JP2005336172A - Medicine for treating or preventing renal ischemic reperfusion disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine having an excellent treating or preventing effect on a renal ischemic reperfusion disorder. <P>SOLUTION: The medicine for treating or preventing a renal ischemic reperfusion disorder comprises as an active ingredient a compound represented by formula (I) [wherein R is a nitrogen-containing non-aromatic-heterocyclic group which may be substituted or a like group; A is a linear or branched alkylene group which may be substituted and may contain a double bond or the like in the chain or a like group; X is an oxygen atom or the like; M is an arylene group or the like; R<SP>1</SP>, R<SP>2</SP>, R<SP>3</SP>, and R<SP>4</SP>are each a hydrogen atom, a hydroxy group, or the like; R<SP>5</SP>is a hydrogen atom or the like; m is 0 or an integer of 1 to 6; R<SP>6</SP>is an aryl group which may be substituted or the like; and R<SP>7</SP>is -CO(Y)<SB>p</SB>R<SP>12</SP>(wherein Y is an oxygen atom or the like; p is 0 or 1; and R<SP>12</SP>is a hydrogen atom, an alkyl group which may be substituted with e.g. a hydroxy group or the like)] or a pharmacologically acceptable acid addition salt. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a therapeutic or prophylactic agent for renal ischemia-reperfusion injury. More specifically, renal ischemia / reperfusion comprising a compound represented by the following formula (I) having a cytokine production inhibitory action or a pharmacologically acceptable acid addition salt thereof as an active ingredient: It relates to a therapeutic or prophylactic agent for disorders.

  Acute renal failure is a syndrome that causes a rapid decline in renal function, and a marked increase in blood urea nitrogen (BUN) and serum creatinine (Cr) is observed as clinical findings. Such acute renal failure often occurs after resumption of blood flow from ischemic conditions such as renal shock or renal transplantation due to renal ischemia-reperfusion, for example, reduced heart blood flow or decreased renal blood flow due to bleeding Caused by disability, it is a major clinical problem. In renal ischemia-reperfusion injury, in addition to hypoxic injury, ATP reduction causes mitochondrial dysfunction and extracellular sodium, calcium and reactive oxygen species accumulation, followed by proteases, NO synthase, phospholipases, Enzyme systems such as endonucleases are activated and eventually lead to cell death. In addition, complements, cytokines, and chemokines (chemotactic cytokines) are activated and become not only cytotoxic themselves, but also attract leukocytes to the ischemic site, causing further damage, and even vascular endothelium. It is known that cell damage prolongs the ischemic state and causes further infiltration of stasis, edema and inflammatory cells (see Non-Patent Document 1).

As mentioned above, inflammatory response is caused as an important process in renal ischemia-reperfusion injury, but cytokines and chemokines produced by renal tubular epithelial cells and infiltrated inflammatory cells are important factors in the inflammatory response. It has been known. For example, renal tubular epithelial cells include TNF-α (tumor necrosis factor-α), IL-1 (interleukin-1), MCP-1 (monocyte chemoattractant protein-1), IL-8, and PDGF (platelet-derived growth). factor), endothelin-1, VEGF (vascular endothelial growth factor), and other cytokines and chemokines, which in renal disorders, such as adhesion of inflammatory cells to endothelial cells and migration to damaged sites It has become clear that it plays an important role (see Non-Patent Document 2).
Therefore, in the kidney that caused ischemia-reperfusion injury, it may be possible to protect the kidney from ischemia-reperfusion injury by suppressing the action or production of cytokines. The present condition is that the treatment and prevention method of the renal ischemia reperfusion injury by inhibiting has not been established.

Patent Documents 1 and 2 describe amide compounds that strongly inhibit the production of inflammatory cytokines such as IL-8, IL-1, IL-6, TNF-α and granulocyte macrophage colony stimulating factor (GM-CSF). Although it is disclosed that it is effective for the prevention and treatment of inflammatory diseases, the effect of the amide compound on renal ischemia-reperfusion injury is not described.
US Pat. No. 6,174,887 International Publication No. 97/08133 Pamphlet “Life Sciences” (Netherlands), 2003, Vol. 74, p. 543-552. “Drug News & Perspectives” (Spain), 2003, Vol. 15, No. 8, p. 477-482.

  An object of the present invention is to provide a medicament exhibiting an excellent therapeutic or preventive effect on ischemia-reperfusion injury of the kidney.

As a result of intensive studies to achieve the above object, the present inventors have surprisingly found that the following compounds having a cytokine production inhibitory activity or pharmacologically acceptable acid addition salts thereof are excellent for renal ischemia-reperfusion injury. The present inventors have found that the present invention exhibits a therapeutic or preventive effect, and have completed the present invention.
That is, the present invention is as follows.
[1] Formula (I)

Substituted with or R _a; where [wherein, R is unsubstituted or optionally nitrogen-containing optionally a non-aromatic heterocyclic group; a hydroxyl group; R _a; alkoxy group substituted with R _a; alkylthio group substituted with R _a An alkylamino group [wherein R _a is an amino group, a guanidino group, an amidino group, a carbamoyl group, a ureido group, a thioureido group, a hydrazino group, a hydrazinocarbonyl group or an imino group (these groups are a lower alkyl group, a halogen atom, An optionally substituted lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group and an amino protecting group, which may be substituted with a substituent.
A represents a linear or branched alkylene group which may be substituted and may have one or more double bonds or triple bonds in the chain; or represents a single bond;
X is an oxygen atom; a sulfur atom; a cycloalkylene group; a divalent aromatic heterocyclic group having 1 or 2 or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom; _{SO 2 -; - C = C} -; - C≡C -; - CO -; - COO -; - OOC -; - CS -; - COS -; - O-COO -; - NH-CO-NH ——— NH—CS—NH—; —NH—C (═NH) —NH—; —NR ⁸ —; —NR ⁸ CO—; —CONR ⁸ —; —NR ⁸ SO ₂ —; —SO ₂ NR ^{8 -; - NR 8 -COO -;} - OOC-NR 8 -; or ^-CR 9 ^{R 10} - [wherein, ^{R 8} is a hydrogen atom; an alkyl group; a cycloalkyl group; an aryl group; an aralkyl group; or an amino protecting group are shown, ^{R 9} and ^{R 10} are the same or different, a hydrogen atom; an alkyl group; Shows the shows or aralkyl group]; a cycloalkyl group; an aryl group;
M is an arylene group; a cycloalkylene group; or a divalent heterocyclic ring having one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and may form a condensed ring Indicate a group;
R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom (provided that at least one of R ¹ , R ² , R ³ and R ⁴ is not a hydrogen atom); a hydroxyl group; a halogen atom An alkoxy group, a mercapto group, an alkylthio group, a nitro group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, and a halogen atom. An optionally substituted alkyl group; an amino group optionally substituted with a substituent selected from the group consisting of an alkyl group, an aryl group, an aralkyl group and an amino protecting group; or —O—CO—R ¹¹ [where R ¹¹ is an optionally substituted alkoxy group; an optionally substituted aryl group; an optionally substituted cycloalkyl group; Aryloxy group which may be substituted; aralkyloxy group which may be substituted; alkylthio group which may be substituted; arylthio group which may be substituted; or alkoxycarbonyl group, acyloxy group, aryl group, aryl Oxy group, aryloxycarbonyl group, aralkyloxy group, aralkyloxycarbonyl group, alkylthio group, arylthio group, acyl group, lower alkoxy group, carboxyl group, halogen atom, and optionally substituted with lower alkyl group or acyl group An alkyl group that may be substituted with a substituent selected from the group consisting of amino groups. ]
R ⁵ represents a hydrogen atom; an alkyl group that may be substituted with a halogen atom; an aralkyl group that may be substituted; or an amino protecting group;
m represents 0 or an integer selected from 1 to 6;
R ⁶ represents an optionally substituted aryl group; an optionally substituted cycloalkyl group; an optionally substituted lower alkyl group; an optionally substituted lower alkoxy group; an optionally substituted lower alkylthio A group; an amino group which may be substituted with a substituent selected from the group consisting of a lower alkyl group, an aryl group, an aralkyl group and an amino protecting group; or a nitrogen atom, a sulfur atom and an oxygen atom which may be substituted; A heterocyclic group having one or more heteroatoms selected from the group consisting of:
R ⁷ represents a hydrogen atom; an optionally substituted alkyl group; an optionally substituted aryl group; an optionally substituted one or two selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom An aromatic heterocyclic group having the above hetero atom; or —CO (Y) _P R ¹² [where Y is an oxygen atom; sulfur atom; —NR ¹³ —; or —NR ¹³ —SO ₂ — (R ¹³ is An alkyl group; an aralkyl group; a hydroxyl group; an alkoxy group; an aryl group; or an amino protecting group.), P represents 0 or 1, R ¹² represents a hydrogen atom; an optionally substituted alkenyl group. An optionally substituted alkynyl group; an optionally substituted cycloalkyl group; an optionally substituted aryl group; an optionally substituted aralkyl group; an adamantyl group; a cycloalkylyl group; A denamino group; a heterocyclic group which may be substituted and has one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom; or a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxy group A heterocyclic group having one or more heteroatoms selected from the group consisting of a carbonyl group, an acyloxy group, a carboxyl group, a nitrogen atom, a sulfur atom and an oxygen atom, and an amino group (the amino group is an alkyl group, an aryl group, An alkyl group which may be substituted with a substituent selected from the group consisting of a group selected from the group consisting of a group, an aralkyl group and an amino protecting group. ] Is shown. Or a pharmacologically acceptable acid addition salt thereof [hereinafter these are also referred to as compound (I). ] As an active ingredient, a therapeutic or prophylactic agent for renal ischemia-reperfusion injury.

[2] Piperazinyl group optionally substituted with a lower alkyl group, R piperidyl group or amino group optionally substituted with a lower alkyl group (the amino group may be substituted with a lower alkyl group) Is;
A is a linear alkylene group;
X is an oxygen atom, a sulfur atom, —NH— or —CH ₂ —;
M is an arylene group;
R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom (provided that at least one of R ¹ , R ² , R ³ and R ⁴ is not a hydrogen atom); a hydroxyl group; a halogen An atom or —O—CO—R ¹¹ ′ (wherein R ¹¹ ′ is a lower alkyl group which may be substituted with a substituent selected from the group consisting of an amino group, an acyloxy group and a benzyloxycarbonyl group; or a lower alkyl group Represents a phenyl group which may be substituted with
R ⁵ is a hydrogen atom;
m is 1;
R ⁶ is a phenyl group;
R ⁷ is —COO—R ¹² ′ (where R ¹² ′ is a hydrogen atom; an aralkyl group; an adamantyl group; a cycloalkylideneamino group; a cyclohexyl group which may be substituted with a lower alkyl group; a substituted with a lower alkyl group; An optionally substituted piperidyl group; a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, a piperazinyl group and an amino group optionally substituted by a lower alkyl group The therapeutic or prophylactic agent according to the above-mentioned [1], which is an alkyl group which may be substituted with.

[3] Compound (I) is converted to (−)-ethyl N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} -L-phenyl The therapeutic or prophylactic agent according to [1] above, which is alaninate or a pharmacologically acceptable acid addition salt thereof.
[4] Compound (I) is converted to (−)-ethyl N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} -L-phenyl The therapeutic or prophylactic agent according to [1] above, which is alaninate dihydrochloride.
[5] The therapeutic or prophylactic agent according to any one of [1] to [4] above, wherein the compound (I) has an inhibitory action on inflammatory cytokine production.
[6] The treatment according to [5] above, wherein the inflammatory cytokine is tumor necrosis factor (TNF) -α, IL-6, IL-8, CINC-1 (Cytokine-induced neutrophil chemoattractant-1) or a combination thereof. Or prophylactic drugs.
[7] The therapeutic or prophylactic agent according to any one of [1] to [6] above, which is a dosage form of an intravenous injection preparation.

  Compound (I) suppresses renal damage by inhibiting the production of inflammatory cytokines such as TNF-α, IL-6, IL-8, CINC-1 and the like produced at the site of ischemia-reperfusion injury in the kidney. Improve. Therefore, the agent of the present invention containing Compound (I) is an excellent therapeutic or preventive agent for renal ischemia-reperfusion injury.

Hereinafter, the present invention will be described in detail.
The therapeutic or prophylactic agent for renal ischemia-reperfusion injury of the present invention contains compound (I) as an active ingredient. Compound (I) can be produced by the method described in Patent Document 1 or 2.

In formula (I), R, the nitrogen may be substituted containing non-aromatic heterocyclic group; a hydroxyl group; R _a; alkoxy group substituted with R _a; alkylthio group substituted with R _a; or R _a Wherein R _a is an amino group, a guanidino group, an amidino group, a carbamoyl group, a ureido group, a thioureido group, a hydrazino group, a hydrazinocarbonyl group, or an imino group (these groups are lower alkyl Group, a halogenated lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group and an amino protecting group, which may be substituted with a substituent selected from the group consisting of A piperazinyl group which may be substituted, a piperidyl group which may be substituted with a lower alkyl group, an amide which may be substituted with a lower alkyl group Is an amino group.

  A represents a linear or branched alkylene group which may be substituted and may have one or more double bonds or triple bonds in the chain; or represents a single bond, An alkylene group of the chain.

X is an oxygen atom; a sulfur atom; a cycloalkylene group; a divalent aromatic heterocyclic group having 1 or 2 or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom; _{SO 2 -; - C = C} -; - C≡C -; - CO -; - COO -; - OOC -; - CS -; - COS -; - O-COO -; - NH-CO-NH ——— NH—CS—NH—; —NH—C (═NH) —NH—; —NR ⁸ —; —NR ⁸ CO—; —CONR ⁸ —; —NR ⁸ SO ₂ —; —SO ₂ NR ^{8 -; - NR 8 -COO -;} - OOC-NR 8 -; or ^-CR 9 ^{R 10} - [wherein, ^{R 8} is a hydrogen atom; an alkyl group; a cycloalkyl group; an aryl group; an aralkyl group; or an amino protecting group R ⁹ and R ¹⁰ are the same or different and each represents a hydrogen atom; an alkyl group; Represents an alkyl group; an aryl group; or an aralkyl group], preferably an oxygen atom, a sulfur atom, —NH— or —CH ₂ —.

  M is an arylene group; a cycloalkylene group; or a divalent heterocyclic ring having one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and may form a condensed ring Represents an arylene group.

R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom (provided that at least one of R ¹ , R ² , R ³ and R ⁴ is not a hydrogen atom); a hydroxyl group; a halogen atom An alkoxy group, a mercapto group, an alkylthio group, a nitro group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, and a halogen atom. An optionally substituted alkyl group; an amino group optionally substituted with a substituent selected from an alkyl group, an aryl group, an aralkyl group and an amino protecting group; or —O—CO—R ¹¹ wherein R ¹¹ is a substituted group; An optionally substituted alkoxy group; an optionally substituted aryl group; an optionally substituted cycloalkyl group; An optionally substituted aryloxy group; an optionally substituted aralkyloxy group; an optionally substituted alkylthio group; an optionally substituted arylthio group; or an alkoxycarbonyl group, an acyloxy group, an aryl group, an aryloxy group, From an aryloxycarbonyl group, an aralkyloxy group, an aralkyloxycarbonyl group, an alkylthio group, an arylthio group, an acyl group, a lower alkoxy group, a carboxyl group, a halogen atom, and an amino group optionally substituted with a lower alkyl group or an acyl group An alkyl group which may be substituted with a substituent selected from the group consisting of And preferably a hydrogen atom (provided that at least one of R ¹ , R ² , R ³ and R ⁴ is not a hydrogen atom); a hydroxyl group; a halogen atom; or —O—CO—R ¹¹ ′ [ Here, R ¹¹ ′ represents a lower alkyl group which may be substituted with a substituent selected from the group consisting of an amino group, an acyloxy group and a benzyloxycarbonyl group; a phenyl group which may be substituted with a lower alkyl group . ].

R ⁵ represents a hydrogen atom; an alkyl group which may be substituted with a halogen atom; an aralkyl group which may be substituted; or an amino protecting group, and preferably a hydrogen atom.

  m represents an integer selected from 0 or 1 to 6, and is preferably 1.

R ⁶ represents an optionally substituted aryl group; an optionally substituted cycloalkyl group; an optionally substituted lower alkyl group; an optionally substituted lower alkoxy group; an optionally substituted lower alkylthio A group; an amino group which may be substituted with a substituent selected from the group consisting of a lower alkyl group, an aryl group, an aralkyl group and an amino protecting group; or a nitrogen atom, a sulfur atom and an oxygen atom which may be substituted; Represents a heterocyclic group having 1 or 2 or more heteroatoms selected from the group consisting of, preferably a phenyl group.

R ⁷ represents a hydrogen atom; an optionally substituted alkyl group; an optionally substituted aryl group; an optionally substituted one or two selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom An aromatic heterocyclic group having the above hetero atom; or —CO (Y) _p R ¹² [where Y is an oxygen atom; sulfur atom; —NR ¹³ —; or —NR ¹³ —SO ₂ — (R ¹³ is An alkyl group; an aralkyl group; a hydroxyl group; an alkoxy group; an aryl group; or an amino protecting group.), P represents 0 or 1, R ¹² represents a hydrogen atom; an optionally substituted alkenyl group. An optionally substituted alkynyl group; an optionally substituted cycloalkyl group; an optionally substituted aryl group; an optionally substituted aralkyl group; an adamantyl group; a cycloalkylyl group; A denamino group; a heterocyclic group which may be substituted and has one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom; or a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxy group A heterocyclic group having one or more heteroatoms selected from the group consisting of a carbonyl group, an acyloxy group, a carboxyl group, a nitrogen atom, a sulfur atom and an oxygen atom, and an amino group (the amino group is an alkyl group, an aryl group, An alkyl group which may be substituted with a substituent selected from the group consisting of a group selected from the group consisting of a group, an aralkyl group and an amino protecting group. -COO-R ¹² ′ [wherein R ¹² ′ represents a hydrogen atom; an aralkyl group; an adamantyl group; a cycloalkylideneamino group; a cyclohexyl group optionally substituted with a lower alkyl group; a lower alkyl group; An optionally substituted piperidyl group; a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, a piperazinyl group, and an amino group optionally substituted with a lower alkyl group The alkyl group which may be substituted by group is shown. ].

“Alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, sec -Butoxy group, tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, isohexyloxy group, neohexyloxy group and the like. Preferred is a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert- It is a butoxy group. The “alkoxy group” of the alkoxy group substituted by R ^a in R is preferably a linear alkoxy group such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a pentyloxy group, a hexyloxy group, and more particularly a methoxy group A straight-chain alkoxy group having 1 to 4 carbon atoms such as a group, an ethoxy group, a propoxy group, or a butoxy group is preferable.

  The “lower alkoxy group” means a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, Examples thereof include a sec-butoxy group and a tert-butoxy group. A methoxy group and an ethoxy group are preferable.

The “alkylthio group” means a linear or branched alkylthio group having 1 to 6 carbon atoms, specifically a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, an isobutylthio group, Examples include sec-butylthio group, tert-butylthio group, pentylthio group, isopentylthio group, neopentylthio group, tert-pentylthio group, hexylthio group, isohexylthio group, neohexylthio group and the like. The “alkylthio group” of the alkylthio group substituted by R ^a of R is preferably a linear alkylthio group such as a methylthio group, an ethylthio group, a propylthio group, a butylthio group, a pentylthio group, a hexylthio group, particularly a methylthio group, A linear alkylthio group having 1 to 4 carbon atoms such as an ethylthio group, a propylthio group and a butylthio group is preferred.

  The “lower alkylthio group” means a linear or branched alkylthio group having 1 to 4 carbon atoms, specifically, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group. , Sec-butylthio group, tert-butylthio group and the like.

  “Alkylamino group” means a linear or branched monoalkylamino group or dialkylamino having 1 to 6 carbon atoms, specifically, methylamino group, dimethylamino group, ethylamino group, diethylamino group. , Methylethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, sec-butylamino group, tert-butylamino group, pentylamino group, isopentylamino group, neopentylamino group, tert- A pentylamino group, a hexylamino group, an isohexylamino group, a neohexylamino group, etc. are mentioned, preferably a methylamino group, a dimethylamino group, an ethylamino group, a diethylamino group, a propylamino group, a butylamino group, a pentylamino group. A straight-chain alkyl group such as a hexylamino group Is an amino group. Particularly preferred are straight-chain alkylamino groups having 1 to 4 carbon atoms, specifically, methylamino group, dimethylamino group, ethylamino group, diethylamino group, propylamino group, butylamino group and the like.

  “Nitrogen-containing non-aromatic heterocyclic group” means a 3- to 7-membered non-aromatic heterocyclic group having at least one nitrogen atom and optionally having a sulfur atom or an oxygen atom, These may be condensed with a benzene ring. Specifically, aziridinyl group, thiazetidinyl group, azetidinyl group, pyrrolidinyl group, pyrrolinyl group, imidazolidinyl group, imidazolinyl group, pyrazolidinyl group, pyrazolinyl group, morpholinyl group, morpholino group, oxazinyl group, thiazinyl group, piperidinyl group, piperidyl group, piperidyl group Group, dioxazepinyl group, thiazepinyl group, diazepinyl group, perhydrodiazepinyl group, azepinyl group, perhydroazepinyl group, indolinyl group, isoindolinyl group and the like. Preferred are aziridinyl group, azetidinyl group, pyrrolidinyl group, pyrazolidinyl group, morpholinyl group, morpholino group, piperazinyl group, piperidyl group, piperidino group, perhydroazepinyl group, particularly preferably pyrrolidinyl group, morpholino group, piperazinyl group, A piperidyl group and a piperidino group;

  “Alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec- Examples thereof include a butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a tert-pentyl group, a hexyl group, an isohexyl group, and a neohexyl group.

  The “lower alkyl group” means a linear or branched alkyl group having 1 to 4 carbon atoms, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec -A butyl group, a tert- butyl group, etc. are mentioned.

  The “halogen atom” is specifically a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

  The “halogenated lower alkyl group” is a group in which a halogen atom is substituted on the above lower alkyl group. Specifically, fluoromethyl group, chloromethyl group, bromomethyl group, difluoromethyl group, dichloromethyl group, trifluoromethyl group, trichloromethyl group, difluoroethyl group, dichloroethyl group, pentatrifluoroethyl group, trichloroethyl group, A fluoropropyl group etc. are mentioned, Preferably they are a fluoromethyl group, a chloromethyl group, a difluoromethyl group, a dichloromethyl group, and a trifluoromethyl group.

  “Cycloalkyl group” means a cycloalkyl group having 3 to 7 carbon atoms, and specifically includes a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and the like, preferably a cyclopentyl group Or a cycloalkyl group having 5 or 6 carbon atoms such as a cyclohexyl group.

  The “aralkyl group” is a group in which the above-described alkyl group is substituted with the aryl group described below, and specifically includes a benzyl group, a benzhydryl group, a trityl group, a phenethyl group, a 3-phenylpropyl group, and a 2-phenylpropyl group. Group, 4-phenylbutyl group, naphthylmethyl group and the like, and benzyl group and phenethyl group are preferable.

  The “aralkyloxy group” is an aralkyloxy group having the above-mentioned aralkyl group, specifically, a benzyloxy group, a benzhydryloxy group, a trityloxy group, a phenethyloxy group, a 3-phenylpropyloxy group, 2 -Phenylpropyloxy group, 4-phenylbutyloxy group, naphthylmethoxy group, etc. are mentioned. A benzyloxy group and a phenethyloxy group are preferred.

  The “aralkyloxycarbonyl group” is an aralkyloxycarbonyl group having the above-mentioned aralkyl group, specifically, a benzyloxycarbonyl group, a benzhydryloxycarbonyl group, a trityloxycarbonyl group, a phenethyloxycarbonyl group, 3- Examples thereof include a phenylpropyloxycarbonyl group, a 2-phenylpropyloxycarbonyl group, a 4-phenylbutyloxycarbonyl group, and a naphthylmethoxycarbonyl group. A benzyloxycarbonyl group and a phenethyloxycarbonyl group are preferred.

The “aryl group” means a phenyl group, a naphthyl group, an anthryl group, a phenanthryl group, a biphenyl group, and the like, preferably a phenyl group or a naphthyl group.
The “aryloxy group” is an aryloxy group having the above aryl group, and specific examples thereof include a phenoxy group and a naphthyloxy group.

  The “aryloxycarbonyl group” is an aryloxycarbonyl group having the above aryl group, and specific examples include a phenoxycarbonyl group and a naphthyloxycarbonyl group.

  The “arylthio group” is an arylthio group having the above aryl group, and specific examples include a phenylthio group and a naphthylthio group.

  The “amino protecting group” is a commonly used protecting group and is not particularly limited as long as it protects the amino group from various reactions. Specifically, an acyl group (for example, formyl group, acetyl group, propionyl group, butyryl group, oxalyl group, succinyl group, pivaloyl group, 2-chloroacetyl group, 2-bromoacetyl group, 2-iodoacetyl group, 2 , 2-dichloroacetyl group, 2,2,2-trichloroacetyl group, 2,2,2-trifluoroacetyl group, phenylacetyl group, phenoxyacetyl group, benzoyl group, 4-chlorobenzoyl group, 4-methoxybenzoyl group 4-nitrobenzoyl group, naphthylcarbonyl group, adamantylcarbonyl group, phthaloyl group, etc.); alkoxycarbonyl group (for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, pentyl) Oxycarboni Group, isopentyloxycarbonyl group, cyclohexyloxycarbonyl group, 2-chloroethoxycarbonyl group, 2-iodoethoxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group, 2,2,2-trichloro-tert-butoxycarbonyl Group, benzhydryloxycarbonyl group, bis- (4-methoxyphenyl) methoxycarbonyl group, phenacyloxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-triphenylsilylethoxycarbonyl group, fluorenyl-9-methoxycarbonyl group Alkenyloxycarbonyl group (for example, vinyloxycarbonyl group, 2-propenyloxycarbonyl group, 2-chloro-2-propenyloxycarbonyl group, 3-methoxycarbonyl-2-propenyl group) Cicarbonyl group, 2-methyl-2-propenyloxycarbonyl group, 2-butenyloxycarbonyl group, cinnamyloxycarbonyl group, etc.); Aralkyloxycarbonyl group (eg, benzyloxycarbonyl group, 4-bromobenzyloxycarbonyl group) 2-chlorobenzyloxycarbonyl group, 3-chlorobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 2-nitrobenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group 2-nitro-4,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyloxycarbonyl group, phenethyloxycarbonyl group, etc.); lower alkylsilyl group (for example, trimethylsilyl group, t ert-butyldimethylsilyl group); alkylene bis (dialkylsilyl) group (for example, ethylene bis (dimethylsilyl) group, propylene bis (dimethylsilyl) group, ethylene bis (diethylsilyl) group, etc.); alkylthiocarbonyl group (for example, , Methylthiocarbonyl group, ethylthiocarbonyl group, butylthiocarbonyl group, tert-butylthiocarbonyl group, etc.); aralkylthiocarbonyl group (for example, benzylthiocarbonyl group, etc.); phosphoryl group (for example, dicyclohexylphosphoryl group, diphenylphosphoryl group) , Dibenzylphosphoryl group, di- (4-nitrobenzyl) phosphoryl group, phenoxyphenylphosphoryl group, etc.); phosphinyl groups (for example, diethylphosphinyl group, diphenylphosphinyl group, etc.) and the like.

  "The linear or branched alkylene group which may have 1 or 2 or more double bonds or triple bonds in the chain" means a linear or branched chain having 1 to 10 carbon atoms. It means an alkylene group which may have one or more double bonds or triple bonds, specifically methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, hepta. Methylene, octamethylene, nonamethylene, decamethylene, dimethylmethylene, diethylmethylene, propylene, methylethylene, ethylethylene, propylethylene, isopropylethylene, methylpentaethylene, ethylhexamethylene, Dimethylethylene group, methyltriethylene group, dimethyltrimethylene group, vinylene group, propenylene group, butenile Group, butadienylene group, pentenylene group, pentadienylene group, hexenylene group, hexadienylene group, hexatrienylene group, heptenylene group, heptadienylene group, heptatrienylene group, octenylene group, octadienylene group, octatrienylene group, octatetraenylene group, Examples thereof include a propynylene group, a butynylene group, a pentynylene group, and a methylpropynylene group. Preferably methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, heptamethylene group, octamethylene group, nonamethylene group, decamethylene group, vinylene group, propenylene group, butenylene group, butadienylene group, pentenylene Group, pentadienylene group, hexenylene group, hexadienylene group, hexatrienylene group, heptenylene group, heptadienylene group, heptatrienylene group, octenylene group, octadienylene group, octatrienylene group, octatetraenylene group, propynylene group, butynylene group, A linear alkylene group such as a pentynylene group, particularly preferably a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a heptamethylene group, Kutamechiren a linear alkylene group having 1 to 8 carbon atoms in the group.

  “Divalent aromatic heterocyclic group having one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen” is selected from the group consisting of nitrogen, sulfur and oxygen A 5- or 6-membered divalent aromatic heterocyclic group having 1 or 2 or more heteroatoms, specifically a tetrazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, an oxazole ring, Bivalent groups such as oxazole ring, thiazole ring, isothiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiophene ring, tetrazine ring, triazine ring, pyrazine ring, pyridazine ring, pyrimidine ring, pyridine ring It is done. Preferably it is a 5-membered divalent aromatic heterocyclic group, specifically, a tetrazole ring, an oxadiazole ring, a thiadiazole ring, a triazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, an imidazole ring. , A pyrazole ring, a pyrrole ring, a furan ring, and a thiophene ring. Particularly preferred are divalent groups of an oxadiazole ring, a thiadiazole ring, and a triazole ring.

  “Cycloalkylene group” means a cycloalkylene group having 3 to 7 carbon atoms, that is, a divalent cycloalkyl group. Specifically, a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group. And cycloheptylene group. Preferred is a cycloalkylene group having 5 or 6 carbon atoms, specifically a cyclopentylene group or a cyclohexylene group.

  The “arylene group” specifically includes a phenylene group, a naphthylene group, an anthrylene group, a phenanthrylene group, a biphenylene group, and the like, and preferably a phenylene group, a naphthylene group, and a biphenylene group.

  Specifically, “a divalent heterocyclic group having one or two or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom and which may form a condensed ring” Dioxolane ring, dithiol ring, pyrrolidine ring, morpholine ring, oxazine ring, piperazine ring, piperidine ring, pyrroline ring, imidazolidine ring, imidazoline ring, pyrazolidine ring, pyrazoline ring, thiatriazole ring, tetrazole ring, oxadiazole ring, thiadiazole Ring, triazole ring, isoxazole ring, oxazole ring, thiazole ring, imidazole ring, pyrazole ring, pyrrole ring, furan ring, thiophene ring, tetrazine ring, triazine ring, pyrazine ring, pyridazine ring, pyrimidine ring, pyridine ring, furoiso Oxazole ring, imidazothiazole ring, thienoisothi Zole ring, thienothiazole ring, imidazopyrazole ring, cyclopentapyrazole ring, pyrrolopyrrole ring, thienothiophene ring, thiadiazolopyrimidine ring, thiazolothiazine ring, thiazolopyrimidine ring, thiazolopyridine ring, oxazolopyrimidine ring, oxazolo Pyridine ring, benzoxazole ring, benzoisothiazole ring, benzothiazole ring, imidazopyrazine ring, purine ring, pyrazolopyrimidine ring, imidazopyridine ring, benzimidazole ring, indazole ring, benzooxathiol ring, benzodioxole ring, Benzodithiol ring, indolizine ring, indoline ring, isoindoline ring, furopyrimidine ring, furopyridine ring, benzofuran ring, isobenzofuran ring, thienopyrimidine ring, thienopyridine ring, benzothiophene , Cyclopentaoxazine ring, cyclopentafuran ring, benzoxazine ring, benzothiazine ring, quinazoline ring, naphthyridine ring, quinoline ring, isoquinoline ring, benzopyran ring, pyridopyridazine ring, pyridopyrimidine ring, etc. Is mentioned. Preferred are divalent heterocyclic groups such as a piperazine ring, piperidine ring, pyridine ring, benzoxazole ring, benzoisothiazole ring, benzothiazole ring, and benzimidazole ring.

  “Alkoxycarbonyl group” means a linear or branched alkoxycarbonyl group having 2 to 7 carbon atoms, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxy group. Carbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert-pentyloxycarbonyl group, hexyloxycarbonyl group, iso Hexyloxycarbonyl group, neohexyloxycarbonyl group, etc. are mentioned, preferably methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbo Group, a isobutoxycarbonyl group, sec- butoxycarbonyl group, tert- butoxycarbonyl linear or branched alkoxycarbonyl group having 2 to 5 carbon atoms such as a group.

  The “lower alkoxycarbonyl group” means a linear or branched alkoxycarbonyl group having 2 to 5 carbon atoms, specifically a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, A butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxycarbonyl group, a tert-butoxycarbonyl group and the like can be mentioned, and a methoxycarbonyl group and an ethoxycarbonyl group are preferable.

  `` Acyl group '' specifically includes formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, caproyl group, isocaproyl group, acryloyl group, propioroyl group, methacryloyl group, Crotonoyl group, isocrotonoyl group, benzoyl group, naphthoyl group, toluoyl group, hydroatropoyl group, atropoyl group, cinnamoyl group, furoyl group, glyceroyl group, tropoyl group, benzyloyl group, salicyloyl group, anisoyl group, vanilloyl group, veratroyl group , Piperoniloyl group, protocatechuyl group, galloyl group, etc., preferably formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, benzoyl , A naphthoyl group.

  The “acyloxy group” is an acyloxy group having the above-mentioned acyl group, specifically, formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group. Group, pivaloyloxy group, caproyloxy group, isocaproyloxy group, acryloyloxy group, propioloyloxy group, methacryloyloxy group, crotonoyloxy group, isocrotonoyloxy group, benzoyloxy group, naphthoyloxy group, toluoyl Oxy group, hydroatropoyloxy group, atropoyloxy group, cinnamoyloxy group, furoyloxy group, glyceroyloxy group, tropoyloxy group, benzyloyloxy group, salicyloyloxy group, anisoyloxy group, vanilloylo group Ci group, veratroyloxy group, piperonyloxy group, protocatechuyloxy group, galloyloxy group, etc., preferably formyloxy group, acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group , Valeryloxy group, isovaleryloxy group, pivaloyloxy group, benzoyloxy group, naphthoyloxy group.

“A heterocyclic group having one or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen atoms” means 1 or 2 selected from the group consisting of nitrogen, sulfur and oxygen atoms Meaning a 3-7 membered heterocyclic group having the above heteroatoms, specifically aziridinyl group, oxiranyl group, azetyl group, azetidinyl group, oxetanyl group, thiatriazolyl group, tetrazolyl group, dithiazolyl group, oxadiazolyl group, thiadiazolyl Group, triazolyl group, oxazolyl group, isoxazolyl group, thiazolyl group, isothiazolyl group, imidazolyl group, pyrazolyl group, dioxolanyl group, pyrrolyl group, pyrrolidinyl group, furanyl group, thienyl group, tetrazinyl group, dithiadiazinyl group, thiadiazinyl group, triazinyl group, Morpholinyl group, Horino group, oxazinyl group, thiazinyl group, piperazinyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, piperidyl group, piperidino group, a pyridyl group, a pyranyl group, thiopyranyl group, Jiokisazepiniru group, diazepinyl group, azepinyl group and the like. Preferably a 5- or 6-membered heterocyclic group, specifically, a thiatriazolyl group, a tetrazolyl group, a dithiazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, Pyrazolyl group, dioxolanyl group, pyrrolyl group, pyrrolidinyl group, furanyl group, thienyl group, tetrazinyl group, dithiadiazinyl group, thiadiazinyl group, triazinyl group, morpholinyl group, morpholino group, oxazinyl group, thiazinyl group, piperazinyl group, pyrazinyl group, pyridazinyl group , Pyrimidinyl group, piperidyl group, piperidino group, pyridyl group, pyranyl group, thiopyranyl group, and R ⁶ is particularly preferably pyrrolyl group, furanyl group, thienyl group, piperazinyl group, piperidinyl group, A peridyl group, a piperidino group and a pyridyl group; R ¹² is particularly preferably a pyrrolyl group, piperazinyl group, piperidyl group, piperidino group or pyridyl group.

  “Aromatic heterocyclic group having 1 or 2 or more heteroatoms selected from the group consisting of nitrogen, sulfur and oxygen” is 1 or 2 selected from the group consisting of nitrogen, sulfur and oxygen Means a 5- or 6-membered aromatic heterocyclic group having 2 or more heteroatoms, specifically a tetrazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, Examples include imidazolyl group, pyrazolyl group, pyrrolyl group, furanyl group, thienyl group, tetrazinyl group, triazinyl group, pyrazinyl group, pyridazinyl group, pyrimidinyl group, pyridyl group and the like. Preferably a 5-membered aromatic heterocyclic group, specifically, a tetrazolyl group, an oxadiazolyl group, a thiadiazolyl group, a triazolyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a pyrazolyl group, a pyrrolyl group, A furanyl group and a thienyl group; Particularly preferred are an oxadiazolyl group, a thiadiazolyl group, and a triazolyl group.

  The term “alkoxyalkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms that is substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms. Specifically, Methoxymethoxy group, ethoxymethoxy group, propoxymethoxy group, isopropoxymethoxy group, butoxymethoxy group, isobutoxymethoxy group, sec-butoxymethoxy group, tert-butoxymethoxy group, pentyloxymethoxy group, isopentyloxymethoxy group, neo Pentyloxymethoxy group, tert-pentyloxymethoxy group, hexyloxymethoxy group, isohexyloxymethoxy group, neohexyloxymethoxy group, tert-hexyloxymethoxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group, isopropoxy group Et Si group, butoxyethoxy group, isobutoxyethoxy group, sec-butoxyethoxy group, tert-butoxyethoxy group, pentyloxyethoxy group, isopentyloxyethoxy group, neopentyloxyethoxy group, tert-pentyloxyethoxy group, hexyloxy Ethoxy group, isohexyloxyethoxy group, neohexyloxyethoxy group, tert-hexyloxyethoxy group, methoxypropoxy group, ethoxypropoxy group, propoxypropoxy group, isopropoxypropoxy group, butoxypropoxy group, isobutoxypropoxy group, sec- Butoxypropoxy group, tert-butoxypropoxy group, pentyloxypropoxy group, isopentyloxypropoxy group, neopentyloxypropoxy group, tert-pen Ruoxypropoxy group, hexyloxypropoxy group, isohexyloxypropoxy group, neohexyloxypropoxy group, tert-hexyloxypropoxy group, methoxybutoxy group, ethoxybutoxy group, propoxybutoxy group, isopropoxybutoxy group, butoxybutoxy group, Isobutoxybutoxy group, sec-butoxybutoxy group, tert-butoxybutoxy group, pentyloxybutoxy group, isopentyloxybutoxy group, neopentyloxybutoxy group, tert-pentyloxybutoxy group, hexyloxybutoxy group, isohexyloxybutoxy group Group, neohexyloxybutoxy group, tert-hexyloxybutoxy group, methoxypentyloxy group, ethoxypentyloxy group, propoxypentyloxy group, Isopropoxypentyloxy group, butoxypentyloxy group, isobutoxypentyloxy group, sec-butoxypentyloxy group, tert-butoxypentyloxy group, pentyloxypentyloxy group, isopentyloxypentyloxy group, neopentyloxypentyloxy group Tert-pentyloxypentyloxy group, hexyloxypentyloxy group, isohexyloxypentyloxy group, neohexyloxypentyloxy group, tert-hexyloxypentyloxy group, methoxyhexyloxy group, ethoxyhexyloxy group, propoxyhexyloxy group Group, isopropoxyhexyloxy group, butoxyhexyloxy group, isobutoxyhexyloxy group, sec-butoxyhexyloxy group, tert-buto Sihexyloxy group, pentyloxyhexyloxy group, isopentyloxyhexyloxy group, neopentyloxyhexyloxy group, tert-pentyloxyhexyloxy group, hexyloxyhexyloxy group, isohexyloxyhexyloxy group, neohexyloxyhexyl Examples thereof include an oxy group and a tert-hexyloxyhexyloxy group. Preferably, it is a linear or branched alkoxy group having 1 to 4 carbon atoms substituted by a linear or branched alkoxy group having 1 to 4 carbon atoms, specifically, a methoxymethoxy group or an ethoxymethoxy group. , Propoxymethoxy group, isopropoxymethoxy group, butoxymethoxy group, isobutoxymethoxy group, sec-butoxymethoxy group, tert-butoxymethoxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group, isopropoxyethoxy group, butoxyethoxy Group, isobutoxyethoxy group, sec-butoxyethoxy group, tert-butoxyethoxy group, methoxypropoxy group, ethoxypropoxy group, propoxypropoxy group, isopropoxypropoxy group, butoxypropoxy group, isobutoxypropoxy group, sec-butoxy Propoxy, tert- butoxy propoxy group, methoxy butoxy group, Etokishibutokishi group, propoxy butoxy group, isopropoxide Shiv butoxy group, Butokishibutokishi group, isobutoxy butoxy group, sec- Butokishibutokishi group, a tert- Butokishibutokishi group.

  The “lower alkoxy lower alkoxy group” is a linear or branched alkoxy group having 1 to 4 carbon atoms substituted with a linear or branched alkoxy group having 1 to 4 carbon atoms. Specifically, Is a methoxymethoxy group, ethoxymethoxy group, propoxymethoxy group, isopropoxymethoxy group, butoxymethoxy group, isobutoxymethoxy group, sec-butoxymethoxy group, tert-butoxymethoxy group, methoxyethoxy group, ethoxyethoxy group, propoxyethoxy group , Isopropoxyethoxy group, butoxyethoxy group, isobutoxyethoxy group, sec-butoxyethoxy group, tert-butoxyethoxy group, methoxypropoxy group, ethoxypropoxy group, propoxypropoxy group, isopropoxypropoxy group, butoxypropoxy group, isobutoxy Propoxy group, sec-butoxypropoxy group, tert-butoxypropoxy group, methoxybutoxy group, ethoxybutoxy group, propoxybutoxy group, isopropoxybutoxy group, butoxybutoxy group, isobutoxybutoxy group, sec-butoxybutoxy group, tert-butoxy group A butoxy group is exemplified, and a methoxymethoxy group, an ethoxymethoxy group, a methoxyethoxy group, and an ethoxyethoxy group are preferable.

  The “alkenyl group” means a straight or branched alkenyl group having 2 to 6 carbon atoms, and specifically includes an allyl group, a vinyl group, a propenyl group, an isopropenyl group, and 1-methyl-2-propenyl. Group, 2-methyl-2-propenyl group, 1-methyl-1-butenyl group, crotyl group, 1-methyl-3-butenyl group, 3-methyl-2-butenyl group, 1-pentenyl group, 1-methyl- 2-pentenyl group, 4-pentenyl group, 1-hexenyl group, 3-hexenyl group, 4-hexenyl group and the like can be mentioned.

  “Alkynyl group” means a linear or branched alkynyl group having 2 to 6 carbon atoms, specifically, propargyl group, 2-butynyl group, 1-methyl-2-butynyl group, 2-pentynyl. Group, 1-methyl-3-pentynyl group, 1-methyl-4-pentynyl group, 1-hexynyl group, 5-hexynyl group and the like.

  Specific examples of the “cycloalkylideneamino group” include a cyclopropylideneamino group, a cyclobutylideneamino group, a cyclopentylideneamino group, a cyclohexylideneamino group, a cycloheptylideneamino group, and preferably A cyclopentylideneamino group and a cyclohexylideneamino group;

  The “optionally substituted” in the “optionally substituted nitrogen-containing non-aromatic heterocyclic group” means that it may be substituted by 1 to 3 substituents, and the substituents May be the same or different. Further, the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include the aforementioned lower alkyl group; the aforementioned halogenated lower alkyl group; the aforementioned cycloalkyl group; the aforementioned aralkyl group; the aforementioned aryl group; the aforementioned amino protecting group. A lower alkyl group and an amino protecting group are preferred.

  “Optionally substituted” of “straight chain or branched alkylene group which may be substituted and may have one or more double bonds or triple bonds in the chain” means It means that it may be substituted with one or two or more substituents, and the substituents may be the same or different. Specific examples of the substituent include the above halogen atom; hydroxyl group; amino group (the above lower alkyl group, the above halogenated lower alkyl group, the above cycloalkyl group, the above aralkyl group, the above aryl group, and the above group). And may be substituted with a substituent selected from the group consisting of amino-protecting groups.); The aforementioned lower alkoxy group; the aforementioned aralkyl group; the aforementioned cycloalkyl group and the like.

The “optionally substituted alkoxy” in the “optionally substituted alkoxy group” and the “optionally substituted alkylthio group” in R ¹¹ may be substituted with one or more substituents. The substituents may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include the aforementioned halogen atom; the aforementioned lower alkoxy group; the aforementioned alkylthio group; the amino group (which may be substituted with the aforementioned lower alkyl group or the aforementioned acyl group); the carboxyl group; The aforementioned acyloxy group; the aforementioned aryl group; the aforementioned aryloxy group; the aforementioned arylthio group; the aforementioned aryloxycarbonyl group; the aforementioned aralkyloxy group; the aforementioned aralkyloxycarbonyl group. Etc. Preferred are an amino group; a lower alkoxy group; a halogen atom; a carboxyl group; an alkoxycarbonyl group; and an aralkyloxycarbonyl group.

“Optionally substituted aryl group”, “optionally substituted cycloalkyl group”, “optionally substituted aryloxy group”, “optionally substituted aralkyloxy group” in R ¹¹ and In the “optionally substituted arylthio group”, “optionally substituted” means that 1 to 3 substituents may be present on the ring, and the substituents are the same or The positions of the substituents are arbitrary and are not particularly limited. Specific examples of the substituent include the aforementioned lower alkyl group; the aforementioned halogen atom; the aforementioned lower alkoxy group; the aforementioned alkylthio group; the amino group (which may be substituted with the aforementioned lower alkyl group or the aforementioned acyl group). Carboxyl group; the aforementioned alkoxycarbonyl group; the aforementioned acyl group; the aforementioned acyloxy group; the aforementioned aryl group; the aforementioned aryloxy group; the aforementioned arylthio group; the aforementioned aryloxycarbonyl group; the aforementioned aralkyloxy group; Examples include the aforementioned aralkyloxycarbonyl group. A lower alkyl group; an amino group; a lower alkoxy group; a halogen atom; a carboxyl group; an alkoxycarbonyl group; an aralkyloxycarbonyl group, and particularly preferably a lower alkyl group.

The “optionally substituted” in the “optionally substituted aralkyl group” in R ⁵ means that 1 to 3 substituents may be present on the aryl group, The groups may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include the aforementioned lower alkyl group; the aforementioned lower alkoxy group; the aforementioned acyl group; the amino group (which may be substituted with the aforementioned lower alkyl group or the aforementioned acyl group); Examples include carbonyl group; the above aryloxycarbonyl group; the above aryloxy group; the above alkylthio group; the above arylthio group; the above aryl group; Preferred is a lower alkyl group; a lower alkoxy group; a halogen atom, and particularly preferred is a lower alkyl group.

The “optionally substituted” in the “optionally substituted lower alkyl group”, “optionally substituted lower alkoxy group” and “optionally substituted lower alkylthio group” in R ⁶ is: It means that the substituent may be substituted with one or more substituents, and the substituents may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include the aforementioned halogen atom; hydroxyl group; the aforementioned alkoxy group; the aforementioned aryloxy group; the amino group (which may be substituted with the aforementioned lower alkyl or the aforementioned acyl group); the mercapto group; The aforementioned alkylthio group; the aforementioned arylthio group; the carboxyl group; the aforementioned alkoxycarbonyl group; the aforementioned aryloxycarbonyl group; the carbamoyl group; the aforementioned halogenated lower alkyl group; the sulfamoyl group; the cyano group; the nitro group; Examples, methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, etc.); alkylsulfinyl groups (eg, methylsulfinyl group, ethylsulfinyl group, isopropylsulfinyl group, etc.); arylsulfonyl groups (eg, phenylsulfonyl group, etc.), etc. It is done. Preferred are a halogen atom; a hydroxyl group; an alkoxy group; an amino group; a carboxyl group; and an alkoxycarbonyl group.

1 which is selected from the group consisting of “optionally substituted aryl group”, “optionally substituted cycloalkyl group” and “optionally substituted and a nitrogen atom, sulfur atom and oxygen atom” in R ⁶ Or the “optionally substituted” in the “heterocyclic group having two or more heteroatoms” means that it may be substituted by one or more substituents, and the substituents are the same Alternatively, the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include the aforementioned lower alkyl group; the aforementioned halogen atom; the hydroxyl group; the aforementioned alkoxy group; the aforementioned aryloxy group; the amino group (substituted with the aforementioned lower alkyl group or the aforementioned acyl group). A mercapto group; an alkylthio group; an arylthio group; a carboxyl group; an alkoxycarbonyl group; an aryloxycarbonyl group; a carbamoyl group; a halogenated lower alkyl group; a sulfamoyl group; a cyano group; Nitro group; alkylsulfonyl group (eg, methylsulfonyl group, ethylsulfonyl group, isopropylsulfonyl group, etc.); alkylsulfinyl group (eg, methylsulfinyl group, ethylsulfinyl group, isopropylsulfinyl group, etc.); arylsulfonyl group (eg, phenyl) Sulfonyl group, etc.) Etc. The. Preferred are a lower alkyl group; a halogen atom; a hydroxyl group; an alkoxy group; an amino group; a carboxyl group;

The “optionally substituted” in the “optionally substituted alkyl group” in R ⁷ means that it may be substituted by one or more substituents, and the substituents are the same. Alternatively, the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include: hydroxyl group; the aforementioned lower alkoxy group; mercapto group; the aforementioned lower alkylthio group; carboxyl group; the aforementioned lower alkoxycarbonyl group; halogen atom; amino group (the aforementioned lower alkyl group or the aforementioned acyl group). And may be substituted with a group). Preferred are hydroxyl group; halogen atom; lower alkoxy group.

Aromatic heterocycle having one or more heteroatoms selected from the group consisting of “optionally substituted aryl group” and “optionally substituted and nitrogen atom, sulfur atom and oxygen atom” in R ⁷ The “optionally substituted” in the “ring group” means that 1 to 3 substituents may be present on the ring, and the substituents may be the same or different, The position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include the aforementioned lower alkyl group; hydroxyl group; the aforementioned lower alkoxy group; mercapto group; the aforementioned lower alkylthio group; carboxyl group; the aforementioned lower alkoxycarbonyl group; halogen atom; And may be substituted with an alkyl group or the aforementioned acyl group). Preferred are hydroxyl group; lower alkyl group; halogen atom; lower alkoxy group.

The “optionally substituted” in the “optionally substituted alkenyl group” and the “optionally substituted alkynyl group” in R ¹² may be substituted with one or more substituents. The substituents may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include: hydroxyl group; the aforementioned alkoxy group; carboxyl group; the aforementioned alkoxycarbonyl group; the aforementioned acyloxy group; the amino group (the aforementioned aralkyl, the aforementioned aryl group, the aforementioned aralkyl group, or the aforementioned amino protection. And may be substituted with a group). Preferred are hydroxyl group; alkoxy group; carboxyl group; alkoxycarbonyl group; acyloxy group.

1 which is selected from the group consisting of “optionally substituted cycloalkyl group”, “optionally substituted aryl group” and “optionally substituted and a nitrogen atom, sulfur atom and oxygen atom” in R ¹² Or “heterocyclic group having 2 or more heteroatoms” means “may be substituted” means that the ring may have 1 to 3 substituents, and the substituent May be the same or different, and the position of the substituent is not particularly limited. Specific examples of the substituent include: a hydroxyl group; the aforementioned lower alkoxy group; a mercapto group; the aforementioned lower alkylthio group; the carboxyl group; the aforementioned lower alkoxycarbonyl group; the aforementioned lower alkyl group; and the amino group (the aforementioned lower alkyl group). Halo group; cyano group; acyl group; nitro group; sulfamoyl group; alkoxythiocarbonyl group; thioalkanoyl group; alkylsulfonyl group (eg, methylsulfonyl group, ethyl) Sulfonyl group, etc.); azomethine group (which may be substituted with the aforementioned lower alkyl group, the aforementioned aryl group or the aforementioned aralkyl group); an alkoxyamino group (eg, methoxyamino group, isopropoxyamino group, etc.); hydrazino Group (the aforementioned lower alkyl group, the aforementioned aryl group or the aforementioned a An aminooxy group (which may be substituted with the above-mentioned lower alkyl group, the above-mentioned aryl group or the above-mentioned aralkyl group); an alkylsulfinyl group (eg, a methylsulfinyl group) Etc. Preferred are hydroxyl group; lower alkyl group; halogen atom; lower alkoxy group; amino group; carboxyl group.

The “optionally substituted” in the “optionally substituted aralkyl group” in R ¹² means that 1 to 3 substituents may be present on the aryl group. The groups may be the same or different, and the position of the substituent is arbitrary and is not particularly limited. Specific examples of the substituent include the aforementioned lower alkyl group; the aforementioned lower alkoxy group; the aforementioned acyl group; the amino group (which may be substituted with the aforementioned lower alkyl group or the aforementioned acyl group); Examples include carbonyl group; the above aryloxycarbonyl group; the above aryloxy group; the above alkylthio group; the above arylthio group; the above aryl group; Preferably they are a lower alkyl group; a lower alkoxy group; and a halogen atom.

  Acid addition salts in compound (I) include inorganic acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, nitric acid) or organic acids (eg, oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, And acid addition salts formed from succinic acid, citric acid, acetic acid, lactic acid, methanesulfonic acid, paratoluenesulfonic acid, benzoic acid, valeric acid, malonic acid, nicotinic acid, propionic acid). A preferred acid addition salt of the present invention is a salt with hydrochloric acid, more preferably a dihydrochloride.

  In compound (I), one or more stereoisomers based on asymmetric carbon may exist. The present invention also includes the isomers and mixtures thereof. Further, hydrates of compound (I), solvates with pharmacologically acceptable organic solvents (for example, ethanol and the like), and prodrugs are also encompassed in the present invention.

A “prodrug” is a derivative of a compound of the present invention that has a group that can be chemically or metabolically decomposed and is restored to the original compound after administration to a living body and exhibits its original medicinal effect. Non-conforming complexes and salts.
As a prodrug of the compound (I), the carboxyl group of the compound (I) is ethyl group, pivaloyloxymethyl group, 1- (acetyloxy) ethyl group, 1- (ethoxycarbonyloxy) ethyl group, 1- Compound modified with (cyclohexyloxycarbonyloxy) ethyl group, carboxylmethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group, phenyl group, o-tolyl group, etc. Compound in which hydroxyl group of (I) is modified with acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoyl group, 4-methylbenzoyl group, dimethylcarbamoyl group, sulfo group; amino group of compound (I) is hexyl Carbamoyl group, 3-methylthio-1- (acetylamino) propylcarbonyl group, 1-sulfo-1- 3-ethoxy-4-hydroxyphenyl) methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) compounds modified with a methyl group and the like.

  Compound (I) is preferably of formula (II)

(-)-Ethyl N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} -L-phenylalaninate represented by N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} -L-phenylalanine ethyl ester) or a pharmaceutically acceptable acid addition thereof Salt [hereinafter also referred to as compound (II). ].

  More preferably, the compound (I) has the formula (II-a)

(-)-Ethyl N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} -L-phenylalaninate represented by Salt (ie, N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} -L-phenylalanine ethyl ester dihydrochloride) Also referred to as (II-a). ].

  Compound (I) is a compound produced by various inflammatory cytokines (eg, rats, mice, pigs, cats, dogs, cows, horses, monkeys, humans, etc.) at the site of ischemia-reperfusion injury (eg, Production of TNF-α, IL-6, IL-8, CINC-1, GM-CSF, etc.). Although the compound (I) of the present invention directly inhibits the upstream of the signal pathway of inflammatory cytokine production, it is considered that various organs causing ischemia-reperfusion injury can be effectively protected. A remarkable protective effect is seen especially in the kidney. Thus, the compound (I) of the present invention is useful as a pharmaceutical agent effective in treating or preventing various diseases and pathologies associated with renal ischemia / reperfusion injury, that is, as an active ingredient of a therapeutic agent or prophylactic agent for renal ischemia / reperfusion injury. . For example, the compound (I) is applied to a disease or pathological condition associated with renal ischemia / reperfusion injury, and the compound (I) is applied to a shocked kidney due to a decrease in cardiac blood flow or a decrease in renal blood flow associated with bleeding. Or post-administration by continuous infusion; reduction of renal blood flow due to contraction or stenosis of renal artery or aorta, reduction of renal blood flow due to bleeding, renal ischemic renal failure associated with renal arteriovenous clamp associated with renal surgery ( I) Post-administration by single or continuous infusion; Compound for recipients to prevent renal ischemia-reperfusion injury caused by ischemia due to blood flow disruption of the isolated kidney after renal transplantation and resumption of blood flow accompanying renal vascular anastomosis Pre-administration by single or continuous infusion of (I); single pre-administration of compound (I) for preventing renal ischemia-reperfusion injury associated with blood flow disruption of isolated kidney from donor in kidney transplantation; Surgery Of renal blood flow due to aortic blockade in rats, reduction of renal blood flow due to aortic damage, etc., after single or continuous infusion of compound (I) for renal ischemia associated with renal arteriovenous clamp associated with renal surgery Administration or prophylactic pre-administration if known in advance; post-administration by single or continuous infusion of compound (I) for renal vascular injury associated with decreased renal blood flow; renal blood with decreased cardiac output, bleeding, etc. Post-administration by single or continuous infusion of compound (I) for renal flow reduction due to decreased flow or renal artery contraction; Compound for renal artery stenosis with decreased renal blood flow due to physical compression of blood vessels ( Prophylactic pre-administration by single or continuous infusion of I); Compound (I) for acute renal failure associated with shock kidney, acute ischemic renal failure, renal ischemia, renal vascular injury, decreased renal blood flow, renal artery stenosis, etc. Single or continuous infusion Post-administration; prophylactic pre-administration by single or continuous infusion of compound (I) for artificial cardiopulmonary retrorenal disorder associated with decreased cardiac output or decreased renal blood flow associated with bleeding, etc .; or acute postrenal renal failure , Acute renal failure, acute prerenal renal failure, renal dysfunction, renal function decline, renal thrombus, renal infarction, renal embolism, renal artery thrombosis, renal artery embolism, renal artery injury, renal artery occlusion, etc. Application.

  Compound (I) is used for the treatment or prevention of renal ischemia-reperfusion injury in mammals such as animals (eg rats, mice, pigs, cats, dogs, cows, horses, monkeys, humans, preferably humans (male and female). )) Can be administered by conventional methods. Compound (I) can be administered as it is, but is preferably administered as a pharmaceutical composition. The pharmaceutical composition contains compound (I) together with one or more pharmacologically acceptable carriers or excipients, and may further contain other therapeutic agents and / or ingredients. The carrier or excipient may be compatible with other components and may be non-toxic.

  When used as a pharmaceutical composition containing Compound (I) as an active ingredient, it is usually a pharmacologically acceptable carrier, excipient, diluent, extender, disintegrant, stabilizer, preservative, buffer. Agents, emulsifiers, fragrances, colorants, sweeteners, thickeners, flavoring agents, solubilizers and / or other additives (eg, water, vegetable oil, alcohol (eg, ethanol or benzyl alcohol), polyethylene glycol, Mixed with glycerol triacetate, gelatin, lactose, carbohydrates (starch, etc.), magnesium stearate, talc, lanolin, white petrolatum, etc., and mixed with tablets, pills, powders, granules, suppositories, injections, eye drops, solutions , Capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like.

  For oral administration, it may contain diluents, dispersants and / or surfactants in the form of fines or granules, for example, in water, in syrup, in dry capsules or sachets, suspensions In non-aqueous solutions or suspensions, or in tablets that may contain binders and lubricants. Sweetening agents, flavoring agents, preservatives (eg antimicrobial preservatives), suspending agents, thickening agents and / or emulsifiers may also be present in the pharmaceutical composition.

  For parenteral administration, the pharmaceutical composition is in the form of a solution or suspension and can contain Compound (I) and purified water. Components that may be included in the liquid or suspension include preservatives (eg, antimicrobial preservatives), buffers, solutions and mixtures thereof. The components of the pharmaceutical composition may perform one or more functions. Pharmaceutical compositions can be stored in lyophilized form in single or multiple dose containers, such as sealed vials and ampoules, and sterilized liquid carriers (eg, water or saline) prior to use. It may be added to. In a preferred embodiment, compound (I) is formulated as a lyophilized formulation containing with D-mannitol. The lyophilized formulation is preferably diluted with saline prior to use.

  Pharmaceutical compositions containing compound (I) can be prepared by methods well known in the pharmaceutical art [eg, Gennaro et al., “Pharmaceutical Science of Remington” 1990, 18th edition, Remington's Pharmaceutical Sciences, 18th ed. , Mack Publishing Co., 1990), in particular, Chapter 8 “Part 8: Pharmaceutical Preparations and their Manufacture”]. The method includes the step of associating compound (I) with other components of the pharmaceutical composition.

  The therapeutic / prophylactic agent of the present invention can be administered by several appropriate methods, and the administration route is not particularly limited, but oral, buccal, intranasal, transdermal, injection, sustained release, controlled release, ion Examples include introduction (iontophoresis) and ultrasonic introduction (sonophoresis). Injection is not particularly limited, but intravenous, intramuscular, subcutaneous, intraperitoneal, intraspinal, intrathecal, intracerebroventricular And parenteral routes such as intraarterial and other injection routes. For parenteral administration, the pharmaceutical composition can be a liquid or non-liquid sterilized injection preparation, preferably an intravenous injection preparation.

The appropriate dose of compound (I) varies depending on the type and symptoms of ischemia-reperfusion injury, administration route, sex difference, body weight, etc. of the patient. In the case of oral administration for adults, for example, the daily dose of compound (I) (especially compound (II) or (II-a)) is usually about 0.01 to 1,000 mg (for example, about 0.05 mg, About 0.1 mg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, About 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or a range thereof), preferably about 0.1 to 100 mg.
When Compound (I) (especially Compound (II) or (II-a)) is intravenously administered to an adult, for example, the daily dose is usually about 0.01 to 100 mg / kg (eg about 0 .05 mg / kg, about 0.1 mg / kg, about 1 mg / kg, about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg kg, about 90 mg / kg, about 95 mg / kg, or range thereof), preferably about 0.01-50 mg / kg, once or several times (e.g. 2, 3, 4, 5, 6, 7, 8, 9, 10 times It can be administered in more). Alternatively, compound (I) (especially compound (II) or (II-a)) may be continuously intravenously administered over a selected period (eg, several hours to one day or more). The total daily dose for continuous administration is usually the same as the daily dose used for non-continuous intravenous administration.

  The therapeutic or prophylactic agent of the present invention is administered at an appropriate time for treating or preventing renal ischemia-reperfusion injury. For example, from about 2 hours before reperfusion to about 30 minutes after reperfusion (eg, about 1.75 hours before reperfusion, about 1.5 hours before reperfusion, about 1.25 hours before reperfusion) About 1 hour before reperfusion, about 50 minutes before reperfusion, about 40 minutes before reperfusion, about 30 minutes before reperfusion, about 20 minutes before reperfusion, about 10 minutes before reperfusion, About 5 minutes after reperfusion, about 10 minutes after reperfusion, about 15 minutes after reperfusion, about 20 minutes after reperfusion, about 25 minutes after reperfusion, or a range thereof. Can be administered in between.

It is known that inflammatory cytokines are elevated after ischemia-reperfusion in animals including humans, and that inflammatory cytokines directly affect the decrease in renal function. For example, IL-1β, IL-6, IL-8, interferon (IFN) -γ, TNF-α, CINC-1 and the like have been reported to increase following a wide range of ischemia. Therefore, the present invention provides the production of one or more (eg, 2, 3, 4, 5, or more) inflammatory cytokines by administering Compound (I) having an inhibitory action on inflammatory cytokine production. It is intended to provide a medicament for inhibiting or treating or preventing renal ischemia / reperfusion injury, that is, a therapeutic or prophylactic agent for renal ischemia / reperfusion injury containing a specific inflammatory cytokine production inhibitor. The inflammatory cytokine whose production is inhibited is preferably TNF-α, IL-1β, IL-6, IL-8, IL-10, granulocyte colony stimulating factor (GM-CSF) or CINC-1. More preferably, IL-6, IL-8, TNF-α, CINC-1 or a combination thereof. Furthermore, an aspect in which the production of two or more inflammatory cytokines (for example, 3 or more, 4 or more, 5 or more) is combined and inhibited is most preferable.
CINC-1 is a neutrophil chemotactic factor in rats and has low sequence homology with IL-8, which is a human neutrophil chemotactic factor. It is similar and is positioned as a cytokine corresponding to IL-8 in rats (see Pharmaceutical Journal, 2002, Vol. 122, No. 4, P.263-268).

  Hereinafter, in order to show the usefulness of this invention, it demonstrates more concretely, giving a test example, but this invention is not limited at all by these. The evaluation test is (-)-ethyl N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazin-1-yl) ethoxy] benzoyl} -L-phenyl as compound (I) Alaninate dihydrochloride [Compound (II-a)] was used.

Test Example 1: Evaluation of inhibitory effect on rat renal ischemia / reperfusion injury Male Wistar rats (300-350 g) were treated with normal group (N group, n = 8), control group (C group, n = 8) and compound ( II-a) The group was divided into administration groups (referred to as group J, n = 8). All rats were anesthetized by intraperitoneal administration of Nembutal (50 mg / kg), exposed the left femoral vein of rats in groups C and J, saline (0.6 mL) for group C, compound for group J A 5% mannitol solution (15 mg / mL) of (II-a) was intravenously administered as a bolus at a dose of about 30 mg / kg (about 0.6 to 0.7 mL). Next, the right kidney was removed, 30 minutes after drug administration, the left kidney was exposed from the back, the hilar portion was pinched with a clip, and after 45 minutes ischemia, the clip was removed and blood flow was reperfused. .
Serum, urine and kidney were collected 24 hours after ischemia reperfusion. Blood urea nitrogen (BUN), serum creatinine (Cr) and urinary N-acetyl-β-glucosaminidase (NAG) were measured according to a conventional method as renal function parameters, and renal dysfunction was evaluated. The results are shown in Table 1.

  BUN, Cr, and NAG were significantly increased by renal ischemia-reperfusion, suggesting that renal function was impaired (Table 1, Group C). It was found that administration of compound (II-a) suppressed the increase in BUN, Cr and NAG and improved renal damage (Table 1, Group J).

Test Example 2: Evaluation of CINC-1 production inhibitory action in rat renal ischemia-reperfusion injury (1) Male Wistar rats (300-350 g) were treated with renal ischemia-reperfusion in the same manner as in Test Example 1, Created. Prior to ischemia / reperfusion treatment (pre group), kidneys were collected 1, 2, 3, 6 and 12 hours after renal ischemia / reperfusion (referred to as group C, n = 7 × 6), and CINC-1 protein was obtained according to a conventional method. The amount was measured. The results are shown in Table 2.

(2) A sham operation group (N group, n = 7) and a compound (II-a) administration group (30 mg / kg, J group, n = 7) were prepared in the same manner as in Test Example 1. . In the above (1), the kidneys were collected from each group at the time when the production amount of CINC-1 protein in group C showed the maximum value (2 hours after renal ischemia reperfusion), and the same as in (1) above. The CINC-1 protein production was measured by the method and compared. The results are shown in Table 3.

  Renal ischemia / reperfusion increased CINC-1 protein expression and peaked after 2 hours. By the pre-ischemic compound (II-a) administration, the CINC-1 protein expression level was significantly suppressed at the peak time.

These results suggest that the production of CINC-1, a rat neutrophil chemotactic factor, is increased by rat renal ischemia-reperfusion injury, which plays an important role in renal ischemia-reperfusion injury It was done. It was suggested that CINC-1 production at the site of renal ischemia / reperfusion injury was suppressed by administration of pre-ischemic compound (II-a), and as a result, renal injury was prophylactically improved.
CINC-1 is a neutrophil chemotactic factor corresponding to IL-8 in humans. In human renal ischemia-reperfusion injury, administration of compound (I) of the present invention also causes IL-8 to occur. As a result, the prophylactic or therapeutic effect on renal injury can be expected.

Formulation Example 1: Intravenous injection formulation (lyophilized formulation)
1) Compound (II-a) 1 mg
2) D-mannitol 10 mg
3) Glycine 10 mg
4) Polysorbate 80 0.1mg
Total 21.1mg
1) to 4) were dissolved in water and filled into vials. An intravenous injection preparation was produced by lyophilizing a vial filled with a drug solution.

Claims (7)

Formula (I)

Substituted with or R _a; where [wherein, R is unsubstituted or optionally nitrogen-containing optionally a non-aromatic heterocyclic group; a hydroxyl group; R _a; alkoxy group substituted with R _a; alkylthio group substituted with R _a An alkylamino group [wherein R _a is an amino group, a guanidino group, an amidino group, a carbamoyl group, a ureido group, a thioureido group, a hydrazino group, a hydrazinocarbonyl group or an imino group (these groups are a lower alkyl group, a halogen atom, An optionally substituted lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group and an amino protecting group, which may be substituted with a substituent.
A represents a linear or branched alkylene group which may be substituted and may have one or more double bonds or triple bonds in the chain; or represents a single bond;
X is an oxygen atom; a sulfur atom; a cycloalkylene group; a divalent aromatic heterocyclic group having 1 or 2 or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom; _{SO 2 -; - C = C} -; - C≡C -; - CO -; - COO -; - OOC -; - CS -; - COS -; - O-COO -; - NH-CO-NH ——— NH—CS—NH—; —NH—C (═NH) —NH—; —NR ⁸ —; —NR ⁸ CO—; —CONR ⁸ —; —NR ⁸ SO ₂ —; —SO ₂ NR ^{8 -; - NR 8 -COO -;} - OOC-NR 8 -; or ^-CR 9 ^{R 10} - [wherein, ^{R 8} is a hydrogen atom; an alkyl group; a cycloalkyl group; an aryl group; an aralkyl group; or an amino protecting group are shown, ^{R 9} and ^{R 10} are the same or different, a hydrogen atom; an alkyl group; Shows the shows or aralkyl group]; a cycloalkyl group; an aryl group;
M is an arylene group; a cycloalkylene group; or a divalent heterocyclic ring having one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom, and an oxygen atom, and may form a condensed ring Indicate a group;
R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom (provided that at least one of R ¹ , R ² , R ³ and R ⁴ is not a hydrogen atom); a hydroxyl group; a halogen atom An alkoxy group, a mercapto group, an alkylthio group, a nitro group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an acyl group, a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, and a halogen atom. An optionally substituted alkyl group; an amino group optionally substituted with a substituent selected from the group consisting of an alkyl group, an aryl group, an aralkyl group and an amino protecting group; or —O—CO—R ¹¹ [where R ¹¹ is an optionally substituted alkoxy group; an optionally substituted aryl group; an optionally substituted cycloalkyl group; Aryloxy group which may be substituted; aralkyloxy group which may be substituted; alkylthio group which may be substituted; arylthio group which may be substituted; or alkoxycarbonyl group, acyloxy group, aryl group, aryl Oxy group, aryloxycarbonyl group, aralkyloxy group, aralkyloxycarbonyl group, alkylthio group, arylthio group, acyl group, lower alkoxy group, carboxyl group, halogen atom, and optionally substituted with lower alkyl group or acyl group An alkyl group that may be substituted with a substituent selected from the group consisting of amino groups. ]
R ⁵ represents a hydrogen atom; an alkyl group that may be substituted with a halogen atom; an aralkyl group that may be substituted; or an amino protecting group;
m represents 0 or an integer selected from 1 to 6;
R ⁶ represents an optionally substituted aryl group; an optionally substituted cycloalkyl group; an optionally substituted lower alkyl group; an optionally substituted lower alkoxy group; an optionally substituted lower alkylthio A group; an amino group which may be substituted with a substituent selected from the group consisting of a lower alkyl group, an aryl group, an aralkyl group and an amino protecting group; or a nitrogen atom, a sulfur atom and an oxygen atom which may be substituted; A heterocyclic group having one or more heteroatoms selected from the group consisting of:
R ⁷ represents a hydrogen atom; an optionally substituted alkyl group; an optionally substituted aryl group; an optionally substituted one or two selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom An aromatic heterocyclic group having the above hetero atom; or —CO (Y) _P R ¹² [where Y is an oxygen atom; sulfur atom; —NR ¹³ —; or —NR ¹³ —SO ₂ — (R ¹³ is An alkyl group; an aralkyl group; a hydroxyl group; an alkoxy group; an aryl group; or an amino protecting group.), P represents 0 or 1, R ¹² represents a hydrogen atom; an optionally substituted alkenyl group. An optionally substituted alkynyl group; an optionally substituted cycloalkyl group; an optionally substituted aryl group; an optionally substituted aralkyl group; an adamantyl group; a cycloalkylyl group; A denamino group; a heterocyclic group which may be substituted and has one or more heteroatoms selected from the group consisting of a nitrogen atom, a sulfur atom and an oxygen atom; or a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an alkoxy group A heterocyclic group having one or more heteroatoms selected from the group consisting of a carbonyl group, an acyloxy group, a carboxyl group, a nitrogen atom, a sulfur atom and an oxygen atom, and an amino group (the amino group is an alkyl group, an aryl group, An alkyl group which may be substituted with a substituent selected from the group consisting of a group selected from the group consisting of a group, an aralkyl group and an amino protecting group. ] Is shown. Or a pharmacologically acceptable acid addition salt thereof as an active ingredient. A therapeutic or prophylactic agent for renal ischemia-reperfusion injury, comprising: R is a piperazinyl group which may be substituted with a lower alkyl group, a piperidyl group or an amino group which may be substituted with a lower alkyl group (the amino group may be substituted with a lower alkyl group);
A is a linear alkylene group;
X is an oxygen atom, a sulfur atom, —NH— or —CH ₂ —;
M is an arylene group;
R ¹ , R ² , R ³ and R ⁴ are the same or different and each is a hydrogen atom (provided that at least one of R ¹ , R ² , R ³ and R ⁴ is not a hydrogen atom); a hydroxyl group; a halogen An atom or —O—CO—R ¹¹ ′ (wherein R ¹¹ ′ is a lower alkyl group which may be substituted with a substituent selected from the group consisting of an amino group, an acyloxy group and a benzyloxycarbonyl group; or a lower alkyl group Represents a phenyl group which may be substituted with
R ⁵ is a hydrogen atom;
m is 1;
R ⁶ is a phenyl group;
R ⁷ is —COO—R ¹² ′ (where R ¹² ′ is a hydrogen atom; an aralkyl group; an adamantyl group; a cycloalkylideneamino group; a cyclohexyl group which may be substituted with a lower alkyl group; a substituted with a lower alkyl group; An optionally substituted piperidyl group; or a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkoxycarbonyl group, an acyloxy group, a piperazinyl group and an amino group optionally substituted with a lower alkyl group The therapeutic or prophylactic agent according to claim 1, which is an alkyl group which may be substituted with a group.   The compound represented by the formula (I) or a pharmaceutically acceptable acid addition salt thereof is (-)-ethyl N- {3,5-dichloro-2-hydroxy-4- [2- (4-methyl). The therapeutic or prophylactic agent according to claim 1, which is piperazin-1-yl) ethoxy] benzoyl} -L-phenylalaninate or a pharmacologically acceptable acid addition salt thereof.   The pharmacologically acceptable acid addition salt of the compound represented by formula (I) is (-)-ethyl N- {3,5-dichloro-2-hydroxy-4- [2- (4-methylpiperazine). The therapeutic or prophylactic agent according to claim 1, which is -1-yl) ethoxy] benzoyl} -L-phenylalaninate / dihydrochloride.   The therapeutic or prophylactic agent according to any one of claims 1 to 4, wherein the compound represented by formula (I) or a pharmacologically acceptable acid addition salt thereof has an inhibitory action on inflammatory cytokine production. .   The therapeutic or prophylactic agent according to claim 5, wherein the inflammatory cytokine is tumor necrosis factor (TNF) -α, IL-6, IL-8, CINC-1 (Cytokine-induced neutrophil chemoattractant-1) or a combination thereof.   The therapeutic or prophylactic agent according to any one of claims 1 to 6, which is a dosage form of an intravenous injection preparation.