Pharmaceutical composition for preventing and / or treating kidney injury, and autophagy activator

Abstract

The present invention addresses the problem of providing: a pharmaceutical composition for preventing and / or treating acute kidney injury; and an autophagy activator. The present invention relates to: a pharmaceutical composition for preventing and / or treating acute kidney injury, the pharmaceutical composition containing a compound represented by general formula (1) [wherein A represents a benzene ring that may be substituted; B represents an aryl group that may be substituted or a heteroaryl group that may be substituted; X represents an oxygen atom or a sulfur atom; Y represents a nitrogen atom or a carbon atom and, in formula (2-1), formula (2-2) represents a single bond or a double bond when Y represents a carbon atom, and formula (2-2) represents a single bond when Y represents a nitrogen atom; R1's independently represent a lower alkyl group, or two R1's may be bonded to each other to form a spiro ring or a crosslinked structure, or two R1's may be bonded to each other to form a saturated condensed heterocyclic ring in conjunction with a carbon atom and a nitrogen atom that constitute the ring containing Y; and p represents 0, 1 or 2, or (R1)p represents an oxo group], a salt of the compound, or a prodrug of the compound or the salt; and others.

Description

Pharmaceutical composition for preventing and / or treating kidney damage, and autophagy activator

[0001] The present invention relates to a pharmaceutical composition for preventing and / or treating kidney damage, and an autophagy activator.

[0002] With the aging population and the rise of lifestyle-related diseases, the number of patients with chronic kidney disease (CKD), end-stage renal failure (ESRD), and dialysis is increasing year by year, posing both medical and social challenges. In recent years, onconephrology, a new field of nephrology that explores the relationship between the kidney and cancer, has attracted attention. In Japan alone, over one million prescriptions for platinum-containing anticancer drugs are filled annually. Cisplatin, in particular, is widely used to treat various malignant tumors, including head and neck, lung, testicular, ovarian, and bladder cancer. However, cisplatin has side effects, including nephrotoxicity, which occurs even at low doses. Because cisplatin is partially filtered through the glomerulus and partially secreted from the proximal tubule and excreted in urine, cisplatin concentrations in the deep cortex are several times higher than in other organs. Renal damage is observed in the proximal tubule of the kidney and can clinically result in acute tubular necrosis. As described above, acute kidney injury (AKI) frequently occurs during cisplatin use, but adequate prevention and treatment methods have not yet been established. Therefore, if repeated AKI caused by cisplatin administration progresses to CKD and kidney function does not fully recover, the cisplatin dose must be reduced, making it difficult to continue treatment of malignant tumors and worsening the life prognosis of cancer patients.

[0003] Autophagy is a general term for the degradation of cytoplasmic components in lysosomes. Research on autophagy in renal disease has shown that autophagy plays a protective role in AKI due to ischemia-reperfusion injury, AKI due to cisplatin administration, and CKD due to aging or obesity (Non-Patent Documents 1-3). More importantly, despite the increasingly important role of autophagy in CKD, stagnation in the late lysosomal phase of autophagy results in insufficient disease response and worsens the condition, leading to the concept of "autophagy stagnation" (Non-Patent Documents 4-6). Furthermore, dietary components that reverse autophagy stagnation have been explored, and eicosapentaenoic acid (EPA) has been reported to restore autophagy and reduce renal lipotoxicity (Non-Patent Document 7). Autophagy dysfunction has been reported to be involved in a wide variety of diseases, including not only renal disease but also Parkinson's disease and diabetes, creating a global demand for the discovery and development of drugs that enhance autophagy.

[0004] Kimura T, Takabatake Y, Takahashi A, Kaimori JY, Matsui I, Namba T, Kitamura H, Niimura F, Matsusaka T, Soga T, Rakugi H, Isaka Y. Autophagy protects the proximal tubule from degeneration and acute ischemic injury. J Am Soc Nephrol. 2011 May;22(5):902-13. doi: 10.1681 / ASN.2010070705. Epub 2011 Apr 14. PMID: 21493778; PMCID: PMC3083312.Takahashi A, Kimura T, Takabatake Y, Namba T, Kaimori J, Kitamura H, Matsui I, Niimura F, Matsusaka T, Fujita N, Yoshimori T, Isaka Y, Rakugi H. Autophagy guards against cisplatin-induced acute kidney injury. Am J Pathol. 2012 Feb;180(2):517-25. doi: 10.1016 / j.ajpath.2011.11.001. PMID: 22265049.Namba T, Takabatake Y, Kimura T, Takahashi A, Yamamoto T, Matsuda J, Kitamura H, Niimura F, Matsusaka T, Iwatani H, Matsui I, Kaimori J, Kioka H, ​​Isaka Y, Rakugi H. Autophagic clearance of mitochondria in the kidney copes with metabolic acidosis. J Am Soc Nephrol. 2014 Oct;25(10):2254-66. doi: 10.1681 / ASN.2013090986. Epub 2014 Apr 3 .PMID: 24700866; PMCID: PMC4178439.Yamamoto T, Takabatake Y, Kimura T, Takahashi A, Namba T, Matsuda J, Minami S, Kaimori JY, Matsui I, Kitamura H, Matsusaka T, Niimura F, Yanagita M, Isaka Y, Rakugi H. Time-dependent dysregulation of autophagy: Implications in aging and mitochondrial homeostasis in the kidney proximal tubule. Autophagy. 2016 May 3;12(5):801-13. doi: 10.1080 / 15548627.2016.1159376. Epub 2016 Mar 17. PMID: 26986194; PMCID: PMC4854554.Yamamoto T, Takabatake Y, Takahashi A, Kimura T, Namba T, Matsuda J, Minami S, Kaimori JY, Matsui I, Matsusaka T, Niimura F, Yanagita M, Isaka Y. High-Fat Diet-Induced Lysosomal Dysfunction and Impaired Autophagic Flux Contribute to Lipotoxicity in the Kidney. J Am Soc Nephrol. 2017 May;28(5):1534-1551. doi: 10.1681 / ASN.2016070731. Epub 2016 Dec 8. PMID: 27932476; PMCID: PMC5407727.Takabatake Y, Yamamoto T, Isaka Y. Stagnation of autophagy: A novel mechanism of renal lipotoxicity. Autophagy. 2017 Apr 3;13(4):775-776. doi: 10.1080 / 15548627.2017.1283084. Epub 2017 Feb 6. PMID: 28165842; PMCID: PMC5388212.Yamamoto T, Takabatake Y, Minami S, Sakai S, Fujimura R, Takahashi A, Namba-Hamano T, Matsuda J, Kimura T, Matsui I, Kaimori JY, Takeda H, Takahashi M, Izumi Y, Bamba T, Matsusaka T, Niimura F, Yanagita M, Isaka Y. Eicosapentaenoic acid attenuates renal lipotoxicity by restoring autophagic flux. Autophagy. 2020 Jun 28:1-14. doi: 10.1080 / 15548627.2020.1782034. Epub ahead of print. PMID: 32546086.

[0005] The present invention addresses the problem of providing a pharmaceutical composition for preventing and / or treating acute kidney injury, for example, kidney injury caused by the administration of a platinum-containing drug, and an autophagy activator.

[0006] The present inventors conducted extensive research to solve the above problems and found that a compound represented by general formula (1), a compound represented by general formula (2), a salt thereof, or a prodrug thereof, which will be described later, can alleviate acute kidney injury, such as kidney injury caused by the administration of a platinum-containing drug, and activate cellular autophagy, thereby completing the present invention. Representative aspects of the present invention are as follows.

[0007] Item 1. General formula (1) [Wherein, A is an optionally substituted benzene ring, B is an optionally substituted aryl or an optionally substituted heteroaryl, X is an oxygen atom or a sulfur atom, and Y is a nitrogen atom or a carbon atom. R １ are each independently a lower alkyl, or two R １may be bonded to each other to form a spiro ring or a bridged structure, or two R １ may be bonded to each other to form a saturated fused heterocyclic ring together with the carbon atoms and nitrogen atoms constituting the ring containing Y. p is 0, 1, or 2. Alternatively, (R １ ) ｐItem 1. A pharmaceutical composition for preventing and / or treating acute kidney injury, comprising a compound represented by the following formula (1): [wherein R is 1 or 2; or a salt thereof, or a prodrug thereof. Item 2. The pharmaceutical composition according to Item 1, wherein, in general formula (1), B is an optionally substituted monocyclic aryl or an optionally substituted monocyclic or bicyclic nitrogen-containing heteroaryl. Item 3. Item 3. The pharmaceutical composition according to Item 1 or 2, wherein, in general formula (1), A is a benzene ring optionally substituted with at least one group selected from the group consisting of A-1) to A-16): A-1) halogen, A-2) hydroxyl group, A-3) nitro, A-4) cyano, A-5) carboxyl, A-6) optionally substituted amino, A-7) optionally substituted cyclic amino, A-8) optionally substituted lower alkyl, A-9) optionally substituted lower alkoxy, A-10) lower alkoxycarbonyl, A-11) lower alkylsulfonyl, A-12) carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl, A-13) optionally substituted cyclic aminocarbonyl, A-14) sulfamoyl optionally substituted with lower alkyl, A-15) optionally substituted cyclic aminosulfonyl, and A-16) tetrazolyl.Item 4. A pharmaceutical composition according to any one of Items 1 to 3, wherein, in general formula (1), B is a monocyclic aryl or a monocyclic or bicyclic heteroaryl, the monocyclic aryl being optionally substituted with at least one group selected from the group consisting of B-1) to B-16) below, and the monocyclic or bicyclic heteroaryl being optionally substituted with at least one group selected from the group consisting of B-1) to B-17) below: B-1) halogen, B-2) hydroxyl group, B-3) nitro, B-4) cyano, B-5) carboxyl, B-6) optionally substituted amino, B-7) optionally substituted cyclic amino, B-8) optionally substituted lower alkyl, B-9) optionally substituted lower alkoxy, B-10) lower alkoxycarbonyl, B-11) lower alkylsulfonyl, B-12) carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl, B-13) optionally substituted cyclic aminocarbonyl, B-14) sulfamoyl optionally substituted with lower alkyl, B-15) cyclic aminosulfonyl optionally substituted, B-16) tetrazolyl, and B-17) oxo. Item 5. The pharmaceutical composition according to any one of Items 1 to 4, wherein in general formula (1), the 4-position of the benzisoxazole or benzisothiazole skeleton is substituted. Item 6. The pharmaceutical composition according to any one of Items 1 to 3, wherein in general formula (1), B is substituted pyridyl or substituted phenyl, and at least the carbon atom in the ortho position relative to the carbon atom on the pyridine or benzene ring bonded to Y is substituted.Item 7. In general formula (1), A is a benzene ring optionally substituted with at least one group selected from the group consisting of halogen, lower alkoxy, and lower alkyl optionally substituted with halogen, B is pyridyl or phenyl, and optionally substituted with at least one group selected from the group consisting of B-1), B-5), B-8), B-10), B-12), and B-13) below: B-1) halogen, B-5) carboxyl, B-8) optionally substituted lower alkyl, B-10) lower alkoxycarbonyl, B-12) carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl, and B-13) optionally substituted cyclic aminocarbonyl, R. １ are each independently C1-C3 alkyl, or two R １ are bonded to each other to form a methylene group, a dimethylene group, or a trimethylene group, or (R １ ) ｐ Item 8. The pharmaceutical composition according to any one of Items 1 to 4, wherein the compound represented by general formula (1) is a compound represented by general formula (1A): wherein Z is a nitrogen atom or CH; and Y is a nitrogen atom or a carbon atom. R １１ are, independently of each other, methyl or ethyl, or two R １１ may be bonded to each other to form a bridged structure by methylene, dimethylene, or trimethylene. p is 0, 1, or 2. Alternatively, (R １１ ) ｐ is oxo. ２１ , R ２２ , and R ２３ are each independently a hydrogen atom, a halogen atom, a carbamoyl group, or a trifluoromethyl group. ３１ , R ３２ , and R ３３and each independently represent a hydrogen atom, a halogen atom, a lower alkyl substituted with a halogen atom, a methyl group, a carboxyl group, a lower alkoxycarbonyl group, a monomethylaminocarbonyl group, or a dimethylaminocarbonyl group. ２１ is a chlorine atom or trifluoromethyl, R ２２ and R ２３ is a hydrogen atom, and R ３１ is a chlorine atom, and R ３２ is a hydrogen atom, and R ３３ is a hydrogen atom, carboxyl, or lower alkoxycarbonyl. Item 10. The composition according to any one of Items 1 to 4, wherein the compound represented by general formula (1) is Compound 011, Compound 021, Compound 031, Compound 041, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 191, Compound 221, Compound 281, Compound 311, Compound 321, Compound 331, Compound 341, Compound 351, Compound 361, Compound 371, Compound 381, Compound 391, Compound 401, or Compound 431, each of which has the following structure: Item 11. General formula (2) wherein A is an optionally substituted benzene ring, B is an optionally substituted aryl or an optionally substituted heteroaryl, and Y is a nitrogen atom or a carbon atom. R １ are each independently a lower alkyl, or two R １ may be bonded to each other to form a spiro ring or a bridged structure, or two R １ may be bonded to each other to form a saturated fused heterocyclic ring together with the carbon atoms and nitrogen atoms constituting the ring containing Y. p is 0, 1, or 2. Alternatively, (R １ ) ｐis oxo.], a salt thereof, or a prodrug thereof for preventing and / or treating acute kidney injury. Item 12. The pharmaceutical composition according to any one of Items 1 to 11, which is for oral administration. Item 13. The pharmaceutical composition according to any one of Items 1 to 12, wherein the acute kidney injury is kidney injury caused by administration of a platinum-containing drug. Item 14. The pharmaceutical composition according to Item 13, wherein the platinum-containing drug is cisplatin. Item 15. A compound represented by general formula (1) [Wherein, A is an optionally substituted benzene ring, B is an optionally substituted aryl or an optionally substituted heteroaryl, X is an oxygen atom or a sulfur atom, and Y is a nitrogen atom or a carbon atom. R １ are each independently a lower alkyl, or two R １ may be bonded to each other to form a spiro ring or a bridged structure, or two R １ may be bonded to each other to form a saturated fused heterocyclic ring together with the carbon atoms and nitrogen atoms constituting the ring containing Y. p is 0, 1, or 2. Alternatively, (R １ ) ｐ Item 16. An autophagy activator comprising a compound represented by general formula (2): wherein A is an optionally substituted benzene ring, B is an optionally substituted aryl or an optionally substituted heteroaryl, and Y is a nitrogen atom or a carbon atom. R １ are each independently a lower alkyl, or two R １ may be bonded to each other to form a spiro ring or a bridged structure, or two R １ may be bonded to each other to form a saturated fused heterocyclic ring together with the carbon atoms and nitrogen atoms constituting the ring containing Y. p is 0, 1, or 2. Alternatively, (R １ ) ｐ is oxo.], a salt thereof, or a prodrug thereof.

[0008] The compound represented by general formula (1), the compound represented by general formula (2), a salt thereof, or a prodrug thereof has an effect of preventing and / or treating acute kidney injury, such as kidney injury caused by the administration of a platinum-containing drug, and has an effect of activating cellular autophagy. The pharmaceutical composition and autophagy activator of the present invention are rare in that they exhibit the above-mentioned effects even when administered orally.

[0009] Figure 1 is a micrograph (400x magnification) of a PAS-stained renal cortical section sample obtained in Test Example 1. The upper left photograph is a photograph of the vehicle-administered group, the lower left is a photograph of the test compound-administered group, the upper right is a photograph of the cisplatin-administered group, and the lower right is a photograph of the cisplatin and test compound-administered group. Figure 2 is a graph showing the renal tubular injury score (PAS Injury Score) obtained in Test Example 1. Figure 3 is a graph showing the creatinine concentration and urea nitrogen (BUN) concentration obtained in Test Example 1. In Figure 3, Cre represents the creatinine concentration, and BUN represents the urea nitrogen concentration. Figure 4 is a micrograph (200x magnification) of a p53-stained renal cortical section sample obtained in Test Example 2. The upper left photograph is a photograph of the vehicle-administered group, the lower left is a photograph of the test compound-administered group, the upper right is a photograph of the cisplatin-administered group, and the lower right is a photograph of the cisplatin and test compound-administered group. Arrows in Figure 4 indicate p53-positive cells. Figure 5 is a graph showing the number of p53-positive cells (mean value) obtained in Test Example 2. Figure 6 is a micrograph (400x magnification) of a renal cortical section sample stained for p62 obtained in Test Example 2. The upper left photograph is a photograph of the vehicle-administered group, the lower left is a photograph of the test compound-administered group, the upper right is a photograph of the cisplatin-administered group, and the lower right is a photograph of the cisplatin and test compound-administered group. Circles in Figure 6 indicate p62-positive dots. Figure 7 is a graph showing the number of p62-positive dots (mean value) obtained in Test Example 2. Figure 8 is a micrograph (2400x magnification) of a renal cortical section sample from a GFP-LC3 transgenic mouse obtained in Test Example 3. The upper left photograph is a photograph of the control group (administered only cisplatin), the lower left is a photograph of the chloroquine-administered group, the upper right is a photograph of the test compound-administered group, and the lower right is a photograph of the chloroquine and test compound-administered group. Figure 9 shows the number of GFP-positive dots obtained in Test Example 3. Figure 10 shows the electrophoresis results for Test Example 4. Fig. 11 shows the amount of LC3-II protein obtained in Test Example 4. Fig. 12 shows the difference obtained by subtracting the amount of LC3-II protein without Bafilomycin A1 treatment from the amount of LC3-II protein obtained in Test Example 4 with Bafilomycin A1 treatment.

[0010] One embodiment of the present invention is a pharmaceutical composition for preventing and / or treating acute kidney injury, comprising a compound represented by the following general formula (1), a salt thereof, or a prodrug thereof:

[0011] General formula (1)

[0012] [Wherein, A is an optionally substituted benzene ring, B is an optionally substituted aryl or an optionally substituted heteroaryl, X is an oxygen atom or a sulfur atom, and Y is a nitrogen atom or a carbon atom. R １ are each independently a lower alkyl, or two R １ may be bonded to each other to form a spiro ring or a bridged structure, or two R １ may be bonded to each other to form a saturated fused heterocyclic ring together with the carbon atoms and nitrogen atoms constituting the ring containing Y. p is 0, 1, or 2. Alternatively, (R １ ) ｐ is oxo.]

[0013] In the present invention, examples of the substituent of the "optionally substituted benzene ring" include halogen, hydroxyl group, nitro, cyano, carboxyl, optionally substituted amino, optionally substituted cyclic amino, optionally substituted lower alkyl, optionally substituted lower alkoxy, lower alkoxycarbonyl, lower alkylsulfonyl, carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl, optionally substituted cyclic aminocarbonyl, sulfamoyl optionally substituted with lower alkyl, optionally substituted cyclic aminosulfonyl, tetrazolyl, etc. The substituent may be one type alone or two or more types.

[0014] In the present invention, "aryl" includes, for example, monocyclic or bicyclic aryl, and specific examples thereof include phenyl, naphthyl, etc.

[0015] In the present invention, the aryl in "optionally substituted aryl" is as defined above. Examples of the substituent of the optionally substituted aryl include halogen; hydroxyl group; nitro; cyano; carboxyl; optionally substituted amino; optionally substituted cyclic amino; optionally substituted lower alkyl; optionally substituted lower alkoxy; lower alkoxycarbonyl; lower alkylsulfonyl; carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl; optionally substituted cyclic aminocarbonyl; sulfamoyl optionally substituted with lower alkyl; optionally substituted cyclic aminosulfonyl; tetrazolyl; oxo, etc. The substituent may be one type alone or two or more types.

[0016] In the present invention, "oxo" is a group represented by "=O".

[0017] In the present invention, examples of "heteroaryl" include monocyclic or bicyclic nitrogen-containing heteroaryl, and specific examples include monocyclic or bicyclic nitrogen-containing heteroaryl containing one or more (e.g., 1 to 3, 1 or 2, or 1) nitrogen atoms on the ring and optionally containing one or more (e.g., 1 to 3, 1 or 2, or 1) sulfur atoms or oxygen atoms as other heteroatoms. Specific examples of heteroaryl include pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, indolyl, isoindolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, quinolyl, isoquinolyl, purinyl, phthalazinyl, pteridyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofurazanyl, benzothiadiazolyl, benzotriazolyl, isoxazolo[4,5-d]pyridazyl, benzisoxazolyl, benzisothiazolyl, etc. Preferred are monocyclic nitrogen-containing heteroaryls or benzimidazolyl.

[0018] In the present invention, the heteroaryl in "optionally substituted heteroaryl" is as defined above. Examples of the substituent of the optionally substituted heteroaryl include halogen; hydroxyl group; nitro; cyano; carboxyl; optionally substituted amino; optionally substituted cyclic amino; optionally substituted lower alkyl; optionally substituted lower alkoxy; lower alkoxycarbonyl; lower alkylsulfonyl; carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl; optionally substituted cyclic aminocarbonyl; sulfamoyl optionally substituted with lower alkyl; optionally substituted cyclic aminosulfonyl; tetrazolyl; oxo, etc. The substituent may be one type alone or two or more types.

[0019] In the present invention, examples of "lower alkyl" include C1 to C8 alkyl having a linear, branched, or cyclic structure, preferably C1 to C6 alkyl, more preferably C1 to C4 alkyl, and particularly preferably C1 to C3 alkyl. Specific examples of linear or branched lower alkyl include methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, isobutyl, t-butyl, n-pentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, etc., and examples of lower alkyl having a cyclic structure include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl, etc. Preferred examples include methyl, ethyl, 2-propyl, t-butyl, cyclopropyl, etc.

[0020] In the present invention, "halogen" includes a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc., and is preferably a fluorine atom or a chlorine atom.

[0021] In the present invention, "optionally substituted amino" refers to an optionally substituted acyclic amino, and examples of the substituents include lower alkyl (e.g., methyl, ethyl, propyl, etc.), C1 to C8 acyl (e.g., acetyl, propionyl, etc.), aryl (e.g., phenyl, etc.), or heteroaryl. The substituents may be one type alone or two or more types. Preferred examples of the optionally substituted amino include amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclohexylamino, acetylamino, benzoylamino, phenylamino, etc.

[0022] In the present invention, the "cyclic amino" refers to, for example, a 5- to 7-membered cyclic amino having a nitrogen atom as a ring-constituting atom and optionally further containing one or more oxygen atoms (for example, 1 to 3, 1 or 2, or 1), and examples thereof include pyrrolidino, piperidino, piperazino, morpholino, etc., and preferably includes pyrrolidino, morpholino, etc.

[0023] In the present invention, the cyclic amino in the "optionally substituted cyclic amino" is as defined above. Examples of substituents for the cyclic amino include lower alkyl, lower alkoxy, amino, hydroxyl, nitro, cyano, carboxyl, and oxo. The cyclic amino may be substituted with at least one group selected from the group consisting of the above-mentioned substituents. The number of substituents may be, for example, 0, 1, 2, or 3, and preferably 0, 1, or 2. Specific examples of the optionally substituted cyclic amino include pyrrolidino, piperidino, piperazino, 4-methylpiperidino, morpholino, and 2-pyrrolidonyl, and preferably include pyrrolidino and morpholino.

[0024] In the present invention, the lower alkyl in "optionally substituted lower alkyl" is as defined above. Examples of the substituent of the lower alkyl include a hydroxyl group; amino; C1-C8 alkylamino (e.g., methylamino, ethylamino, propylamino, t-butylamino, etc.); C1-C8 alkoxy (e.g., methoxy, ethoxy, 1-propyloxy, 2-propyloxy, t-butyloxy, etc.); halogen (e.g., fluorine atom, chlorine atom, bromine atom, etc.); haloC1-C8 alkoxy (e.g., trifluoromethoxy, etc.); aliphatic heterocyclic groups (e.g., morpholino, piperidinyl, pyrrolidinyl, 4-methyl-1-piperazino, etc.); aryl (e.g., phenyl, 1-naphthyl, 2-hydroxybenzo ... heteroaryl (for example, pyridyl, thienyl, furanyl, etc.); carboxyl; C1-C8 alkoxycarbonyl (for example, methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, t-butoxycarbonyl, etc.); carbamoyl optionally substituted by lower alkyl (for example, carbamoyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, etc.); cyclic aminocarbonyl (for example, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, etc.), and the like. Preferred substituents include methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, 2-propyloxy, t-butoxycarbonyl, hydroxyl group, fluorine atom, chlorine atom, trichloromethyl, trifluoromethyl, trifluoromethoxy, morpholino, piperidino, pyrrolidino, carboxyl, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl, phenyl, pyridyl, etc. The optionally substituted lower alkyl may be substituted with at least one group selected from the group consisting of the above-mentioned substituents, and the number of substituents may be, for example, 0, 1, 2 or 3, preferably 0, 1 or 2.

[0025] In the present invention, "lower alkyl substituted with halogen" refers to alkyl in which all hydrogen atoms have been substituted with halogen. The halogen and lower alkyl in the halogen-substituted lower alkyl are as defined above. It is preferred that the halogens substituting the alkyl are the same. The halogen-substituted lower alkyl is preferably trichloromethyl or trifluoromethyl, and more preferably trifluoromethyl.

[0026] In the present invention, examples of "lower alkoxy" include C1 to C8 alkoxy having a straight-chain, branched, or cyclic structure, preferably C1 to C6 alkoxy, more preferably C1 to C4 alkoxy, and particularly preferably C1 to C3 alkoxy. Specific examples of straight-chain or branched alkoxy include methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, isobutoxy, t-butoxy, n-pentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, and the like. Examples of alkoxy having a cyclic structure include cyclopropoxy, cyclopropylmethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclopentyloxy, cyclopentylmethoxy, cyclohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, and the like. Preferred examples include methoxy, ethoxy, 2-propoxy, t-butoxy, cyclopropoxy, and the like.

[0027] In the present invention, the lower alkoxy in "optionally substituted lower alkoxy" is as defined above. Examples of the substituent of the lower alkoxy include a hydroxyl group; amino; C1-C8 alkylamino (e.g., methylamino, ethylamino, propylamino, t-butylamino, etc.); C1-C8 alkoxy (e.g., methoxy, ethoxy, 1-propyloxy, 2-propyloxy, t-butoxy, etc.); halogen (e.g., fluorine atom, chlorine atom, bromine atom, etc.); haloC1-C8 alkoxy (e.g., trifluoromethoxy, etc.); aliphatic heterocyclic groups (e.g., morpholino, piperidinyl, pyrrolidinyl, 4-methyl-1-piperazino, etc.); aryl (e.g., phenyl, 1-naphthyl, etc.); etc.); heteroaryl (e.g., pyridyl, thienyl, furanyl, etc.); carboxyl; C1-C8 alkoxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, 1-propyloxycarbonyl, 2-propyloxycarbonyl, t-butoxycarbonyl, etc.); carbamoyl optionally substituted with lower alkyl (e.g., carbamoyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, etc.); cyclic aminocarbonyl (e.g., pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, etc.). Preferred substituents include methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, 2-propyloxy, t-butoxycarbonyl, hydroxyl group, fluorine atom, chlorine atom, trifluoro, morpholino, piperidino, pyrrolidino, carboxyl, methoxycarbonyl, morpholinocarbonyl, phenyl, pyridyl, etc. The optionally substituted lower alkoxy may be substituted with at least one group selected from the group consisting of the above-mentioned substituents, and the number of the substituents may be, for example, 0, 1, 2 or 3, preferably 0, 1 or 2.

[0028] In the present invention, the lower alkoxy in "lower alkoxycarbonyl" is as defined above. Lower alkoxycarbonyl is a group in which the above-mentioned lower alkoxy is bonded to a carbonyl. Examples of lower alkoxycarbonyl include C1-C8 alkoxycarbonyl including linear, branched, or cyclic structures. Specific examples of linear or branched alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl, etc. Examples of C1-C8 alkoxycarbonyl containing a cyclic structure include cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, cyclobutyloxycarbonyl, cyclobutylmethoxycarbonyl, cyclopentyloxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexyloxycarbonyl, cyclohexylmethoxycarbonyl, cyclohexylethoxycarbonyl, etc. Preferred lower alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, 2-propoxycarbonyl, cyclopropoxycarbonyl, etc.

[0029] In the present invention, the lower alkyl in "lower alkylsulfonyl" is as defined above. Lower alkylsulfonyl is a group in which the above-mentioned lower alkyl is bonded to sulfonyl. Examples of lower alkylsulfonyl include C1 to C8 alkylsulfonyl groups having a linear, branched, or cyclic structure. Specific examples of linear or branched alkylsulfonyl groups include methanesulfonyl, ethanesulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, 1-butylsulfonyl, 2-butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl, and the like. Examples of C1 to C8 alkylsulfonyl groups having a cyclic structure include cyclopropylsulfonyl, cyclopropylmethylsulfonyl, cyclobutylsulfonyl, cyclobutylmethylsulfonyl, cyclopentylsulfonyl, cyclopentylmethylsulfonyl, cyclohexylsulfonyl, cyclohexylmethylsulfonyl, cyclohexylethylsulfonyl, and the like. Preferred examples include methanesulfonyl, ethanesulfonyl, 2-propanesulfonyl, cyclopropanesulfonyl, and the like.

[0030] In the present invention, in "carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl," lower alkyl and lower alkylsulfonyl are as defined above. Carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl includes "carbamoyl optionally substituted with lower alkyl" and "carbamoyl optionally substituted with lower alkylsulfonyl."

[0031] "Carbamoyl optionally substituted with lower alkyl" refers to a group in which one or two of the above-mentioned lower alkyls may be bonded to the carbamoyl. When two lower alkyls are bonded, the lower alkyls may be the same or different. Examples of carbamoyl optionally substituted with lower alkyl include carbamoyl and aminocarbonyl substituted with C1 to C8 alkyl, including linear, branched, or cyclic structures. Specific examples of carbamoyl optionally substituted with lower alkyl include carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 2-propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, ethylmethylaminocarbonyl, methylpropylaminocarbonyl, dicyclohexylaminocarbonyl, etc.

[0032] "Carbamoyl optionally substituted with lower alkylsulfonyl" refers to a carbamoyl group to which one or two lower alkylsulfonyl groups as described above may be bonded. When two lower alkylsulfonyl groups are bonded, the lower alkylsulfonyl groups may be the same or different. Examples of carbamoyl optionally substituted with lower alkylsulfonyl groups include carbamoyl and aminocarbonyl groups substituted with C1-C8 alkylsulfonyl groups, including linear, branched, or cyclic structures. Examples of linear or branched C1-C8 alkylsulfonylaminocarbonyl groups include methanesulfonylaminocarbonyl, ethanesulfonylaminocarbonyl, 1-propylsulfonylaminocarbonyl, 2-propylsulfonylaminocarbonyl, 1-butylsulfonylaminocarbonyl, 2-butylsulfonylaminocarbonyl, isobutylsulfonylaminocarbonyl, t-butylsulfonylaminocarbonyl, and the like. Examples of C1-C8 alkylsulfonylaminocarbonyl containing a cyclic structure include cyclopropylsulfonylaminocarbonyl, cyclopropylmethylsulfonylaminocarbonyl, cyclobutylsulfonylaminocarbonyl, cyclobutylmethylsulfonylaminocarbonyl, cyclopentylsulfonylaminocarbonyl, cyclopentylmethylsulfonylaminocarbonyl, cyclohexylsulfonylaminocarbonyl, cyclohexylmethylsulfonylaminocarbonyl, cyclohexylethylsulfonylaminocarbonyl, etc. Preferred carbamoyl optionally substituted with lower alkylsulfonyl includes carbamoyl, methanesulfonylaminocarbonyl, ethanesulfonylaminocarbonyl, 2-propylsulfonylaminocarbonyl, cyclopropylsulfonylaminocarbonyl, etc.

[0033] In the present invention, the optionally substituted cyclic amino in the "optionally substituted cyclic aminocarbonyl" is as defined above. The optionally substituted cyclic aminocarbonyl is a group in which the above-mentioned optionally substituted cyclic amino is bonded to a carbonyl. Specific examples of the optionally substituted cyclic aminocarbonyl include pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, 4-methylpiperidino, morpholinocarbonyl, 2-pyrrolidonylcarbonyl, etc., and preferred examples include pyrrolidinocarbonyl, morpholinocarbonyl, etc.

[0034] In the present invention, the lower alkyl in "sulfamoyl optionally substituted with lower alkyl" is as defined above. Sulfamoyl optionally substituted with lower alkyl is a group in which one or two of the above-mentioned lower alkyls may be bonded to sulfamoyl. When two lower alkyls are bonded, the lower alkyls may be the same or different. Examples of sulfamoyl optionally substituted with lower alkyl include sulfamoyl; aminosulfonyl substituted with C1 to C8 alkyl having a linear, branched, or cyclic structure, and the like, and specific examples include sulfamoyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, 2-propylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, ethylmethylaminosulfonyl, methylpropylaminosulfonyl, dicyclohexylaminosulfonyl, and the like.

[0035] In the present invention, the optionally substituted cyclic amino in the "optionally substituted cyclic aminosulfonyl" is as defined above. The optionally substituted cyclic aminosulfonyl is a group in which the above-mentioned optionally substituted cyclic amino is bonded to a sulfonyl. Specific examples of the optionally substituted cyclic aminosulfonyl include pyrrolidinosulfonyl, piperidinosulfonyl, piperazinosulfonyl, 4-methylpiperidinosulfonyl, morpholinosulfonyl, 4-piperidonylsulfonyl, etc., and preferred examples include pyrrolidinosulfonyl, morpholinosulfonyl, etc.

[0036]

[0037] In the compound represented by general formula (1), A is an optionally substituted benzene ring. The substituent of A includes, for example, at least one selected from the group consisting of A-1) to A-16) below, and when there are multiple substituents, they may be the same or different. A-1) halogen, A-2) hydroxyl group, A-3) nitro, A-4) cyano, A-5) carboxyl, A-6) optionally substituted amino, A-7) optionally substituted cyclic amino, A-8) optionally substituted lower alkyl, A-9) optionally substituted lower alkoxy, A-10) lower alkoxycarbonyl, A-11) lower alkylsulfonyl, A-12) carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl, A-13) optionally substituted cyclic aminocarbonyl, A-14) sulfamoyl optionally substituted with lower alkyl, A-15) optionally substituted cyclic aminosulfonyl, A-16) tetrazolyl.

[0038] The number of substituents in A is, for example, 0 to 5, 0 to 4, or 0 to 3, preferably 0, 1, or 2, and more preferably 0 or 1. When a plurality of substituents are present, they may be the same or different.

[0039] Other examples of the substituent for A include at least one selected from the group consisting of A-1 and A-3 to A-16 above, and at least one selected from the group consisting of A-1 and A-3 to A-16 above excluding methoxy.

[0040] A preferred substituent for A is at least one selected from the group consisting of halogen; lower alkoxy; carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl; and lower alkyl optionally substituted with halogen. A more preferred substituent for A is at least one selected from the group consisting of halogen; lower alkoxy; carbamoyl; and lower alkyl optionally substituted with halogen. A still more preferred substituent for A is at least one selected from the group consisting of halogen, methoxy, ethoxy, carbamoyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. A more preferred substituent for A is at least one selected from the group consisting of halogen, methoxy, ethoxy, carbamoyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl. A particularly preferred substituent for A is at least one selected from the group consisting of a chlorine atom, a fluorine atom, and trifluoromethyl.

[0041] In the compound represented by general formula (1), the substituent A may be bonded to any of the carbon atoms at positions 4, 5, 6, and 7 of the benzisoxazole or benzisothiazole skeleton, but is preferably bonded to at least one of the carbon atoms at positions 4, 5, and 6, more preferably to the carbon atom at position 4 and / or 5, and particularly preferably to the carbon atom at position 4. In the present invention, the position numbers of the atoms constituting the benzisoxazole or benzisothiazole skeleton are as follows:

[0042] [wherein A and X are the same as above].

[0043] In the compound represented by general formula (1), A is particularly preferably a benzene ring in which a halogen atom, a lower alkoxy group, or a lower alkyl group which may be substituted with a halogen atom is bonded to the carbon atom at position 4 of the benzisoxazole or benzisothiazole skeleton, and the carbon atoms at positions 5, 6, and 7 are unsubstituted.

[0044] In the compound represented by general formula (1), B is an optionally substituted aryl or an optionally substituted heteroaryl. The optionally substituted aryl or optionally substituted heteroaryl is as defined above. Examples of the aryl include phenyl or naphthyl, with phenyl being preferred. The heteroaryl is preferably a monocyclic nitrogen-containing heteroaryl that does not contain other heteroatoms as ring-constituting atoms, or benzimidazolyl. The monocyclic nitrogen-containing heteroaryl that does not contain other heteroatoms as ring-constituting atoms is preferably a 5- or 6-membered heteroaryl that contains one nitrogen atom as a ring-constituting heteroatom, such as pyrrolyl or pyridyl, with pyridyl being preferred, and 2-pyridyl being even more preferred. The benzimidazolyl is preferably benzimidazol-3-yl.

[0045] When B is a monocyclic aryl, B may be substituted with at least one group selected from the group consisting of B-1) to B-16) below. When B is a monocyclic or bicyclic heteroaryl, B may be substituted with at least one group selected from the group consisting of B-1) to B-17) below. B-1) halogen, B-2) hydroxyl group, B-3) nitro, B-4) cyano, B-5) carboxyl, B-6) optionally substituted amino, B-7) optionally substituted cyclic amino, B-8) optionally substituted lower alkyl, B-9) optionally substituted lower alkoxy, B-10) lower alkoxycarbonyl, B-11) lower alkylsulfonyl, B-12) carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl, B-13) optionally substituted cyclic aminocarbonyl, B-14) sulfamoyl optionally substituted with lower alkyl, B-15) optionally substituted cyclic aminosulfonyl, B-16) tetrazolyl, B-17) oxo.

[0046] The number of substituents in B is, for example, 0 or at least 1, 0 to 5, 0 to 4, preferably 0 to 3, and more preferably 0, 1, or 2. When a plurality of substituents are present, they may be the same or different.

[0047] The substituent for B is preferably at least one selected from the group consisting of halogen, carboxyl, optionally substituted lower alkyl, lower alkoxycarbonyl, carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl, and optionally substituted cyclic aminocarbonyl, and specifically at least one selected from the group consisting of halogen, carboxyl, methyl, ethyl, 1-propyl, 2-propyl, hydroxymethyl, carboxymethyl, trichloromethyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, methanesulfonylaminocarbonyl, pyrrolidinocarbonyl, and morpholinocarbonyl.

[0048] More preferably, the substituent for B is at least one selected from the group consisting of halogen; carboxyl; lower alkyl; lower alkyl substituted with halogen; lower alkoxycarbonyl; and carbamoyl optionally substituted with lower alkyl, and specifically, at least one selected from the group consisting of halogen, carboxyl, methyl, ethyl, trichloromethyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, monomethylaminocarbonyl, and dimethylaminocarbonyl.

[0049] Particularly preferred examples of the substituent for B include at least one selected from the group consisting of a chlorine atom, a fluorine atom, methyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, and dimethylaminocarbonyl.

[0050] In the compound represented by general formula (1), when Y is a nitrogen atom, B is preferably an optionally substituted phenyl or an optionally substituted pyridyl, and when Y is a carbon atom, B is preferably an optionally substituted phenyl, an optionally substituted pyridyl, or 2-oxobenzimidazol-3-yl, and more preferably an optionally substituted phenyl or an optionally substituted pyridyl.

[0051] In the compound represented by general formula (1), when B is substituted pyridyl or substituted phenyl, it is preferred that one or two, preferably one, of the carbon atoms at the ortho position relative to the carbon atom on the pyridine or benzene ring bonded to Y are substituted. The substituent bonded to the carbon atom at the ortho position may be any of the substituents for B described above, but is preferably a halogen, more preferably a chlorine atom or a fluorine atom, and even more preferably a chlorine atom.

[0052] In addition, in the compound represented by general formula (1), when B is a substituted pyridyl or a substituted phenyl, it is preferable that the carbon atom at the para-position to the carbon atom on the pyridine or benzene ring bonded to Y is unsubstituted or substituted with carboxyl.

[0053] In addition, in the compound represented by general formula (1), when B is substituted pyridyl or substituted phenyl, it is preferable that all of the carbon atoms at the meta position relative to the carbon atom on the pyridine or benzene ring bonded to Y are unsubstituted.

[0054] In the compound represented by general formula (1), when B is a substituted pyridyl or a substituted phenyl, it is more preferred that one or two, preferably one, of the carbon atoms in the ortho position relative to the carbon atom on the pyridine or benzene ring bonded to Y are substituted with a chlorine atom or a fluorine atom, the meta carbon atom is unsubstituted, and the para carbon atom is unsubstituted or substituted with a carboxyl, methoxycarbonyl, or ethoxycarbonyl. When Y is a nitrogen atom and B is a substituted 2-pyridyl, it is particularly preferred that the carbon atom in the ortho position relative to the carbon atom on the pyridine ring bonded to Y is substituted with a chlorine atom or a fluorine atom, all of the meta carbon atoms are unsubstituted, and the para carbon atom is unsubstituted or substituted with a carboxyl. When Y is a nitrogen atom and B is a substituted phenyl, it is particularly preferred that one of the two carbon atoms in the ortho position relative to the carbon atom on the benzene ring bonded to Y is substituted with a chlorine atom or a fluorine atom, and all other carbon atoms constituting the phenyl are unsubstituted. When Y is a carbon atom and B is a substituted 2-pyridyl, it is particularly preferred that the carbon atom in the ortho position relative to the carbon atom on the pyridine ring bonded to Y is substituted with a chlorine atom or a fluorine atom, all of the carbon atoms in the meta position are unsubstituted, and the carbon atom in the para position is either unsubstituted or substituted with a carboxyl, methoxycarbonyl, or ethoxycarbonyl. When Y is a carbon atom and B is a substituted phenyl, it is particularly preferred that one of the two carbon atoms in the ortho position relative to the carbon atom on the benzene ring bonded to Y is substituted with a chlorine atom or a fluorine atom, the other carbon atom in the ortho position is either unsubstituted, all of the carbon atoms in the meta position are unsubstituted, and the carbon atom in the para position is either unsubstituted or substituted with a carboxyl, methoxycarbonyl, or ethoxycarbonyl.

[0055] In the compound represented by formula (1), X is an oxygen atom or a sulfur atom, and is preferably an oxygen atom.

[0056] In the compound represented by formula (1), Y is a nitrogen atom or a carbon atom, and is preferably a nitrogen atom.

[0057] In the compound represented by formula (1), Y is a nitrogen atom or a carbon atom, and is preferably a nitrogen atom.

[0058]

[0059] In the compound represented by general formula (1), R １ are each independently a lower alkyl, or two R １ may be bonded to each other to form a spiro ring or a bridged structure, or two R １ may be bonded to each other to form a saturated condensed heterocyclic ring together with the carbon atom and nitrogen atom that constitute the ring containing Y.

[0060] R １ When R is lower alkyl, preferred R １ Examples of the alkyl include straight-chain or branched C1 to C3 alkyl, more preferably methyl and ethyl, and even more preferably methyl.

[0061] Two R's １ are bonded to each other to form a spiro ring or a bridged structure, the formation of a spiro ring means that two R １ is bonded, and the R １ and bond to each other to form a ring together with the carbon atom.

[0062] Two R's １ are bonded to each other to form a spiro ring or a bridged structure, the formation of a bridged structure means that one R is bonded to each of two of the carbon atoms constituting the ring including Y in the general formula (1). １ is bonded, and the R １ This refers to the case where two molecules are bonded to each other.

[0063] Two R's １ are bonded to each other to form a spiro ring or a bridged structure, for example, when two R １are bonded to each other to form a methylene, dimethylene, trimethylene, or tetramethylene to form a bridged structure, or to form a dimethylene or trimethylene to form a spiro ring, and preferably two R １ are bonded to each other to form a methylene, dimethylene, or trimethylene to form a crosslinked structure. Particularly preferred is a crosslinked structure formed by dimethylene as shown in the following structural formula:

[0064] Two R's １ are bonded to each other to form a saturated condensed heterocyclic ring together with the carbon atoms and nitrogen atoms constituting the ring containing Y, means that one R is bonded to each of two adjacent carbon atoms constituting the ring containing Y in general formula (1). １ is bonded, and the R １ and R are bonded to each other to form a saturated condensed heterocyclic ring together with the carbon atom and nitrogen atom constituting the ring containing Y. The saturated condensed heterocyclic ring referred to here is a ring formed by combining a heterocyclic ring containing Y (a pyrazine ring or a piperidine ring) with R. １ means a fused bicyclic ring with a saturated carbocyclic ring containing:

[0065] Examples of saturated fused heterocycles include fused rings of a pyrazine ring or a piperidine ring with a cyclopentane ring or a cyclohexane ring. Specific examples of saturated fused heterocycles include octahydrocyclopentapyridine, octahydrocyclopentapyrazine, decahydroquinoline, and decahydroquinoxaline.

[0066] Preferred R １ is a bridged structure formed by C1-C3 alkyl or dimethylene, and more preferred R １ is a bridged structure formed by methyl, ethyl or dimethylene shown in the above structural formula.

[0067] In the compound represented by the general formula (1), p is 0, 1, or 2.

[0068] In the compound represented by general formula (1), (R １ ) p can be oxo.

[0069] Among the compounds represented by general formula (1), salts thereof, and prodrugs thereof, compounds represented by the following general formula (1A), salts thereof, and prodrugs thereof are preferred. A pharmaceutical composition for preventing and / or treating acute kidney injury, which contains a compound represented by the following general formula (1A), salts thereof, or prodrugs thereof, is also encompassed by the present invention.

[0070] wherein Z is a nitrogen atom or CH; and Y is a nitrogen atom or a carbon atom. R １１ are, independently of each other, methyl or ethyl, or two R １１ may be bonded to each other to form a bridged structure by methylene, dimethylene, or trimethylene. p is 0, 1, or 2. Alternatively, (R １１ ) ｐ is oxo. ２１ , R ２２ , and R ２３ are each independently a hydrogen atom, a halogen atom, a carbamoyl group, or a trifluoromethyl group. ３１ , R ３２ , and R ３３ are each independently a hydrogen atom, a halogen atom, a lower alkyl substituted with a halogen atom, a methyl group, a carboxyl group, a lower alkoxycarbonyl group, a monomethylaminocarbonyl group, or a dimethylaminocarbonyl group.

[0071] In the compound represented by formula (1A), Z is a nitrogen atom or CH. When Y is a nitrogen atom, Z is preferably a nitrogen atom.

[0072] In the compound represented by general formula (1A), Y is a nitrogen atom or a carbon atom.

[0073] In the compound represented by general formula (1A), R １１ are, independently of each other, methyl or ethyl, or two R １１ may be bonded to each other to form a bridged structure with methylene, dimethylene, or trimethylene.

[0074] R １１is preferably a crosslinked structure consisting of methyl or ethyl, or dimethylene or trimethylene, and more preferably a crosslinked structure consisting of methyl or diethylene.

[0075] Two R's １１ are bonded to each other to form a bridged structure with methylene, dimethylene, or trimethylene, one R is attached to each of two of the carbon atoms constituting the ring containing Y in general formula (1A). １１ is bonded, and the R １１ These groups bond with each other to form methylene, dimethylene, or trimethylene, forming a bridged structure in the piperazine ring.

[0076] The ring containing Y in general formula (1A) is R １１ When substituted with (R １１ ) ｐ is oxo or is shown in the following structural formula:

[0077] [wherein * represents the side bonded to the carbon atom at position 3 of isobenzoxazole, R １１１ represents a C1-C3 alkyl. １１１ is preferably methyl or ethyl, more preferably methyl.

[0078] In general formula (1A), (R １１ ) ｐ may be oxo.

[0079] In the compound represented by general formula (1A), R ２１ , R ２２ , and R ２３ are each independently a hydrogen atom, a halogen atom, a carbamoyl group, or a trifluoromethyl group, and R ２１ , R ２２ , and R ２３ It is preferred that at least one of R is halogen, carbamoyl, or trifluoromethyl. ２１ is preferably a chlorine atom, a fluorine atom, carbamoyl, or trifluoromethyl, and more preferably a chlorine atom or trifluoromethyl. ２２is preferably a hydrogen atom, a chlorine atom or trifluoromethyl, and more preferably a hydrogen atom. ２３ is preferably a hydrogen atom, a chlorine atom, or trifluoromethyl, and more preferably a hydrogen atom. ２１ is halogen (preferably a chlorine atom or a fluorine atom) or trifluoromethyl, and R ２２ and R ２３ It is particularly preferred that both are hydrogen atoms.

[0080] In the compound represented by general formula (1A), R ３１ , R ３２ , and R ３３ are each independently a hydrogen atom, a halogen atom, a lower alkyl substituted with a halogen atom, a methyl group, a carboxyl group, a lower alkoxycarbonyl group, a monomethylaminocarbonyl group, or a dimethylaminocarbonyl group. ３１ is preferably a hydrogen atom, halogen, trichloromethyl, trifluoromethyl, or methyl, more preferably halogen, trichloromethyl, trifluoromethyl, or methyl, and particularly preferably a chlorine atom. ３２ is preferably a hydrogen atom, halogen or methyl, more preferably a hydrogen atom. ３３ is preferably a hydrogen atom, halogen, carboxyl, methoxycarbonyl, ethoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl, more preferably a hydrogen atom, carboxyl, methoxycarbonyl, or ethoxycarbonyl, and particularly preferably a hydrogen atom or carboxyl.

[0081] R ３１ , R ３２ , and R ３３ A preferred example of ３１ is a halogen (preferably a chlorine atom or a fluorine atom), and R ３２ is a hydrogen atom, and R ３３ is a hydrogen atom or a carboxyl group. ２１ When is a halogen (preferably a chlorine atom), R ３１is a halogen (preferably a chlorine atom or a fluorine atom), and R ３２ is a hydrogen atom, and R ３３ is preferably a hydrogen atom. ２１ When R is trihalomethyl (preferably trifluoromethyl), ３１ is a halogen (preferably a chlorine atom or a fluorine atom), and R ３２ is a hydrogen atom, and R ３３ is preferably a hydrogen atom, carboxyl, methoxycarbonyl, or ethoxycarbonyl. ２１ When is carbamoyl, R ３１ is a halogen (preferably a chlorine atom or a fluorine atom, more preferably a chlorine atom), and R ３２ is a hydrogen atom, and R ３３ is preferably a hydrogen atom. ２１ is a chlorine atom or trifluoromethyl, and R ２２ and R ２３ is a hydrogen atom, and R ３１ is a chlorine atom, and R ３２ is a hydrogen atom, and R ３３ is preferably a hydrogen atom or a carboxyl group.

[0082] Specific examples of the compound represented by general formula (1), its salt, or its prodrug include, for example, Compound 011, Compound 021, Compound 031, Compound 041, Compound 051, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 181, Compound 191, Compound 201, Compound 211, Compound 221, Compound 231, Compound 241, Compound 251, Compound 261, Compound 271, Compound 281, Compound 291, Compound 301, Compound 311, Compound 321, Compound 331, Compound 341, Compound 351, Compound 361, Compound 371, Compound 381, Compound 391, Compound 401, Compound 411, Compound 421, Compound 431, Compound 441, Compound 451, Compound 461, Compound 471, Compound 481, Compound 491, Compound 501, Compound 511, Compound 521, Compound 531, Compound 541, Compound 551, Compound 561, Compound 571, Compound 581, Compound 591, Compound 601, Compound 612, Compound 613, Compound 614, Compound 615, Compound 616, Compound 617, Compound 618, Compound 621, Compound 622, Compound 623, Compound 624, Compound 625, Compound 631, Compound 632, Compound 633, Compound 634, Compound 641, Compound 642, Compound 643, Compound 644, Compound 645 Compounds include Compound 221, Compound 231, Compound 241, Compound 251, Compound 261, Compound 271, Compound 281, Compound 291, Compound 301, Compound 311, Compound 321, Compound 331, Compound 341, Compound 351, Compound 361, Compound 371, Compound 381, Compound 391, Compound 401, Compound 411, Compound 421, and Compound 431, and preferably include the following compounds, salts thereof, or prodrugs thereof:

[0083]

[0084]

[0085] The compound represented by general formula (1), a salt thereof, or a prodrug thereof is more preferably Compound 011, Compound 021, Compound 031, Compound 041, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 191, Compound 221, Compound 281, Compound 311, Compound 321, Compound 331, Compound 341, Compound 351, Compound 361, Compound 371, Compound 381, Compound 391, Compound 401, or Compound 431, a salt thereof, or a prodrug thereof, and more preferably Compound 011, Compound 021, Compound 031, Compound 041, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 191, Compound 321, Compound 351, Compound 361, Compound 371, Compound 381, Compound 401, or Compound 431, a salt thereof, or a prodrug thereof, and even more preferably Compound 011, Compound 031, Compound 041, Compound 061, Compound 071, or Compound 191, Compound 361, Compound 371, Compound 381, Compound 401, or Compound 431, a salt thereof, or a prodrug thereof, and particularly preferably Compound 011, Compound 031, Compound 041, Compound 061, Compound 071, or Compound 191, Compound 361, Compound 371, Compound 381, or Compound 401, a salt thereof, or a prodrug thereof.

[0086] One embodiment of the present invention includes a pharmaceutical composition for preventing and / or treating acute kidney injury, comprising a compound represented by the following general formula (2), a salt thereof, or a prodrug thereof. Because this compound has a similar structure to the compound represented by general formula (1), this compound, its salt, or its prodrug may have the effect of preventing and / or treating acute kidney injury. Furthermore, this compound, its salt, or its prodrug may activate autophagy. Furthermore, this compound or its salt may also be an intermediate compound for the compound represented by general formula (1).

[0087]

[0088]

[0089]

[0090] In general formula (2), it is preferable that the carbon atom ortho to the carbon atom of ring A (benzene ring) bonded to the carbon atom constituting the oxime structure has a substituent. Unless otherwise specified, the substituent is the same as the substituent in ring A (benzene ring) in general formula (1). Therefore, the substituent may be, for example, at least one group selected from the group consisting of A-1) to A-16) above. Furthermore, in general formula (2), the bond between the nitrogen atom and the hydroxyl group is represented by a wavy line, i.e., the line shown below, which indicates that the compound represented by general formula (2) may be any of the geometric isomers, E-isomer, Z-isomer, or a mixture thereof, that exist due to the partial structure ">C=N-OH." This also applies to compounds other than general formula (2) represented by a wavy line.

[0091] Among the compounds represented by general formula (2), salts thereof, or prodrugs thereof, compounds represented by the following general formula (2A), salts thereof, or prodrugs thereof are preferred.

[0092]

[0093] Among the compounds represented by general formula (2), salts thereof, and prodrugs thereof, the compounds represented by the following general formula (2B), salts thereof, and prodrugs thereof are preferred. Furthermore, the compounds represented by the following general formula (2B) or salts thereof are preferred as intermediate compounds in the production of the compounds represented by general formula (1).

[0094] G １ is halogen, lower alkylsulfonyl which may be substituted with halogen, or benzenesulfonyl which may be substituted with lower alkyl or nitro.

[0095] The compound represented by general formula (2B) or a salt thereof has two geometric isomers, E and Z, which exist due to the partial structure ">C=N-OH", and when the compound represented by general formula (2B) or a salt thereof is used as an intermediate compound in the production of the compound represented by general formula (1), the E isomer is preferred.

[0096] G １ Examples of the halogen represented by the formula (I) include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.

[0097] G １ The lower alkylsulfonyl in the optionally halogen-substituted lower alkylsulfonyl represented by the formula (I) is as defined above. The lower alkylsulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen. Examples of the optionally halogen-substituted lower alkylsulfonyl include linear or branched C1-C6 alkyl (preferably C1-C4 alkyl, more preferably C1-C3 alkyl)sulfonyl optionally substituted with 1 to 3 halogens, and specific examples include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, etc.

[0098] G １Examples of benzenesulfonyl optionally substituted with lower alkyl include benzenesulfonyl optionally substituted with 1 to 3 (preferably 1 or 2, more preferably 1) linear or branched C1-C6 alkyl (preferably C1-C4 alkyl, more preferably C1-C3 alkyl), and specific examples include p-toluenesulfonyl.

[0099] G １ Examples of the benzenesulfonyl optionally substituted with nitro group(s) represented by the formula (I) include benzenesulfonyl optionally substituted with 1 to 3 (preferably 1) nitro group(s), and specific examples thereof include o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, etc.

[0100] Preferred G １ is a chlorine atom, a fluorine atom, a bromine atom, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or p-nitrobenzenesulfonyl. １ is a chlorine atom or a bromine atom.

[0101] The compound represented by formula (2), a salt thereof, or a prodrug thereof includes, for example, the following compounds, a salt thereof, or a prodrug thereof.

[0102] The compound represented by general formula (2), a salt thereof, or a prodrug thereof is preferably Compound 062, Compound 202, Compound 362, or Compound 372, a salt thereof, or a prodrug thereof, and more preferably the (E) isomer of Compound 202, the (E) isomer of Compound 362, the (Z) isomer of Compound 362, or the (Z) isomer of Compound 372, a salt thereof, or a prodrug thereof.

[0103] The above compounds can be produced by, for example, Production Methods 1 to 3 described in detail below, methods similar thereto, or known methods, with appropriate modifications or combinations. The compounds used as starting compounds may be used as their respective salts. The methods described below are merely illustrative, and other methods may be used as appropriate based on the knowledge of those skilled in organic synthesis. Furthermore, when using non-commercially available 1,2-benzisothiazole or its derivatives or 1,2-benzisoxazole or its derivatives as starting compounds, they can be produced and procured by referring to the methods described in the following publications: Advances in heterocyclic chemistry, Heterocyclic Chemistry in the 21st Century: A Tribute to Alan Katritzky, Elsevier, Cambridge (2017); and R.A. Shastri, Review on Synthesis of 3-Substituted 1,2-Benzisoxazole Derivatives, Chem. Sci. Trans., 2016: 5; 8-20.

[0104] In each reaction in the production, functional groups can be protected as necessary. Protecting groups and techniques for their protection and deprotection can be appropriately applied using known methods, such as those described in T.W. Greene and P.G.M. Butts, "Protective Groups in Organic Synthesis," 3rd Ed., John Wiley and Sons, Inc., New York (1999).

[0105] [Production Method 1] In one embodiment, the compound represented by general formula (1) can be produced by the synthesis scheme shown in the following reaction scheme 1. That is, the compound represented by general formula (1) can be produced from a compound represented by general formula (3) and a compound represented by general formula (4).

[0106]

[0107] G ２is halogen, lower alkylsulfonyl which may be substituted with halogen, or benzenesulfonyl which may be substituted with lower alkyl or nitro.

[0108]

[0109] G ２ Examples of the halogen represented by the formula (I) include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.

[0110] G ２ The lower alkyl in the optionally halogen-substituted lower alkylsulfonyl represented by the formula (I) is as defined above. The lower alkylsulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen. Examples of optionally halogen-substituted lower alkylsulfonyl include linear or branched C1-C6 alkyl (preferably C1-C4 alkyl, more preferably C1-C3 alkyl)sulfonyl optionally substituted with 1 to 3 halogens, and specific examples include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, etc.

[0111] G ２ Examples of the benzenesulfonyl optionally substituted with lower alkyl represented by the formula (I) include benzenesulfonyl optionally substituted with 1 to 3 linear or branched C1-C6 alkyls (preferably C1-C4 alkyls, more preferably C1-C3 alkyls), and specific examples include p-toluenesulfonyl.

[0112] G ２ Examples of the benzenesulfonyl optionally substituted with nitro group(s) represented by the formula (I) include benzenesulfonyl optionally substituted with 1 to 3 (preferably 1) nitro group(s), and specific examples thereof include o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, etc.

[0113] Preferred G ２is a chlorine atom, a fluorine atom, a bromine atom, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or p-nitrobenzenesulfonyl.

[0114] The reaction of the compound represented by general formula (3) with the compound represented by general formula (4) can be carried out, for example, in an inert solvent in the presence or absence of a base. If necessary, an activator may be added to the reaction system. The compound represented by general formula (3) and the compound represented by general formula (4) are known compounds and can be produced by known methods.

[0115] Examples of the inert solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene, and xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride, ketone solvents such as acetone, aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide (DMF), and acetonitrile, and pyridine. Two or more of these solvents may be mixed in an appropriate ratio and used.

[0116] Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, metal carbonates such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.

[0117] The amount of the base used is usually 1 mole or more, preferably 1 to 5 moles, more preferably 1 to 2 moles, per mole of the compound represented by formula (4).

[0118] The amount of the compound represented by formula (3) used is usually 0.2 moles or more, preferably 0.2 to 2 moles, more preferably 0.2 to 1.5 moles, per mole of the compound represented by formula (4).

[0119] The reaction temperature is usually −50° C. to 180° C., preferably −30° C. to 180° C., more preferably −10° C. to 180° C. Microwaves may be used to promote the reaction, and in that case, the reaction temperature is, for example, 80° C. to 180° C., preferably 100° C. to 180° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.

[0120] [Production Method 2] In one embodiment, the compound represented by general formula (1B) can be produced by the synthesis scheme shown in the following reaction scheme-2. That is, the compound represented by general formula (1B) can be produced from the compound represented by general formula (5) and the compound represented by general formula (6).

[0121]

[0122] [In the formula, A, B, X, R １ , and p are the same as above. ３ is halogen, lower alkylsulfonyl which may be substituted with halogen, or benzenesulfonyl which may be substituted with lower alkyl or nitro.

[0123] In Reaction Scheme 2, A, B, X, R １ , and p is as above.

[0124] G ３ Examples of the halogen represented by the formula (I) include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.

[0125] G ３The lower alkyl in the optionally halogen-substituted lower alkylsulfonyl represented by the formula (I) is as defined above. The lower alkylsulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen. Examples of optionally halogen-substituted lower alkylsulfonyl include linear or branched C1-C6 alkyl (preferably C1-C4 alkyl, more preferably C1-C3 alkyl)sulfonyl optionally substituted with 1 to 3 halogens, and specific examples include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, etc.

[0126] G ３ Examples of the benzenesulfonyl optionally substituted with lower alkyl represented by the formula (I) include benzenesulfonyl optionally substituted with 1 to 3 linear or branched C1-C6 alkyls (preferably C1-C4 alkyls, more preferably C1-C3 alkyls), and specific examples include p-toluenesulfonyl.

[0127] G ３ Examples of the benzenesulfonyl optionally substituted with nitro group(s) represented by the formula (I) include benzenesulfonyl optionally substituted with 1 to 3 (preferably 1) nitro group(s), and specific examples thereof include o-nitrobenzenesulfonyl, p-nitrobenzenesulfonyl, etc.

[0128] Preferred G ３ is a chlorine atom, a fluorine atom, a bromine atom, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or p-nitrobenzenesulfonyl.

[0129] A compound represented by general formula (1B) can be obtained by coupling a compound represented by general formula (5) with a compound represented by general formula (6). The compound represented by general formula (5) and the compound represented by general formula (6) are known compounds and can be produced by known methods.

[0130] This reaction can be carried out, for example, in an inert solvent in the presence of a base.

[0131] Examples of the inert solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene, and xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride, ketone solvents such as acetone, aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide (DMF), and acetonitrile, and pyridine. Two or more of these solvents may be mixed in an appropriate ratio and used.

[0132] Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, metal carbonates such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.

[0133] The amount of the compound represented by general formula (6) used is usually 0.5 moles or more, further 1 mole or more, preferably 0.9 to 2 moles, more preferably 0.9 to 1.5 moles, relative to 1 mole of the compound represented by general formula (5).

[0134] The amount of the base used is usually 1 mole or more, preferably 1 to 5 moles, more preferably 1 to 2 moles, per mole of the compound represented by formula (5).

[0135] The reaction temperature is usually 30°C to a temperature 10°C higher than the boiling point of the solvent, and preferably 80°C to a temperature 10°C higher than the boiling point of the solvent. Microwaves may be used to promote the reaction, and in that case, the reaction temperature is, for example, 80°C to 180°C, and preferably 100°C to 180°C. The reaction time is usually 10 minutes to 48 hours, and preferably 10 minutes to 24 hours.

[0136] Furthermore, the reaction between the compound represented by general formula (5) and the compound represented by general formula (6) can also be carried out by utilizing the Buchward reaction. For example, the compound represented by general formula (5) is reacted with the compound represented by general formula (6) in a solvent in the presence of a palladium catalyst, a phosphine ligand, and a base.

[0137] Examples of the palladium catalyst include divalent palladium catalysts such as Pd(OAc)2, PdCl2, allylpalladium(II) chloride (dimer), bis(acetonitrile)palladium(II) dichloride, and bis(benzonitrile)palladium(II) dichloride; Pd ２ (dba) ３ (tris(dibenzylideneacetone)dipalladium(0)), bis(dibenzylideneacetone)palladium(0), palladium on carbon (Pd / C), and the like are included.

[0138] Examples of the phosphine ligand include bidentate phosphine ligands such as BINAP (2,2'-bis(diphenylphosphanyl)-1,1'-bisnaphthalene) and Xphos (2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl).

[0139] The base may be a strong base such as t-BuONa (sodium tert-butoxide).

[0140] In this reaction, the amount of the compound represented by general formula (6) used is usually 0.5 moles or more, further 1 mole or more, preferably 0.9 to 2 moles, more preferably 1 to 1.5 moles, relative to 1 mole of the compound represented by general formula (5).

[0141] The amount of the palladium catalyst used is usually 0.005 to 1 mole, preferably 0.01 to 0.2 mole, per mole of the compound represented by formula (5).

[0142] The amount of the phosphine ligand used is usually 0.5 to 5 moles, preferably 1 to 2 moles, per mole of the palladium catalyst.

[0143] The amount of the base used is usually 0.5 moles or more, preferably 1 mole or more, and preferably 1 to 2 moles per mole of the compound represented by formula (5).

[0144] The reaction temperature is usually 40° C. to 150° C., preferably 80° C. to 110° C., and the reaction time is usually 1 to 24 hours, preferably 3 to 12 hours.

[0145] [Production Method 3] In one embodiment, the compound represented by general formula (1) or (2) can be produced by the synthesis scheme shown in the following reaction scheme-3. That is, the compound represented by general formula (1C) can be produced by converting the compound represented by general formula (7) to the compound represented by general formula (8), reacting it with the compound represented by general formula (4) to produce the oxime compound represented by general formula (2B), and then ring-closing the oxime compound. Note that a person skilled in the art would understand that the compound represented by general formula (2) can be produced by using an appropriate corresponding compound having an optionally substituted benzene ring A instead of the compound represented by general formula (7) or (8) in the reaction shown in reaction scheme-3. In addition, the compound represented by general formula (7) is a known compound and can be produced by a known method.

[0146]

[0147]

[0148]

[0149] G ４ Examples of the halogen represented by the formula (I) include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.

[0150] Step 1, i.e., a step of converting a compound represented by general formula (7) into a compound represented by general formula (8), can be performed, for example, by reacting a compound represented by general formula (7) with a halogenating agent in an inert solvent.

[0151] Examples of inert solvents used in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene, and xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride, ketone solvents such as acetone, aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide (DMF), and acetonitrile, and pyridine. Two or more of these solvents may be mixed in an appropriate ratio for use.

[0152] Examples of the halogenating agent include common halogenating agents such as N-bromosuccinimide and N-chlorosuccinimide.

[0153] The amount of the halogenating agent used is usually equimolar to excess molar amount, preferably 1 to 5 times molar amount, more preferably 1 to 2 times molar amount, relative to the compound represented by formula (7).

[0154] The reaction temperature is usually −30 to 150° C., preferably −10 to 100° C., and more preferably −10 to 40° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably 30 minutes to 18 hours.

[0155] Step 2, i.e., a step of reacting a compound represented by general formula (8) with a compound represented by general formula (4) to synthesize a compound represented by general formula (2B), can be carried out, for example, in an inert solvent in the presence of a base.

[0156] Examples of inert solvents used in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene, and xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride, ketone solvents such as acetone, aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide (DMF), and acetonitrile, and pyridine. Two or more of these solvents may be mixed in an appropriate ratio for use.

[0157] Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, metal carbonates such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.

[0158] The amount of the compound represented by general formula (8) used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 to 2 mol, more preferably 0.9 to 1.5 mol, relative to 1 mol of the compound represented by general formula (4).

[0159] The amount of the base used is usually 1 mole or more, preferably 1 to 5 moles, more preferably 1 to 2 moles, per mole of the compound represented by formula (4).

[0160] The reaction temperature is usually −20° C. to a temperature 10° C. higher than the boiling point of the solvent, preferably 0° C. to 40° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, more preferably 30 minutes to 18 hours.

[0161] Step 3, that is, a step of converting a compound represented by general formula (2B) into a compound represented by general formula (1) by ring closure, can be carried out, for example, in an inert solvent in the presence of a base.

[0162] The compound represented by formula (2B) exists as geometric isomers, (E) and (Z) isomers, and the (E) isomer is preferred since less heating is required during the ring-closing reaction.

[0163] Examples of inert solvents used in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane, and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene, and xylene, halogenated hydrocarbon solvents such as dichloromethane, chloroform, dichloroethane, and carbon tetrachloride, ketone solvents such as acetone, aprotic solvents such as dimethyl sulfoxide, N,N-dimethylformamide (DMF), and acetonitrile, and pyridine. Two or more of these solvents may be mixed in an appropriate ratio for use.

[0164] Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, metal carbonates such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate, alkylamines such as triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.

[0165] The amount of the base used is usually 1 mole or more, preferably 1 to 5 moles, more preferably 1 to 2 moles, per mole of the compound represented by formula (2B).

[0166] The reaction temperature is usually 50° C. to a temperature 10° C. higher than the boiling point of the solvent, preferably 80° C. to a temperature 10° C. higher than the boiling point of the solvent. Microwaves may be used to promote the reaction, and in that case, the reaction temperature is, for example, 80° C. to 180° C., preferably 100° C. to 180° C. The reaction time is usually 10 minutes to 8 hours, preferably 10 minutes to 2 hours.

[0167] The compounds represented by general formula (1) or (2) according to the present invention, their intermediate compounds, and starting material compounds can be produced by the above-mentioned synthesis methods. They can also be produced based on the synthesis methods described in the Examples of this specification, taking into consideration techniques that were known at the time of filing or were publicly known (e.g., B.R. Kiran et al., SYNTHESIS, EVALUATION OF ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES OF SUBSTITUTED 1,2-BENZOXAZOLONE AND 3-CHLORO-1,2-BENZOXAZOLE DERIVATIVES, International Journal of Pharmaceutical Sciences and Research, 2015; 6: 2918-2925.).

[0168] Before being subjected to the reaction, the functional groups of the starting material compounds and intermediate compounds shown in each of the above reaction schemes can be protected with appropriate protecting groups using a known method, if necessary, and after completion of the reaction, the protecting groups can be deprotected using a known method.

[0169] Each of the target compounds obtained according to the above reaction schemes can be isolated and purified. For example, after cooling the reaction mixture, an isolation procedure such as filtration, concentration, extraction, etc. is carried out to separate the crude reaction product, and the crude reaction product can then be isolated and purified from the reaction mixture by subjecting it to a common purification procedure such as column chromatography, recrystallization, etc.

[0170] The starting material compounds shown in each of the above reaction schemes and the compounds represented by general formula (1) or (2) include compounds in the form of solvates to which a solvent is added (for example, hydrates, ethanol solvates, etc.).

[0171] In the compounds represented by general formula (1) or (2), the intermediate compounds obtained in the above reaction schemes, and the starting compounds, isomers (E, Z, cis, trans isomers) at double bonds, rings, and fused rings, isomers due to the presence of asymmetric carbons (R, S isomers, α, β isomers, enantiomers, diastereomers), optically active isomers with optical rotation (D, L, d, l isomers), polar isomers obtained by chromatographic separation (high polarity, low polarity), equilibrium compounds, rotational isomers, mixtures of these in any proportions, racemic mixtures, geometric isomers, stereoisomers, optical isomers, and other isomers are all included. For example, optical isomers can be separated using various known resolution methods (e.g., optical resolution by crystallization, direct optical resolution by chromatography, etc.).

[0172] Salts of the compounds represented by general formula (1) or (2) include all pharmaceutically acceptable salts. Pharmaceutically acceptable salts are not particularly limited, and examples include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic metal salts such as zinc salts; organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids; inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; and organic acid salts such as acetate, carbonate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, and ascorbate. These salts can be produced according to conventional methods.

[0173] Various isomers can be isolated by known separation methods. For example, racemic compounds can be converted into stereochemically pure isomers by common optical resolution methods (e.g., optical resolution by crystallization, direct optical resolution by chromatography, etc.). Optically active compounds can also be produced by using appropriate optically active starting materials.

[0174] The starting compounds, intermediate compounds, and target compounds shown in each of the above reaction schemes can be used in the form of a suitable salt.

[0175] In the present invention, in the compound represented by general formula (1) or (2), a salt thereof, or a prodrug thereof, one or more atoms can be substituted with one or more isotope atoms, such as deuterium (H), tritium (H), C, N, and O.

[0176] The pharmaceutical composition of the present invention may be a compound represented by formula (1) or (2), a salt thereof, or a prodrug thereof formulated in the form of a conventional pharmaceutical composition, and may be prepared using the compound, a salt thereof, or a prodrug thereof and a pharmaceutically acceptable carrier. Examples of the carrier include commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and lubricants.

[0177] In the present invention, a prodrug refers to a compound that is converted into a compound represented by general formula (1) or (2) by a reaction in vivo (for example, an enzymatic reaction or a reaction with gastric acid). For example, when the compound represented by general formula (1) or (2) has a carboxyl group, the prodrug is a compound in which the carboxyl group is converted into an ester. Examples of such esters include methyl ester, ethyl ester, 1-propyl ester, 2-propyl ester, pivaloyloxymethyl ester, acetyloxymethyl ester, cyclohexylacetyloxymethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester, ethyloxycarbonyloxy-1-ethyl ester, and cyclohexyloxycarbonyloxy-1-ethyl ester.

[0178] The pharmaceutical composition of the present invention can be selected from various forms depending on the therapeutic purpose, and representative forms include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (liquids, suspensions, etc.), ointments, inhalants, ear drops, etc. Among these, oral administration preparations, topical (preferably intraaural) administration preparations, and injections are preferred, with oral administration preparations being more preferred.

[0179] A wide variety of known carriers can be used for tablet formation, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, methylcellulose, potassium phosphate, polyvinylpyrrolidone, carboxymethylcellulose, and shellac; sodium alginate, dry starch, agar powder, laminarin powder, calcium carbonate, and carbonated water. disintegrants such as sodium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; absorption promoters such as quaternary ammonium bases and sodium lauryl sulfate; disintegration inhibitors such as stearin, cocoa butter, hydrogenated oils; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as purified talc, stearates, boric acid powder, and polyethylene glycol.

[0180] Furthermore, the tablets may be coated with conventional tablets as required, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multi-layered tablets.

[0181] A wide variety of known carriers can be used to form pills, including excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, and talc; binders such as powdered gum arabic, powdered tragacanth, gelatin, and ethanol; and disintegrants such as laminaran and agar.

[0182] As the carrier used for forming suppositories, a wide variety of known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like.

[0183] When prepared as an injection, the solution, emulsion, and suspension are preferably sterilized and isotonic with blood.The diluents used in preparing these solutions, emulsions, and suspensions can be widely known, such as water, ethanol, propylene glycol, polyoxylated isostearyl alcohol, ethoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc.In addition, in the case of an injection, the pharmaceutical preparation can contain sufficient amounts of salt, glycerin, glucose, etc. to prepare an isotonic solution, and can also contain common solubilizers, buffers, soothing agents, etc., and can further contain colorants, preservatives, fragrances, flavors, sweeteners, etc. and other pharmaceuticals as needed.

[0184] Ointments are available in the form of paste, cream, gel, etc., and when preparing these forms, diluents such as white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silicone, bentonite, etc. can be used.

[0185] Inhalants are formulations intended to be administered to the bronchi or lungs by inhaling the active ingredient as an aerosol, and include powder inhalants, inhalation solutions, inhalation aerosols, etc. Powder inhalants are formulations inhaled as an aerosol of powdered solid particles. They are typically prepared by forming the active ingredient into fine particles and blending them with additives such as lactose, if necessary, to form a homogeneous mixture. Inhalation solutions are liquid inhalants administered using a nebulizer, etc., and typically prepared by adding a solvent and an appropriate isotonicity agent, pH adjuster, etc. to the active ingredient and blending them together. Inhalation aerosols are metered-dose inhalants that spray a predetermined amount of the active ingredient together with a propellant filled in a container. Inhalation aerosols are typically prepared by adding a solvent and an appropriate dispersant, stabilizer, etc. to the active ingredient to form a solution or suspension, filling this into a pressure-resistant container together with the liquid propellant, and attaching a metering valve.

[0186] The pharmaceutical composition of the present invention may contain coloring agents, preservatives, perfumes, flavoring agents, sweeteners and other pharmaceutical agents as needed.

[0187] The amount of the compound represented by general formula (1) or (2), a salt thereof, or a prodrug thereof contained in the pharmaceutical composition of the present invention is not particularly limited and can be appropriately selected from a wide range, but is usually 0.5 to 90% by weight, 1 to 85% by weight, and preferably 1 to 80% by weight in the pharmaceutical composition.

[0188] The method of administration of the pharmaceutical composition of the present invention is not particularly limited and may be determined according to the dosage form, the patient's age, sex, disease state, and other conditions. For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally. Injections may be administered intravenously, either alone or in combination with conventional fluids such as glucose or amino acids, or may be administered intramuscularly, intradermally, subcutaneously, or intraperitoneally, as needed. Suppositories are administered rectally. Inhalants are administered nasally. Ear drops are administered intraaurally. Preferred administration methods are oral administration, injections (including subcutaneous, intramuscular, intravenous, and intrathecal administration), and intraaural administration, with oral administration being more preferred.

[0189] The dosage of the pharmaceutical composition of the present invention may be selected taking into consideration the method of use, the patient's age, sex, severity of the disease, and other conditions, and is generally administered in an amount of 0.01 to 100 mg, preferably 0.1 to 50 mg, of the active ingredient, a compound represented by general formula (1) or (2), a salt thereof, or a prodrug thereof per kg of body weight per day, in one or several divided doses per day, or at intervals of once every 2, 3, 4, 5, or 6 days, or once every 1, 2, or 4 weeks. The dosage varies depending on various conditions, and therefore a dosage lower than the above range may be sufficient in some cases, while a dosage exceeding the above range may be necessary in other cases.

[0190] The pharmaceutical composition of the present invention can also be used as a concomitant drug in combination with other drugs, such as drugs that have the effect of alleviating acute kidney injury, for example, kidney injury caused by the administration of platinum-containing drugs.

[0191] The present invention may include a method for preventing and / or treating acute kidney injury, which comprises administering an effective amount of a compound represented by general formula (1) or (2), a pharmaceutically acceptable salt thereof, or a prodrug thereof to a patient in need of such prevention and / or treatment.

[0192] The compound represented by general formula (1) or (2), its salt, or prodrug thereof has the effect of preventing and / or treating acute kidney injury (in other words, the effect of alleviating acute kidney injury). The compound represented by general formula (1) or (2), its salt, or prodrug thereof also has the effect of activating autophagy. Therefore, the effect of preventing and / or treating acute kidney injury may be the effect of preventing and / or treating acute kidney injury obtained by activating autophagy. Acute kidney injury may be prerenal, renal, or postrenal. Examples of acute kidney injury include renal ischemia-reperfusion injury in kidney transplantation, prerenal acute kidney injury associated with hypovolemia due to massive bleeding, etc., drug-induced renal acute kidney injury caused by administration of drugs (e.g., anticancer drugs (e.g., platinum-containing preparations), anti-inflammatory drugs, etc.), and postrenal acute kidney injury such as urinary tract obstruction. However, acute kidney injury caused by administration of platinum-containing drugs is particularly preferred. The platinum-containing drug may be a platinum complex chemotherapeutic agent, typified by cisplatin. Platinum-containing drugs include, for example, cisplatin, carboplatin, nedaplatin, and oxaliplatin, with cisplatin and nedaplatin being preferred, and cisplatin being particularly preferred.

[0193] One embodiment of the present invention encompasses an autophagy activator containing a compound represented by general formula (1) or (2), a salt thereof, or a prodrug thereof. The compound represented by general formula (1), a salt thereof, or a prodrug thereof may have an autophagy activating effect, and the compound represented by general formula (2), a salt thereof, or a prodrug thereof may also have an autophagy activating effect due to its similar structure to the compound represented by general formula (1). Therefore, the compound represented by general formula (1) or (2), a salt thereof, or a prodrug thereof is useful as an autophagy activator.

[0194] The compounds represented by general formula (1) or (2), their salts, or prodrugs thereof are also useful as pharmaceutical compositions for preventing and / or treating diseases that can be improved by enhancing autophagy activity, such as aging-related kidney diseases (e.g., renal aging, age-related decline in kidney function, etc.), diabetic kidney disease, obesity-related kidney diseases (e.g., obesity-related tubulopathy, etc.), Parkinson's disease, Huntington's disease, and psoriasis.

[0195] Furthermore, compounds represented by general formula (1) or (2) are not easily metabolized in the liver. Furthermore, they have high PBS solubility, which is advantageous for formulation, and high membrane permeability, which is advantageous in terms of bioavailability. These findings suggest that compounds represented by general formula (1) or (2) have excellent pharmacokinetics. Therefore, compared to conventional autophagy activators or conventional agents for preventing and / or treating kidney damage caused by the administration of platinum-containing drugs, they can exert autophagy activity or prevent and / or treat kidney damage caused by the administration of platinum-containing drugs for a long period of time at low doses.

[0196] The present invention may include a method for activating autophagy, comprising administering to a patient in need of autophagy activation treatment an effective amount of a compound represented by general formula (1) or (2), a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0197] The present invention may include a method for preventing or treating a disease that can be improved by enhancing autophagy activity, comprising administering to a patient in need thereof an effective amount of a compound represented by general formula (1) or (2), a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0198] The present invention may include use of a compound represented by general formula (1) or (2), a pharmaceutically acceptable salt thereof, or a prodrug thereof for the manufacture of an agent for the prevention or treatment of a disease that is ameliorated by enhancing autophagy activity.

[0199] The present invention will be specifically explained below with reference to Reference Examples and Examples, but the present invention is not limited to these.

[0200] [Production Example] According to the method described in Examples 1 to 43 of WO 2021 / 079962, the following: Compounds represented by general formula (1), namely Compound 011, Compound 021, Compound 031, Compound 041, Compound 051, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 181, Compound 191, Compound 201, Compound 211, Compound 221, Compound 231, Compound 241, Compound 251, Compound 261, Compound 271, Compound 281, Compound 291, Compound 301, Compound 311, Compound 321, Compound 331, Compound 341, Compound 351, Compound 361, Compound 371, Compound 381, Compound 391, Compound 401, Compound 411, Compound 421, and Compound 431; Compounds represented by general formula (2), namely Compound 012, Compound 052, Compound 062, Compound 072, Compound 082, Compound 092, Compound 102, Compound 112, Compound 132, Compound 192, Compound 202, Compound 212, Compound 282, Compound 342, Compound 362, Compound 372, and Compound 412, were produced.

[0201] 5-chloro-6-(4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 011), (E)-5-chloro-6-(4-((2-fluoro-6-(trifluoromethyl)phenyl)(hydroxyimino)methyl)piperazin-1-yl)nicotinic acid (Compound 012(E)) and its Z isomer (Compound 012(Z)), 5-chloro-N-methyl-6-(4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinamide (Compound 021), (S)-5-chloro-6-(3-methyl-4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 031) (R)-5-chloro-6-(3-methyl-4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 041), 5-chloro-6-(4-(4-(methoxy)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 051), 5-chloro-6-(4-((2-fluoro-6-methoxyphenyl(hydroxyimino)methyl)piperazin-1-yl)nicotinic acid (Compound 052), 4-chloro-3-(4-(2-chlorophenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 061), (E)-(4-(2-chlorophenyl)piperazin-1-yl)(2,6-dichlorophenyl)methanone oxime (Compound 062(E)) and its Z isomer (Compound 062(Z)). 4-Chloro-3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)benzo[d]isoxazole (Compound 071) (E)-(4-(3-chloropyridin-2-yl)piperazin-1-yl)(2,6-dichlorophenyl)methanone oxime (Compound 072(E)) and its Z isomer (Compound 072(Z)) 5-chloro-6-(4-(4-chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 081) 5-chloro-6-(4-((2,(6-dichlorophenyl)(hydroxyimino)methyl)piperazin-1-yl)nicotinic acid (Compound 082), 5-chloro-6-(4-(4-chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)N,N-dimethylnicotinamide (Compound 091), (E)-5-chloro-6-(4-((2,6-dichlorophenyl)(hydroxyimino)methyl)piperazin-1-yl)-N,N-dimethylnicotinamide (Compound 092(E) and its Z isomer (Compound 092(Z)), 3-chloro-4-(4-(4-chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)benzoic acid (Compound 101), 3-chloro-4-(4-((2,6-dichlorophenyl)(hydroxyimino)methyl)piperazin-1-yl)benzoic acid methyl ester (Compound 102) 5-chloro-3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)benzo[d]isoxazole (Compound 111) (E)-4-(3-chloropyridin-2-yl)piperazin-1-yl)(2,5-dichlorophenyl)methanone oxime (Compound 112(E)) and its Z isomer (Compound 112(Z)) 5-chloro-6-(4-(5-chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 121) 5-chloro-6-(4-(5-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 131) 5-chloro-6-(4-((2-chloro-5-(trifluoromethyl)phenyl)(hydroxyimino)methyl)piperazin-1-yl)nicotinic acid (Compound 132) 3-(4-(pyridin-2-yl)piperazin-1-yl)benzo[d]isoxazole (Compound 141) 3-(4-(2-chlorophenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 151) 3-(4-(2,3-dimethylphenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 161)4-Dichlorophenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 171) 3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)benzo[d]isothiazole (Compound 181) 5-chloro-6-(8-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)-3,8-diazabicyclo[3,2,1]octan-3-yl)nicotinic acid (Compound 191) 5-chloro-6-(8-((2-fluoro-6-(trifluoromethyl)phenyl(hydroxyimino)methyl)-3,8-diazabicyclo[3,2,1]octan-3-yl)nicotinic acid (Compound 192) 7-chloro-3-(4-(2-chlorophenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 201) (E)-(4-(2-chlorophenyl)piperazin-1-yl)(2,3-dichlorophenyl)methanone oxime (Compound 202(E)) and its Z isomer (Compound 202(Z)) 6-chloro-3-(4-(2-chlorophenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 211) (E)-(4-(2-chlorophenyl)piperazin-1-yl)(2,4-Dichlorophenyl)methanone oxime (Compound 212(E)) and its Z isomer (Compound 212(Z)); 5-chloro-6-(4-(4-chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)pyridin-3-yl)(morpholino)methanone (Compound 221); 5-chloro-6-(4-(4-chlorobenzo[d]isoxazol-3-yl)piperazin-1-yl)-N-(methylsulfonyl)nicotinamide (Compound 231); 5-chloro-6-(4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid methyl ester (Compound 241) (5-chloro-6-(4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)pyridin-3-yl)methanol (Compound 251), 3-(4-(3-methylpyridin-2-yl)piperazin-1-yl)-4-(trifluoromethyl)benzo[d]isoxazole (Compound 261), 4-methoxy-3-(4-(2-chlorophenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 271), 1-(1-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 281). 1-(1-((2-fluoro-6-(trifluoromethyl)phenyl(hydroxyimino)methyl)piperidin-4-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (Compound 282) 2-(2-oxo-3-(1-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperidin-4-yl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)acetic acid tert-butyl ester (Compound 291) 2-(2-oxo-3-(1-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperidin-4-yl)-2,3-Dihydro-1H-benzo[d]imidazol-1-yl)acetic acid (Compound 301) 3-(4-(2-chloropyridin-3-yl)piperazin-1-yl)benzo[d]isoxazole (Compound 311) 3-(4-(3-chloropyridin-2-yl)piperazin-1-yl)benzo[d]isoxazole (Compound 321) 3-(4-(3,5-dichlorophenyl)piperazin-1-yl)benzo[d]isoxazole (Compound 331) 5-chloro-6-(1-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperidin-4-yl)methyl nicotinate (Compound 341) 5-chloro-6-(1-((2-fluoro-6-(trifluoromethyl)phenyl)(hydroxyimino)methyl)piperidin-4-yl)methyl nicotinate (Compound 342) 5-chloro-6-(1-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperidin-4-yl)nicotinic acid (Compound 351), 3-(4-(2-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)-4-(trifluoromethyl)benzo[d]isoxazole (Compound 361), E-(4-(2-chlorophenyl)-3,6-dihydropyridin-1(2H)-yl)(2-fluoro-6-(trifluoromethyl)phenyl)methanone oxime (Compound 362(E)) and its Z isomer (Compound 362(Z)), ethyl 5-chloro-6-(2-oxo-4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinate (Compound 371). (Z)-5-chloro-6-(4-((2-fluoro-6-(trifluoromethyl)phenyl)(hydroxyimino)methyl)-2-oxopiperazin-1-yl) ethyl nicotinate (Compound 372(Z)) 5-chloro-6-(2-oxo-4-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)piperazin-1-yl)nicotinic acid (Compound 381) 3-chloro-4-(1-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid methyl ester (Compound 391) 3-chloro-4-(1-(4-(trifluoromethyl)benzo[d]isoxazol-3-yl)-1,2,3,6-tetrahydropyridin-4-yl)benzoic acid methyl ester (Compound 392)Methyl 2,3,6-tetrahydropyridin-4-yl)benzoate (Compound 401), 3-(4-(2-chlorophenyl)piperazin-1-yl)-4-iodobenzo[d]isoxazole (Compound 411), (E)-(4-(2-chlorophenyl)piperazin-1-yl)(2-fluoro-6-iodophenyl)methanone oxime (Compound 412(E)) and its Z isomer (Compound 412(Z)), 3-(4-(2-chlorophenyl)piperazin-1-yl)-4-cyanobenzo[d]isoxazole (Compound 421), 3-(4-(2-chlorophenyl)piperazin-1-yl)benzo[d]isoxazole-4-carboxamide (Compound 431),

[0202] In the following test examples, all quantitative analyses of histological staining were performed by two nephrologists in a blinded manner, evaluating at least 10 high-power fields for each tissue. [Test Example 1] Effect of Compound 011 on Cisplatin-Induced Renal Damage (Test Method) Wild-type male mice were used as test animals. Mice were allowed to freely access water and standard mouse chow. Cisplatin (Sigma-Aldrich) was dissolved in saline at a concentration of 1 mg / mL to prepare a cisplatin solution. Eight-week-old mice were intraperitoneally administered the cisplatin solution at a dose of 15 mg / kg body weight. The control group received an equal volume of saline intraperitoneally. Compound 011 (test compound) was suspended in PBS to prepare a sample solution. The test compound was orally administered at a dose of 10 mg / kg body weight daily for three days, starting the day before cisplatin administration. The control group received an equal volume of PBS orally. Three days after cisplatin administration, the mice were anesthetized and their blood and kidney samples were collected. In addition, mice were treated in the same manner except that they were not administered cisplatin, and their blood and kidney samples were collected. Therefore, the mice were divided into four groups.

[0203] (Histological Analysis) Mice were transcardially perfused with PBS (pH 7.4). The excised kidneys were sliced, post-fixed in 4% PFA (paraformaldehyde), and either embedded in paraffin or frozen in OCT compound to prepare renal cortical sections. Sections from the four groups were stained with Periodic Acid-Schiff (PAS) and observed under a light microscope (400x magnification) (Figure 1). Cisplatin administration revealed significant tubular damage, including necrosis of tubular cells, flattening, dilation, and cast formation of the tubular epithelium (upper right photograph in Figure 1 (cisplatin-treated group)). Administration of the test compound clearly reduced cisplatin-induced renal tubule damage (see the photograph at the bottom right of Figure 1 (cisplatin and test compound administration group)). No clear changes were observed with test compound administration (see the photograph at the bottom left of Figure 1 (test compound administration group)) compared to vehicle administration (see the photograph at the top left of Figure 1 (vehicle administration group)).

[0204] Tubular injury was quantitatively assessed using PAS-stained sections. More specifically, at least 10 high-power fields (200x) were examined for each of the four sections. A 10-point PAS Injury Score (mean) was calculated based on the percentage of damaged tubules. Tubular injury was defined as cell necrosis, tubular dilation, and cast formation. The results are shown in Figure 2. In the bar graph in Figure 2, "Normal saline" refers to the group treated with cisplatin-free saline (vehicle), and "Cisplatin" refers to the group treated with cisplatin-containing saline. This is also true for the bar graphs shown in other figures. While cisplatin significantly increased tubular injury, administration of the test compound clearly reduced it.

[0205] (Biochemical Analysis) Plasma was obtained from blood collected from mice, and creatinine and urea nitrogen concentrations were measured (n = 2–4 per group). Creatinine concentrations were measured using the BioAssay Systems Creatinine Assay Kit (DICT-500), and urea nitrogen concentrations were measured using BUN-test-Wako. The results are shown in Figure 3. In Figure 3, "Normal saline" refers to the group administered saline without cisplatin, and "Cisplatin" refers to the group administered saline containing cisplatin. Also in Figure 3, "Cre" refers to creatinine concentration, and "BUN" refers to serum urea nitrogen concentration. Administration of the test compound normally has little effect on creatinine and serum urea nitrogen concentrations. In contrast, administration of cisplatin significantly increases creatinine and serum urea nitrogen concentrations. However, administration of the test compound clearly inhibited these increases. This confirmed that the test compound can attenuate the decline in renal function caused by cisplatin.

[0206] Experimental Example 2: (1) Effect of Compound 011 on DNA Damage Induced by Cisplatin Administration and (2) Organelle Degradation by Autophagy After Cisplatin Administration (Histological Analysis) Mouse kidneys were harvested as described in Experimental Example 1. The kidneys were autoclaved in 0.01 mmol / L citrate buffer (pH 6.0) at 120°C for 10 minutes for antigen inactivation, blocked with 1.5% bovine serum albumin in PBS for 60 minutes, and then paraffin-embedded and sectioned to prepare four groups of renal cortex section samples. The sections were incubated overnight with primary antibodies against p53 or p62 at 4°C. For each group (n = 2-4), the number of p53-positive cells or p62-positive dots was counted at 200x magnification (p53) or 400x magnification (p62), and the average was calculated. Micrographs using p53 (200x magnification) are shown in Figure 4, the mean number of p53-positive cells is shown in Figure 5, and micrographs using p62 (400x magnification) are shown in Figure 6, with the mean number of p62-positive dots shown in Figure 7. In Figure 4, p53-positive cells are indicated by arrows. In Figure 6, p62-positive dots are circled. p53 is known as a tumor suppressor gene and plays a role in cell cycle arrest, apoptosis, DNA repair, and other processes depending on the degree of cellular stress. The appearance of p53 is considered to indicate severe damage to nuclear DNA. Furthermore, p62 is a substrate selectively degraded by autophagy, and the appearance of p62 indicates a state in which autophagy is unable to sufficiently degrade the substrate, i.e., an autophagy defect. Administration of the test compound significantly reduced the appearance of p53 and p62 levels induced by cisplatin. These results confirmed that administration of the test compound inhibited DNA damage and impaired autophagy.

[0207] Test Example 3: Effect of Compound 011 on Autophagy Flux Test animals were 8-week-old male autophagy monitor mice (GFP-LC3 transgenic mice). Mice were allowed to freely access water and standard mouse chow. Mice were intraperitoneally administered a cisplatin solution at a dose of 15 mg / kg body weight. A sample solution was prepared by suspending the test compound (Compound 011) in PBS. The sample solution was orally administered daily for 3 days, at a dose of 10 mg / kg body weight, starting the day before cisplatin administration. Two days after cisplatin administration, mice were dissected under anesthesia, and kidneys were collected. Six hours before anesthesia, mice were intraperitoneally administered a lysosomal inhibitor, chloroquine solution, at 50 μg / g body weight. A separate group was also prepared without chloroquine solution. Chloroquine solution was prepared by dissolving chloroquine (Sigma-Aldrich) in distilled water at a concentration of 5 mg / mL. (Histological Analysis) Autophagy flux was assessed by quantifying GFP-LC3 dots (GFP-positive dots). Kidney sections were immunostained for LRP2 / MEGALIN, a marker for proximal tubule cells (red), and counterstained with DAPI (blue). The number of GFP-LC3 dots (green) per proximal tubule in each group (n = 5) was quantified in 10 high-magnification fields (600x) and evaluated as the average. Micrographs of the sections (2400x magnification) are shown in Figure 8, and the number of GFP-LC3 dots is shown in Figure 9. The green color in the micrographs reflects autophagosomes that have not been degraded within the cells.

[0208] LC3 is a protein that binds to the autophagosomal membrane. The steady-state appearance of LC3 dots (autophagosomes with LC3-bound membranes) in renal tubules is low. The number of LC3 dots increases when autophagy is induced by various stresses. It has generally been recognized that an increase in GFP-LC3 dots in GFP-LC3 transgenic mice indicates an increase in autophagosomes and thus activation of autophagy. However, accurate methods for assessing autophagy activity in disease pathology remain complex, and careful interpretation is required. For example, an increase in the number of autophagosomes or LC3 does not necessarily indicate activation of autophagy; it may indicate a blockage (bottleneck) in a later step of autophagy, such as dysfunction of the lysosome, the site of substrate degradation.

[0209] To address this issue, we previously established a method for assessing autophagy activity by administering the lysosomal inhibitor chloroquine and comparing the number of GFP-LC3 dots with and without administration (Non-Patent Documents 5-7). Specifically, administration of chloroquine to mice with high autophagy activity significantly increased the number of GFP-LC3 dots. In contrast, administration of chloroquine to mice with low or stagnant autophagy activity did not increase the number of GFP-LC3 dots compared to before administration. Cisplatin administration of GFP-LC3 transgenic mice resulted in numerous GFP-LC3 dots (increased autophagosomes) (Figure 8, upper left). However, administration of chloroquine on the second day after cisplatin administration did not result in an increase in GFP-LC3 dots (Figure 8, lower left). This indicates that although autophagy was induced by cisplatin administration, autophagic flux had already stagnated. Meanwhile, in the test compound-treated group (Figure 8, upper right), the number of GFP-LC3 dots decreased two days after cisplatin administration. This suggests that the blockage of autophagic flux had been relieved. In fact, the number of GFP-LC3 dots significantly increased in the test compound and chloroquine-treated groups (Figure 8, bottom right), indicating that the blockage of autophagic flux had been relieved and autophagy had been enhanced. These findings confirm that administration of the test compound relieved the blockage of autophagic flux caused by cisplatin and enhanced autophagy.

[0210] [Test Example 4] Effect of Compound 011 on Autophagy Activity in Lung Tumor Cells (Western Blotting) Human lung tumor cells, A549 cells (1.0 × 10 5Cells (cells / well) were seeded and cultured for 1 day. The cells were then washed with PBS. DMEM media containing Bafilomycin A1 (final concentration 250 nM; also referred to as Baf) (Baf(+)) and without Bafilomycin A1 (Baf(-)) were prepared. Additionally, Baf-containing DMEM media containing DMSO or Compound 011 (test compound) and Baf-free DMEM media containing DMSO or Compound 011 (test compound) were also prepared, for a total of six media types. The final DMSO concentration was 0.1%, and the final test compound concentration was 10 μM. Baf-containing Earle's Balanced Salt Solution (EBSS; starvation) and Baf-free EBSS were also prepared. After washing, 3 mL of one of the six media types or two EBSS types was added to each well and cultured for 6 hours. After washing the cells three times with PBS, RIPA buffer was added at 4°C and the cells were incubated on ice for 30 minutes. The cells were then quickly and carefully harvested from the wells. After harvesting, the cells were centrifuged (15,000 rpm, 4°C, 30 minutes) and the supernatant was collected to prepare the protein solution. The protein solution was denatured with sample buffer, electrophoresed on a 15% polyacrylamide gel, and transferred to a nitrocellulose membrane. Blocking was performed with blocking buffer. Primary antibodies used were anti-LC3 (1:1000 dilution) and anti-β-actin (1:10,000 dilution), and secondary antibodies were anti-rabbit (1:2000 dilution) and anti-mouse (1:2000 dilution). Detection was performed using ELC Western Blotting Detection Reagents (Amersham Bioscience). Image J was used for analysis.

[0211] The electrophoresis results are shown in Figure 10. In Figure 10, "nutrient" refers to the DMEM medium group without DMSO or test compound, "DMSO" refers to the DMEM medium group containing DMSO, "starvation" refers to the EBSS group, and "011" refers to the test compound group. The LC3-II protein levels (luminescence intensity) for each group are shown in Figure 11. Figure 12 also shows the difference (Δ) between the protein levels with Baf treatment and those without Baf treatment for each group. LC3-II protein is a marker of autophagy and increases upon autophagy induction. A portion of the increased LC3-II is degraded during autophagy. Baf inhibits this degradation. Therefore, the increase in LC3-II levels with Baf treatment compared to those without Baf treatment can be used to assess the degree of autophagy enhancement. As shown in Figure 12, the test compound significantly increased LC3-II levels with Baf treatment, comparable to those observed with starvation, confirming its autophagy-inducing effect.

[0212] It has been observed or reported that autophagy flux stagnation occurs in acute kidney injury caused by renal ischemia-reperfusion injury, unilateral urinary tract ligation (urinary tract obstruction), and other conditions, despite autophagy being protective. Furthermore, the test compounds were confirmed to have autophagy-enhancing effects in the present test examples. Based on these findings, the test compounds are expected to be effective in treating acute kidney injury.

Claims

1. General formula (1) 【Chemical 1】 [wherein,[ A is a benzene ring which may be substituted with at least one group selected from the group consisting of halogen and lower alkyl substituted with halogen. B is a pyridyl which may be substituted with at least one group selected from the group consisting of halogen and carboxyl. X is an oxygen atom. Y is a nitrogen atom. 【Chemical 2】 R １ is independently a lower alkyl or two Rs １ may be bonded to each other to form a spiro ring or a crosslinked structure. p is 0, 1, or 2.] A pharmaceutical composition for preventing and / or treating acute kidney injury, containing the compound represented by the formula or a salt thereof.

2. The pharmaceutical composition according to Claim 1, wherein the 4-position of the benzisoxazole skeleton is substituted in general formula (1).

3. In general formula (1), B is a pyridyl substituted with at least one group selected from the group consisting of halogen and carboxyl, and at least the carbon atom in the ortho position to the carbon atom on the pyridine ring bonded to Y is substituted. The pharmaceutical composition according to Claim 1.

4. The compound represented by general formula (1) is a compound represented by general formula (1A) [Chemical Formula 3] [wherein,[ Z is a nitrogen atom. Y is a nitrogen atom. 【Chemical 4】 R １１ is, independently of one another, methyl or ethyl, or two R １１ groups may be bonded to each other to form a crosslinked structure with methylene, dimethylene, or trimethylene. p is 0, 1, or 2. R ２１ , R ２２ , and R ２３ are, independently of one another, a hydrogen atom, a halogen, or trifluoromethyl. R ３１ , R ３２ , and R ３３ are, independently of one another, a hydrogen atom, a halogen, or a carboxyl.] is a compound represented by The pharmaceutical composition according to Claim 1.

5. In general formula (1A), R ２１ is a chlorine atom or trifluoromethyl, and R ２２ and R ２３ are hydrogen atoms, R ３１ is a chlorine atom, R ３２ is a hydrogen atom, R ３３ is carboxyl, The pharmaceutical composition according to Claim 4.

6. The pharmaceutical composition according to Claim 1, wherein the compound represented by the general formula (1) is Compound 011 or Compound 191 represented by the following structure. 【Chemical Formula 5】

7. The pharmaceutical composition according to Claim 1, wherein the compound represented by the general formula (1) is Compound 011 represented by the following structure. 【Chemical Formula 6】

8. The pharmaceutical composition according to any one of Claims 1 to 7, which is for oral administration.

9. The pharmaceutical composition according to any one of Claims 1 to 7, wherein the acute kidney injury is kidney injury caused by administration of a platinum-containing agent.

10. The pharmaceutical composition according to Claim 9, wherein the platinum-containing agent is cisplatin.

11. General formula (1) [Chemical Formula 7] [wherein,[ A is a benzene ring which may be substituted with at least one group selected from the group consisting of halogen and lower alkyl substituted with halogen. B is a pyridyl which may be substituted with at least one group selected from the group consisting of halogen and carboxyl. X is an oxygen atom. Y is a nitrogen atom. 【Chemical Formula 8】 R １ is independently lower alkyl or two R's １ may be bonded to each other to form a spiro ring or a crosslinked structure. p is 0, 1, or 2.] An autophagy activator containing the compound represented by the formula or a salt thereof.

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