Therapeutic drug for chronic kidney disease, and screening method for therapeutic drug for chronic kidney disease

Abstract

Provided are: a therapeutic drug for chronic kidney disease, which is capable of significantly improving the chronic kidney disease; and a screening method for a therapeutic drug for chronic kidney disease. This therapeutic drug for chronic kidney disease comprises an Nrf2 activator to be used in combination with a renin-angiotensin inhibitor. This therapeutic drug for chronic kidney disease comprises a renin-angiotensin inhibitor to be used in combination with an Nrf2 activator. This therapeutic drug for chronic kidney disease comprises a renin-angiotensin inhibitor and an Nrf2 activator.

Description

Therapeutic agent for chronic kidney disease and screening method for therapeutic agent for chronic kidney disease

[0001] The present invention relates to a therapeutic agent for chronic kidney disease (hereinafter also simply referred to as "CKD") that is suitable for improving renal function and / or renal pathology, and a method for screening a therapeutic agent for chronic kidney disease.

[0002] Conventional drugs for chronic kidney disease are ineffective, and more than half of patients ultimately progress to end-stage renal failure. However, no drugs have been found to significantly prevent the progression to renal failure. Therefore, there is an urgent need to develop new treatments for chronic kidney disease.

[0003] 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. Under normal conditions, 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, thereby maintaining its transcriptional activity at a low level. However, under oxidative stress conditions, highly reactive cysteine ​​residues in Keap1 are modified, causing a structural change in the Nrf2-trapping 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 discovery targeting the Nrf2 pathway has attracted attention (Non-Patent Document 1).

[0004] Deshmukh P, Unni S, Krishnappa G, Padmanabhan B: The Keap1-Nrf2 pathway: Promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases. Biophys Rev 9:41-56, 2017.10.1007 / s12551-016-0244-4

[0005] The present invention has been made in consideration of the above-mentioned problems of 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, and a method for screening such a therapeutic agent.

[0006] As a result of extensive research into the above-mentioned problems, the present inventors have found that the combined use of a renin-angiotensin (RAS) inhibitor and an Nrf2 activator can significantly improve renal function and / or renal pathology in chronic kidney disease (for example, significantly extending survival rates and significantly extending the transition period to renal failure, etc.).

[0007] The present invention has been completed based on the above findings. That is, the present invention is as follows.

[0008] <1> A therapeutic agent for chronic kidney disease, comprising an Nrf2 activator, for use in combination with a renin-angiotensin inhibitor. <2> A therapeutic agent for chronic kidney disease, comprising a renin-angiotensin inhibitor, for use in combination with an Nrf2 activator. <3> A therapeutic agent for chronic kidney disease, comprising a renin-angiotensin inhibitor and an Nrf2 activator. <4> The therapeutic agent according to any one of <1> to <3>, wherein the 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: (In the above formula (I), 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 which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be 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 which may be substituted with 1 to 5 substituents independently selected from group E; R３ , R ４ , and R ６ are each independently a hydrogen atom, a halogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from group E, 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; R ５ is (i) a hydrogen atom, or (ii) an alkyl group which may be substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a cycloalkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, a phenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, and an alkoxy group which may be substituted with 1 to 5 substituents independently selected from Group E; A is a group represented by the following formula (II): R ７ and R ８ are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E; or R ７ and R ８are taken together with the carbon atoms to which they are attached to form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E; 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, and a cyano group; represents the point of attachment to the rest of the molecule; and Group E is a group consisting of a halogen atom, a hydroxy group, and an alkoxy group optionally substituted with 1 to 5 halogen atoms.) <5> The therapeutic agent according to <4>, wherein A in the above formula (I) has a structure represented by the following formula (II-1-1): (In the above formula, 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; X １ and X ２ are each independently CR ９ and Y １ , Y ２ , Y ３ , and Y ４ any one of the above is a nitrogen atom, and the other three are each independently CR １０ and R ９ are each a hydrogen atom; １０are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group.) <6> The therapeutic agent according to <4>, wherein the compound represented by the general formula (I) above includes a compound represented by the following formula (I-1-1) or a pharmaceutically acceptable salt thereof: (In the above formula (I-1-1), 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; 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 phenyl group, and an alkoxy group; 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 which may be substituted with 1 to 5 substituents independently selected from group E; R １０ is a hydrogen atom, a halogen atom, an alkyl 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, or a cyano group; Group E is a group consisting of a halogen atom, a hydroxy group, and an alkoxy group which may be substituted with 1 to 5 halogen atoms.) <7> The therapeutic agent according to <4>, wherein the compound represented by 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, and R ａ represents a group capable of forming an anion or a group capable of converting into such an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having a chain of two atoms or less, and n represents an integer of 1 or 2.) <9> The therapeutic agent according to any one of <1> to <3>, wherein 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. <10> A method for screening a therapeutic agent for chronic kidney disease to be used in combination with a renin-angiotensin inhibitor, the method comprising a 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. <11> The method according to <10>, wherein the screening step further comprises screening using suppression of excessive urine filtration function in glomeruli as an index. <12> A method for screening a therapeutic agent for chronic kidney disease to be used in combination with an Nrf2 activator, the method comprising a step of screening using suppression of excessive urine filtration function in glomeruli as an index. <13> The method according to <12>, wherein the Nrf2 activator comprises a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: (In the above formula (I), 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 ２are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be 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 which may be 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 which may be substituted with 1 to 5 substituents independently selected from group E, 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; R ５ is (i) a hydrogen atom, or (ii) an alkyl group which may be substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a cycloalkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, a phenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, and an alkoxy group which may be substituted with 1 to 5 substituents independently selected from Group E; A is a group represented by the following formula (II): R ７ and R ８are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E; or R ７ and R ８ are taken together with the carbon atoms to which they are attached to form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E; 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, and a cyano group; represents the point of attachment to the rest of the molecule; Group E is a group consisting of a halogen atom, a hydroxy group, and an alkoxy group optionally substituted with 1 to 5 halogen atoms.) <14> The method according to <9>, 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, and R ａrepresents a group capable of forming an anion or a group capable of converting into such an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having a chain of two atoms or less, and n represents an integer of 1 or 2.) <15> The method according to <10>, wherein 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. <16> A method for treating chronic kidney disease, comprising administering to a subject a renin-angiotensin inhibitor and an Nrf2 activator in combination.

[0009] According to 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, that can significantly increase the survival rate, significantly extend the transition period to renal failure, etc.), and a method for screening a therapeutic agent for chronic kidney disease. According to the present invention, the survival rate can be significantly (preferably, markedly or synergistically) increased or the transition period to renal failure can be significantly extended compared to the administration of an existing therapeutic agent alone, 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.

[0010] This is a schematic diagram showing the administration schedule of Compound 1, an Nrf2 activator, to CKD mice. The results shown in Figures 2 to 5 below were obtained from the individual used in this Reference Example. This figure shows the results of Compound 1 improving glomerular damage, inflammation, and fibrotic pathology in CKD mice. This figure shows the results of Compound 1 improving renal function in CKD mice. This figure shows the results of Compound 1 transiently increasing proteinuria and albuminuria in CKD mice. This figure 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. This is a schematic diagram showing the administration schedule of 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 in Figures 7 to 9 below were obtained from the individual used in this Example. This figure shows the results showing that a combination of losartan potassium and Compound 1 significantly extended the survival time of CKD mice compared to either losartan potassium or Compound 1 administered alone. Figure 7A shows a summary of the results, and Figures 7B, 7C, and 7D show individual results for the Nrf2 activator 0.3 mg / kg / day, 1 mg / kg / day, and 3 mg / kg / day groups, respectively. This figure shows that compound 1 transiently increases proteinuria in CKD mice, losartan potassium decreases it, and the combination of compound 1 and losartan potassium shows intermediate values. This figure shows that the combination of losartan potassium and compound 1 improves renal function parameters in CKD mice more than losartan or compound 1 alone. This figure is a schematic diagram showing the administration schedule for compound 1, losartan potassium, and the combination of compound 1 and losartan potassium to CKD mice starting at 6 weeks of age. The primary purpose of this example was pathological evaluation, and the results in Figures 11, 12, and 15 below were obtained from the individuals used in this example. This figure shows that the combination of losartan potassium and compound 1 improves glomerular injury and fibrotic pathology in CKD mice more than losartan potassium or compound 1 alone. 1 is a diagram showing that the combined use of losartan potassium and Compound 1 improves the renal function of CKD mice more than either losartan potassium or Compound 1 alone. 2 is a diagram showing a schematic diagram of the administration schedule for losartan potassium and the combined use of Compound 1 and losartan potassium to CKD mice from the age of 12 weeks.In this example, assuming therapeutic intervention from the CKD stage, administration was initiated at 12 weeks of age, after the onset of proteinuria. The results in Figures 14 and 15 below were obtained from the individuals used in this example. This figure shows that while losartan potassium is largely ineffective in therapeutic intervention from the CKD stage, the combination of losartan potassium and Compound 1 significantly improves renal function in CKD mice. This figure shows that the combination of losartan potassium and Compound 1 improves plasma albumin oxidation levels in CKD mice more than either losartan potassium or Compound 1 alone. This figure shows the results of an Nrf2 activator improving renal pathology in a renal-ischemia-reperfusion (U-IR) model.

[0011] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments and can be implemented with appropriate modifications within the scope of the object of the present invention.

[0012] The definitions of the terms used in this specification are as follows. As used herein, a "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom. As used herein, an "alkyl group" refers to an alkyl group having 1 to 6 carbon atoms (C １ -C ６ ), for example, a carbon number of 1 to 4 (C １ -C ４ ) and includes, for example, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, isobutyl, n-pentyl, and n-hexyl groups, as well as various branched isomers thereof. As used herein, the term "alkenyl group" refers to an alkenyl group having one carbon-carbon double bond and 2 to 6 carbon atoms (C ２ ~C ６ ), for example, a carbon number of 2 to 4 (C ２ ~C ４ ) straight-chain or branched-chain unsaturated hydrocarbon groups, such as vinyl, propenyl, isopropenyl, butenyl, and various branched-chain isomers thereof. As used herein, the term "alkynyl group" refers to an alkynyl group having one carbon-carbon triple bond and 2 to 6 carbon atoms (C ２ ~C ６), for example, a carbon number of 2 to 4 (C ２ ~C ４ ) and includes, for example, 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. As used herein, the term "alkoxy group" refers to a group in which an oxygen atom is bonded to the above-mentioned straight-chain or branched-chain alkyl group and includes, for example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, an isobutoxy group, and various branched-chain isomers thereof.

[0013] The "cycloalkyl group" as used herein refers to a group having 3 to 8 ring carbon atoms (C ３ ~C ８ ), for example, a ring having 3 to 6 carbon atoms (C ３ ~C ６) monocyclic alicyclic saturated hydrocarbon groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. As used herein, the term "non-aromatic heterocyclyl group" refers to a 4- to 8-membered monocyclic non-aromatic heterocyclic group or a 6- to 12-membered bicyclic non-aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen atoms, such as azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, piperidinyl, piperidino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl (i.e., thiolanyl), piperazinyl, morpholinyl, morpholino, perhydroazepinyl, perhydroazocinyl, 6- to 12-membered azabicycloalkyl groups (e.g., azabicyclohexyl, azabicyclohexyl, and the like). Examples of the "aryl group" as used herein include an azabicycloalkenyl group having 6 to 11 ring carbon atoms (e.g., azabicyclohexenyl, azabicycloheptenyl, azabicyclooctenyl, azabicyclononenyl, azabicyclodecenyl, azabicycloundecenyl, or azabicyclododecenyl), a 6- to 12-membered azaspiroalkyl group (e.g., azaspirohexyl, azaspiroheptyl, azaspirooctyl, azaspirononyl, azaspirodecyl, azaspironundecyl, or azaspirododecyl). ６ ~C １１ ) monocyclic or bicyclic aromatic hydrocarbon groups, for example, monocyclic aryl groups such as phenyl groups; ９ ~C １１The term "heteroaryl group" as used herein refers to a 5- to 11-membered monocyclic or bicyclic aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, and examples thereof include 5- to 6-membered monocyclic heteroaryl groups containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as a pyrrolyl group, a furyl group, a thienyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, a thiadiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, and a triazinyl group; an indolyl group, an indolinyl group, an isoindolinyl group, an indazolyl group, a tetrahydrogen group, and the like. Examples of such heteroaryl groups include 8- to 11-membered bicyclic heteroaryl groups containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, such as benzoindazolyl group, benzofuranyl group, dihydrobenzofuranyl group, dihydroisobenzofuranyl group, benzothiophenyl group, dihydrobenzothiophenyl group, dihydroisobenzothiophenyl group, benzoxazolyl group, dihydrobenzoxazolyl group, benzothiazolyl group, dihydrobenzothiazolyl group, quinolyl group, tetrahydroquinolyl group, isoquinolyl group, tetrahydroisoquinolyl group, naphthyridinyl group, tetrahydronaphthyridinyl group, quinoxalinyl group, tetrahydroquinoxalinyl group, and quinazolinyl group.

[0014] The "monocyclic carbocycle" described herein includes, for example, >CR １ R ２ and >CR ７ R ８ (R １ , R ２ , R ７ , and R ８ has the same meaning as above), in the group represented by １ and R ２ or R ７ and R ８ The number of carbon atoms constituting the ring is 3 to 8 (C ３ -C ８ ), for example, 3 to 6 (C３ -C ６ The term "bicyclic ring" as used herein refers to a saturated or unsaturated 6- to 12-membered, for example 9- or 10-membered, bicyclic ring which may contain, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, and examples thereof include a ring composed of ring C and ring D below. When the bicyclic ring in ring B of compound (I) is a ring composed of ring C and ring D, ring B is bonded to the oxazepine ring at ring C. As used herein, a "5- to 6-membered carbocyclic ring" means a 5- or 6-membered monocyclic carbocyclic ring, and examples thereof include ring D of the above "bicyclic ring" that does not contain a heteroatom. As used herein, a "5- to 6-membered heterocyclic ring" means a 5- or 6-membered monocyclic heterocyclic ring that contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms, and nitrogen atoms, and examples thereof include ring D of the above "bicyclic ring" that contains a heteroatom.

[0015] <<Therapeutic Agent for Chronic Kidney Disease>> A first aspect of the present invention is a therapeutic agent for chronic kidney disease comprising an Nrf2 activator for use in combination with a renin-angiotensin inhibitor. A second aspect of the present invention is a therapeutic agent for chronic kidney disease comprising a renin-angiotensin inhibitor for use in combination with an Nrf2 activator. A third aspect of the present invention is a therapeutic agent for chronic kidney disease comprising a renin-angiotensin inhibitor and an Nrf2 activator.

[0016] The present invention also relates to a compound that activates Nrf2 for use in combination with a renin-angiotensin inhibitor for the treatment of chronic kidney disease.The present invention also relates to a compound that inhibits renin-angiotensin for use in combination with an Nrf2 activator for the treatment of chronic kidney disease.The present invention also relates to a compound that inhibits renin-angiotensin and a compound that activates Nrf2 for the treatment of chronic kidney disease.

[0017] In the first to third aspects, the Nrf2 activator preferably 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 inhibits excessive urine filtration function in pathological glomeruli. In this specification, albumin includes reduced albumin and / or modified albumin. The 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 inhibits the reabsorption of toxic modified albumin from the renal tubules, promotes excretion of modified albumin, and prevents proximal tubule (cell) damage caused by the reabsorption of modified albumin, thereby improving renal function. Furthermore, the inhibitory effect of excessive urine filtration in pathological glomeruli can significantly improve renal function and / or renal pathology, similar to the effect of the renin-angiotensin inhibitors described below. Renin-angiotensin inhibitors have the effect of inhibiting excessive urine filtration in pathological glomeruli. This normalizes urine filtration function in glomeruli and inhibits the excretion of proteinuria (particularly albumin (preferably reduced albumin)), thereby significantly improving renal function and / or renal pathology.

[0018] As used herein, renal function refers to a function such as excretion of waste products (e.g., blood waste products), and includes a urine filtration function, etc. More specific examples of renal function include an increase in GFR value, a decrease in blood and / or urinary creatinine level (e.g., mg / dl), a decrease in blood and / or urinary urea nitrogen (BUN) level (e.g., mg / dl), a decrease in blood and / or urinary cystatin C level (e.g., mg / gCre), a decrease in blood and / or urinary KIM-1 level (e.g., μg / gCre), a decrease in blood and / or urinary NGAL level (e.g., mg / gCre), a decrease in blood and / or urinary clusterin level (e.g., mg / gCre), a decrease in blood and / or urinary TFF level (e.g., μg / gCre), a decrease in blood and / or urinary β ２- Reduction in the amount of microglobulin (e.g., μg / gCre), etc. Renal pathologies include the above-mentioned decline in renal function, sclerosis of glomeruli, and the development of inflammatory and fibrotic areas in the kidney. As used herein, "modified albumin" includes oxidized albumin, toxin-bound albumin, and / or free fatty acid-bound albumin.

[0019] In the present specification and claims, chronic kidney disease, as known in the art, refers to a variety of diseases that generally impair the structure and function of the kidney (e.g., chronically and / or for three months or more), including severe kidney disease and / or renal failure. Chronic kidney disease is preferably a chronic kidney disease accompanied by at least one selected from the group consisting of a decrease in glomerular urinary filtration function (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 renal tubules, sclerosis, fibrosis, and / or inflammation of renal tissues (e.g., glomeruli, renal tubules), and increased intraglomerular pressure due to arteriolar blood flow. Chronic kidney disease is more preferably a chronic kidney disease accompanied by at least one selected from the group consisting of a decrease in glomerular urinary filtration function (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 renal tubules, and sclerosis and / or fibrosis of renal tissues (e.g., glomeruli, renal tubules). In the first to third aspects, the chronic kidney disease is not particularly limited as long as the present invention is applicable, but examples include Alport syndrome, diabetic nephropathy (hereinafter also simply referred to as "DKD"), and chronic glomerulonephritis, with Alport syndrome or diabetic nephropathy being preferred. Alport syndrome is an intractable glomerulosclerosis caused by a mutation in the type IV collagen gene, which constitutes the renal glomerular basement membrane. Alport syndrome is the second most common hereditary kidney disease in children, and in severe cases, progression to end-stage renal failure occurs in the late teens to twenties, making it a major cause of the initiation of dialysis at a young age. In the first to third aspects, the drug is preferably a therapeutic agent to be administered to patients with chronic kidney disease. In the first to third aspects, from the viewpoints that 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, it is preferable to administer the two drugs in combination to patients for whom either a renin-angiotensin inhibitor or an Nrf2 activator is effective, for example, patients in whom administration of one of the drugs has been confirmed to improve chronic kidney disease, by administering the other drug as well.

[0020] (Nrf2 activator) The Nrf2 activator (for example, an agent containing a compound that activates Nrf2) can have an effect of improving renal function, such as an effect of 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. Novel Keap1-Nrf2 Protein-Protein Interaction Inhibitor UBE-1099 Ameliorates Progressive Phenotype in Alport Syndrome Mouse Model Kaseda et. al., KIDNEY360 3:687-699, 2022.) In the first to third aspects, the Nrf2 activator may or may not be a covalent Nrf2 activator that induces Nrf2 activation by irreversibly covalently binding to a cysteine ​​residue in 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. In the first to third aspects, the Nrf2 activator is preferably a Keap1-Nrf2 inhibitor. In the first to third aspects, 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.Furthermore, as described above, it is preferable that 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 an effect of inhibiting excessive urine filtration function in pathological glomeruli. (In the above formula (I), 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 which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be 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 which may be 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 which may be substituted with 1 to 5 substituents independently selected from group E, 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; R ５is (i) a hydrogen atom, or (ii) an alkyl group which may be substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a cycloalkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, a phenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, and an alkoxy group which may be substituted with 1 to 5 substituents independently selected from Group E; A is a group represented by the following formula (II): R ７ and R ８ are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E; or R ７ and R ８ are taken together with the carbon atoms to which they are attached to form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E; 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, and a cyano group; indicates the point of attachment to the rest of the molecule; Group E is a group consisting of halogen atoms, hydroxy groups, and alkoxy groups optionally substituted with 1 to 5 halogen atoms.

[0021] In this specification, for convenience, "compounds represented by general formula (I)" and the like are also referred to as "compound (I)". In addition, compound (I) and compounds included in 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. Furthermore, embodiments in which the respective embodiments defined below are arbitrarily selected and combined are also encompassed by the present invention.

[0022] Embodiments of each substituent of compound (I) are described below. The present invention also encompasses embodiments in which any of the embodiments of each substituent below are arbitrarily selected and combined. (Embodiment 1) A compound or a pharmaceutically acceptable salt thereof in any of compound (I), wherein R is a hydrogen atom or an alkyl group optionally substituted with 1 to 5 substituents independently selected from Group E. (Embodiment 2) A compound or a pharmaceutically acceptable salt thereof in any of compound (I), wherein R is a hydrogen atom or an alkyl group optionally substituted with 1 to 5 halogen atoms. (Embodiment 3) A compound or a pharmaceutically acceptable salt thereof in any of compound (I), wherein R is a hydrogen atom or an alkyl group. (Embodiment 4) A compound or a pharmaceutically acceptable salt thereof in any of compound (I), wherein R is a hydrogen atom or a methyl group. (Embodiment 5) A compound or a pharmaceutically acceptable salt thereof in any of compound (I), wherein R is a hydrogen atom.

[0023] (Embodiment 6) In compound (I) or any of embodiments 1 to 5, R １ and R ２ are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or R １ and R ２are taken together with the carbon atom to which they are attached to form a monocyclic carbocycle which may be substituted with 1 to 5 substituents independently selected from Group E. (Embodiment 7) In compound (I) or any of embodiments 1 to 5, 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 are taken together with the carbon atom to which they are attached to form a monocyclic carbocycle which may be substituted with 1 to 5 substituents independently selected from Group E. (Embodiment 8) In compound (I) or any of embodiments 1 to 5, 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 are taken together with the carbon atoms to which they are attached to form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof. (Embodiment 9) In compound (I) or any of embodiments 1 to 5, 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 are taken together with the carbon atoms to which they are attached to form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof. (Embodiment 10) In compound (I) or any of embodiments 1 to 5, R １ and R ２ are each independently a hydrogen atom or an alkyl group, or R １ and R ２ taken together with the carbon atom to which they are attached form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof.

[0024] (Embodiment 11) In compound (I) or any of embodiments 1 to 5, R１ and R ２ are each independently a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof. (Embodiment 12) In compound (I) or any of embodiments 1 to 5, R １ and R ２ and R are each independently an alkyl group, or a pharmaceutically acceptable salt thereof. １ and R ２ are all methyl groups, or R １ and R ２ and R are taken together with the carbon atoms to which they are attached to form a cyclobutane ring or a cyclopentane ring, or a pharmaceutically acceptable salt thereof. (Embodiment 14) In compound (I) or any of embodiments 1 to 5, R １ and R ２ and R are each a methyl group. (Embodiment 15) 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 which may be substituted with 1 to 5 substituents independently selected from Group E, 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, or a pharmaceutically acceptable salt thereof.

[0025] (Embodiment 16) 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 substituents independently selected from Group E, or an alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E. (Embodiment 17) 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, or a pharmaceutically acceptable salt thereof. ３ , R ４ , and R ６ are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, or a pharmaceutically acceptable salt thereof. ３ is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, and R ４ and R ６ are each independently a hydrogen atom, an alkyl group, or an alkoxy group, or a pharmaceutically acceptable salt thereof. ３ is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, and R ４ is a hydrogen atom or an alkyl group, and R ６ is a hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0026] (Embodiment 21) In compound (I) or any of embodiments 1 to 14, R ３ is an alkyl group, and R ４ is an alkyl group, and R ６ (Embodiment 22) In compound (I) or any of embodiments 1 to 14, R is a hydrogen atom, or a pharmaceutically acceptable salt thereof. ３is a methyl group, and R ４ is a methyl group, and R ６ (Embodiment 23) In compound (I) or any of embodiments 1 to 22, R is a hydrogen atom, or a pharmaceutically acceptable salt thereof. 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 24) In compound (I) or any of embodiments 1 to 22, 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 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 25) In compound (I) or any of embodiments 1 to 22, 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 phenyl group, and an alkoxy group, or a pharmaceutically acceptable salt thereof.

[0027] (Embodiment 26) In compound (I) or any of embodiments 1 to 22, R ５ (Embodiment 27) In compound (I) or any of embodiments 1 to 22, R is a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof. ５ (Embodiment 28) In compound (I) or any of embodiments 1 to 22, R is an alkyl group, or a pharmaceutically acceptable salt thereof. ５(Embodiment 29) In compound (I) or any of embodiments 1 to 28, R is a methyl group or an ethyl group, or a pharmaceutically acceptable salt thereof. ７ and R ８ are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or R ７ and R ８ are taken together with the carbon atoms to which they are attached to form a monocyclic carbocycle which may be substituted with 1 to 5 substituents independently selected from Group E. (Embodiment 30) In compound (I) or any of embodiments 1 to 28, 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 are taken together with the carbon atom to which they are attached to form a monocyclic carbocycle which may be substituted with 1 to 5 substituents independently selected from Group E, or a pharmaceutically acceptable salt thereof.

[0028] (Embodiment 31) In compound (I) or any of embodiments 1 to 28, R ７ and R ８ are each independently a hydrogen atom or an alkyl group, or R ７ and R ８ are taken together with the carbon atoms to which they are attached to form a monocyclic carbocycle optionally substituted with 1 to 5 substituents independently selected from Group E. (Embodiment 32) In compound (I) or any of embodiments 1 to 28, R ７ and R ８ are each independently a hydrogen atom or an alkyl group, or R ７ and R ８and R are taken together with the carbon atom to which they are attached to form a monocyclic carbocycle, or a pharmaceutically acceptable salt thereof. ７ and R ８ are each independently a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof. ７ and R ８ are each independently a hydrogen atom, a methyl group, an ethyl group, or a propyl group, or R ７ and R ８ and R are taken together with the carbon atom to which they are attached to form a cyclopropane ring, or a pharmaceutically acceptable salt thereof. ７ and R ８ are each independently a hydrogen atom, a methyl group, or an ethyl group, or a pharmaceutically acceptable salt thereof.

[0029] (Embodiment 36) In compound (I) or any of Embodiments 1 to 35, a compound or a pharmaceutically acceptable salt thereof, wherein 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, and a cyano group. (Embodiment 37) In compound (I) or any of embodiments 1 to 35, a compound or a pharmaceutically acceptable salt thereof, wherein 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 alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E, and a cyano group. (Embodiment 38) In compound (I) or any of embodiments 1 to 37, X １ and X ２ However, each independently, CR ９ or a nitrogen atom. (Embodiment 39) In compound (I) or any of embodiments 1 to 37, X is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. １ and X ２ However, each independently, CR ９ (Embodiment 40) In compound (I) or any of embodiments 1 to 37, X is １ and X ２ and each represent a nitrogen atom, or a pharmaceutically acceptable salt thereof.

[0030] (Embodiment 41) In compound (I) or any of embodiments 1 to 37, X １ is CR ９ and X ２ (Embodiment 42) In the compound (I) or any of embodiments 1 to 37, X is a nitrogen atom, or a pharmaceutically acceptable salt thereof. １ is a nitrogen atom, and X ２ is CR ９ (Embodiment 43) In compound (I) or any of embodiments 1 to 42, R ９ 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 alkoxy group optionally substituted with 1 to 5 substituents independently selected from Group E, or a cyano group, or a pharmaceutically acceptable salt thereof. (Embodiment 44) In compound (I) or any of embodiments 1 to 42, R ９ are each independently a hydrogen atom, a halogen atom, or an alkyl group optionally substituted with 1 to 5 halogen atoms, or a pharmaceutically acceptable salt thereof. ９ are each independently a hydrogen atom, a halogen atom, or an alkyl group, or a pharmaceutically acceptable salt thereof.

[0031] (Embodiment 46) In compound (I) or any of embodiments 1 to 42, R ９ are each independently a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof. ９ are each independently a hydrogen atom, a fluorine atom, or a chlorine atom, or a pharmaceutically acceptable salt thereof. ９ are each independently a hydrogen atom or a fluorine atom, or a pharmaceutically acceptable salt thereof. ９and each represent a hydrogen atom. (Embodiment 50) In compound (I) or any of embodiments 1 to 49, Y １ , Y ２ , Y ３ , and Y ４ However, each independently, CR １０ or a nitrogen atom, or a pharmaceutically acceptable salt thereof.

[0032] (Embodiment 51) In compound (I) or any of embodiments 1 to 49, Y １ , Y ２ , Y ３ , and Y ４ However, each independently, CR １０ or a pharmaceutically acceptable salt thereof. (Embodiment 52) ​​In compound (I) or any of embodiments 1 to 49, Y １ , Y ２ , Y ３ , and Y ４ is a nitrogen atom, and the other three are each independently CR １０ or a pharmaceutically acceptable salt thereof. (Embodiment 53) In compound (I) or any of embodiments 1 to 49, Y １ , Y ２ , Y ３ , and Y ４ any two of the groups are nitrogen atoms, and the other two are independently CR １０ or a pharmaceutically acceptable salt thereof. (Embodiment 54) In compound (I) or any of embodiments 1 to 49, Y １ , Y ２ , Y ３ , and Y ４ three of which are nitrogen atoms, and the remaining one is CR １０ or a pharmaceutically acceptable salt thereof. (Embodiment 55) In compound (I) or any of embodiments 1 to 49, Y １ , Y ２ , Y ３ , and Y ４ are both nitrogen atoms, or a pharmaceutically acceptable salt thereof.

[0033] (Embodiment 56) In compound (I) or any of embodiments 1 to 49, Y １ and Y ２ However, each independently, CR １０ or a nitrogen atom. (Embodiment 57) In compound (I) or any of embodiments 1 to 49, Y is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable salt thereof. １ and Y ２ However, each independently, CR １０ or a pharmaceutically acceptable salt thereof. (Embodiment 58) In compound (I) or any of embodiments 1 to 49, Y １ and Y ２ is a nitrogen atom, and the other is CR １０ or a pharmaceutically acceptable salt thereof. (Embodiment 59) In compound (I) or any of embodiments 1 to 49, Y １ and Y ２ and R are each a nitrogen atom. (Embodiment 60) In compound (I) or any of embodiments 1 to 59, R １０ are each independently a hydrogen atom, a halogen atom, an alkyl 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, or a cyano group, or a pharmaceutically acceptable salt thereof.

[0034] (Embodiment 61) In compound (I) or any of embodiments 1 to 59, R １０ 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, or a pharmaceutically acceptable salt thereof. １０ are each independently a hydrogen atom, a halogen atom, or an alkyl group optionally substituted with 1 to 5 halogen atoms, or a pharmaceutically acceptable salt thereof. １０are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, or a pharmaceutically acceptable salt thereof. １０ are each independently a hydrogen atom, a halogen atom, or an alkyl group, or a pharmaceutically acceptable salt thereof. １０ are each independently a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, or a methoxy group, or a pharmaceutically acceptable salt thereof.

[0035] (Embodiment 66) In compound (I) or any of embodiments 1 to 59, R １０ are each independently a hydrogen atom, a fluorine atom, or a methyl group, or a pharmaceutically acceptable salt thereof. １０ and each represent a hydrogen atom. (Embodiment 68) In compound (I) or any of embodiments 1 to 67, Q is a compound or a pharmaceutically acceptable salt thereof. １ and Q ２ However, each independently, CR １１ R １２ , N.R. １３ , an oxygen atom, a sulfur atom, SO, or SO ２ (Embodiment 69) In compound (I) or any of embodiments 1 to 67, Q is １ and Q ２ However, each independently, CR １１ R １２ , N.R. １３ (Embodiment 70) In the compound (I) or any of embodiments 1 to 67, Q is an oxygen atom, or a pharmaceutically acceptable salt thereof. １ and Q ２ However, each independently, CR １１ R １２ or a pharmaceutically acceptable salt thereof.

[0036] (Embodiment 71) In compound (I) or any of embodiments 1 to 67, Q １ and Q ２ and each represent an oxygen atom. (Embodiment 72) In compound (I) or any of embodiments 1 to 71, R １１ and R １２ are each independently a hydrogen atom, a halogen atom, or an alkyl group, or a pharmaceutically acceptable salt thereof. １１ and R １２ are each independently a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof. １１ and R １２ are each independently a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. １１ and R １２ and each represent a hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0037] (Embodiment 76) In compound (I) or any of embodiments 1 to 75, R １３ are each independently a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof. １３ are each independently a hydrogen atom or a methyl group, or a pharmaceutically acceptable salt thereof. １３ and each represent a hydrogen atom. (Embodiment 79) In compound (I) or any of embodiments 1 to 78, Z is NR １４ , an oxygen atom, or a sulfur atom. (Embodiment 80) In compound (I) or any of embodiments 1 to 78, Z is NR １４or a pharmaceutically acceptable salt thereof.

[0038] (Embodiment 81) In compound (I) or any of embodiments 1 to 80, R １４ is a hydrogen atom or an alkyl group, or a pharmaceutically acceptable salt thereof. １４ is a hydrogen atom or a methyl group. (Embodiment 83) In compound (I) or any of embodiments 1 to 80, R １４ (Embodiment 84) In compound (I) or any of embodiments 1 to 83, Q is a hydrogen atom, or a pharmaceutically acceptable salt thereof. ３ However, (CU １ U ２ ) ｎ and U １ and U ２ are each independently a hydrogen atom, a halogen atom, or an alkyl group; and n is 1, 2, or 3. (Embodiment 85) In compound (I) or any of embodiments 1 to 83, Q is a compound or a pharmaceutically acceptable salt thereof. ３ However, (CU １ U ２ ) ｎ and U １ and U ２ are each independently a hydrogen atom, a halogen atom, or an alkyl group; and n is 1 or 2. (Embodiment 86) In compound (I) or any of embodiments 1 to 83, Q is a compound or a pharmaceutically acceptable salt thereof. ３ However, (CU １ U ２ ) ｎ and U １ and U ２ are each independently a hydrogen atom, a halogen atom, or an alkyl group; and n is 1. (Embodiment 87) In compound (I) or any of embodiments 1 to 83, Q is a compound or a pharmaceutically acceptable salt thereof. ３ However, (CU １ U ２ ) ｎ and U １and U ２ are each independently a hydrogen atom, a fluorine atom, or a methyl group; and n is 1. (Embodiment 88) In compound (I) or any of embodiments 1 to 83, Q is a compound or a pharmaceutically acceptable salt thereof. ３ However, (CU １ U ２ ) ｎ and U １ and U ２ are both hydrogen atoms; and n is 1. (Embodiment 89) In compound (I) or any of embodiments 1 to 83, Q is a compound or a pharmaceutically acceptable salt thereof. ３ However, (CU １ U ２ ) ｎ and U １ and U ２ are both fluorine atoms; and n is 1. (Embodiment 90) In compound (I) or any of embodiments 1 to 83, Q is a compound or a pharmaceutically acceptable salt thereof. ３ However, (CU １ U ２ ) ｎ and U １ and U ２ are both methyl groups; and n is 1, or a pharmaceutically acceptable salt thereof.

[0039] (Embodiment 91) In compound (I) or any of Embodiments 1 to 90, 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. (Embodiment 92) In compound (I) or any of Embodiments 1 to 90, 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. (Embodiment 93) A compound or a pharmaceutically acceptable salt thereof in compound (I) or any of embodiments 1 to 90, wherein 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. (Embodiment 94) A compound or a pharmaceutically acceptable salt thereof in compound (I) or any of embodiments 1 to 90, wherein 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 fluorine atom and a methyl group. (Embodiment 95) A compound or a pharmaceutically acceptable salt thereof represented by the following general formula (I-1): 94. A compound having the structure represented by the formula: wherein the symbols have the same meaning as defined in compound (I) or any of embodiments 1 to 94, or a pharmaceutically acceptable salt thereof.

[0040] (Embodiment 96) In compound (I) or compound (I-1), 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 ３is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group; R ４ and R ６ are each independently a hydrogen atom, an alkyl group, or an alkoxy group; R ５ A compound or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom or an alkyl group; and A has the same meaning as defined in compound (I) or any of embodiments 1 to 94. (Embodiment 97) In compound (I) or compound (I-1), R is a hydrogen atom; 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 is an alkyl group; R ４ is an alkyl group; R ５ is an alkyl group; R ６ A compound or a pharmaceutically acceptable salt thereof, wherein R is a hydrogen atom; and A has the same meaning as defined in compound (I) or any of embodiments 1 to 94. (Embodiment 98) In compound (I) or compound (I-1), R is a hydrogen atom; １ and R ２ are each independently a hydrogen atom or an alkyl group; R ３ is an alkyl group; R ４ is an alkyl group; R ５ is an alkyl group; R ６ is a hydrogen atom; and A has the same meaning as defined in compound (I) or any of embodiments 1 to 94. (Embodiment 99) A compound or a pharmaceutically acceptable salt thereof in compound (I) or any of embodiments 1 to 98, wherein A is a group represented by 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.] or a pharmaceutically acceptable salt thereof. (Embodiment 100) A compound or a pharmaceutically acceptable salt thereof having a structure represented by any of formulas (II-1) to (II-3), wherein R ７ and R８ 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 which may be substituted with 1 to 5 substituents independently selected from group E; X １ and X ２ However, each independently, CR ９ or a nitrogen atom; R ９ are each independently a hydrogen atom, a halogen atom, an alkyl 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, or a cyano group; and 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 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, and a cyano group, or a pharmaceutically acceptable salt thereof.

[0041] (Embodiment 101) In compound (I) or any of embodiments 1 to 100, A is the following formula (II-1-1) to (II-3-4): [wherein the symbols have the same meanings as defined in compound (I) or any of embodiments 1 to 100.] or a pharmaceutically acceptable salt thereof. (Embodiment 102) In compound (I) or any of embodiments 1 to 100, A is a compound represented by the following formula (II-1-1) or (II-3-1): [wherein the symbols have the same meaning as defined in compound (I) or any of embodiments 1 to 100.] (Embodiment 103) A compound or a pharmaceutically acceptable salt thereof, having a structure represented by any one of formulas (II-1-1) to (II-3-4), wherein R ７ and R ８ are each independently a hydrogen atom or an alkyl group; or R ７ and R ８together with the carbon atoms to which they are attached form a monocyclic carbocyclic ring which may be 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; Y １ , Y ２ , Y ３ , and Y ４ are each independently CR １０ or a nitrogen atom; R ９ and R １０ are each independently a hydrogen atom, a halogen atom, an alkyl 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, or a cyano group; Q １ and Q ２ are each independently CR １１ R １２ , N.R. １３ , an oxygen atom, a sulfur atom, SO, or SO ２ and R １１ and R １２ are each independently a hydrogen atom, a halogen atom, or an alkyl group; R １３ are each independently a hydrogen atom or an alkyl group; Z is NR １４ , an oxygen atom, or a sulfur atom; R １４ is a hydrogen atom or an alkyl group; Q ３ (CU １ U ２ ) ｎ and U １ and U ２ are each independently a hydrogen atom, a halogen atom, or an alkyl group; and n is 1, 2, or 3. (Embodiment 104) Q １ and Q ２ However, each independently, CR １１ R １２ , N.R. １３(Embodiment 105) In compound (I) or any of embodiments 1 to 104, A is a group represented by the following formula (II-1-1): 104. A compound having the structure: wherein the symbols have the same meaning as defined in compound (I) or any of embodiments 1 to 104, or a pharmaceutically acceptable salt thereof.

[0042] (Embodiment 106) In the structure represented by formula (II-1-1), 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; X １ and X ２ are each independently CR ９ and Y １ , Y ２ , Y ３ , and Y ４ any one of the above is a nitrogen atom, and the other three are each independently CR １０ and R ９ are each a hydrogen atom; １０ and R are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group, or a pharmaceutically acceptable salt thereof. ７ and R ８ are each independently a hydrogen atom or an alkyl group; R １０ and each independently represent a hydrogen atom, a halogen atom, or an alkyl group. (Embodiment 108) The compound according to embodiment 106, or a pharmaceutically acceptable salt thereof, in compound (I) or any of embodiments 1 to 104, wherein A is a group represented by 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.] or a pharmaceutically acceptable salt thereof. (Embodiment 109) A compound having a structure represented by formula (II-3-1), wherein R ７ and R８ are each independently a hydrogen atom or an alkyl group; １ and X ２ is a nitrogen atom and the other is CR ９ and Y １ , Y ２ , Y ３ , and Y ４ However, each independently, CR １０ and R ９ are each a hydrogen atom; １０ are each independently a hydrogen atom, a halogen atom, or an alkyl group, or a pharmaceutically acceptable salt thereof. 94. A compound having the structure represented by the formula: wherein the symbols have the same meaning as defined in compound (I) or any of embodiments 1 to 94, or a pharmaceutically acceptable salt thereof.

[0043] (Embodiment 111) In the compound (I-1-1), 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; 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 phenyl group, and an alkoxy group; 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 which may be substituted with 1 to 5 substituents independently selected from group E; R １０is 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; Group E is the group consisting of a halogen atom, a hydroxy group, and an alkoxy group optionally substituted with 1 to 5 halogen atoms, or a pharmaceutically acceptable salt thereof. (Embodiment 112) In the compound (I-1-1), 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 is a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group; R ４ is a hydrogen atom or an alkyl group; R ５ is an alkyl group; R ６ 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, or a pharmaceutically acceptable salt thereof.

[0044] 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:

[0045] In the above 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.

[0046] Compound (I) can be produced in accordance with the method described in paragraphs 0105 to 0112 of WO 2020 / 241853.

[0047] 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) encompasses tautomeric or stereoisomeric mixtures or pure or substantially pure isomers. When compound (I) or its synthetic intermediates are obtained in the form of diastereomers or enantiomers, they can be separated by conventional methods well known in the art, such as chromatography or fractional crystallization. Compound (I) or its synthetic intermediates may contain isotopes (e.g., ２ H. ３ H. １３ C. １４ C. １５ N. １８ F. ３２ P. ３５ S. １２５ I, etc.), and deuterium-labeled compounds.

[0048] 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, ethanesulfonic acid, and benzenesulfonic acid; and salts with acidic amino acids such as aspartic acid and glutamic acid. The synthetic intermediate of Compound (I) may be in a free form or in a salt form. Salts of synthetic intermediates of compound (I) include the same salts as those exemplified above in "Pharmaceutically acceptable salts of compound (I)" and pharmaceutically unacceptable salts.

[0049] Furthermore, compound (I) or a pharmaceutically acceptable salt thereof, and a synthetic intermediate of compound (I) or a salt thereof include their internal salts, hydrates, and solvates. In this specification, "pharmaceutically acceptable" generally means that the compound is not harmful to a recipient and that the components are compatible with each other when preparing a pharmaceutical composition, and includes compounds that are useful not only for use as human medicine but also for use in veterinary medicine.

[0050] (Renin-angiotensin inhibitors) As described above, renin-angiotensin inhibitors (e.g., agents containing compounds that inhibit renin-angiotensin) suppress excessive urinary filtration function in pathological glomeruli. This normalizes urinary filtration function in glomeruli, suppresses excretion of proteinuria (particularly albumin), and can improve renal function and / or renal pathology. For example, it is known that renin-angiotensin inhibitors suppress the progression of renal dysfunction in autosomal recessive, X-linked, and other types of CKD. (Gross O, Licht C, Anders HJ et al., Early angiotensin-converting enzyme inhibition in Alport syndrome delays Renal Failure and improves life expectancy. Kidney Int 2012; 81:494-501., Temme J, Peters F, Lange K et al. failure and nephroprotection by RAAS inhibition in heterozygous carriers of X-chromosomal and autosomal recessive Alport mutations. Kidney Int 2012;81:779-83. , Gross O, Licht C, Anders HJ et al. , Early angiotensin-converting enzyme inhibition in Alport syndrome delays renal failure and improves life expectation. Kidney Int 2012;81:494-501. )

[0051] In the first to third aspects, the renin-angiotensin inhibitor preferably comprises at least one selected from the group consisting of angiotensin receptor blockers (ARBs) that selectively (preferably specifically) bind to angiotensin II receptors, angiotensin-converting enzyme (ACE) inhibitors that prevent an increase in blood pressure by suppressing the production of angiotensin II, which increases blood pressure, and renin inhibitors that suppress the conversion of angiotensinogen to angiotensin I. Efferent arterioles are known to be highly sensitive to angiotensin II. Therefore, when an ACE inhibitor / ARB that suppresses the action of angiotensin II is used, the efferent arteriole dilates relatively (compared to the afferent arteriole). ACE inhibitors / ARBs can be considered to be both antihypertensive drugs and intraglomerular hypertension-reducing drugs. Examples of ARBs include losartan potassium, candesartan cilexetil, irbesartan, telmisartan, valsartan, eprosartan, olmesartan medoxomil, and azilsartan. Preferred are losartan potassium, valsartan, candesartan cilexetil, irbesartan, telmisartan, and olmesartan medoxomil, and more preferred are losartan potassium and candesartan cilexetil. Examples of ACE inhibitors 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. Examples of renin inhibitors include aliskiren.

[0052] In particular, in the first to third aspects, it is more preferable that 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, and R ａ represents a group capable of forming an anion or a group capable of converting into an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atom chain of 2 or less, and n represents an integer of 1 or 2.

[0053] In the above formula (A), the "optionally substituted nitrogen-containing heterocycle" represented by ring BB is preferably an optionally substituted nitrogen-containing aromatic heterocycle. Furthermore, the "optionally substituted nitrogen-containing heterocycle" represented by ring BB is preferably an optionally substituted 5- to 6-membered nitrogen-containing heterocycle, and particularly preferably an optionally substituted 5- to 6-membered nitrogen-containing aromatic heterocycle (e.g., an 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 imidazole ring which may have a substituent, a benzimidazole ring which may have a substituent, etc.). In the above formula (A), R ａ Examples of the group capable of forming an anion as a carboxylic acid (a group having a hydrogen atom capable of being liberated as a proton) include (1) a carboxyl group, (2) a tetrazolyl group, and (3) a trifluoromethanesulfonic acid amide group (—NHSO ２ CF ３(4) a phosphate group, (5) a sulfonate group, (6) a 5- to 7-membered (preferably 5- to 6-membered) monocyclic heterocyclic residue which may be substituted and contains one or more of N, S, and O. Examples of the substituent in the above "optionally substituted" 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.

[0054] 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, and the like, and R ａ When g in the above formula represents -NH- or the like, the bond between the heterocyclic residue represented by the formula and the phenyl group to which the heterocyclic residue is bonded may be not only via a carbon-carbon bond as shown above, but also via one of the multiple nitrogen atoms present. For example, R ａ but

[0055] In the above formula, g is —CH ２ -, -NH-, -O- or -S(O) ｍ-, and >=Z, >=Z' and >=Z'' each represent a carbonyl group, a thiocarbonyl group or an optionally oxidized sulfur atom (e.g., S, S(O), S(O) ２ and the like) (preferably a carbonyl or thiocarbonyl group, more preferably a carbonyl group), and m is an integer of 0, 1 or 2.

[0056] R ａ Preferred examples of the heterocyclic residue represented by the formula (I) 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. ａ The heterocyclic residue represented by the formula (I) may be bonded to a cyclic substituent to form a condensed ring, but R ａ The heterocyclic residue represented by the formula (I) is preferably a 5- or 6-membered ring residue, more preferably a 5-membered ring residue. ａ As the heterocyclic residue represented by the formula [wherein i represents -O- or -S-, and j represents >=O, >=S, or >=S(O)] ｍ and m is as defined above] (among which, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl, 2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl, and especially 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl) are preferred.

[0057] In addition, the heterocyclic residue (R ａ ) exists as a tautomer 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 (I) includes all of the above a', b' and c'. ａ The group capable of forming an anion as １－４ ) alkyl group or acyl group (e.g., lower (C ２－５) alkanoyl, benzoyl, etc.) and the like. １－４ ) alkyl groups include, for example, (1) halogen atoms, nitro, lower (C １－４ ) alkyl, lower (C １－４ ) lower (C) optionally substituted with 1 to 3 phenyl groups which may have alkoxy or the like; １－４ ) alkyl groups (e.g., methyl, triphenylmethyl, p-methoxybenzyl, p-nitrobenzyl, etc.), (2) lower (C １－４ ) alkoxy-lower (C １－４ ) alkyl groups (e.g., methoxymethyl, ethoxymethyl, etc.), (3) groups of the formula —CH(R ４ )-OCOR ５ [In the formula, 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 atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.), and R ５ is (a) a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), (b) a straight-chain or branched lower alkenyl group having 2 to 6 carbon atoms, (c) a cycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., a halogen atom, nitro, lower (C １－４ ) alkyl, lower (C １－４ (d) a lower alkyl group having 1 to 3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy or the like (e.g., benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyl, etc.), (e) a cycloalkyl group having 3 to 8 carbon atoms or an optionally substituted aryl group (e.g., a halogen atom, nitro, lower (C １－４ ) alkyl, lower (C １－４(e) a lower alkenyl group having 2-3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy or the like (e.g., vinyl such as cinnamyl, those having an alkenyl moiety such as propenyl, allyl, isopropenyl, etc.), (f) an aryl group which may be substituted (e.g., phenyl, p-tolyl, naphthyl, etc., which may have a halogen atom, nitro, lower (C １－４ ) alkyl, lower (C １－４ (f) a straight-chain or branched lower alkoxy group having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (g) a straight-chain or branched lower alkenyloxy group having 2 to 8 carbon atoms (e.g., aryloxy, isobutenyloxy, etc.), (h) a cycloalkyloxy group having 3 to 8 carbon atoms (e.g., cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), (i) a cycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., a halogen atom, nitro, lower (C １－４ ) alkyl, lower (C １－４ (j) a lower alkoxy group having 1 to 3 carbon atoms substituted with a phenyl or naphthyl group which may have an alkoxy moiety such as methoxy, ethoxy, n-propoxy, isopropoxy, etc., such as benzyloxy, phenethyloxy, cyclopentylmethoxy, cyclohexylmethoxy, etc., or a cycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group (e.g., a halogen atom, nitro, lower (C １－４ ) alkyl, lower (C １－４(k) a lower alkenyloxy group having 2-3 carbon atoms (e.g., a phenyl or naphthyl group which may have an alkoxy or the like) (e.g., a vinyloxy such as cinnamyloxy, a propenyloxy, an allyloxy, an isopropenyloxy, or the like having an alkenyloxy moiety) or (k) an optionally substituted aryloxy group (e.g., a halogen atom, nitro, a lower (C １－４ ) alkyl, lower (C １－４ ) a phenoxy or naphthoxy group which may have an alkoxy group or the like. １ The group capable of forming an anion as a substituted or unsubstituted alkyl group is the above-mentioned optionally substituted lower (C １－４ ) alkyl group or acyl group (e.g., lower (C ２－５ In addition to protecting groups such as alkanoyl, benzoyl, etc., optionally substituted lower (C １－４ ) alkyl group (as defined above in R ａ The "optionally substituted lower (C １－４ ) alkyl group), a halogen atom, nitro, cyano, lower (C １－４ ) alkoxy, 1 to 2 lower (C １－４ ) may have a substituent such as amino optionally substituted with alkyl. ａ The group capable of being converted into a group capable of forming an anion as a proton (a group having a hydrogen atom capable of being liberated as a proton) 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 in vivo enzymes, etc.) (a so-called prodrug), and may also be a cyano, N-hydroxycarbamimidoyl group (-C(=N-OH)-NH ２ ), or optionally substituted lower (C １－４ (1) a carboxyl group, (2) a tetrazolyl group, or (3) a trifluoromethanesulfonic acid amide group (—NHSO ), each protected with an alkyl group or an acyl group. ２ CF ３), (4) a phosphate group, (5) a sulfonic acid group, or (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. ａ The group may be a group that can be converted into a group that can form an anion represented by the following formula (a so-called synthetic intermediate).

[0058] R ａ Examples of the alkyl group include optionally substituted lower alkyl groups (C １－４ ) alkyl (e.g., methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl group (e.g., lower (C ２－５ Preferred are carboxyl which may be protected by a hydroxyl group such as alkanoyl, benzoyl, tetrazolyl, 2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl (preferably tetrazolyl), cyano, and N-hydroxycarbamimidoyl (preferably cyano), and particularly preferably tetrazolyl.

[0059] In the above formula (A), X indicates that adjacent phenylene groups and phenyl groups are bonded directly or via a spacer having a chain of 2 or less atoms (preferably a direct bond), and the spacer having a chain of 2 or less atoms may be any divalent chain having 1 or 2 atoms constituting a linear part, and may have a side chain. Specifically, it is a lower (C １－４ ) alkylene, —CO—, —O—, —S—, —NH—, —CO—NH—, —O—CH ２ -, -S-CH ２ In the above formula (A), n represents an integer of 1 or 2 (preferably 1).

[0060] The compound represented by formula (A) may be itself or a pharmacologically acceptable salt. When the compound represented by formula (A) has an acidic group such as a carboxyl group, examples of 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). When the compound represented by formula (A) has a basic group such as an amino group, examples of the salt include salts with inorganic acids or organic acids (e.g., hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, carbonic acid, bicarbonate, formic acid, acetic acid, propionic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.), acidic amino acids such as aspartic acid and glutamic acid, etc.

[0061] In the first to third aspects, it is particularly preferred that the renin-angiotensin inhibitor comprises 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 encompasses its pharmacologically acceptable salts (such as losartan potassium salt).

[0062] In the first to third aspects, the Nrf2 activator and the renin-angiotensin inhibitor can be administered simultaneously or at intervals. Furthermore, when administered multiple times, they do not necessarily have to be administered simultaneously in all doses; some doses may involve the administration of either drug alone. When these drugs are used in combination, each drug can be formulated separately or simultaneously with a pharmacologically acceptable carrier, excipient, binder, diluent, etc., and administered orally or parenterally as a pharmaceutical composition. When the drugs are formulated separately, they can be mixed with a diluent or the like at the time of use and administered, or the separately formulated drugs can be administered simultaneously or at intervals to the same subject. The pharmaceutical of the present invention also includes kit products in which separately formulated drugs are mixed with a diluent or the like at the time of use and administered (for example, an injection kit containing ampoules containing individual drugs in powder form and a diluent or the like for mixing and dissolving two or more drugs at the time of use), and kit products in which separately formulated drugs are administered simultaneously or separately with a time lag to the same subject (for example, a tablet kit in which tablets containing individual drugs are placed in the same or separate bags and, if necessary, have a column for writing the time of drug administration, for administering two or more tablets simultaneously or separately with a time lag). The present invention is also an invention relating to a pharmaceutical composition containing a therapeutic agent for chronic kidney disease according to any of the first to third aspects.

[0063] The dosage forms of the first to third aspects are preferably a combination drug (combination drug) or the above-mentioned kit product, from the viewpoints that, as described above, the Nrf2 activator and the renin-angiotensin inhibitor have different actions or mechanisms of action, and that the renin-angiotensin inhibitor can suppress the transient increase in proteinuria caused by the Nrf2 activator. The present invention also relates to the application of an Nrf2 activator to the manufacture of a therapeutic drug 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 drug for chronic kidney disease to be used in combination with an Nrf2 activator. The present invention also relates to the application of a renin-angiotensin inhibitor and an Nrf2 activator to the manufacture of a therapeutic drug for chronic kidney disease. As described above, the dosage form of the therapeutic drug is preferably a combination drug (combination drug) or the above-mentioned kit product.

[0064] In the first to third aspects, the dosage (i.e., effective amount) of the Nrf2 activator varies depending on the administration method and the age, weight, and condition of the patient, 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.

[0065] In the first to third aspects, the dosage of the renin-angiotensin inhibitor varies depending on the subject, administration route, target disease, symptoms, and the like. However, when administered (preferably orally) to a mammal, particularly an adult (e.g., weighing 50 kg), for example, 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 to three times a day. In the first to third aspects, the mass ratio of the Nrf2 activator to the renin-angiotensin inhibitor may be 1 / 3 to 5, preferably 1 / 2 to 3, more preferably 2 / 3 to 2, and even more preferably 3 / 4 to 1.5.

[0066] Here, various organic or inorganic carrier substances commonly used as pharmaceutical ingredients are used as pharmacologically acceptable carriers. These are formulated as excipients, lubricants, binders, and disintegrants in solid formulations; and as solvents, solubilizers, suspending agents, isotonicity agents, buffers, and soothing agents in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, and sweeteners can also be used as needed. Suitable examples of 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. Suitable examples of 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. Suitable examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, light anhydrous silicic acid, low-substituted hydroxypropylcellulose, etc. Suitable examples of solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil, etc. Suitable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.Suitable examples of suspending agents include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like. Suitable examples of isotonic agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of buffering agents include buffer solutions such as phosphates, acetates, carbonates, and citrates. Suitable examples of soothing agents include benzyl alcohol, and the like.

[0067] Suitable examples of preservatives include parahydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid, etc. Suitable examples of antioxidants include sulfites, ascorbic acid, etc. 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, Food Blue No. 1 and No. 2, water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble food tar dyes), natural dyes (e.g., β-carotene, chlorophyll, red iron oxide, etc.), etc. Suitable examples of sweeteners include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia, etc.

[0068] Examples of dosage forms of pharmaceutical compositions include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions, and suspensions; and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, and intravitreal injections), infusions, topical preparations (e.g., intranasal preparations, transdermal preparations, ointments, etc.), suppositories (e.g., rectal suppositories, vaginal suppositories, etc.), pellets, infusions, and sustained-release preparations, each of which can be safely administered orally or parenterally. Pharmaceutical compositions can be prepared by conventional methods in the pharmaceutical technology field, such as those described in the Japanese Pharmacopoeia. Specific preparation 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.

[0069] For example, oral preparations are produced by adding, to the active ingredient, 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.), and compressing the mixture. If necessary, the mixture is coated with a coating base by a method known per se for the purposes of taste masking, enteric coating, or sustained release. Examples of such coating bases 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 be used in combination. Examples of water-soluble film coating bases include cellulose 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 Co., Ltd.), and polyvinylpyrrolidone; and polysaccharides such as pullulan.

[0070] Examples of enteric film coating bases include 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. Examples of sustained-release film coating bases include 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-mentioned coating bases may be mixed in an appropriate ratio. In addition, a light-shielding agent such as titanium oxide or iron sesquioxide may be used during coating.

[0071] Injectable preparations are prepared by dissolving, suspending, or emulsifying the active ingredient in an aqueous solvent (e.g., distilled water, physiological 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 a dispersing agent (e.g., polysorbate 80, polyoxyethylene hydrogenated castor oil 60, etc.), polyethylene glycol, carboxymethylcellulose, sodium alginate, etc.), a preservative (e.g., methylparaben, propylparaben, benzyl alcohol, chlorobutanol, phenol, etc.), an isotonic agent (e.g., sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.). In this case, additives such as solubilizing agents (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.

[0072] <Method for Treating Chronic Kidney Disease> 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. 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.

[0073] Screening Method 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, comprising a screening step using at least one selected from the group consisting of inhibition of albumin reabsorption from the renal tubules and inhibition of damage to renal tubular cells by modified albumin reabsorbed from the renal tubules as an index. In the fourth aspect, the screening step preferably further comprises screening using inhibition of excessive urinary filtration function in pathological glomeruli as an index. A fifth aspect of the present invention is a method for screening therapeutic agents for chronic kidney disease to be used in combination with an Nrf2 activator, comprising a screening step using inhibition of excessive urinary filtration function in pathological glomeruli as an index. In the fourth and fifth aspects, screening means at least narrowing the population of test substances, and preferably selecting candidate therapeutic agents for chronic kidney disease.

[0074] The reason why the fourth aspect, when used in combination with a renin-angiotensin inhibitor, can at least narrow the population of candidate therapeutic agents for chronic kidney disease that can significantly improve renal function and / or renal pathology in chronic kidney disease compared to existing therapeutic agents alone is believed to be as follows: If the test substance has an inhibitory effect on albumin reabsorption from the renal tubules and / or an inhibitory effect on tubular cell damage caused by modified albumin reabsorbed from the renal tubules, it can inhibit the reabsorption of toxic modified albumin from the renal tubules and promote the excretion of modified albumin (see Examples below). This is because it prevents proximal tubule (cell) damage caused by the reabsorption of modified albumin, and thus the test substance can significantly improve renal function and / or renal pathology (see Examples below). Furthermore, if the test substance has the effect of "inhibiting excessive urine filtration function in pathological glomeruli," it can significantly improve renal function and / or renal pathology, similar to renin-angiotensin inhibitors (see Examples below).

[0075] In the fourth aspect, 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 produced in combination with a renin-angiotensin inhibitor as a fixed drug (combination drug) or kit product.

[0076] The reason why 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 can 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 an 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 an Nrf2 activator (see the Examples described below).

[0077] In a fifth aspect, the therapeutic agent for chronic kidney disease to be used in combination with an Nrf2 activator is preferably a therapeutic agent for chronic kidney disease to be used or manufactured in combination with an Nrf2 activator as a combination drug (compound drug) or kit product.

[0078] In the fourth aspect, the "screening step using at least one index selected from the group consisting of inhibition of albumin reabsorption from renal tubules and inhibition of renal tubular cell damage caused by modified albumin reabsorbed from renal tubules" preferably comprises the steps of: administering a test substance to an animal in vivo; determining a quantitative or qualitative state regarding at least one index selected from the group consisting of albumin reabsorption from renal tubules and renal tubular cell damage caused by modified albumin reabsorbed from renal tubules (e.g., the % localization rate of albumin within proximal tubule cells (the percentage of proximal tubules that have taken up albumin) and the % localization rate of albumin outside proximal tubule cells (the percentage of proximal tubules that have not taken up albumin)); and selecting candidate therapeutic agents for chronic kidney disease based on the determination results. In the fourth aspect, from the viewpoint of screening therapeutic agents for chronic kidney disease to be used in combination with a renin-angiotensin inhibitor, the "step of administering a test substance to an animal in vivo" preferably refers to a step of administering a test substance and a renin-angiotensin inhibitor in combination to an animal in vivo. A step of determining a quantitative or qualitative state regarding renal tubular cell damage caused by modified albumin reabsorbed from the renal tubule is preferred. The step of determining a quantitative or qualitative state regarding renal tubular cell damage caused by modified albumin reabsorbed from the renal tubule preferably includes a step of determining the above-mentioned % localization rate of albumin within proximal tubule cells and the above-mentioned % localization rate of albumin outside proximal tubule cells, as well as a step of determining the degree of albumin oxidation in 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. The "step of determining the quantitative or qualitative state of at least one selected from the group consisting of reabsorption of albumin from the renal tubules and damage to renal tubular cells due to modified albumin reabsorbed from the renal tubules" preferably further comprises a step of determining the GFR value as an index of excessive urine filtration function in pathological glomeruli. The animal may be any mammal (mouse, rat, pig, cow, monkey, human, etc.), and a chronic kidney disease model (CKD mouse, etc.) is preferred.For example, a chronic kidney disease model mouse (e.g., B6.Col4a5-G5X) is a chronic kidney disease model with high clinical reproducibility that exhibits a gradual decline in renal function over a period of six months, and its usefulness has been recognized by many pharmaceutical companies both in Japan and abroad. The fourth aspect may or may not further include a step of screening using as an indicator at least one selected from the group consisting of: an increase in proteinuria as described below in the Examples, suppression of megalin expression as described below in the Examples, an increase in the expression level of NAD(P)H quinone reductase (NQO-1) protein, and a reduction in glomerulosclerosis score, reduction in inflammatory area %, reduction in fibrotic area %, and suppression of tubular damage % in kidney tissue by staining.

[0079] The degree of inhibition or reduction is more preferably 3 / 4 or less, even more preferably 3 / 5 or less, particularly preferably 1 / 2 or less, especially preferably 1 / 3 or less, and most preferably 1 / 4 or less, compared to the control condition. There is no particular restriction on the lower limit of the degree of inhibition or reduction, but examples include 1 / 30 or more, 1 / 20 or more, and 1 / 10 or more. The degree of increase is more preferably 1.2-fold or more, even more preferably 1.5-fold or more, especially preferably 2-fold or more, especially preferably 3-fold or more, and most preferably 4-fold or more, compared to the control condition. There is no particular restriction on the upper limit of the degree of increase, but examples include 30-fold or less, 20-fold or less, 10-fold or less, etc.

[0080] Here, "control conditions" refers to conditions in the absence of a test substance, and means that the difference in response intensity (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") between the presence and absence of the test substance is used as an index. The response intensity S2 under the control conditions may be a value measured before the addition of the test substance, or a statistical value or range obtained by collecting data in advance.

[0081] 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 by modified albumin reabsorbed from the renal tubules" is observed, the test substance is preferably identified as a candidate therapeutic drug for chronic kidney disease. For example, the identification is preferably performed using the response intensity S1 in the presence of the test substance as an index, and more preferably by comparing the response intensity S1 with the response intensity S2 under control conditions.

[0082] Furthermore, the intensity of the response by Compound (I) used in the Reference Examples and Examples described below may or may not be used as a benchmark "control condition."

[0083] In the fourth aspect, the "screening step using at least one index 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" may include measuring the inhibitory activity of the test substance against the binding between Nrf2 and Keap1 in vitro, and selecting candidate therapeutic agents for chronic kidney disease based on the measurement results, using the measured intensity as an index similar to or instead of "at least one index 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."

[0084] The method for measuring activation of Nrf2 by a test substance (e.g., inhibition of binding between Nrf2 and Keap1 by a test substance) is not particularly limited. For example, 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). More specifically, for example, 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).

[0085] In the fifth aspect, the "step of screening using suppression of excessive urine filtration function in pathological glomeruli as an index" preferably includes the steps of: administering a test substance to an animal in vivo; determining a quantitative or qualitative state regarding the excessive urine filtration function in pathological glomeruli (e.g., determining the GFR value and / or urinary protein concentration); and selecting a candidate therapeutic drug for chronic kidney disease based on the determination results. Specific and preferred examples of the animal are as described above. In the fifth aspect, from the perspective of screening therapeutic drugs for chronic kidney disease to be used in combination with an Nrf2 activator, the "step of administering a test substance to an animal in vivo" preferably comprises administering a combination of the test substance and an Nrf2 activator to an animal in vivo. In a fifth aspect, the present invention provides a method for inhibiting blood and / or urinary creatinine levels (e.g., mg / dl), blood and / or urinary urea nitrogen (BUN) levels (e.g., mg / dl), blood and / or urinary cystatin C levels (e.g., mg / gCre), blood and / or urinary KIM-1 levels (e.g., μg / gCre), blood and / or urinary NGAL levels (e.g., mg / gCre), blood and / or urinary clusterin levels (e.g., mg / gCre), blood and / or urinary TFF levels (e.g., μg / gCre), blood and / or urinary β ２ The method may or may not further include a screening step using as indicators suppression of microglobulin levels (for example, μg / gCre), significant extension of survival time of CKD mice, etc.

[0086] The degree of inhibition or reduction is more preferably 3 / 4 or less, even more preferably 3 / 5 or less, particularly preferably 1 / 2 or less, especially preferably 1 / 3 or less, and most preferably 1 / 4 or less, compared to the control condition. There is no particular restriction on the lower limit of the degree of inhibition or reduction, but examples include 1 / 30 or more, 1 / 20 or more, and 1 / 10 or more. The degree of increase is more preferably 1.2-fold or more, even more preferably 1.5-fold or more, especially preferably 2-fold or more, especially preferably 3-fold or more, and most preferably 4-fold or more, compared to the control condition. There is no particular restriction on the upper limit of the degree of increase, but examples include 30-fold or less, 20-fold or less, 10-fold or less, etc.

[0087] Here, "control conditions" refers to conditions in the absence of a test substance, and refers to the difference in response intensity (the above-mentioned "suppression of excessive urine filtration function in pathological glomeruli") depending on the presence or absence of the test substance being used as an index. The response intensity S2 under the control conditions may be a value measured before the addition of the test substance, or a statistical value or range obtained by collecting data in advance.

[0088] For example, when the "suppression of excessive urine filtration function in pathological glomeruli" is observed, the test substance is preferably identified as a candidate therapeutic drug for chronic kidney disease. For example, the identification is preferably performed using the response intensity S1 in the presence of the test substance as an index, and more preferably by comparing the response intensity S1 with the response intensity S2 under control conditions.

[0089] Furthermore, the intensity of the response to losartan or a pharmacologically acceptable salt thereof (such as losartan potassium salt) may or may not be used as a benchmark "control condition."

[0090] In the fifth aspect, the "screening step using the suppression of excessive urinary filtration function in glomeruli as an index" may include measuring the inhibitory activity of the test substance against the angiotensin II receptor in vitro, and selecting candidate therapeutic drugs for chronic kidney disease based on the measurement results, with the measured activity being equivalent to or equivalent to "suppression of excessive urinary filtration function in pathological glomeruli." The method for measuring the inhibition of the angiotensin II receptor by the test substance is not particularly limited. For example, the measurement can be performed by a known method for measuring the binding between substances, such as the inhibition of the above-mentioned binding by a competitive inhibitor. Such techniques include, for example, isothermal titration calorimetry (ITC), surface plasmon resonance (SPR), nuclear magnetic resonance (NMR), and fluorescence correlation spectroscopy (FCS). More specifically, for example, the inhibitory activity of a test substance against angiotensin II receptors can be measured by any binding assay (e.g., fluorometry) (see, for example, paragraph 0071 of International Publication No. 2017 / 002838).

[0091] (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.

[0092] In the fourth aspect, the test substance is preferably selected from any Nrf2 activating drug, more preferably selected from the compound represented by the above general formula (I) or a pharmaceutically acceptable salt thereof, and even more preferably selected from the above (Embodiment 1) to (Embodiment 112).

[0093] In the fifth aspect, the test substance is preferably selected from any renin-angiotensin inhibitor, more preferably selected from the group consisting of any angiotensin receptor blocker (ARB), any angiotensin-converting enzyme (ACE) inhibitor, and any renin inhibitor, and even more preferably selected from the compound represented by the above formula (A) or a pharmaceutically acceptable salt thereof.

[0094] The present invention will be explained in more detail below by showing examples of the present invention, but the present invention is not limited to these examples and various applications are possible within the scope of the technical idea of ​​the present invention.

[0095] <Materials and Experimental Methods> (Mice) Chronic kidney disease model mice (hereinafter simply referred to as "CKD mice") (B6.Cg-Col4a5 ｔｍ１Ｙｓｅｇ CKD mice (strain #006183) were purchased from Jackson Laboratory. In the following examples, offspring mice bred from the purchased CKD mice were used. 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.

[0096] 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 (hereinafter simply referred to as "Compound 1") used in the Reference Examples and Examples corresponds to Example 41 of WO 2020 / 241853 and was synthesized in accordance with the method described in that publication. (Drug) 10 ml / kg of 0.5 w / v% Methylcellulose 400 Solution, Sterilized (133-17815, Fujifilm Corporation) was orally administered as a vehicle. Compound 1 was manufactured by UBE Corporation and dissolved in methylcellulose at 0.3, 1, or 3 mg / kg / day and orally administered. Losartan potassium (L0232, TCI Chemicals) was administered ad libitum via drinking water at a concentration of 250 μg / ml from weeks 6 to 11, and at a concentration of 125 μg / ml from week 12 onward. (Statistical Analysis) In the following Reference Examples and Examples, the significance of differences between two groups was evaluated using a Student's unpaired two-tailed t-test. For comparisons of three or four groups, analysis of variance (ANOVA) with Dunnett's multiple comparison test, Tukey's multiple comparison test, or log-rank (Mantel-Cox) test was used. A P value of <0.05 was considered statistically significant.

[0097] <Reference Example 1> Test on Improvement of Renal Function and / or Renal Pathology in Chronic Kidney Disease by Nrf2 Activator Compound 1 Figure 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.

[0098] (Reference Example 1-1) Test for Improvement of Glomerular Sclerosis, Inflammation, and Fibrosis in CKD Mice by Nrf2 Activator (Compound 1) 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 μm 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. 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. For Masson's trichrome (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 (MCA497R, BIO-RAD) 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 with 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). 0: no lesion, 1: mesangial area expansion, 2: Bowman's epithelial cell expansion, glomerular and Bowman's capsule adhesion, partial sclerosis, 3: sclerotic area in 50-75% of glomeruli, 4: sclerotic area in 75-100% of glomeruli. The MT-positive area was calculated from 10 different points (total area: 3,938,800 μm) for each mouse. ２) and normalized by tissue area. The results are shown in Figure 2.

[0099] Figure 2A shows the results of PAS staining, F4 / 80 immunohistochemistry, and MT staining of kidney sections from WT and CKD mice. In the figure, the scale bar for PAS staining is 50 μm, and the scale bars for other stainings are 100 μm. Figure 2B shows the results of evaluating glomerulosclerosis scores based on PAS-stained sections. Figure 2C shows the percentage of F4 / 80-positive areas (inflammatory areas). Figure 2D shows the percentage of fibrotic areas. In the figure, values ​​are the average of n = 7 to 8 in each group, and the significance levels are *: p<0.05, **: p<0.01, and ***: p<0.001.

[0100] As is clear from the results shown in Figure 2B, while the wild-type mice had a glomerular sclerosis score of 0 in approximately 98%, the pathology in the non-treated CKD mouse group (vehicle group) worsened to 10% for a glomerular sclerosis score of 3 and 60% for a glomerular sclerosis score of 4. In contrast, in the group receiving daily oral administration of an Nrf2 activator, the proportions of glomerular sclerosis score 3 and glomerular sclerosis score 4 significantly decreased in a dose-dependent manner, demonstrating a significant improvement in a dose-dependent manner.

[0101] Furthermore, as is clear from the results shown in Figure 2C, the inflammatory area was approximately 0% in wild-type mice, while the inflammatory area was approximately 5.4% in the non-treated CKD mouse group (vehicle group), indicating a worsening of pathology. In contrast, in the group receiving daily oral administration of an Nrf2 activator, the inflammatory area was significantly reduced to approximately 1% or less, indicating a significant improvement in inflammation. As is clear from the results shown in Figure 2D, the fibrotic area was approximately 0% in wild-type mice, while the fibrotic area was approximately 9.5% in the non-treated CKD mouse group (vehicle group), indicating a worsening of pathology. In contrast, in the group receiving daily oral administration of an Nrf2 activator, the fibrotic area was significantly reduced in a dose-dependent manner, indicating a significant improvement in fibrosis.

[0102] (Reference Example 1-2) Test for Improvement of Renal Function (Urine Filtration Function, etc.) in CKD Mice by Nrf2 Activator (1) For 22-week-old CKD mice with advanced disease (vehicle group), a 22-week-old wild-type control group, and groups orally administered 0.3, 1, and 3 mg / kg / day of an Nrf2 activator alone, the concentrations of plasma biomarkers (GFR, plasma creatinine, blood urea nitrogen (BUN), indoxyl sulfate (IS)), urinary biomarkers (urinary cystatin C, β ２The concentrations of urinary creatinine-microglobulin, NGAL, KIM-1, clusterin, and urinary trefoil factor 3 (TFF3), as well as urinary protein and albumin concentrations (mg / mg Cre normalized to creatinine concentration) were measured. (2) Plasma Biomarkers. For GFR, mice were anesthetized with isoflurane and 20 mg / mL FITC-sinistrin (MedBeacon) was injected into the subclavian vein at 100 μL / mouse. 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 (μl / min) was calculated using MedBeacon software. For other plasma biomarkers (plasma creatine, BUN, and indoxyl sulfate), plasma was collected by centrifuging mouse blood samples obtained from the inferior vena cava or tail at 3,000 rpm for 15 minutes at 4°C. Plasma creatine, BUN, and indoxyl sulfate were measured using a DRI-CHEM (Fujifilm), a 7180 biochemical autoanalyzer (Hitachi), and a PU-4180 HPLC Pump / FP-4020 Fluorescence detector (Jasco), respectively. (3) Urinary biomarkers. Mouse urine samples were collected at predetermined time points over 24 hours using metabolic cages (Aswan Co., Ltd.). Urinary creatinine, as an internal standard, was measured using the Jaffe method (636-51011, Fujifilm). 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.

[0103] The results are shown in Figures 3 and 4. Figure 3A shows the results of Compound 1 improving urinary filtration function (GFR) in CKD mice. Figures 3B to 3D show the results of Compound 1 improving plasma biomarkers (plasma creatine, BUN, and indoxyl sulfate). Figures 3E to 3J show the results of Compound 1 improving urinary biomarkers (urinary cystatin C, β ２ 4A and 4B show the results of improvement of urinary protein levels (mg / mgCre) in CKD mice by Compound 1. FIG. 4A shows the results of improvement of urinary protein levels (mg / mgCre) in CKD mice by Compound 1. FIG. 4B shows the results of improvement of urinary albumin levels (mg / mgCre) in CKD mice by Compound 1. In the figures, values ​​are the average values ​​of n=7 to 8 in each group, and the significance levels are *: p<0.05, **: p<0.01, ***: p<0.001, #: p<0.05, ###: p<0.001.

[0104] (Results) As is clear from the results shown in Figure 3A, the 22-week-old CKD mice (vehicle group) with advanced disease had a significantly decreased GFR (µl / min) compared to the 22-week-old wild-type control group. On the other hand, the 22-week-old Nrf2 activator (3 mg / kg / day orally)-administered group had a significantly increased GFR (µl / min) compared to the 22-week-old CKD mice (vehicle group). This is thought to be due to the Nrf2 activator's inhibitory effect on excessive urine filtration in the glomerulus, thereby significantly improving renal function.

[0105] Furthermore, as is clear from the results shown in Figures 3B to 3J, the 22-week-old CKD mice (vehicle group) with advanced disease showed significantly higher plasma biomarkers (plasma creatine, BUN, and indoxyl sulfate) and urinary biomarkers (urinary cystatin C, β ２It can be seen that all of the plasma biomarkers (IL-1, IL-2, IL-1, IL-2, IL-3, IL-1, IL-2, IL-3, IL-1, IL-2, IL-3, IL-4 ...2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-2, IL-3, IL-3, IL-4, IL-4, IL-1, IL-2, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-2, IL-3

[0106] 4A and 4B, the CKD mice (vehicle group) showed significantly increased levels of proteinuria and albuminuria (mg / mg Cre) compared to the wild-type control group. Furthermore, the Nrf2 activator monotherapy group showed significantly increased levels of proteinuria and albuminuria (mg / mg Cre) compared to the CKD mice (vehicle group). This is thought to be because, as described below, the Nrf2 activator inhibits the reabsorption of modified albumin from the renal tubules, promoting the excretion of modified albumin and preventing proximal tubular damage caused by the reabsorption of modified albumin (toxicity), thereby contributing to the improvement of renal function.

[0107] (Reference Example 1-3) Inhibition of albumin uptake in proximal tubules and suppression of megalin expression by Nrf2 activators Megalin is a protein expressed on the cell membrane of proximal tubules and is an albumin reabsorption transporter. It was confirmed as follows that Nrf2 activators dose-dependently inhibit albumin accumulation in proximal tubule cells and secrete it extracellularly in a dose-dependent manner. At least 200 proximal tubules from 22-week-old CKD mice (vehicle group), those receiving an Nrf2 activator alone at 0.3 mg / kg / day orally, those receiving an Nrf2 activator alone at 1 mg / kg / day orally, and those receiving an Nrf2 activator alone at 3 mg / kg / day orally 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). The tissues were photographed using a BZ-X700 microscope and analyzed using image analysis software (KEYENCE). Areas with strong LTL staining (villi) were defined as extracellular, and areas with weak LTL staining (cell bodies) were defined as intracellular. (The number of LTL-positive proximal tubules was counted and normalized to the cortical area.) The percentage of albumin localization within proximal tubule cells (the percentage of proximal tubules that have taken up albumin) and the percentage of albumin localization outside proximal tubule cells (the percentage of proximal tubules that have not taken up albumin) were measured. The results are shown in Figure 5A. In addition, CKD mice (vehicle group), and groups orally administered 0.3 mg / kg / day, 1 mg / kg / day, and 3 mg / kg / day of an Nrf2 activator alone were subjected to fluorescent staining with anti-megalin antibody (ab76969; Abcam) (stained with HRP or fluorescent secondary antibody), and 10 different points (total area 3,938,800 μm) of each mouse were stained. ２ ) and normalized by the megalin-positive area. The relative staining intensity (%) of megalin was measured, with WT being taken as 100%. The results are shown in Figure 5B. In the figure, values ​​are the average of n = 4 in each group, and the significance levels are **: p < 0.01, ***: p < 0.001.

[0108] As is clear from the results shown in Figure 5A, the percentage (%) of proximal tubules that have taken up albumin significantly decreases with increasing dose of Nrf2 activator alone. On the other hand, the percentage (%) of proximal tubules that have not taken up albumin significantly increases with increasing dose of Nrf2 activator alone.

[0109] Furthermore, as is clear from the results shown in Figure 5B, the relative staining intensity (%) of megalin significantly decreased with increasing dose of the Nrf2 activator alone, indicating that the Nrf2 activator significantly reduced the expression level of megalin. This indicates that the Nrf2 activator significantly reduced the expression level of megalin, thereby significantly inhibiting albumin reabsorption from renal tubular cells.

[0110] 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.

[0111] (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 as Kaplan-Meier survival curves in Figures 7A to 7D. A shows the results when the Nrf2 activator was orally administered at 0.3, 1, and 3 mg / kg / day. B shows the results when the Nrf2 activator was orally administered at 0.3 mg / kg / day. C shows the results when the Nrf2 activator was orally administered at 1 mg / kg / day. D shows the results when the Nrf2 activator was orally administered at 3 mg / kg / day. In the figure, the values ​​are the average values ​​for each group (n=14), and the significance levels are as follows according to the Log-rank (Mantel-Cox) test: *: p<0.05, **: p<0.01, ***: p<0.001.

[0112] (Results) First, as is clear from the results shown in Figure 7A, the survival time of CKD mice was extended in the RAS inhibitor alone-administered group and the Nrf2 activator alone-administered group compared to the CKD mouse group (vehicle group). Next, as is clear from the results shown in Figures 7A to 7D, the group administered a combination of losartan and an Nrf2 activator showed a significant (preferably, markedly or synergistically) extended survival time compared to the group administered a RAS inhibitor alone and the group administered an Nrf2 activator alone. In particular, as is clear from a comparison of the results shown in Figures 7B to 7D, the group administered a combination of a RAS inhibitor and an Nrf2 activator showed a significant (preferably, markedly or synergistically) extended survival time of CKD mice in an Nrf2 activator dose-dependent manner.

[0113] Example 1-2: Suppression of Proteinuria in CKD Mice by Combined Administration of a RAS Inhibitor (Losartan Potassium) and an Nrf2 Activator (Compound 1) Urine samples were collected from 6-, 14-, and 22-week-old wild-type control groups, CKD mice (vehicle group), groups receiving an Nrf2 activator alone at 0.3, 1, or 3 mg / kg / day orally, and groups receiving a RAS inhibitor and an Nrf2 activator (at 0.3, 1, or 3 mg / kg / day orally) in combination, and proteinuria (mg / mg Cre) was measured in the same manner as in Reference Example 1. The results are shown in Figure 8. In the figure, values ​​are the average of n = 8 to 14 in each group, and the significance levels are *: p<0.05, **: p<0.01, and ***: p<0.001.

[0114] (Results) As is clear from the results shown in Figure 8, 14- and 22-week-old CKD mice (vehicle group) showed significantly increased proteinuria (mg / mg Cre) compared to the 14- and 22-week-old wild-type control groups. Furthermore, the 14-week-old group receiving oral administration of an Nrf2 activator alone at 3 mg / kg / day showed significantly increased proteinuria (mg / mg Cre) compared to the 14-week-old CKD mice (vehicle group). This is thought to be because, as described below, the Nrf2 activator inhibits the reabsorption of modified albumin from the renal tubules, promoting the excretion of modified albumin and preventing proximal tubular damage caused by the reabsorption of modified albumin (toxicity), thereby contributing to improved renal function. On the other hand, the 14-week-old group receiving a combination of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day orally) showed a significant decrease in proteinuria (mg / mg Cre) compared to the 14-week-old group receiving an Nrf2 activator alone (3 mg / kg / day orally). This is thought to be because the Nrf2 activator inhibits the reabsorption of modified albumin (toxicity) from the renal tubules, preventing proximal tubular damage, while the RAS inhibitor (losartan) inhibits excessive glomerular urinary filtration, normalizing urinary filtration and suppressing the excretion of proteinuria (especially albumin) in the first place (improvement of renal function by combining active ingredients with different effects).

[0115] In addition, for each of the 6-week-old wild-type control group, CKD mice (vehicle group), Nrf2 activator single oral administration group, and RAS inhibitor and Nrf2 activator combination group, an increase in proteinuria (mg / mg Cre) was observed between the 6-week-old wild-type control group and the CKD mice (vehicle group), but there was no significant difference in proteinuria (mg / mg Cre) between the CKD mice (vehicle group) and the Nrf2 activator single oral administration group or the RAS inhibitor and Nrf2 activator combination group.

[0116] (Examples 1-3) Test for Improvement of Renal Function in CKD Mice by Combined Administration of a RAS Inhibitor (Losartan Potassium) and an Nrf2 Activator (Compound 1) For 22-week-old CKD mice with advanced disease (vehicle group), a 22-week-old wild-type control group, groups orally administered 0.3, 1, or 3 mg / kg / day of an Nrf2 activator alone, and a group administered a RAS inhibitor and an Nrf2 activator in combination, the concentrations of plasma biomarkers (plasma creatinine) and urinary biomarkers (urinary cystatin C, β ２ The concentrations of CKD mice (e.g., α-microglobulin, KIM-1, and NGAL) were measured in the same manner as in Reference Example 1. The results are shown in Figure 9. Figures 9A to 9E are graphs showing that combined use of losartan and Compound 1 improves renal function parameters in CKD mice more than either losartan or Compound 1 alone. In the figures, values ​​are the average values ​​for each group (n=14), and the significance levels are *: p<0.05, **: p<0.01, and ***: p<0.001.

[0117] (Results) As is clear from the results shown in Figures 9A to 9E, the 22-week-old CKD mice (vehicle group) with advanced disease showed significantly higher plasma biomarkers (plasma creatinine) and urinary biomarkers (urinary cystatin C, β ２ It can be seen that all of the plasma biomarkers (IL-1, IL-2, IL-1, IL-3, IL-6, IL-1, IL-2, IL-1, IL-2, IL-3, IL-1, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-3, IL-4, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-3, IL-4, IL-2, IL-3, IL-4, IL-2, IL-3, IL-4, IL-2, IL-3, IL-4, IL-2, IL-3, IL-4, IL-4, IL-2, IL-3, IL-4, IL-4, IL-2, IL-3, IL-4, IL-4, IL-5, IL-5, IL-6, IL-6, IL-1, IL-2, IL-2, IL-3, IL-4, IL-5, IL-6, IL-1, IL-2, IL-2, IL-3, IL-4 ...4, IL-5, IL-1, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2, IL-2, IL-3, IL-4, IL-1, IL-2

[0118] Example 2 Test for Improvement of Renal Function in CKD Mice by Combined Use of RAS Inhibitor and Nrf2 Activator 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.

[0119] Example 2-1: Test for Improvement of Glomerular Sclerosis and Fibrosis in CKD Mice by Combined Administration 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 an Nrf2 activator alone at 3 mg / kg / day, 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 as in Reference Example 1. Glomerular sclerosis score and fibrosis area were evaluated histologically in comparison with the wild-type group and the untreated CKD mouse group (vehicle group) according to the following criteria, as in Reference Example 1. 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 50-75% of glomeruli, 4: Sclerotic areas covering 75-100% of glomeruli. The results are shown in Figures 11A-C. Figure 11B shows the results of evaluating the glomerular sclerosis score based on PAS-stained sections. Figure 11C shows the percentage of fibrotic areas. In the figures, values ​​are the average of n = 7-8 for each group, and the significance levels are *: p<0.05, **: p<0.01, and ***: p<0.001.

[0120] (Results) As is clear from the results shown in Figure 11B, while the wild-type mice had a glomerular sclerosis score of 0 in approximately 98%, the non-treated CKD mouse group (vehicle group) had a glomerular sclerosis score of 3 in 10% and a glomerular sclerosis score of 4 in 60%, demonstrating a worsening of the pathology. In contrast, the group receiving daily oral administration of an Nrf2 activator showed a significant reduction in the proportion of glomerular sclerosis scores of 4, indicating a significant improvement in the pathology. Furthermore, the group receiving a combination of a RAS inhibitor and an Nrf2 activator showed a significantly reduced proportion of glomerular sclerosis scores of 4 compared to the group receiving an Nrf2 activator alone and the group receiving a RAS inhibitor alone, indicating a significant further improvement in the pathology. This is thought to be due to a preferably significant or synergistic improvement in the pathology caused by the combination of a RAS inhibitor and an Nrf2 activator.

[0121] Furthermore, as is clear from the results shown in Figure 11C, the fibrotic area in wild-type mice was approximately 0%, while the fibrotic area in the non-treated CKD mouse group (vehicle group) was approximately 8.1%, indicating a worsening of the pathology. In contrast, the group receiving daily oral administration of an Nrf2 activator showed a reduced fibrotic area, indicating an improvement in fibrosis. Furthermore, the group receiving a combination of a RAS inhibitor and an Nrf2 activator showed a significantly reduced fibrotic area compared with the group receiving an Nrf2 activator alone and the group receiving an RAS inhibitor alone, indicating a significant improvement in fibrosis. This is thought to be due to a preferably significant or synergistic improvement in the pathology caused by the combination of a RAS inhibitor and an Nrf2 activator.

[0122] Example 2-2: Test 1 for Improvement of Renal Function in CKD Mice by Combined Administration of a RAS Inhibitor and an Nrf2 Activator Plasma biomarker concentrations (GFR, indoxyl sulfate) 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 at 3 mg / kg / day orally, and a group receiving a RAS inhibitor in combination with an Nrf2 activator (3 mg / kg / day orally). The results are shown in Figures 12A and 12B. In the figures, values ​​are the average of n = 7 to 8 in each group, and the significance levels are *: p<0.05, **: p<0.01, and ***: p<0.001.

[0123] (Results) As is clear from the results shown in Figure 12A, the GFR (μl / min) of 20-week-old CKD mice (vehicle group) with advanced disease was significantly reduced compared to the 20-week-old wild-type control group. On the other hand, the GFR (μl / min) of the 20-week-old CKD mice (vehicle group) treated with a combination of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day orally) was significantly increased compared to the 20-week-old CKD mice (vehicle group), maintaining a nearly normal value equivalent to that of the 20-week-old wild-type control group. This is thought to be due to the significant improvement in renal function caused by the inhibitory effect of both the RAS inhibitor and the Nrf2 activator on excessive urinary filtration in the glomerulus.

[0124] Furthermore, as is clear from the results shown in Figure 12B, 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. On the other hand, the 20-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 20-week-old CKD mice (vehicle group), maintaining levels close to normal, 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 resulting from the combination of a RAS inhibitor and an Nrf2 activator.

[0125] Example 2-3: Test 2: Improvement of Renal Function in CKD Mice by Combined Use of a RAS Inhibitor and an Nrf2 Activator. Figure 13 is a schematic diagram showing the administration schedule for losartan potassium and a combination of Compound 1 and losartan potassium in CKD mice starting at 12 weeks of age. In this example, administration was initiated at 12 weeks of age, after the onset of proteinuria, assuming therapeutic intervention from the CKD stage. The results shown in Examples 2-3 and 2-4 below (Figures 14 and 15) were obtained from the animals used in these examples. Plasma biomarker concentrations (GFR, plasma creatine, and indoxyl sulfate) 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 oral administration of an Nrf2 activator alone at 3 mg / kg / day, and a group receiving oral administration of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day). The results are shown in Figures 14A-C. In the figure, the values ​​are the average values ​​for each group (n=7 to 8), and the significance levels are *: p<0.05, **: p<0.01, ***: p<0.001.

[0126] (Results) As is clear from the results shown in Figure 14A, the GFR (µl / min) of 24-week-old CKD mice (vehicle group) with advanced disease was significantly reduced compared to the 24-week-old wild-type control group. On the other hand, the GFR (µl / min) of the 24-week-old CKD mice treated with a combination of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day orally) was significantly increased compared to the 24-week-old CKD mice (vehicle group). This is thought to be due to the significant improvement in renal function caused by the inhibitory effect of both the RAS inhibitor and the Nrf2 activator on excessive urinary filtration in the glomerulus.

[0127] Furthermore, as is clear from the results shown in Figure 14B, the 24-week-old CKD mice (vehicle group) with advanced disease showed a significant increase in plasma creatine compared to the 24-week-old wild-type control group. Meanwhile, the 20-week-old group receiving a combination of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day orally) showed a significant decrease in plasma creatine compared to the 24-week-old CKD mice (vehicle group), maintaining levels close to normal, 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 resulting from the combination of a RAS inhibitor and an Nrf2 activator.

[0128] Furthermore, as is clear from the results shown in Figure 14C, 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. On the other hand, 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, 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.

[0129] (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 primarily 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: 1. oxidized albumin 2. uremic toxin (indoxyl sulfate: IS): bound to albumin 3. free fatty acids (FFA): 99% of FFA in plasma exists bound to albumin.

[0130] (1. Oxidized Albumin) 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 has another cysteine ​​attached to this thiol group via an S-S bond, O ２H bonded, O ３ It is known that reduced albumin is converted to oxidized albumin by oxidative stress.

[0131] In addition, in healthy individuals, the proportion of reduced albumin is high, but as the disease progresses to CKD, the proportion of oxidized albumin in serum and / or urine increases, and in end-stage renal failure and / or complications, the proportion of oxidized albumin in serum and / or urine increases further (PLoS One. 8; 9 (1): e85216 (2014)., Sci Rep 5: 14471 (2015), Biol Pharm Bull. 39: 1000-1006 (2016), J Pharm Sci. 105, 1043-1049 (2016), Clin Biochem 81: 20-26 (2020), Diabetes Care. 44 (6): e115-e117 (2021)).

[0132] Furthermore, it is known that, for example, the proportion of oxidized albumin in serum and / or urine increases with the progression of renal pathology in type 2 diabetes.

[0133] (2. Uremic Toxins) The uremic toxin indoxyl sulfate (IS) is a substrate for organic anion transporters (OAT) expressed on the basolateral side of proximal tubular epithelial cells and is known to be excreted in urine by renal tubular secretion (Kidney Int. 65, 162-174 (2004)). P-cresyl sulfate and indoxyl sulfate (IS) are strongly associated with cardiovascular events and all-cause mortality due to chronic kidney disease (CKD) (Clin J Am Soc Nephrol 2009; 4(10): 1551-1558).

[0134] ((3. FFA)) Excessive reabsorption of FFA-bound albumin is known to cause renal tubular damage (Cell Metab. 4; 33 (5): 1042-1061. e7 (2021)). In particular, stearic acid (C18:0), palmitic acid (C16:0), and the like bound to albumin are known to have renal tubular damage effects (Kidney 360 1 (8) 781-79 (2020)). In addition, the present inventors have experimentally confirmed that oral administration of the above-mentioned Nrf2 activator reduces the amount of FFA (C16:0, C18:0) in plasma in wild-type mice and CKD mice by measuring the amount of plasma fatty acids using GC / MS (5975C, manufactured by Agilent).

[0135] The inhibitory effect of the combined use of oxidized albumin, which causes renal tubular damage, was evaluated using the mass spectrometer (ESI-TOFMS) described below for each of the 20-week-old group administered a combination of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day orally) from the age of 6 weeks, the group administered an Nrf2 activator alone at 3 mg / kg / day orally, the 20-week-old CKD mice (vehicle group), and the 20-week-old wild-type control group in Example 2-1 and Example 2-2 above, and the 24-week-old group administered a combination of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day orally) from the age of 12 weeks, the group administered an Nrf2 activator alone at 3 mg / kg / day orally, the CKD mice (vehicle group), and the 24-week-old wild-type control group in Example 2-3 above. Five microliters of serum sample was removed from each mouse, and contaminants were removed by solid-phase extraction. Then, an ESI-TOFMS (microTOF II; Bruker) was used to calculate the plasma albumin oxidation ratio (OAR) from the spectral intensity of oxidized albumin (near mass 66,000) and the spectral intensity of reduced albumin (near mass 65,900). OAR = oxidized albumin / (reduced albumin + oxidized albumin) × 100%. The results are shown in Figures 15A and 15B. In the figures, values ​​are the average of n = 3 for each group, and the significance levels are *: p<0.05, **: p<0.01, ***: p<0.001, ****: p<0.0001.

[0136] 15A, the plasma albumin oxidation degree in wild-type mice was approximately 17%, whereas the plasma albumin oxidation degree in CKD mice (vehicle group) was approximately 23%, indicating a high proportion of oxidized albumin in plasma. In contrast, in both the combination group and the single-drug administration group, the degree of oxidation was significantly reduced to 20% or less, and can be said to have further reduced to a level comparable to that of wild-type mice, indicating a low proportion of oxidized albumin in serum.

[0137] Furthermore, as is clear from the results shown in Figure 15B, the plasma albumin oxidation level in wild-type mice was approximately 15%, while the plasma albumin oxidation level in CKD mice (vehicle group) was approximately 22%, indicating a high proportion of oxidized albumin in plasma. In contrast, the group receiving a combination of a RAS inhibitor and an Nrf2 activator (3 mg / kg / day orally) showed a significant decrease to approximately 17%, which can be said to be comparable to the plasma albumin oxidation level in wild-type mice, indicating a low proportion of oxidized albumin in serum. It can be said that the amount of oxidized albumin that causes renal tubular damage can be suppressed by the above-mentioned combination.

[0138] Reference Example 2: Improvement of renal pathology (atrophy and renal tubular damage) in a renal-ischemia-reperfusion (U-IR) model (acute-chronic kidney disease model) by an Nrf2 activator. Under anesthesia, 10-week-old male C57 / BL / 6J mice were subjected to 45 minutes of ischemia at 37°C, followed by reperfusion and suturing to construct a U-IR model. After awakening, an Nrf2 activator was orally administered at 30 mg / kg / day. This was administered orally daily at 30 mg / kg / day for 14 days. After 14 days, kidney tissue was excised, and the expression level of NAD(P)H quinone reductase (NQO-1) protein in the kidney tissue was measured. Nrf2 is known to enhance the expression of NQO-1, a xenobiotic-metabolizing enzyme. The results are shown in Figure 16.

[0139] As is clear from the results shown in FIG. 16, NQO-1 expression was elevated in the 30 mg / kg / day oral administration group compared to the wild-type group and the non-administered U-IR model group.

Claims

1. A therapeutic agent for chronic kidney disease, including an Nrf2 activator, for use in combination with a renin-angiotensin inhibitor.

2. A treatment for chronic kidney disease, including a renin-angiotensin inhibitor, for use in combination with an Nrf2 activator.

3. Drugs for treating chronic kidney disease, including renin-angiotensin inhibitors and Nrf2 activators.

4. The therapeutic agent according to any one of claims 1 to 3, wherein the Nrf2 activator comprises a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: (In the above formula (I), 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 which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be 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 which may be 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 which may be substituted with 1 to 5 substituents independently selected from group E, 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; R ５ is (i) a hydrogen atom, or (ii) an alkyl group which may be substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a cycloalkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, a phenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, and an alkoxy group which may be substituted with 1 to 5 substituents independently selected from Group E; A is a group represented by the following formula (II): R ７ and R ８ are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E; or R ７ and R ８ are taken together with the carbon atoms to which they are attached to form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E; 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, and a cyano group; indicates the point of attachment to the rest of the molecule; Group E is a group consisting of halogen atoms, hydroxy groups, and alkoxy groups optionally substituted with 1 to 5 halogen atoms.

5. The therapeutic agent according to claim 4, wherein A in formula (I) has a structure represented by formula (II-1-1) below. (In the above formula, 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; X １ and X ２ are each independently CR ９ and Y １ , Y ２ , Y ３ , and Y ４ any one of the above is a nitrogen atom, and the other three are each independently CR １０ and R ９ are each a hydrogen atom; １０ are each independently a hydrogen atom, a halogen atom, an alkyl group, or an alkoxy group.

6. The therapeutic agent according to claim 4, wherein the compound represented by general formula (I) includes a compound represented by the following formula (I-1-1) or a pharmaceutically acceptable salt thereof: (In the above formula (I-1-1), 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; 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 phenyl group, and an alkoxy group; 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 which may be substituted with 1 to 5 substituents independently selected from group E; R １０ represents a hydrogen atom, a halogen atom, an alkyl 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, or a cyano group; Group E is a group consisting of a halogen atom, a hydroxy group, and an alkoxy group which may be substituted with 1 to 5 halogen atoms.

7. The therapeutic agent according to claim 4, wherein the compound represented by 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 claims 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, and R ａ represents a group capable of forming an anion or a group capable of converting into an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atom chain of 2 or less, and n represents an integer of 1 or 2.

9. The therapeutic agent according to any one of claims 1 to 3, wherein 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.

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.

11. The method according to claim 10, wherein the screening step further includes screening for suppression of excessive urine filtration function in glomeruli as an indicator.

12. A method for screening therapeutic agents for chronic kidney disease for use in combination with an Nrf2 activating drug, the method comprising a step of screening using the suppression of excessive urine filtration function in the glomerulus as an indicator.

13. The method according to claim 12, wherein the Nrf2 activator comprises a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof: (In the above formula (I), 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 which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be 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 which may be 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 which may be substituted with 1 to 5 substituents independently selected from group E, 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; R ５ is (i) a hydrogen atom, or (ii) an alkyl group which may be substituted with 1 to 5 substituents independently selected from the group consisting of a halogen atom, a hydroxy group, a cycloalkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, a phenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, and an alkoxy group which may be substituted with 1 to 5 substituents independently selected from Group E; A is a group represented by the following formula (II): R ７ and R ８ are each independently a hydrogen atom, an alkyl group which may be substituted with 1 to 5 substituents independently selected from Group E, an alkenyl group which may be substituted with 1 to 5 substituents independently selected from Group E, or an alkynyl group which may be substituted with 1 to 5 substituents independently selected from Group E; or R ７ and R ８ are taken together with the carbon atoms to which they are attached to form a monocyclic carbocyclic ring optionally substituted with 1 to 5 substituents independently selected from Group E; 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, and a cyano group; indicates the point of attachment to the rest of the molecule; Group E is a group consisting of halogen atoms, hydroxy groups, and alkoxy groups optionally substituted with 1 to 5 halogen atoms.

14. The method according to claim 10, 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, and R ａ represents a group capable of forming an anion or a group capable of converting into an anion, X represents that a phenylene group and a phenyl group are bonded directly or via a spacer having an atom chain of 2 or less, and n represents an integer of 1 or 2.

15. The method of claim 10, wherein 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.

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