinary creatinine levels (e.g., mg/dl); Reduction of blood and/or urinary urea nitrogen (BUN) levels (e.g., mg/dl); Reduction of blood and/or urinary cystatin C levels (e.g., mg/g Cre), Reduction of blood and/or urinary KIM-1 levels (e.g., ⁇ g/g Cre), reduction of blood and/or urinary NGAL levels (e.g., mg/g Cre); Reduction of blood and/or urinary clusterin levels (e.g., mg/g Cre), Reduction of blood and/or urinary TFF (e.g., ⁇ g/g Cre), Examples include a reduction in the amount of ⁇ 2 -microglobulin in the blood and/or urine
  • modified albumin includes oxidized albumin, toxin-conjugated albumin, and/or free fatty acid-conjugated albumin.
  • chronic kidney disease refers generally to a variety of disorders that impair kidney structure and function (e.g., chronically and/or for more than three months), as known in the art, and includes severe kidney disease and/or kidney failure.
  • the chronic kidney disease is preferably a chronic kidney disease accompanied by at least one selected from the group consisting of a decrease in the urinary filtration function in the glomerulus (relative to a healthy state), an increase in proteinuria (relative to a healthy state), damage to tubular cells due to modified albumin reabsorbed from the tubules, sclerosis, fibrosis and/or inflammation of kidney tissues (e.g., glomeruli, tubules), and an increase in intraglomerular pressure due to arteriolar blood flow; More preferred is chronic kidney disease accompanied by at least one selected from the group consisting of a decrease in the urinary filtration function in the glomerulus (relative to a healthy state), an increase in proteinuria (relative to a
  • the chronic kidney disease is not particularly limited as long as the present invention is applicable, but examples thereof include Alport syndrome, diabetic nephropathy (hereinafter also simply referred to as "DKD"), chronic glomerulonephritis, and the like, with Alport syndrome or diabetic nephropathy being preferred.
  • Alport syndrome is an intractable form of glomerular sclerosis caused by a mutation in the type IV collagen gene, which makes up the glomerular basement membrane.
  • Alport syndrome is the second most common hereditary kidney disease in children, and severe cases progress to end-stage renal failure in the late teens or twenties, making it the main reason young people begin dialysis.
  • the first to third aspects are preferably therapeutic drugs to be administered to patients with chronic kidney disease.
  • Nrf2 activators and renin-angiotensin inhibitors have different actions or mechanisms of action, and that renin-angiotensin inhibitors can suppress the transient increase in proteinuria caused by Nrf2 activators
  • Nrf2 activating drug The Nrf2 activator (e.g., an agent containing a compound that activates Nrf2) may have an effect of improving renal function, such as suppressing excessive urine filtration function in pathological glomeruli.
  • the synthetic triterpenoid, RTA 405 increases the glomerular filtration rate and reduces angiotensin II-induced contraction of glomerular mesangial cells. Ding, Y. et al., Kidney International, Volume 83, Issue 5, May 2013, Pages 845-854, Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model Kaseda et. al.
  • the Nrf2 activator may or may not be a covalent Nrf2 activator that induces Nrf2 activation by irreversibly covalently binding to a cysteine residue of Keap1.
  • the covalent Nrf2 activator is preferred because its safety in humans has been confirmed.
  • Examples of the covalent Nrf2 activator include bardoxolone methyl and omaveloxolone.
  • the Nrf2 activator is preferably a Keap1-Nrf2 inhibitor.
  • the Nrf2 activator preferably comprises a compound represented by the following general formula (I) (hereinafter also referred to as compound (I)) or a pharmaceutically acceptable salt thereof.
  • the compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof has the effect of inhibiting Keap1.
  • the compound has at least one effect selected from the group consisting of inhibiting the reabsorption of albumin from the renal tubules and inhibiting damage to renal tubular cells caused by modified albumin reabsorbed from the renal tubules, and further has the effect of suppressing excessive urine filtration function in pathological glomeruli.
  • R is a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E;
  • R 1 and R 2 are each independently a hydrogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group optionally substituted with 1 to 5 substituents independently selected from Group E; or R 1 and R 2 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E;
  • R 3 , R 4 , and R 6 are each independently a hydrogen atom, a halogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from group E, an alkenyl group optionally substituted with 1 to 5 substituents independently selected from group E, an alkynyl group optionally substituted with 1 to
  • compound (I) compounds represented by general formula (I)
  • compound (I) and compounds encompassed by compound (I) such as compound (I-1), compounds (II-1) to (II-3), compounds (II-1-1) to (II-3-4), and compound (I-1-1), are also collectively referred to as “compound (I).”
  • compound (I) and compounds encompassed by compound (I) such as compound (I-1), compounds (II-1) to (II-3), compounds (II-1-1) to (II-3-4), and compound (I-1-1), are also collectively referred to as “compound (I).”
  • the various substituents defined or exemplified below can be arbitrarily selected and combined.
  • embodiments in which the embodiments defined below are arbitrarily selected and combined are also encompassed by the present invention.
  • Embodiments of each substituent of Compound (I) are described below.
  • the present invention also encompasses embodiments in which the following embodiments of each substituent are arbitrarily selected and combined.
  • Embodiment 1 A compound or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E in any of Compounds (I).
  • Embodiment 2 A compound or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom or an alkyl group optionally substituted with 1 to 5 halogen atoms in any of the compounds (I).
  • R 1 and R 2 are each independently a hydrogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or R 1 and R 2 , together with the carbon atom to which they are attached, form a monocyclic carbocycle optionally substituted with 1 to 5 substituents independently selected from Group E, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or R 1 and R 2 , together with the carbon atom to which they are attached, form a monocyclic carbocycle optionally substituted with 1 to 5 substituents independently selected from Group E, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or R 1 and R 2 together with the carbon atom to which they are attached form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group optionally substituted with 1 to 5 halogen atoms, or R 1 and R 2 together with the carbon atom to which they are attached form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group, or R 1 and R 2 together with the carbon atom to which they are attached form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof.
  • (Embodiment 17) A compound or a pharmaceutically acceptable salt thereof, wherein in compound (I) or any of embodiments 1 to 14, R 3 , R 4 , and R 6 are each independently a hydrogen atom, a halogen atom, an alkyl group optionally substituted with 1 to 5 halogen atoms, or an alkoxy group optionally substituted with 1 to 5 halogen atoms.
  • R 3 , R 4 , and R 6 are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group in compound (I) or any of embodiments 1 to 14.
  • R3 is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group
  • R4 and R6 are each independently a hydrogen atom, an alkyl group, or an alkoxy group, or a pharmaceutically acceptable salt thereof.
  • Embodiment 20 In compound (I) or any of embodiments 1 to 14, a compound or a pharmaceutically acceptable salt thereof, wherein R3 is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, R4 is a hydrogen atom or an alkyl group, and R6 is a hydrogen atom.
  • R 5 is (i) a hydrogen atom, or (ii) an alkyl group optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a cycloalkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, a phenyl group optionally substituted with 1 to 5 substituents independently selected from Group E, and an alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E, or a pharmaceutically acceptable salt thereof.
  • (Embodiment 26) The compound or a pharmaceutically acceptable salt thereof in the compound (I) or any of Embodiments 1 to 22, wherein R 5 is a hydrogen atom or an alkyl group.
  • (Embodiment 27) The compound or a pharmaceutically acceptable salt thereof in the compound (I) or any of Embodiments 1 to 22, wherein R 5 is an alkyl group.
  • (Embodiment 28) The compound or a pharmaceutically acceptable salt thereof in the compound (I) or any of Embodiments 1 to 22, wherein R 5 is a methyl group or an ethyl group.
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocycle optionally substituted with 1 to 5 substituents independently selected from Group E, or a pharmaceutically acceptable salt thereof.
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group, or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocycle optionally substituted with 1 to 5 substituents independently selected from Group E, or a pharmaceutically acceptable salt thereof.
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group, or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof.
  • ring B is a bicyclic ring optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkynyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E, a cycloalkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, a non-aromatic heterocyclyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an aryl group optionally substituted with 1 to 5 substituents independently selected from Group E, a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from Group E, a heteroaryl group optionally substituted with 1 to 5 substituents independently selected from Group E, a
  • Q3 is ( CU1U2 ) n ; U1 and U2 are each independently a hydrogen atom, a halogen atom, or an alkyl group; and n is 1, or a pharmaceutically acceptable salt thereof.
  • Q3 is ( CU1U2 ) n ; U1 and U2 are each independently a hydrogen atom, a fluorine atom, or a methyl group; and n is 1, or a pharmaceutically acceptable salt thereof.
  • ring D is a 5- to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E, and a cyano group, or a pharmaceutically acceptable salt thereof.
  • ring D is a 5- to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom and an alkyl group optionally substituted with 1 to 5 halogen atoms, or a pharmaceutically acceptable salt thereof.
  • ring D is a 5- to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of halogen atoms and alkyl groups, or a pharmaceutically acceptable salt thereof.
  • ring D is a 5- to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of fluorine atoms and methyl groups, or a pharmaceutically acceptable salt thereof.
  • Embodiment 95 The following general formula (I-1): wherein the symbols have the same meaning as defined in compound (I) or any of embodiments 1 to 94. A compound having a structure represented by the following formula: or a pharmaceutically acceptable salt thereof.
  • R is a hydrogen atom or an alkyl group
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a monocyclic carbocyclic ring
  • R3 is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group
  • R4 and R6 are each independently a hydrogen atom, an alkyl group, or an alkoxy group
  • R5 is a hydrogen atom or an alkyl group
  • A has the same meaning as defined in compound (I) or any of embodiments 1 to 94;
  • a compound or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
  • R is a hydrogen atom
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a monocyclic carbocyclic ring
  • R3 is an alkyl group
  • R4 is an alkyl group
  • R5 is an alkyl group
  • R6 is a hydrogen atom
  • A has the same meaning as defined in compound (I) or any of embodiments 1 to 94;
  • R is a hydrogen atom
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group
  • R3 is an alkyl group
  • R4 is an alkyl group
  • R5 is an alkyl group
  • R6 is a hydrogen atom
  • A has the same meaning as defined in compound (I) or any of embodiments 1 to 94
  • Embodiment 99 In compound (I) or any of embodiments 1 to 98, A is one of the following formulae (II-1) to (II-3): wherein the symbols have the same meaning as defined in compound (I) or any of embodiments 1 to 94.
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group; or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E;
  • X 1 and X 2 are each independently CR 9 or a nitrogen atom;
  • R 9 is each independently a hydrogen atom, a halogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E, or a cyano group;
  • Ring D is a 5- to 6-membered carbocyclic ring or a 5- to 6-membered heterocyclic ring, each of which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, an
  • R7 and R8 are each independently a hydrogen atom or an alkyl group; or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E;
  • X1 and X2 are each independently CR9 or a nitrogen atom;
  • Y 1 , Y 2 , Y 3 , and Y 4 are each independently CR 10 or a nitrogen atom;
  • R 9 and R 10 each independently represent a hydrogen atom, a halogen atom, an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E, an alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E, or a cyano group;
  • Q 1 and Q 2 are each independently CR 11 R 12 , NR 13 , an oxygen atom, a sulfur atom, SO, or SO 2
  • R7 and R8 are each independently a hydrogen atom or an alkyl group; or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring;
  • X1 and X2 are each independently CR9 ; any one of Y 1 , Y 2 , Y 3 , and Y 4 is a nitrogen atom, and the other three are each independently CR 10 ;
  • R 9 is a hydrogen atom;
  • Each R 10 independently represents a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group.
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group; Each R 10 is independently a hydrogen atom, a halogen atom, or an alkyl group; 107.
  • Embodiment 108 In compound (I) or any of embodiments 1 to 104, A is the following formula (II-3-1): wherein the symbols have the same meaning as defined in Compound (I) or any of Embodiments 1 to 104.
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group; Any one of X1 and X2 is a nitrogen atom, and the other is CR9 ; Y 1 , Y 2 , Y 3 , and Y 4 are each independently CR 10 ; R 9 is a hydrogen atom; Each R 10 is independently a hydrogen atom, a halogen atom, or an alkyl group; A compound or a pharmaceutically acceptable salt thereof.
  • R is a hydrogen atom or an alkyl group
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a monocyclic carbocyclic ring
  • R 3 , R 4 , and R 6 are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group
  • R5 is (i) a hydrogen atom, or (ii) an alkyl group optionally substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a phenyl group, and an alkoxy group
  • R7 and R8 are each independently a hydrogen atom or an alkyl group; or R 7 and R 8 together with the carbon atom to which they are attached form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group
  • R is a hydrogen atom or an alkyl group
  • R 1 and R 2 are each independently a hydrogen atom or an alkyl group; or R 1 and R 2 together with the carbon atoms to which they are attached form a monocyclic carbocyclic ring
  • R3 is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group
  • R4 is a hydrogen atom or an alkyl group
  • R5 is an alkyl group
  • R6 is a hydrogen atom
  • R 7 and R 8 are each independently a hydrogen atom or an alkyl group; or R 7 and R 8 together with the carbon atoms to which they are attached form a monocyclic carbocyclic ring
  • R 10 is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group
  • a preferred example of compound (I) is 3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydro-[1,4]oxazepino[7,6-g]quinolin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid, represented by the following formula:
  • * indicates an asymmetric center.
  • the asymmetric center marked with * in the above 3-(1,4-dimethyl-1H-benzo[d][1,2,3]triazol-5-yl)-3-(3-(((R)-2-ethyl-2,3-dihydro-[1,4]oxazepino[7,6-g]quinolin-4(5H)-yl)methyl)-4-methylphenyl)-2,2-dimethylpropanoic acid may be in the R-configuration or the S-configuration, and the compound as a whole may be a mixture of diastereomers.
  • Compound (I) can be produced in accordance with the method described in paragraphs 0105 to 0112 of WO 2020/241853.
  • Compound (I) or its synthetic intermediates may exist in tautomeric forms or mixtures thereof.
  • Compound (I) may exist in stereoisomeric forms such as enantiomers or diastereomers, or mixtures thereof.
  • Compound (I) includes tautomeric or stereoisomeric mixtures, or pure or substantially pure isomers.
  • compound (I) or a synthetic intermediate thereof is obtained in the form of a diastereomer or an enantiomer, these can be separated by conventional methods well known in the art, such as chromatography or fractional crystallization.
  • Compound (I) or its synthetic intermediates include compounds labeled with isotopes (e.g., 2H , 3H , 13C , 14C , 15N , 18F , 32P , 35S , 125I , etc.) and deuterium-converted compounds.
  • isotopes e.g., 2H , 3H , 13C , 14C , 15N , 18F , 32P , 35S , 125I , etc.
  • Examples of pharmaceutically acceptable salts of Compound (I) include alkali metal salts such as lithium, sodium, and potassium; Group 2 metal salts such as magnesium and calcium; salts with aluminum or zinc; salts with amines such as ammonia, choline, diethanolamine, lysine, ethylenediamine, tert-butylamine, tert-octylamine, tris(hydroxymethyl)aminomethane, N-methyl-glucosamine, triethanolamine, and dehydroabietylamine; salts with inorganic acids such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, nitric acid, and phosphoric acid; salts with organic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid,
  • the synthetic intermediate of compound (I) may be in a free form or in a salt form.
  • Examples of the salt of the synthetic intermediate of compound (I) include the same salts as those exemplified above in "Pharmaceutically acceptable salts of compound (I)" and pharmaceutically unacceptable salts.
  • ACE inhibitors examples include ramipril, enalapril maleate, lisinopril hydrate, benazepril hydrochloride, fosinopril, quinapril hydrochloride, cilazapril (anhydrous), cilazapril hydrate, trandolapril, captopril, perindopril erbumine, delapril hydrochloride, temocapril hydrochloride, imidapril hydrochloride, and alacepril, among which ramipril, enalapril maleate, quinapril hydrochloride, lisinopril hydrate, perindopril erbumine, and imidapril hydrochloride are preferred, and ramipril and enalapril maleate are more preferred.
  • renin inhibitors examples include aliskiren.
  • the renin-angiotensin inhibitor comprises a compound represented by the following formula (A) or a pharmaceutically acceptable salt thereof:
  • ring BB represents an optionally substituted nitrogen-containing heterocycle
  • Ra represents a group capable of forming an anion or a group capable of converting into an anion
  • X represents a phenylene group and a phenyl group bonded directly or via a spacer having an atom chain of 2 or less
  • n represents an integer of 1 or 2.
  • the "optionally substituted nitrogen-containing heterocycle” represented by ring BB is preferably an optionally substituted nitrogen-containing aromatic heterocycle.
  • the "optionally substituted nitrogen-containing heterocycle” represented by ring BB is preferably an optionally substituted 5- or 6-membered nitrogen-containing heterocycle, and particularly preferably an optionally substituted 5- or 6-membered nitrogen-containing aromatic heterocycle (e.g., an optionally substituted imidazole ring which may be fused with an aromatic ring such as an optionally substituted benzene ring and which may have a substituent; specifically, an optionally substituted imidazole ring, an optionally substituted benzimidazole ring, etc.).
  • examples of the group capable of forming an anion (a group having a hydrogen atom that can be liberated as a proton) represented by R a include (1) a carboxyl group, (2) a tetrazolyl group, (3) a trifluoromethanesulfonic acid amide group (—NHSO 2 CF 3 ), (4) a phosphate group, (5) a sulfonic acid group, and (6) a 5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic residue containing one or more of N, S, and O, which may be substituted.
  • substituent for the above "optionally substituted” examples include a halogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E described above for Compound (I), an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkoxy group which may be substituted with 1 to 5 substituents independently selected from Group E, a cycloalkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, a non-aromatic heterocyclyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an aryl group which may be substituted with 1 to 5 substituents independently selected from Group E, a heteroaryl group which may be substituted with 1 to 5 substituents independently selected from Group E, or a cyano group.
  • Examples of the above-mentioned "5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic residue which contains one or more of N, S, and O and which may be substituted” include, for example,
  • the bond between the heterocyclic residue represented by R a and the phenyl group to which the heterocyclic residue is bonded may be via one of the plural nitrogen atoms present, as well as via a carbon-carbon bond as shown above.
  • R a is
  • Preferred examples of the heterocyclic residue represented by R a include groups having simultaneously an -NH- or -OH group as a proton donor and a carbonyl group, a thiocarbonyl group, or a sulfinyl group as a proton acceptor, such as an oxadiazolone ring, an oxadiazolothione ring, or a thiadiazolone ring.
  • the heterocyclic residue represented by R a may be bonded to a cyclic substituent to form a condensed ring, but the heterocyclic residue represented by R a is preferably a 5- or 6-membered ring, and more preferably a 5-membered ring.
  • the heterocyclic residue (R a ) has tautomers as shown below. For example, There are three tautomers a', b' and c' as shown in the formula
  • the heterocyclic residue represented by the formula includes all of the above a', b' and c'.
  • the group capable of forming an anion as R a may be protected at a substitutable position by an optionally substituted lower (C 1-4 ) alkyl group or acyl group (e.g., lower (C 2-5 ) alkanoyl, benzoyl, etc.).
  • Examples of the optionally substituted lower (C 1-4 ) alkyl group include: (1) a lower (C 1-4 ) alkyl group optionally substituted with 1 to 3 phenyl groups which may have a halogen atom, nitro, lower (C 1-4 ) alkyl, lower (C 1-4 ) alkoxy, etc.
  • R 4 represents (a) hydrogen, (b) a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (c) a straight-chain or branched lower alkenyl group having 2 to 6 carbon atoms, or (d) a cycloalkyl group having 3 to 8 carbon
  • the group capable of forming an anion as R1 may have, in addition to the above-mentioned protecting groups such as optionally substituted lower ( C1-4 ) alkyl groups or acyl groups (e.g., lower ( C2-5 ) alkanoyl, benzoyl, etc.), a substituent at a substitutable position such as an optionally substituted lower ( C1-4 ) alkyl group (including the same as the "optionally substituted lower ( C1-4 ) alkyl group” exemplified above as the protecting group for the group capable of forming an anion as R a) , a halogen atom, nitro, cyano, lower ( C1-4 ) alkoxy, amino optionally substituted by 1 or 2 lower ( C1-4 ) alkyl groups.
  • protecting groups such as optionally substituted lower ( C1-4 ) alkyl groups or acyl groups (e.g., lower ( C2-5 ) alkanoyl, benzoyl, etc.)
  • the group capable of being converted into a group capable of forming an anion as R a may be a group capable of being converted into a group capable of forming an anion under biological, i.e., physiological, conditions (for example, in vivo reactions such as oxidation, reduction, or hydrolysis by an in vivo enzyme, etc.) (so-called prodrug), or may be a group capable of being converted into a group capable of forming an anion as R a by a chemical reaction, such as (1) a carboxyl group, (2) a tetrazolyl group, (3) a trifluoromethanesulfonamide group (—NHSO 2 CF 3 ), (4) a phosphate group, (5) a sulfonic acid group, or (6) an optionally substituted 5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic residue containing one or more of N
  • R a is preferably carboxyl which may be protected by an optionally substituted lower (C 1-4 ) alkyl (e.g., methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl group (e.g., lower (C 2-5 ) alkanoyl, benzoyl, etc.), tetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl), cyano, or N-hydroxycarbamimidoyl (preferably cyano), and particularly preferably tetrazolyl.
  • C 1-4 alkyl
  • acyl group e.g., lower (C 2-5 ) alkanoyl, benzoyl, etc.
  • tetrazolyl 2,5-dihydro-5-oxo-1,2,4-oxadiazol
  • the compound represented by formula (A) above may be itself or a pharmacologically acceptable salt.
  • such salts include salts with inorganic bases (e.g., alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, transition metals such as zinc, iron, and copper) and organic bases (e.g., organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, and N,N'-dibenzylethylenediamine, basic amino acids such as arginine, lysine, and ornithine).
  • inorganic bases e.g., alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, transition metals such as zinc, iron, and copper
  • organic bases e.g., organic amines such as trimethylamine, triethylamine, pyridine, picoline, ethanolamine
  • the renin-angiotensin inhibitor includes losartan or a pharmaceutically acceptable salt thereof.
  • Losartan (DUP-753) represented by the following formula has the chemical name 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-methanol, and in this specification, losartan represented by the following formula includes pharmacologically acceptable salts thereof (losartan potassium salt, etc.).
  • the Nrf2 activator and the renin-angiotensin inhibitor can be used in combination simultaneously or at an interval. Furthermore, when administering multiple times, it is not necessary to administer the drugs in combination in all administrations, and in some administrations, either one of the drugs may or may not be administered alone. When these drugs are used in combination, each drug can be mixed with a pharmacologically acceptable carrier, excipient, binder, diluent, etc., separately or simultaneously, to form a pharmaceutical composition, which can be administered orally or parenterally.
  • the separately formulated drugs can be mixed and administered using a diluent or the like at the time of use, or the separately formulated drugs can be administered simultaneously or separately at different times to the same subject.
  • the pharmaceuticals of the present invention also include kit products for mixing and administering the separately formulated drugs using a diluent or the like at the time of use (e.g., an injection kit containing ampoules containing individual powdered drugs and a diluent for mixing and dissolving two or more drugs at the time of use), and kit products for administering the separately formulated drugs simultaneously or separately at different times to the same subject (e.g., a tablet kit for administering two or more tablets simultaneously or separately at different times, in which tablets containing the individual drugs are placed in the same or separate bags and, if necessary, have a column for recording the drug administration time).
  • the present invention also relates to a pharmaceutical composition containing the therapeutic agent for chronic kidney disease according to any one of the first to third aspects.
  • the dosage forms of the first to third aspects are preferably a combination drug (combined drug) or the above-mentioned kit product, from the viewpoints that, as mentioned above, Nrf2 activators and renin-angiotensin inhibitors have different actions or mechanisms of action, and that renin-angiotensin inhibitors can suppress the transient increase in proteinuria caused by Nrf2 activators.
  • the present invention also relates to the application of an Nrf2 activator to the manufacture of a therapeutic agent for chronic kidney disease to be used in combination with a renin-angiotensin inhibitor.
  • the present invention also relates to the application of a renin-angiotensin inhibitor to the manufacture of a therapeutic agent for chronic kidney disease to be used in combination with an Nrf2 activator.
  • the present invention also relates to the application of renin-angiotensin inhibitors and Nrf2 activators to the production of therapeutic agents for chronic kidney disease.
  • the dosage form of the therapeutic agent is preferably a combination drug (compound drug) or the kit product.
  • the dosage (i.e., effective amount) of the Nrf2 activator varies depending on the administration method and the patient's age, weight, and condition, but is typically 0.0001 to 500 mg/kg per day, preferably 0.001 to 300 mg/kg, more preferably 0.01 to 200 mg/kg, and even more preferably 0.01 to 10 mg/kg.
  • the above amount may be administered in divided doses of 0.2 to 4 times a day, or in divided doses of 0.5 to 3 times a day.
  • the dosage of the renin-angiotensin inhibitor varies depending on the subject, administration route, target disease, symptoms, and the like.
  • the active ingredient e.g., a component that has pharmacological activity in the body of an animal including a human, or a component that, upon contact with another substance such as a microbial contaminant, causes a physical or chemical change in the other substance or in the active ingredient itself; examples of physical or chemical changes include bonding, transfer, rearrangement, addition, elimination, decomposition, cleavage, oxidation, reduction, labeling, color development, luminescence, and the like) of the renin-angiotensin inhibitor or a pharmaceutically acceptable salt thereof (preferably losartan potassium) is typically administered in a single dose of about 0.001 to 500 mg, preferably 0.1 to 50 mg, and it is more preferable to administer this amount once
  • pharmacologically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, and are incorporated as excipients, lubricants, binders, and disintegrants in solid formulations; and as solvents, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents in liquid formulations. If necessary, formulation additives such as preservatives, antioxidants, colorants, and sweeteners can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethylcellulose, gum arabic, dextrin, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate.
  • Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.
  • binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.
  • disintegrants include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose, etc.
  • solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc.
  • solubilizing agents include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.
  • suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil.
  • isotonic agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose.
  • buffering agents include buffer solutions such as phosphates, acetates, carbonates, and citrates.
  • soothing agents include benzyl alcohol.
  • Suitable examples of preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.
  • Suitable examples of antioxidants include sulfites and ascorbic acid.
  • Suitable examples of coloring agents include water-soluble food tar dyes (e.g., food dyes such as Food Red No. 2 and No. 3, Food Yellow No. 4 and No. 5, and Food Blue No. 1 and No. 2, water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), and natural dyes (e.g., beta-carotene, chlorophyll, and red iron oxide).
  • Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, and stevia.
  • compositions can be manufactured by methods conventionally used in the pharmaceutical technology field, such as those described in the Japanese Pharmacopoeia. Specific manufacturing methods for formulations are described in detail below.
  • the content of the compound represented by formula (A) and its pharmacologically acceptable salt in the pharmaceutical composition is about 0.001% to about 95% by weight, preferably about 0.1% to about 70% by weight, based on the total weight of the composition.
  • oral preparations are produced by adding excipients (e.g., lactose, sucrose, starch, D-mannitol, etc.), disintegrants (e.g., carboxymethylcellulose calcium, etc.), binders (e.g., pregelatinized starch, gum arabic, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, etc.), or lubricants (e.g., talc, magnesium stearate, polyethylene glycol 6000, etc.) to the active ingredient, compressing the mixture, and then coating it with a coating base by a method known per se, if necessary, for the purposes of taste masking, enteric coating, or sustained release.
  • excipients e.g., lactose, sucrose, starch, D-mannitol, etc.
  • disintegrants e.g., carboxymethylcellulose calcium, etc.
  • binders e.g., pregelatinized starch, gum arabic, carboxy
  • coating bases examples include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases.
  • Sucrose is used as the sugar coating base, and one or more of talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may also be used in combination.
  • water-soluble film coating bases examples include cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma), and polyvinylpyrrolidone; and polysaccharides such as pullulan.
  • cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropylmethyl cellulose, hydroxyethyl cellulose, and methylhydroxyethyl cellulose
  • synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name), Rohm Pharma), and polyvinylpyrrolidone
  • polysaccharides such as pullulan.
  • Enteric film coating bases include, for example, cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid-based polymers such as methacrylic acid copolymer L [Eudragit L (trade name), Rohm Pharma Co., Ltd.], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], and methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]; and natural products such as shellac.
  • cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate
  • acrylic acid-based polymers such as methacrylic acid copolymer L [Eudragit L (
  • Sustained-release film coating bases include, for example, cellulose-based polymers such as ethyl cellulose; and acrylic acid-based polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.] and ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name), Rohm Pharma Co., Ltd.]. Two or more of the above coating bases may be mixed in appropriate ratios. Furthermore, light-blocking agents such as titanium oxide and iron sesquioxide may be used during coating.
  • Injectables are prepared by dissolving, suspending, or emulsifying the active ingredient in an aqueous solvent (e.g., distilled water, saline, Ringer's solution, etc.) or an oily solvent (e.g., vegetable oils such as olive oil, sesame oil, cottonseed oil, and corn oil, propylene glycol, etc.) together with dispersants (e.g., polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc.), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), preservatives (e.g., methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), and isotonic agents (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.).
  • an aqueous solvent e.g., distilled water, saline, Ringer's solution,
  • additives such as solubilizers (e.g., sodium salicylate, sodium acetate, etc.), stabilizers (e.g., human serum albumin, etc.), and soothing agents (e.g., benzyl alcohol, etc.) may be used, if desired.
  • solubilizers e.g., sodium salicylate, sodium acetate, etc.
  • stabilizers e.g., human serum albumin, etc.
  • soothing agents e.g., benzyl alcohol, etc.
  • the present invention also relates to a method for treating chronic kidney disease, which comprises administering to a subject a renin-angiotensin inhibitor and an Nrf2 activator in combination.
  • a method for treating chronic kidney disease which comprises administering to a subject a renin-angiotensin inhibitor and an Nrf2 activator in combination.
  • Specific and preferred examples of the renin-angiotensin inhibitor, Nrf2 activator, subject (administration subject), administration route, dosage, administration frequency, etc. include the same specific and preferred examples as those described above for the first to third aspects.
  • a fourth aspect of the present invention is a method for screening therapeutic agents for chronic kidney disease to be used in combination with a renin-angiotensin inhibitor, the method comprising a step of screening using at least one indicator selected from the group consisting of inhibition of albumin reabsorption from the renal tubules and inhibition of damage to renal tubular cells caused by modified albumin reabsorbed from the renal tubules.
  • the screening step preferably includes screening using suppression of excessive urine filtration function in pathological glomeruli as an additional indicator.
  • test substance can therefore significantly improve renal function and/or renal pathology (see Examples below). Furthermore, if the test substance has the effect of "suppressing excessive urine filtration function in pathological glomeruli," it may significantly improve renal function and/or renal pathology, similar to renin-angiotensin inhibitors (see the examples below).
  • the therapeutic agent for chronic kidney disease to be used in combination with a renin-angiotensin inhibitor is preferably a therapeutic agent for chronic kidney disease to be used or manufactured in combination with a renin-angiotensin inhibitor as a fixed-dose (combined drug) or kit product.
  • the fifth aspect when used in combination with an Nrf2 activator, can at least narrow down the population of candidate therapeutic agents for chronic kidney disease that may significantly improve renal function and/or renal pathology in chronic kidney disease compared to the administration of an existing therapeutic agent alone is thought to be as follows. If the test substance has the effect of suppressing excessive urine filtration function in pathological glomeruli, it can significantly improve renal function and/or renal pathology, and can significantly suppress the increase in proteinuria caused by Nrf2 activating drugs (see the examples below).
  • the above-mentioned "step of administering a test substance to an animal in vivo" is preferably a step of administering a combination of the test substance and a renin-angiotensin inhibitor to an animal in vivo.
  • a step of quantitatively or qualitatively determining the state of damage to renal tubular cells caused by modified albumin reabsorbed from the renal tubules is preferred.
  • the step of determining the quantitative or qualitative state of damage to tubular cells caused by modified albumin reabsorbed from the tubules preferably includes a step of determining the above-mentioned percentage of albumin localization within proximal tubular cells and the above-mentioned percentage of albumin localization outside proximal tubular cells, as well as a step of determining the degree of albumin oxidation in the blood (preferably, inhibition of the degree of oxidation) as described later in the Examples, and/or a step of determining the blood IS concentration (preferably, inhibition of the concentration) as described later in the Examples.
  • control conditions refers to conditions in the absence of the test substance, and means that the difference in the intensity of the response depending on the presence or absence of the test substance (the above-mentioned “at least one selected from the group consisting of inhibition of reabsorption of albumin from the renal tubules, and inhibition of damage to renal tubular cells by modified albumin reabsorbed from the renal tubules") is used as an indicator.
  • the intensity S2 of the response under the control condition may be a value measured before the addition of the test substance, or may be a statistical value or range obtained by collecting data in advance.
  • test substance for example, when the above-mentioned "at least one selected from the group consisting of inhibition of reabsorption of albumin from the renal tubules and inhibition of damage to renal tubular cells caused by modified albumin reabsorbed from the renal tubules" is observed, it is preferable to identify the test substance as a candidate therapeutic drug for chronic kidney disease. For example, it is preferable to identify the response intensity S1 in the presence of the test substance as an index, and it is more preferable to identify the response intensity S1 by comparing it with the response intensity S2 under control conditions.
  • the intensity of the response due to compound (I) used in the Reference Examples and Examples described below may or may not be used as a benchmark "control condition.”
  • the "step of screening using as an index at least one selected from the group consisting of inhibition of reabsorption of albumin from renal tubules and inhibition of damage to renal tubular cells by modified albumin reabsorbed from renal tubules” includes the following steps:
  • the method may include measuring the inhibitory activity of the test substance against the binding between Nrf2 and Keap1 in vitro, and selecting candidate therapeutic drugs for chronic kidney disease based on the measurement results, using the measured activity as an indicator similar to or in place of "at least one indicator selected from the group consisting of inhibition of reabsorption of albumin from the renal tubules, and inhibition of damage to renal tubular cells by modified albumin reabsorbed from the renal tubules.”
  • the method for measuring activation of Nrf2 by a test substance is not particularly limited.
  • it can be measured by a known method for measuring binding between substances, such as inhibition of the above-mentioned binding by a competitive inhibitor.
  • examples of such methods include isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), nuclear magnetic resonance (NMR), and fluorescence correlation spectroscopy (FCS).
  • the inhibitory activity of a test substance against the binding between Nrf2 and Keap1 can be measured by any binding assay (e.g., fluorescence polarization) (e.g., paragraph 0609 of WO 2020/241853).
  • binding assay e.g., fluorescence polarization
  • the "screening step using suppression of excessive urine filtration function in pathological glomeruli as an index” comprises: administering the test substance to the animal in vivo;
  • the method includes a step of determining a quantitative or qualitative state regarding excessive urine filtration function in the pathological glomeruli (e.g., determining the GFR value and/or the urinary protein concentration), and selecting a candidate therapeutic drug for chronic kidney disease based on the determination results.
  • a quantitative or qualitative state regarding excessive urine filtration function in the pathological glomeruli e.g., determining the GFR value and/or the urinary protein concentration
  • the above-mentioned "step of administering a test substance to an animal in vivo" is preferably a step of administering a combination of the test substance and an Nrf2 activator to an animal in vivo.
  • the fifth aspect is Suppression of blood and/or urinary creatinine levels (e.g., mg/dl), Suppression of blood and/or urinary urea nitrogen (BUN) levels (e.g., mg/dl); Suppression of blood and/or urinary cystatin C levels (e.g., mg/g Cre), Suppression of blood and/or urinary KIM-1 levels (e.g., ⁇ g/g Cre), Suppression of blood and/or urinary NGAL levels (e.g., mg/g Cre), Suppression of blood and/or urinary clusterin levels (e.g., mg/g Cre), Suppression of blood and/or urinary TFF levels (e.g., ⁇ g/g Cre); Suppression of blood and/or urinary ⁇ 2 -microglobulin levels (e.g., ⁇ g/g Cre); The method may or may not further include a screening step using as an indicator a significant extension of the survival time of CKD mice.
  • BUN
  • the degree of the above-mentioned inhibition or reduction is more preferably 3/4 or less, even more preferably 3/5 or less, particularly preferably 1/2 or less, particularly preferably 1/3 or less, and most preferably 1/4 or less, compared to the control condition.
  • the degree of increase is more preferably 1.2-fold or more compared to the control condition, even more preferably 1.5-fold or more, particularly preferably 2-fold or more, particularly preferably 3-fold or more, and most preferably 4-fold or more.
  • There is no particular upper limit to the degree of increase but examples include 30 times or less, 20 times or less, and 10 times or less.
  • control conditions refers to conditions in the absence of the test substance, and means that the difference in the intensity of the response (the above-mentioned “suppression of excessive urine filtration function in pathological glomeruli") depending on the presence or absence of the test substance is used as an indicator.
  • the intensity S2 of the response under the control condition may be a value measured before the addition of the test substance, or may be a statistical value or range obtained by collecting data in advance.
  • the test substance is preferably identified as a candidate therapeutic drug for chronic kidney disease.
  • the response intensity S1 in the presence of the test substance is an index, and it is more preferable to identify the response intensity S1 by comparing it with the response intensity S2 under control conditions.
  • the intensity of the response to losartan or its pharmacologically acceptable salts may or may not be used as a benchmark "control condition.”
  • the "screening step using suppression of excessive urine filtration function in glomeruli as an index” comprises:
  • the method may include measuring the inhibitory activity of the test substance against the angiotensin II receptor in vitro, and selecting a candidate therapeutic drug for chronic kidney disease based on the measurement results, with the measured activity being equivalent to or a substitute for "suppression of excessive urine filtration function in pathological glomeruli.”
  • the method for measuring the inhibition of angiotensin II receptor by a test substance is not particularly limited. For example, it can be measured by a known method for measuring the binding between substances, such as the inhibition of the above-mentioned binding by a competitive inhibitor.
  • ITC isothermal titration calorimetry
  • SPR surface plasmon resonance
  • NMR nuclear magnetic resonance
  • FCS fluorescence correlation spectroscopy
  • the inhibitory activity of a test substance against angiotensin II receptors can be measured by any binding assay (e.g., fluorometry) (e.g., paragraph 0071 of WO 2017/002838).
  • test substance The test substance is not particularly limited.
  • the test substance may consist of a single component (i.e., a pure substance) or a combination of two or more components (i.e., a mixture). When the test substance is a mixture, the number of components constituting the mixture and their composition ratios are not particularly limited.
  • the test substance may be a known substance or a novel substance.
  • the test substance may be a natural product or an artificial product.
  • the test substance may be, for example, a compound library created using combinatorial chemistry techniques. Examples of test substances include alcohols, ketones, aldehydes, ethers, esters, hydrocarbons, sugars, organic acids, nucleic acids, amino acids, peptides, lipids, and various other organic or inorganic components.
  • mice The chronic kidney disease model mice (hereinafter also referred to simply as "CKD mice") (B6.Cg-Col4a5 tm1Yseg /J, strain #006183) used in the following Reference Examples and Examples were purchased from Jackson Laboratory. In the following Examples, offspring mice bred from the purchased CKD mice were used. Additionally, C57/BL/6J mice of the same age were purchased from Charles River Japan and used as wild-type (WT) controls. These mice were used in the following Examples.
  • CKD mice The chronic kidney disease model mice (hereinafter also referred to simply as "CKD mice”) (B6.Cg-Col4a5 tm1Yseg /J, strain #006183) used in the following Reference Examples and Examples were purchased from Jackson Laboratory. In the following Examples, offspring mice bred from the purchased CKD mice were used. Additionally, C57/BL/6J mice of the same age were purchased from Charles River Japan and used as wild-type (WT) controls. These mice were used in the
  • FIG. 1 is a schematic diagram showing the administration regimen of an Nrf2 activator (in the following Examples and Figures, the Nrf2 activator will also be simply referred to as "Compound 1") to CKD mice.
  • the results of the following Reference Examples 1-1 to 1-3 (results shown in Figures 2 to 5) were obtained from the individuals used in this Example.
  • Kidney tissue was removed from 22-week-old mice. The removed kidney tissue was fixed in 10% formalin and embedded in paraffin. The tissue block was sliced to a thickness of 2 ⁇ m using a microtome, and the resulting kidney sections were histologically stained with periodic acid-Schiff (PAS) and Masson's trichrome (MT). For PAS staining, after deparaffinization, the sections were treated with 1% periodic acid for 15 minutes and washed with running water.
  • PAS periodic acid-Schiff
  • MT Masson's trichrome
  • the sections were then stained with Schiff's reagent for 15 minutes, washed three times with a sulfite solution for 3 minutes, and then washed with tap water and distilled water. The sections were then incubated with hematoxylin for 1 minute and dehydrated with ethanol and xylene.
  • MT staining After deparaffinization, sections were treated with an equal mixture of 10% trichloroacetic acid and 10% potassium dichromate for 20 minutes, rinsed with tap water, incubated with Carraghe's hematoxylin for 1 minute, rinsed with tap water, and then stained with 0.75% Orange G for 1 minute, Ponceau xylidine acid fuchsin for 20 minutes, 2.5% phosphotungstic acid for 30 minutes, and aniline blue for 15 minutes. After each staining, sections were rinsed twice with 1% acetic acid.
  • Immunostaining with anti-F4/80 was performed by incubating tissue sections with the following primary antibody, anti-F4/80 (MCA497R, BIO-RAD), overnight at 4°C, washing with PBS, and then applying HRP (horseradish peroxidase) or fluorescent secondary antibody for 1 hour.
  • Tissues were photographed using a BZ-X700 microscope and analyzed using image analysis software (Keyence).
  • Glomerulosclerosis score and fibrosis area were evaluated histologically by scoring 100 or more random glomeruli per mouse according to the following criteria, and comparing them with a wild-type group and a non-treated CKD mouse group (vehicle group).
  • FIG. 2A shows the results of PAS staining, F4/80 immunohistochemistry, and MT staining of kidney sections from WT and CKD mice.
  • the scale bar for PAS staining is 50 ⁇ m, and the scale bars for other stainings are 100 ⁇ m.
  • FIG. 2B shows the results of evaluation of glomerulosclerosis scores based on PAS-stained sections.
  • FIG. 2C shows the percentage of F4/80-positive areas (inflammatory areas).
  • the inflamed area was approximately 0% in the wild-type mice, whereas the inflamed area was approximately 5.4% in the non-treated CKD mouse group (vehicle group), indicating a worsening of the pathology.
  • the inflamed area was significantly reduced to approximately 1% or less, indicating a significant improvement in inflammation.
  • the fibrotic area was approximately 0% in the wild-type mice, whereas the fibrotic area was approximately 9.5% in the non-treated CKD mouse group (vehicle group), indicating a worsening of the pathology.
  • the fibrotic area significantly decreased in a dose-dependent manner, indicating a significant improvement in fibrosis.
  • Plasma biomarkers GFR was measured by anesthetizing mice with isoflurane and injecting 20 mg/mL FITC-sinistrin (Medbeacon) at 100 ⁇ L/mouse via the subclavian vein. A transcutaneous GFR monitor (Medbeacon) was attached directly to the shaved skin on the back of the animal, and FITC fluorescence intensity was measured. GFR ( ⁇ l/min) was calculated using Medbeacon software. For other plasma biomarkers (plasma creatine, BUN, and indoxyl sulfate), mouse blood samples obtained from the inferior vena cava or tail were centrifuged at 3,000 rpm at 4°C for 15 minutes to collect the plasma.
  • FITC-sinistrin Medbeacon
  • Plasma creatine, BUN, and indoxyl sulfate were measured using a DRI-CHEM (Fujifilm), a 7180 biochemistry autoanalyzer (Hitachi), and a PU-4180 HPLC Pump/FP-4020 Fluorescence detector (Jasco), respectively.
  • Urinary Biomarkers Mouse urine samples were collected at predetermined time points for 24 hours using metabolic cages (Aswan Co., Ltd.). Urinary creatinine as an internal standard was measured by the Jaffe method (636-51011, Fujifilm Corporation).
  • Urinary KIM-1 and clusterin concentrations were measured using Mouse Kidney Injury Magnetic Bead Panel 1 (MKI1MAG-94K; Merck), and urinary cystatin C and NGAL concentrations were measured using Mouse Kidney Injury Magnetic Bead Panel 2 (MKI2MAG-94K; Merck).
  • Urinary TFF3 concentrations were measured using the Mouse TFF3 SimpleStep ELISA kit (ab253228; Abcam).
  • Urinary protein concentration and albumin concentration (mg/mg Cre) were measured by the Bradford method (5000001, Bio-Rad) and the CBB method, respectively.
  • FIG. 3A shows the results of improving urinary filtration rate (GFR) in CKD mice by Compound 1.
  • 3B to 3D show the results of improvements in plasma biomarkers (plasma creatine, BUN, and indoxyl sulfate) by Compound 1, respectively.
  • 3E to 3J show the results of improvement of urinary biomarkers (urinary cystatin C, ⁇ 2 -microglobulin, NGAL, KIM-1, clusterin, and TFF3) by Compound 1, respectively.
  • FIG. 4A shows the transient increase in urinary protein concentration (mg/mg Cre) in CKD mice by Compound 1.
  • 4B shows the transient increase in urinary albumin concentration (mg/mg Cre) in CKD mice by Compound 1.
  • the CKD mice showed significantly increased proteinuria and albuminuria (mg/mg Cre) compared to the wild-type control group. Furthermore, it can be seen that the group orally administered with a single Nrf2 activator had significantly increased proteinuria and albuminuria (mg/mgCre) compared to the CKD mice (vehicle group). This is thought to be because, as described below, Nrf2 activators inhibit the reabsorption of modified albumin from the renal tubules, promote the excretion of modified albumin, prevent proximal tubular damage caused by the reabsorption of modified albumin (toxicity), and contribute to improving renal function.
  • Nrf2 activators inhibit the reabsorption of modified albumin from the renal tubules, promote the excretion of modified albumin, prevent proximal tubular damage caused by the reabsorption of modified albumin (toxicity), and contribute to improving renal function.
  • At least 200 proximal tubules from 22-week-old CKD mice were stained with biotinylated LTL (Lotus Tetragonolobus Lectin; Vector Laboratories), and albumin was fluorescently stained with an anti-albumin antibody (ab19194; Abcam) (stained with HRP or fluorescent secondary antibody).
  • LTL Litus Tetragonolobus Lectin
  • albumin was fluorescently stained with an anti-albumin antibody (ab19194; Abcam) (stained with HRP or fluorescent secondary antibody).
  • the tissues were photographed using a BZ-X700 microscope and analyzed using image analysis software (KEYENCE).
  • CKD mice (vehicle group), and groups receiving oral administration of an Nrf2 activator alone at 0.3 mg/kg/day, 1 mg/kg/day, and 3 mg/kg/day were fluorescently stained with anti-megalin antibody (ab76969; Abcam) (stained with HRP or fluorescent secondary antibody), and measurements were performed at 10 different points (total area 3,938,800 ⁇ m2 ) in each mouse, normalized to the megalin-positive area, and the relative staining intensity (%) of megalin was measured, with WT set at 100%.
  • Example 1 Test for Improvement of Renal Function (Survival Period Extension, etc.) in CKD Mice by Combined Use of a RAS Inhibitor (Losartan Potassium) and an Nrf2 Activator (Compound 1)
  • Figure 6 is a schematic diagram showing the administration schedule for Compound 1, losartan potassium, and a combination of Compound 1 and losartan potassium to CKD mice.
  • the main purpose of this Example was to measure survival time, and the results of Examples 1-1 to 1-3 below (results shown in Figures 7 to 9) were obtained from the individuals used in this Example.
  • Example 1-1 Test of the effect of combined use of a RAS inhibitor and an Nrf2 activator on extending the survival period of CKD mice The effect of combined use of losartan potassium, a representative RAS inhibitor, and Compound 1 on extending the survival period of CKD mice was tested. The results are shown in Figures 7A to 7D as Kaplan-Meier survival curves. A shows the results when an Nrf2 activator was orally administered at 0.3, 1 and 3 mg/kg/day. B shows the results when an Nrf2 activator was orally administered at 0.3 mg/kg/day. C shows the results when an Nrf2 activator was orally administered at 1 mg/kg/day.
  • D shows the results when an Nrf2 activator was orally administered at 3 mg/kg/day.
  • Example 1-3 Test for Improvement of Renal Function in CKD Mice by Combined Use of a RAS Inhibitor (Losartan Potassium) and an Nrf2 Activator (Compound 1)
  • a RAS Inhibitor Lisartan Potassium
  • an Nrf2 Activator Compound 1
  • the concentrations of plasma biomarkers plasma creatinine
  • urinary biomarkers urinary cystatin C, ⁇ 2 -microglobulin, KIM-1, and NGAL
  • 9A to 9E are graphs showing that the combined use of losartan and Compound 1 improves renal function parameters in CKD mice more than either losartan or Compound 1 alone.
  • Figure 10 is a schematic diagram showing the administration schedule for Compound 1, losartan potassium, and a combination of Compound 1 and losartan potassium to CKD mice from the age of 6 weeks.
  • the main purpose of this example was pathological evaluation, and the results shown in Examples 2-1, 2-2, and 2-4 below (results shown in Figures 11, 12, and 15) were obtained from the individuals used in this example.
  • Example 2-1 Test for improvement of glomerular sclerosis and fibrosis in CKD mice by combined use of a RAS inhibitor and an Nrf2 activator.
  • Kidney tissue was excised from 20-week-old CKD mice with advanced disease (vehicle group), a 20-week-old wild-type control group, a group orally administered 3 mg/kg/day of an Nrf2 activator alone, and a group orally administered a RAS inhibitor and an Nrf2 activator (3 mg/kg/day).
  • the excised kidney tissue was histologically stained with PAS and MT in the same manner as in Reference Example 1.
  • the glomerular sclerosis score and fibrosis area were evaluated histologically in the same manner as in Reference Example 1, by scoring 100 or more random glomeruli per mouse according to the following criteria, and comparing them with a wild-type group and a non-treated CKD mouse group (vehicle group).
  • 0 no lesion
  • 1 expansion of mesangial area
  • 2 expansion of Bowman's epithelial cells, adhesion of glomeruli and Bowman's capsule, partial sclerosis
  • 3 sclerotic areas covering 50 to 75% of glomeruli
  • 4 sclerotic areas covering 75 to 100% of glomeruli.
  • the results are shown in Figures 11A to 11C.
  • FIG. 11B shows the results of evaluation of glomerulosclerosis scores based on PAS-stained sections.
  • the group receiving a combination of a RAS inhibitor and an Nrf2 activator showed a significantly lower proportion of glomerular sclerosis score 4 than either the group receiving an Nrf2 activator alone or the group receiving a RAS inhibitor alone, indicating a significant further improvement in the condition. This is thought to be due to preferably significant or synergistic improvement of the pathological condition by the combination of a RAS inhibitor and an Nrf2 activator.
  • the fibrotic area was approximately 0% in the wild-type mice, whereas the fibrotic area was approximately 8.1% in the non-administered CKD mouse group (vehicle group), indicating a worsening of the pathology.
  • the fibrotic area was reduced, indicating an improvement in fibrosis.
  • the group receiving a combination of a RAS inhibitor and an Nrf2 activator showed a significantly smaller area of fibrosis than the group receiving an Nrf2 activator alone and the group receiving a RAS inhibitor alone, indicating a significant improvement in fibrosis. This is thought to be due to preferably significant or synergistic improvement of the pathological condition by the combination of a RAS inhibitor and an Nrf2 activator.
  • Example 2-2 Test for improving renal function in CKD mice by combined use of a RAS inhibitor and an Nrf2 activator
  • Plasma biomarker (GFR, indoxyl sulfate) concentrations were measured in the same manner as in Reference Example 1 for 20-week-old CKD mice with advanced disease (vehicle group), a 20-week-old wild-type control group, a group receiving an Nrf2 activator alone orally at 3 mg/kg/day, and a group receiving a combination of a RAS inhibitor and an Nrf2 activator (orally at 3 mg/kg/day).
  • the 20-week-old CKD mice (vehicle group) with advanced disease showed a significant increase in indoxyl sulfate compared to the 20-week-old wild-type control group.
  • the 20-week-old group treated with a combination of a RAS inhibitor and an Nrf2 activator showed a significant decrease in indoxyl sulfate compared to the 20-week-old CKD mice (vehicle group), maintaining levels close to normal levels comparable to those of the 20-week-old wild-type control group. This is thought to be due to a preferably significant or synergistic improvement in renal function caused by the combination of a RAS inhibitor and an Nrf2 activator.
  • Example 2-3 Test for improving renal function in CKD mice by combined use of a RAS inhibitor and an Nrf2 activator
  • Part 2 13 is a schematic diagram showing the administration schedule of losartan potassium and a combination of Compound 1 and losartan potassium to CKD mice from the age of 12 weeks.
  • administration was initiated from the age of 12 weeks, after the onset of proteinuria.
  • FIGGS. 14 and 15 The results shown in Examples 2-3 and 2-4 below (FIGS. 14 and 15) were obtained from the individuals used in this example.
  • Plasma biomarker concentrations were measured in the same manner as in Reference Example 1 for 24-week-old CKD mice with advanced disease (vehicle group), a 24-week-old wild-type control group, a group receiving an Nrf2 activator alone at 3 mg/kg/day orally, and a group receiving a combination of a RAS inhibitor and an Nrf2 activator (3 mg/kg/day orally).
  • the 24-week-old CKD mice (vehicle group) with advanced disease showed a significant increase in indoxyl sulfate compared to the 24-week-old wild-type control group.
  • the 24-week-old group treated with a combination of a RAS inhibitor and an Nrf2 activator (3 mg/kg/day orally) showed a significant decrease in indoxyl sulfate compared to the 24-week-old CKD mice (vehicle group), maintaining levels close to normal levels comparable to those of the 24-week-old wild-type control group. This is thought to be due to a preferably significant or synergistic improvement in renal function caused by the combination of a RAS inhibitor and an Nrf2 activator.
  • Example 2-4 Suppression of oxidized albumin-induced tubular damage by combined use of a RAS inhibitor and an Nrf2 activator
  • Albumin-induced proximal tubule (upper cell) damage is known to be mainly due to the following three factors, and the present inventors demonstrated in this Example 2-4 that this damage can be suppressed by an Nrf2 activator.
  • Oxidized albumin 2.
  • Uremic toxin indoxyl sulfate: IS
  • albumin bound to albumin 3.
  • Reduced albumin has a thiol group at Cys34 (the 34th cysteine), which is the main oxidation site of albumin. This accounts for approximately 80% of the thiol groups in the blood.
  • Oxidized albumin refers to albumin to which another cysteine is further bonded via an S—S bond, O 2 H is bonded, O 3 H is bonded, or the like. It is known that reduced albumin is converted to oxidized albumin by oxidative stress.
  • Indoxyl sulfate ((2. Uremic toxins)) Indoxyl sulfate (IS), a uremic toxin, is a substrate for organic anion transporters (OATs) expressed on the basolateral membrane of proximal tubular epithelial cells and is known to be excreted in urine via tubular secretion (Kidney Int. 65, 162-174 (2004)).
  • OATs organic anion transporters
  • P-cresyl sulfate and indoxyl sulfate (IS) are strongly associated with cardiovascular events and all-cause mortality in chronic kidney disease (CKD) (Clin J Am Soc Nephrol 2009;4(10):1551-1558).
  • ESI-TOFMS mass spectrometer
  • the degree of plasma albumin oxidation in wild-type mice was approximately 15%, whereas the degree of plasma albumin oxidation in CKD mice (vehicle group) was approximately 22%, indicating a higher proportion of oxidized albumin in plasma.
  • the group receiving a combination of a RAS inhibitor and an Nrf2 activator (3 mg/kg/day orally) showed a significant decrease of around 17%, and furthermore, it can be said that the degree of oxidation of plasma albumin was decreased to a level equivalent to that of wild-type mice, indicating that the proportion of oxidized albumin in the serum was low. It can be said that the amount of oxidized albumin that causes renal tubular damage can be suppressed by the above-mentioned combined use.
  • NAD(P)H quinone reductase NQO-1
  • Figure 16 NAD(P)H quinone reductase
  • NQO-1 expression was elevated in the 30 mg/kg/day oral administration group compared to the wild-type group and the untreated U-IR model group.

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Abstract

L'invention concerne : un médicament thérapeutique pour une maladie rénale chronique, qui est capable d'améliorer significativement la maladie rénale chronique; et un procédé de criblage d'un médicament thérapeutique pour une maladie rénale chronique. Ce médicament thérapeutique pour maladie rénale chronique comprend un activateur de Nrf2 à utiliser en combinaison avec un inhibiteur de la rénine-angiotensine. Ce médicament thérapeutique pour maladie rénale chronique comprend un inhibiteur de la rénine-angiotensine à utiliser en combinaison avec un activateur de Nrf2. Ce médicament thérapeutique pour maladie rénale chronique comprend un inhibiteur de la rénine-angiotensine et un activateur de Nrf2.
PCT/JP2025/009121 2024-03-12 2025-03-11 Médicament thérapeutique pour maladie rénale chronique, et procédé de criblage de médicament thérapeutique pour maladie rénale chronique Pending WO2025192605A1 (fr)

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