JP2015166329A - Novel bioactive substance - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a novel compound useful as an aminopeptidase A inhibitor.SOLUTION: This invention provides a compound represented by formula (I) or salt thereof, and a pharmaceutical composition comprising the same, wherein R-Rare H, a hydroxy group, a halogen atom or the like; R-Rare H or the like; *1 and *2 are asymmetric carbon atoms and may be any of D and L configurations; Y is a carboxyl group or the like; and Z is H or a substituted benzoylamino imino methyl group or the like.

Description

  The present invention relates to a compound that inhibits aminopeptidase A and an iron chelator.

Aminopeptidase A (APA) is a type II membrane-bound protein and belongs to the M1 aminopeptidase family. APA is a monoaminopeptidase that releases acidic amino acids present at the N-terminus of substrate peptides such as angiotensin II and neurokinin B, and its activity is greatly enhanced by Ca ²⁺ (Non-patent Document 1). APA is not only involved in the metabolism of substrate peptides, but is also the same molecule as the differentiation antigen BP-1 / 6C3 of mouse pre-B cells (Non-patent Document 2), and as a molecule expressed at the neovascular site of cancer Is known (Non-patent Document 3), but its physiological role is unknown. So far, amastatin (Non-patent Document 4) has been found from microbial metabolites as an inhibitor of APA, but its APA inhibitory activity is inferior in the presence of Ca ²⁺ compared to that in the absence. There is a need to develop new compounds that inhibit APA activity in the presence of Ca ²⁺ . On the other hand, the development of new compounds suitable for the development of therapeutic drugs for kidneys with chronic iron overload and ischemic reperfusion injury is also desired (Non-patent Document 5).

Goto, Y. et al. J. Biol. Chem., 2006, 281, 23503-23513. Wu, Q. et al. Proc. Natl. Acad. Sci., 1990, 87, 993-997. Kubota, R. et al. Biochem. Biophys. Res. Commun., 2010, 402, 396-401. Aoyagi, T. et al. J. Antibiot., 1978, 31, 636-638. Mori, K. et al. J. Clin. Invest. 2005, 115, 610-625.

  In view of the above background art, an object of the present invention is to provide an APA inhibitor, a therapeutic agent for diseases such as cancer involving APA, and a novel compound and a pharmaceutical useful as a therapeutic agent for chronic iron overload and ischemic reperfusion injury. It is to provide a composition.

  As a result of diligent search for physiologically active substances contained in the microorganism culture solution, the present inventors have purified the compound isolated from actinomycetes culture solution to suit the purpose of the present invention. Furthermore, the analogs were synthesized using novel compounds derived from actinomycetes as lead compounds, and these compounds were found to be useful as APA inhibitors and siderophores.

The present invention provides the following compounds or physiologically acceptable salts thereof, APA inhibitors, iron chelators, and pharmaceutical compositions.
Item 1. The following formula (I):

[Wherein R ^{1 to} R ⁵ are the same or different and represent OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyl. Oxy group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, A carbamoyl group is shown. However, two or three adjacent groups among R ^{1 to} R ⁵ are OH, and two adjacent groups of R ^{1 to} R ⁵ may be combined to form a methylenedioxy group.
R ^a and R ^b are the same or different and each represents a hydrogen atom or a methyl group. R ^c represents a hydrogen atom or OH.
* 1 and * 2 represent asymmetric carbon atoms, and may have any configuration of D and L.
Y represents COOH, CN, CHO, CH ₂ OH, an alkoxymethyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-substituted carbamoyl group.
Z is a hydrogen atom or the following formula

(Wherein R ^{6 to} R ¹⁰ are the same or different and represent OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyl. Oxy group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, Represents a carbamoyl group, provided that two or three adjacent groups of R ^{6 to} R ¹⁰ are OH, and two adjacent groups of R ^{1 to} R ⁵ together form a methylenedioxy group. Also good.
R ^d represents a hydrogen atom or a cyano group. R ^e represents a hydrogen atom or a methyl group.
* Indicates a bond with an NH group. ) Is represented. ]
Or a physiologically acceptable salt thereof.
Item 2. The following formula (IA):

[Wherein R ^{1 to} R ⁵ are the same or different and represent OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyl. Oxy group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, A carbamoyl group is shown. However, two or three adjacent groups among R ^{1 to} R ⁵ are OH, and two adjacent groups of R ^{1 to} R ⁵ may be combined to form a methylenedioxy group.
R ^{6 to} R ¹⁰ are the same or different and are OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyloxy group, alkoxy Alkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, carbamoyl group . However, two or three adjacent groups of R ^{6 to} R ¹⁰ are OH, and two adjacent groups of R ^{1 to} R ⁵ may be combined to form a methylenedioxy group.
R ^a and R ^b are the same or different and each represents a hydrogen atom or a methyl group. R ^c represents a hydrogen atom or OH. R ^d represents a hydrogen atom or a cyano group. R ^e represents a hydrogen atom or a methyl group.
* 1 and * 2 represent asymmetric carbon atoms, and may have any configuration of D and L.
Y represents COOH, CN, CHO, CH ₂ OH, an alkoxymethyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-substituted carbamoyl group. ]
The compound of Claim 1 represented by these, or its physiologically acceptable salt.
Item 3. Item 3. An aminopeptidase A inhibitor comprising the compound according to Item 1 or 2. Item 5. An iron chelator agent comprising the compound according to Item 1 or 2. Item 3. A pharmaceutical composition comprising the compound according to Item 1 or 2 and a pharmaceutical carrier.
Item 6. Item 6. The pharmaceutical composition according to Item 5, which is a preventive or therapeutic agent for cancer.
Item 7. Item 6. The pharmaceutical composition according to Item 5, which is a therapeutic agent for chronic iron overload.

  Since the compound of the present invention effectively inhibits APA, it is useful as a preventive or therapeutic agent for cancer. Further, since it is a siderophore, it is useful as a therapeutic agent for chronic iron overload and ischemic reperfusion injury.

A protocol for purifying compounds 1 to 3 by culturing Streptomyces actinomycetes ML93-86F2 is shown.

In the present specification, the following abbreviations are used.
DIEA: N, N-diisopropylethylamine
HATU: 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridine-1-ium 3-oxide hexafluorophosphate
HOAT: 1-hydroxy-7-azabenzotriazole
HOBT: 1-Hydroxybenzotriazole In the present specification, the “halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom or a chlorine atom.

The alkyl group may be linear, branched or cyclic, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, C _1-10 alkyl groups such as heptyl, octyl, nonyl and decyl, preferably C _1-6 alkyl groups, more preferably C _1-4 alkyl groups, still more preferably C _1-3 alkyl groups, especially C _1-2 An alkyl group is mentioned.

The C _1-6 alkyl group may be linear or branched. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl and hexyl.

The C _1-4 alkyl group may be linear or branched. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl.

The C _1-3 alkyl group may be linear or branched. For example, methyl, ethyl, n-propyl, and isopropyl are mentioned.

AC _1-2 alkyl group is methyl or ethyl.

Specific examples of the cycloalkyl group include C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

“Mono-substituted” in a mono- or di-substituted amino group or mono- or di-substituted carbamoyl group means that one of hydrogen atoms bonded to the nitrogen atom of the amino group or carbamoyl group is substituted with C _1-6 alkyl. The term “disubstituted” means that two hydrogen atoms bonded to the nitrogen atom of the amino group or carbamoyl group are substituted with the same or different C _1-6 alkyl, or 3 to 8 members, preferably 5 Alternatively, it is substituted with a 6-membered nitrogen-containing cyclic group. Specific examples of the nitrogen-containing cyclic group include morpholino, 1-pyrrolidinyl, piperidino and 4-methyl-1-piperazinyl.

The amino group monosubstituted by C _1-6 alkyl includes methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert-butylamino, n-pentylamino, isopentylamino. And hexylamino.

_{Examples of} the amino group disubstituted with C _1-6 alkyl include dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, di-n-butylamino, diisobutylamino, ditert-butylamino, di-n-pentylamino, Examples include diisopentylamino and dihexylamino.

Examples of the carbamoyl group mono-substituted with C _1-6 alkyl include methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, n-butylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl, n-pentylcarbamoyl, isopentylcarbamoyl And hexylcarbamoyl.

Examples of the carbamoyl group di-substituted with C _1-6 alkyl include dimethylcarbamoyl, diethylcarbamoyl, di-n-propylcarbamoyl, diisopropylcarbamoyl, di-n-butylcarbamoyl, diisobutylcarbamoyl, ditert-butylcarbamoyl, din-pentylcarbamoyl. , Diisopentylcarbamoyl, and dihexylcarbamoyl.

  The aryl group means a monocyclic or polycyclic group composed of a 5- or 6-membered aromatic hydrocarbon ring. Specific examples include phenyl, naphthyl, fluorenyl, anthryl, biphenylyl, tetrahydronaphthyl, chromanyl, 2 , 3-dihydro-1,4-dioxanaphthalenyl, indanyl and phenanthryl.

Acyloxy means C _1-6 alkylcarbonyloxy, arylcarbonyloxy or aryl-substituted C _1-4 alkylcarbonyloxy.

Specific examples of C _1-6 alkylcarbonyloxy include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentyl. Examples include carbonyloxy, isopentylcarbonyloxy, hexylcarbonyloxy.

  Specific examples of arylcarbonyloxy include phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1 , 4-Dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy and phenanthrylcarbonyloxy.

Specific examples of the aryl-substituted C _1-4 alkylcarbonyloxy include benzylcarbonyloxy, naphthylmethylcarbonyloxy, fluorenylmethylcarbonyloxy, anthrylmethylcarbonyloxy, biphenylylmethylcarbonyloxy, tetrahydronaphthylmethylcarbonyloxy, chromanyl Rumethylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylmethylcarbonyloxy, indanylmethylcarbonyloxy and phenanthrylmethylcarbonyloxy, phenethylcarbonyloxy, naphthylethylcarbonyloxy, fluorenylethyl Carbonyloxy, anthrylethylcarbonyloxy, biphenylylethylcarbonyloxy, tetrahydronaphthylethylcarbonyloxy, chroman Examples include ruethylcarbonyloxy, 2,3-dihydro-1,4-dioxanaphthalenylethylcarbonyloxy, indanylethylcarbonyloxy and phenanthrylethylcarbonyloxy.

Acylamino means C _1-6 alkylcarbonylamino, arylcarbonylamino or aryl-substituted C _1-4 alkylcarbonylamino.

Specific examples of C _1-6 alkylcarbonylamino include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, tert-butylcarbonylamino, n-pentyl. Examples include carbonylamino, isopentylcarbonylamino, and hexylcarbonylamino.

  Specific examples of arylcarbonylamino include phenylcarbonylamino, naphthylcarbonylamino, fluorenylcarbonylamino, anthrylcarbonylamino, biphenylylcarbonylamino, tetrahydronaphthylcarbonylamino, chromanylcarbonylamino, 2,3-dihydro-1 , 4-dioxanaphthalenylcarbonylamino, indanylcarbonylamino and phenanthrylcarbonylamino.

Specific examples of the aryl-substituted C _1-4 alkylcarbonylamino include benzylcarbonylamino, naphthylmethylcarbonylamino, fluorenylmethylcarbonylamino, anthrylmethylcarbonylamino, biphenylylmethylcarbonylamino, tetrahydronaphthylmethylcarbonylamino, chromanyl Rumethylcarbonylamino, 2,3-dihydro-1,4-dioxanaphthalenylmethylcarbonylamino, indanylmethylcarbonylamino and phenanthrylmethylcarbonylamino, phenethylcarbonylamino, naphthylethylcarbonylamino, fluorenylethyl Carbonylamino, anthrylethylcarbonylamino, biphenylylethylcarbonylamino, tetrahydronaphthylethylcarbonylamino, chroman Examples include ruethylcarbonylamino, 2,3-dihydro-1,4-dioxanaphthalenylethylcarbonylamino, indanylethylcarbonylamino and phenanthrylethylcarbonylamino.

Specific examples of the alkoxy group have linear or branched methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, tert-butyloxy, n-pentyloxy, isopentyloxy, hexyloxy and the like. C _1-6 alkyloxy is mentioned.

Specific examples of the alkoxyalkyl group include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, n-propoxymethyl, n-propoxyethyl, isopropoxymethyl, isopropoxyethyl, n-butyloxymethyl, isobutyloxymethyl, tert Examples thereof include linear or branched C _1-6 alkoxyalkyl such as -butyloxymethyl, n-butyloxyethyl, isobutyloxyethyl, tert-butyloxyethyl and the like.

Specific examples of the alkoxymethyl group include straight chain or branched C ₁ -such as methoxymethyl, ethoxymethyl, n-propoxymethyl, isopropoxymethyl, n-butyloxymethyl, isobutyloxymethyl, tert-butyloxymethyl and the like. ₆ alkoxyalkyl is mentioned.

  Specific examples of aryloxy include phenyloxy, naphthyloxy, fluorenyloxy, anthryloxy, biphenylyloxy, tetrahydronaphthyloxy, chromanyloxy, 2,3-dihydro-1,4-dioxanaphthalenyl Examples include oxy, indanyloxy and phenanthryloxy.

  Specific examples of aralkyloxy include benzyloxy, naphthylmethyloxy, fluorenylmethyloxy, anthrylmethyloxy, biphenylylmethyloxy, tetrahydronaphthylmethyloxy, chromanylmethyloxy, 2,3-dihydro-1,4. -Dioxanaphthalenylmethyloxy, indanylmethyloxy and phenanthrylmethyloxy, 0 phenethyloxy, naphthylethyloxy, fluorenylethyloxy, anthrylethyloxy, biphenylylethyloxy, tetrahydronaphthylethyloxy, chroman Examples include ruethyloxy, 2,3-dihydro-1,4-dioxanaphthalenylethyloxy, indanylethyloxy and phenanthrylethyloxy.

Specific examples of the alkoxycarbonyl group include C _1-6 alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl and the like. Groups.

  Specific examples of the aralkyl group include benzyl, naphthylmethyl, fluorenylmethyl, anthrylmethyl, biphenylylmethyl, tetrahydronaphthylmethyl, chromanylmethyl, 2,3-dihydro-1,4-dioxanaphthalenylmethyl. , Indanylmethyl and phenanthrylmethyl, phenethyl, naphthylethyl, fluorenylethyl, anthrylethyl, biphenylylethyl, tetrahydronaphthylethyl, chromanylethyl, 2,3-dihydro-1,4-dioxanaphthale Examples include nylethyl, indanylethyl and phenanthrylethyl.

The alkylthio group may be linear or branched. Examples thereof include C _1-6 alkylthio groups such as methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, tert-butylthio, n-pentylthio, isopentylthio, hexylthio and the like.

  Examples of physiologically acceptable salts of the compounds represented by formulas (I) and (IA) include, for example, salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, bases And salts with acidic or acidic amino acids. Preferable examples of the salt with inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt and ammonium salt. Preferable examples of the salt with an organic base include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine and the like. Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p -Salts with toluenesulfonic acid and the like. Preferable examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid, for example. It is done.

  The compounds represented by formulas (I) and (IA) or physiologically acceptable salts thereof may be crystalline or non-crystalline, in the form of hydrates and / or solvates. These hydrates and / or solvates are also included in the compounds represented by formulas (I) and (IA) or physiologically acceptable salts thereof. Compounds containing various amounts of water obtained by methods such as stoichiometric amounts of hydrates and lyophilization also include compounds of formulas (I) and (IA) or physiologically acceptable salts thereof. Is in range.

  The compounds represented by the formulas (I) and (IA) have * 1 and * 2 asymmetric carbon atoms. These two asymmetric carbons originate from ornithine or a derivative thereof, and may have any configuration of D and L, and (* 1, * 2) combinations include (D, D), ( Any combination of (D, L), (L, D), and (L, L) may be used. The compounds of the present invention include enantiomers, diastereomers, or mixtures and racemates of these isomers. Compounds of formula (I) and (IA) substituted with isotopes are also encompassed by the present invention.

Preferred groups represented by R ^{1 to} R ⁵ include OH, SH, hydrogen atom, halogen atom, alkyl group, alkoxy group, alkylthio group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, carbamoyl group, more preferably OH, SH, hydrogen atom, Cl, F, methyl , Ethyl, methoxy, ethoxy, methylthio, methoxymethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, CN, CF ₃ , acetyl group, amino group, dimethylamino group, dimethylcarbamoyl group, acetylamino group, acetyloxy group Carbamoyl group More preferred are OH, hydrogen atom, Cl, F, methyl, methoxy, methoxymethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl, CN, CF ₃ , acetylamino group, and acetyloxy group.

Of R ^{1 to} R ⁵ , the adjacent two or three groups are OH. That is, R ¹ = R ² = OH, R ² = R ³ = OH, R ³ = R ⁴ = OH, R ⁴ = R ⁵ = OH, or R ¹ = R ² = R ³ = OH, R ² = Either R ³ = R ⁴ = OH or R ³ = R ⁴ = R ⁵ = OH. The remaining group may be any of the groups described above.

Preferred groups represented by R ^{6 to} R ¹⁰ include OH, SH, hydrogen atom, halogen atom, alkyl group, alkoxy group, alkylthio group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, carbamoyl group, more preferably OH, SH, hydrogen atom, Cl, F, methyl , Ethyl, methoxy, ethoxy, methylthio, methoxymethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, CN, CF ₃ , acetyl group, amino group, dimethylamino group, dimethylcarbamoyl group, acetylamino group, acetyloxy group A carbamoyl group, More preferred are OH, hydrogen atom, Cl, F, methyl, methoxy, methoxymethyl, methoxyethyl, methoxycarbonyl, ethoxycarbonyl, CN, CF ₃ , acetylamino group, and acetyloxy group.

Of R ^{6 to} R ¹⁰ , two or three adjacent groups are OH. That is, R ¹ = R ⁷ = OH, R ⁷ = R ⁸ = OH, R ⁸ = R ⁹ = OH, R ⁹ = R ¹⁰ = OH, or R ¹ = R ⁷ = R ⁸ = OH, R ⁷ = Either of R ⁸ = R ⁹ = OH and R ⁸ = R ⁹ = R ¹⁰ = OH. The remaining group may be any of the groups described above.

R ^a and R ^b are the same or different and each represents a hydrogen atom or a methyl group, preferably R ^a = R ^b = hydrogen atom.

R ^c represents a hydrogen atom or OH, preferably OH.

Y represents COOH, CN, CHO, CH ₂ OH, alkoxymethyl group, alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, mono- or di-substituted carbamoyl group, preferably COOH, CN, CHO, An alkoxycarbonyl group, a carbamoyl group, a mono- or di-substituted carbamoyl group;

  The structures of preferred compounds 1 to 8 of the present invention are shown below.

  The above compounds 1 to 3 were obtained from a culture solution of Streptomyces actinomycetes ML93-86F2.

  Compounds 4 to 8 are compounds obtained by chemical synthesis by the present inventors as analogs of compounds 1 to 3.

  The production method of the compound of the present invention is not particularly limited. For example, a method of separating and collecting from a culture of microorganisms capable of producing the compound of the present invention (extraction method), or a compound having a similar structure contained in a culture of microorganisms. Examples of the starting material include a chemical synthesis method (synthetic method or semi-synthetic method). In the extraction method, a microorganism capable of producing the compound of the present invention is cultured using a medium and conditions used for normal fermentation production, and the target product can be separated and collected from the obtained culture. Examples of the microorganism capable of producing the compound of the present invention include Streptomyces actinomycetes ML93-86F2.

  The microorganism was deposited as a label “ML93-86F2” on December 5, 2013 at the Patent Microorganism Depositary Center of the National Institute of Technology and Evaluation (2-5-8 Kazusa Kamashichi, Kisarazu City, Chiba Prefecture) The accession number is “NITE P-01778”.

  The medium for producing the compound of the present invention is not particularly limited, and any synthetic medium or natural medium can be suitably used as long as it appropriately contains a carbon source, a nitrogen source and an inorganic salt. A pressed wheat medium is a preferred medium. If necessary, vitamins or other nutrient substances may be added as appropriate.

Examples of carbon sources include sugars such as glucose, maltose, fructose, sucrose and starch, alcohols such as glycerol and mannitol, amino acids such as glycine, alanine and asparagine, and fats and oils such as soybean oil and olive oil. One kind or two or more kinds may be appropriately selected from various carbon sources in consideration of assimilability of microorganisms. Nitrogen sources include soy flour, corn steep liquor, beef extract, peptone, yeast extract, amino acid mixture, organic nitrogen-containing compounds such as fish meal, or inorganic nitrogen compounds such as ammonium salts and nitrates, taking into consideration the assimilability of microorganisms Thus, one or more kinds may be appropriately selected and used. As the inorganic salt, for example, calcium carbonate, sodium chloride, potassium chloride, magnesium sulfate, copper sulfate, cobalt chloride, and various phosphates may be added as necessary. Further, an antifoaming agent such as vegetable fat, polypropylene alcohol and the like can be added as necessary.
The culture temperature can be appropriately changed within the range in which the microorganism grows and the compound of the present invention is produced, but is preferably 10 to 32 ° C, more preferably 20 to 28 ° C. The initial pH is desirably around 6-8, and the culture time is usually from about a few days to several weeks, but when the production amount of the compound of the present invention reaches an amount that can be collected, preferably when it reaches the maximum. Just finish. The culture method is not particularly limited, and any commonly used method such as solid layer culture or normal stirring culture can be suitably used.

  Separation and collection of the compound of the present invention from the culture solution can be carried out by appropriately utilizing means commonly used for obtaining microbial metabolites. For example, various ion exchange resins, nonionic adsorption resins, gel filtration chromatography, or chromatography with an adsorbent such as activated carbon, alumina, silica gel, or the means of crystallization, vacuum concentration, or lyophilization alone or in combination Or can be used repeatedly.

  Compound (I) of the present invention can be chemically synthesized, for example, according to the following scheme 1.

<Scheme 1>

[Wherein, R ^{1 to} R ⁵ , R ^a , R ^b , * 1, * 2, and Z are as defined above. R ^c1 represents a hydrogen atom or O-benzyl, Y ¹ represents COO (benzyl), CN, CHO, CH ₂ OH, alkoxymethyl, alkoxycarbonyl group, aryloxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, mono Or a di-substituted carbamoyl group is shown. ]

STEP1
About 1 to 2 moles of compound I-2, about 0.5 to 2 moles of diisopropylethylamine (DIEA), and HAU, HBTU, TBTU, HATU, DCC, WSC, etc. 1 mol to an excess amount, and if necessary, a benzotriazole derivative such as HOAt, HOBt, HBTU, HATU, etc. is used in an excess amount from 1 mol, and the reaction is carried out in a solvent at a temperature from −10 ° C. to the boiling point of the solvent. Compound I-3 can be obtained. Examples of the solvent include DMF, dimethylacetamide, DMSO, N-methylpyrrolidone, dioxane and the like.

STEP2
When Y ¹ and R ^c1 have a protecting group (benzyl group), about 1 mg of compound I-3 is used about 10 mg to 500 mg of a catalyst such as Pd / C, Raney nickel, THF, ether, diisopropyl ether, dioxane, etc. In the presence of hydrogen gas (normal pressure or pressure) in the solvent, the benzyl group is deprotected by reacting at a temperature of about 0 to 40 ° C. for 1 to 12 hours to obtain the target compound (I). Can do. The protecting group may be other than a benzyl group, and deprotection can be performed under appropriate conditions depending on the protecting group.

  Each compound obtained by the above-described production method is isolated and purified according to conventional methods such as extraction, silica gel column chromatography, recrystallization, and reprecipitation. As the extraction solvent, diethyl ether, ethyl acetate, chloroform, dichloromethane, toluene or the like is used. Purification by silica gel column chromatography uses acidic, basic, or various chemically treated silica gel or alumina, and developing solvents include, for example, hexane / ethyl acetate, hexane / chloroform, ethyl acetate / methanol, chloroform / methanol, Acetonitrile / water, methanol / water, etc. can be used.

  When the compounds of formulas (I) and (IA) are racemic, chromatography using an optically active column, optical resolution using an optically active acid or a synthetic chiral resolving agent, preferred crystallization method, diastereomer method According to a conventional method such as the above, each enantiomer can be separated and purified. For example, separation into enantiomers using an optically active acid is performed by forming a diastereomeric salt according to a conventional method, separating the diastereomeric salt, and then converting this into a free base. Examples of the optically active acid used as the optical resolution agent include (+)-or (-)-camphoric acid, (1S)-(+)-or (1R)-(-)-camphor-10-sulfonic acid, L -(+)-Or D-(-)-tartaric acid, (+)-or (-)-mandelic acid, (S)-(-)-or (R)-(+)-malic acid, L-pyroglutamic acid , (S)-(+)-or (R)-(−)-1,1′-binaphthyl-2,2′-diyl, (+)-dibenzoyl-D-tartaric acid or (−)-dibenzoyl-L— Examples include tartaric acid.

  In the said manufacturing method, each reaction can also be performed after introduce | transducing a protective group into the functional group (Hydroxy group, a carboxyl group, an amino group, etc.) contained in a raw material compound as needed. The target compound can be obtained by subjecting the obtained reaction product to a deprotection treatment. The protection and deprotection of the functional group can be easily performed by those skilled in the art according to a conventional method.

  The compounds of formulas (I) and (IA) can be obtained in the form of a free base or an acid addition salt depending on the type of functional group present in the structural formula, the selection of raw material compounds, and the reaction treatment conditions. It can be converted to compounds of (I) and (IA). On the other hand, the compounds of formulas (I) and (IA) can be converted into acid addition salts by treating with an appropriate acid according to a conventional method depending on the type of functional group present in the structural formula.

  The synthetic routes of compounds 1 to 8 of the present invention are shown in the following schemes 2 to 4.

(Scheme 2. Synthesis route of compounds 1 and 4)

  Using the known compound 9 as a starting material, the reaction was carried out using the reagents, temperature, and reaction time shown in Scheme 2 above, using each reagent in an equivalent or excess amount according to a conventional method, and the yield shown in Scheme 2 was obtained. Compounds 10-14 were synthesized.

  Next, using the known compound 15 as a starting material, the reaction was carried out using the reagents, temperature, and reaction time shown in Scheme 2 above, using each reagent in an equivalent or excess amount according to a conventional method, and the reaction shown in Scheme 2 was performed. Compounds 16-23 were synthesized at the rate.

  Further, compound 14 is reacted with an appropriate amount of TFA (trifluoroacetic acid) in DCM (dichloromethane) at room temperature for 30 minutes to deprotect the BOC group, and then DIEA, HATU, HOAt is used from 0 ° C. in DMF. Reaction was performed at room temperature for 3 hours to obtain a condensation product 24. The amount of DIEA, HATU, and HOAt can be easily determined by those skilled in the art according to conventional methods of peptide synthesis.

  The compound 24 was reacted in THF at room temperature for 30 minutes using an equimolar or excess amount of LiOH aqueous solution with respect to the compound 24 to hydrolyze the COOBn ester to obtain a compound 25 in a yield of 96%.

  Compound 1 was obtained by using 0.1 to 0.5 times the amount of Pd / C with respect to Compound 25 and reacting at room temperature for 2 hours while bubbling hydrogen gas in THF.

  Compound 4 uses compound 22 and 2,3-dibenzyloxybenzoic acid, and reacts D-Arg having an amino group protected with Cbz or the like with an acid chloride of 2,3-dibenzyloxybenzoic acid to react with N- The 2,3-dibenzyloxybenzoyl group was bonded to the guanidyl group of the protected D-Arg, then the amino protecting group was removed, and the acid chloride of compound 22 was reacted to synthesize the corresponding compound of compound 23. It can obtain by reacting similarly to the scheme 2 below.

(Scheme 3. Synthesis route of compounds 5, 6, 7)

  Using the known compound 26 as a starting material, the reaction was carried out using the reagents, temperature, and reaction time shown in Scheme 3 above, using each reagent in an equivalent or excess amount according to a conventional method, and the yield shown in Scheme 3 was obtained. Compounds 27-30 were synthesized.

Further, Compound 22 obtained in Scheme 2 and (COCl) ₂ were reacted in catalytic amount of DMF and DCM at room temperature for 30 minutes to lead to acid chloride, and then at room temperature in the presence of L-Arg and NaOH in dioxane. The compound 31 was obtained by reacting for 4 hours.

  Compound 32 is reacted with an appropriate amount of TFA (trifluoroacetic acid) in DCM (dichloromethane) for 1 hour at room temperature to deprotect the BOC group, then DIEA, HATU, HOAt are used in DMF from 0 ° C. to room temperature. Reaction was performed for 4 hours to obtain a condensation product 33. The amount of DIEA, HATU, and HOAt can be easily determined by those skilled in the art according to conventional methods of peptide synthesis.

  The compound 33 was reacted in THF at room temperature for 20 minutes using an equimolar or excessive amount of LiOH aqueous solution to hydrolyze the COOBn ester to obtain a compound 34 in a yield of 73% (3 steps).

  0.1 to 0.5 times the amount of Pd / C was used with respect to compound 34, and reacted at room temperature for 2.5 hours while bubbling hydrogen gas in THF to obtain compound 5.

  Compound 6 uses Compound 22 and 2,3-dibenzyloxybenzoic acid, and reacts D-Arg having an amino group protected with Cbz or the like with an acid chloride of 2,3-dibenzyloxybenzoic acid to react with N- The 2,3-dibenzyloxybenzoyl group was bonded to the guanidyl group of the protected D-Arg, then the amino protecting group was removed, and the acid chloride of compound 22 was reacted to synthesize the corresponding compound of compound 31. It can obtain by reacting similarly to the scheme 3 below.

  Compound 7 uses Compound 22 and 2,3-dibenzyloxybenzoic acid, and reacts D-Arg in which the amino group is protected with Cbz or the like and the acid chloride of Compound 22 to react the guanidyl group of N-protected D-Arg. 2,3-dibenzyloxy-4-chlorobenzoyl group is bound to the amino group, the amino protecting group is removed, and the acid chloride of 2,3-dibenzyloxybenzoic acid is reacted to react with compound 31 The compound can be synthesized and then reacted in the same manner as in Scheme 3 below.

(Scheme 4. Synthesis route of compound 8)

Compound 8 can be obtained by reacting in the same manner as in Scheme 2 using Compound 35 instead of Compound 21 in Scheme 2.

  Next, the pharmaceutical composition containing the compound of the present invention will be described below.

  The present invention relates to a pharmaceutical composition comprising a compound represented by formulas (I) and (IA) or a physiologically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient, diluent or carrier. Also provide. Preparation of a compound represented by formulas (I) and (IA) or a physiologically acceptable salt thereof as a pharmaceutical composition together with pharmaceutically acceptable conventionally known excipients, diluents, carriers and the like. Can do.

  Examples of the excipient include starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like, and they are used alone or in combination of two or more.

  Examples of the diluent include distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, propylene glycol, polyethylene glycol and the like, and are used alone or in combination of two or more.

  Examples of the carrier include magnesium carbonate, magnesium stearate, talc, sucrose, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and the like, one kind alone or a combination of two or more kinds. used.

  In addition to the above, as additives, for example, binders, disintegrants, surfactants, absorption promoters, humectants, adsorbents, lubricants, fillers, fillers, moisturizers, preservatives, stabilizers, An emulsifier, a solubilizer, a salt that adjusts osmotic pressure, and the like can be appropriately selected and used according to the dosage unit form of the resulting preparation. Furthermore, in the pharmaceutical composition of the present invention, a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like can be blended and prepared as necessary.

  The dosage form of the pharmaceutical composition of the present invention may be oral or parenteral (eg, topical, rectal, intravenous administration, etc.), tablets (including sugar-coated tablets, film-coated tablets), powders, granules, capsules Agents (including soft capsules), solutions, injections, suppositories, sustained-release agents and the like can be mentioned. In the case of preparation in the form of injection, intravenous, intramuscular, subcutaneous, intraorgan, intranasal, intradermal, ophthalmic, intracerebral, rectal, vaginal and intraperitoneal, intratumoral, intratumoral It can be administered proximally or directly to the lesion.

  In addition, when the pharmaceutical composition of the present invention is in a liquid state, it may be stored after removing moisture by freeze storage or freeze drying. The freeze-dried preparation is used by adding distilled water for injection at the time of use and dissolving it again.

  The dosage of the pharmaceutical composition can be appropriately set according to the desired therapeutic effect, administration method, treatment period, patient age, sex, and other conditions. Usually, the compound of the present invention, which is an active ingredient, The daily dose is about 1 μg to 10 g, preferably about 100 μg to 1 g, more preferably about 1 mg to 500 mg, and further preferably about 5 mg to 200 mg. The pharmaceutical composition of the present invention can be administered once or several times a day.

  The content of the compound represented by the formulas (I) and (IA) or a salt thereof contained in the pharmaceutical composition of the present invention varies depending on the form of the preparation, and is appropriately set based on the dose usually employed. Examples thereof include 0.0001 to 99.9999% by weight.

  Since the compounds represented by formulas (I) and (IA) or physiologically acceptable salts thereof have APA inhibitory activity, they are useful as anticancer agents. Further, since it has siderophore activity, it is useful as a therapeutic agent for chronic iron overload and ischemic reperfusion injury.

  Since the compound represented by the formula (I) or a physiologically acceptable salt thereof has low toxicity and is safe, it can be used as a medicine or mixed with a pharmaceutically acceptable carrier known per se as a human. Can be administered to mammals (eg, horses, cows, dogs, cats, rats, mice, rabbits, pigs, monkeys, humans, etc.) to prevent or treat cancer in the mammals.

  Hereinafter, the present invention will be described in more detail with reference to Reference Examples, Examples and Test Examples, but these do not limit the present invention.

Example 1: Synthesis of compounds 1 and 4 to 8 or purification of compounds 1 to 3 from a culture medium and physical properties of compounds 1 to 8

(1) Chemical synthesis of compounds 1 and 4 (Scheme 2)
Compounds 1 and 4 were prepared according to Scheme 2 above. Scheme 2 above describes the chemical reaction formula, reagents used in each step, solvent, reaction temperature, reaction time, and yield. The solvent was used in an amount of about 20 to 100 times the amount of the reagent to be dissolved, and the reagent was used in an equivalent amount or an equimolar to excess amount (for example, 2 equivalents or 2 mols) relative to 1 mol of the raw material compound. However, Pd / C was used in an amount 0.1 to 0.5 times that of the starting compound.

(2) Chemical synthesis of compounds 5, 6 and 7 (Scheme 3)
Compounds 5, 6, 7 were prepared according to Scheme 3 above. In Scheme 3 above, chemical reaction formulas, reagents used in each step, solvent, reaction temperature, reaction time, and yield are described. The solvent was used in an amount of about 20 to 100 times the amount of the reagent to be dissolved, and the reagent was used in an amount of 1 equivalent or 1 mole to an excess amount (for example, 2 equivalents or 2 moles) per mole of the raw material compound. However, Pd / C was used in an amount 0.1 to 0.5 times that of the starting compound.

(3) Chemical synthesis of compound 8 (Scheme 4)
Compound 8 was prepared according to Scheme 4 above. In Scheme 4 above, chemical reaction formulas, reagents used in each step, solvent, reaction temperature, reaction time, and yield are described. The solvent was used in an amount of about 20 to 100 times the amount of the reagent to be dissolved, and the reagent was used in an amount of 1 equivalent or 1 mole to an excess amount (for example, 2 equivalents or 2 moles) per mole of the raw material compound. However, Pd / C was used in an amount 0.1 to 0.5 times that of the starting compound.

(4) Culture of Streptomyces actinomycetes ML93-86F2 and purification of compounds 1-3
Streptomyces actinomycetes ML93-86F2 was cultured in pressed wheat medium (pressed wheat 840 g, water 1400 mL, 30 ° C., 14 days), extracted with ethanol, and fractionation proceeded using APA inhibitory activity as an indicator. That is, the ethanol extract (49.0 g) was divided into two phases under the conditions of THF / brine (pH 9.2), THF / brine (pH 4.6) and then 60% MeOH / CHCl ₃ and then separated by reversed-phase column chromatography. I drew it. The fraction eluted with 60% MeOH was purified by one reverse phase HPLC (gradient 20-80% MeCN) to give active compound 1 (75.6 mg). On the other hand, the fraction eluted with 30% MeOH was purified by two reverse-phase HPLC (15% MeCN + 0.1% TFA, 10% MeCN + 0.1% TFA) to give compound 2 (16.6 mg), compound 3 ( 0.7 mg) was obtained.

(5) Physicochemical properties of compounds 1 to 8 The physicochemical properties of compounds 1 to 8 obtained in the above (1) to (4) are shown below.

  In addition, Table 1 shows 1H-NMR and 13C-NMR data of Compounds 1-3.

Compound 1:
Color and shape: Brown amorphous molecular formula: C ₂₆ H ₃₀ Cl ₂ N ₆ O ₁₁
High resolution ESI MS: m / z 673.1432 ([M + H] ⁺ , △ + 1.0 mmu).
Specific rotation: [α] ²⁰ _D +2.6 (c 0.63, MeOH)
UV (MeOH): λ _max nm (log ε) 212 (4.62), 261 (4.29), 315 (3.60)
IR (neat): ν _max 3297, 2987, 1659, 1645, 1592, 1543, 1439, 1315, 1219 cm ⁻¹ .
NMR: Table 1 shows the data measured in DMSO.

Compound 2:
Color and shape: Brown amorphous molecular formula: C ₁₈ H ₂₅ ClN ₄ O ₈
High resolution ESI MS: m / z 461.1433 ([M + H] ⁺ , △ -0.1 mmu)
Specific rotation: [α] ²⁰ _D -7.7 (c 0.70, MeOH)
UV (MeOH): λ _max nm (logε) 210 (4.38), 256 (4.01), 309 (3.33)
IR (neat): ν _max 3162, 3085, 2936, 1669, 1653, 1558, 1541, 1437 cm ⁻¹ .
NMR: Data measured in CD ₃ OD are shown in Table 1.

Compound 3: Molecular formula C ₁₈ H ₂₅ ClN ₄ O ₇ : HRMS (ESI) m / z 445.1506 [M + H] ⁺ calcd for C ₁₈ H ₂₆ ClN ₄ O ₇ , 445.1485
NMR: Data measured in CD ₃ OD are shown in Table 1.

Compound 4: Molecular formula C ₂₆ H ₃₁ ClN ₆ O ₁₁ : LRMS (ESI) m / z 639.19 [M + H] ⁺ calcd for C ₂₆ H ₃₂ ClN ₆ O ₁₁ , 639.18
Compound 5: Molecular formula C ₂₆ H ₃₀ Cl ₂ N ₆ O ₁₁ : LRMS (ESI) m / z 673.15 [M + H] ⁺ calcd for C ₂₆ H ₃₁ Cl ₂ N ₆ O ₁₁ , 673.14
Compound 6: Molecular formula C ₂₆ H ₃₁ ClN ₆ O ₁₁ : LRMS (ESI) m / z 639.19 [M + H] ⁺ calcd for C ₂₆ H ₃₂ ClN ₆ O ₁₁ , 639.18
Compound 7: Molecular formula C ₂₆ H ₃₁ ClN ₆ O ₁₁ : LRMS (ESI) m / z 639.19 [M + H] ⁺ calcd for C ₂₆ H ₃₂ ClN ₆ O ₁₁ , 639.18
Compound 8: Molecular formula C ₂₆ H ₃₂ N ₆ O ₁₁ : LRMS (ESI) m / z 605.23 [M + H] ⁺ calcd for C ₂₆ H ₃₃ N ₆ O ₁₁ , 605.22

Test example 1
Secreted recombinant APA was expressed and purified using a baculovirus expression system. The aminopeptidase activity of APA was measured as follows.

APA (500 ng / mL) and Glu-AMC (7-amino-4-methylcoumarin, 100 μM) were mixed in 25 mM Tris buffer (pH 8.0), reacted at 37 ° C for 30 minutes, and then 0.5 M acetate buffer (pH 4.15) was added to terminate the enzyme reaction. The enzyme activity was quantified by measuring the fluorescence intensity (excitation 380 nm, detection 460 nm) of this reaction solution. The activity of each compound 1-8 was evaluated by evaluating the APA inhibitory activity in the presence / absence of 1 mM Ca ²⁺ .

As a result, compounds 1, 4, and 6 showed particularly strong APA inhibitory activity in the presence of Ca ²⁺ , indicating that the compound of the present invention is promising as an APA inhibitor and a therapeutic agent for cancers involving APA. It was.

Test Example 2 (Measurement of metal binding ability)
Compounds 1 and 4 have a catecholate structure and a structure characteristic of the siderophore called N-hydroxyformamide. The binding ability of compounds 1 and 4 to Fe ³⁺ and Ga ^3+, which are known to form stable bonds with siderophores, was investigated. When compounds 1 and 4 were added with 1 equivalent of FeCl ₃ or GaCl ₃ were analyzed by LC-MS, metal-added ions could be detected in either case. This result indicates that compounds 1 and 4 have a metal chelator ability and are useful as therapeutic agents for chronic iron overload and ischemic reperfusion injury. On the other hand, from the measurement results of the reduction potential of the Fe (III) complex, it was clarified that 1 has stronger Fe (III) affinity than deferoxamine B.

Claims (7)

The following formula (I):
[Wherein R ^{1 to} R ⁵ are the same or different and represent OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyl. Oxy group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, A carbamoyl group is shown. However, two or three adjacent groups among R ^{1 to} R ⁵ are OH, and two adjacent groups of R ^{1 to} R ⁵ may be combined to form a methylenedioxy group.
R ^a and R ^b are the same or different and each represents a hydrogen atom or a methyl group. R ^c represents a hydrogen atom or OH.
* 1 and * 2 represent asymmetric carbon atoms, and may have any configuration of D and L.
Y represents COOH, CN, CHO, CH ₂ OH, an alkoxymethyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-substituted carbamoyl group.
Z is a hydrogen atom or the following formula
(Wherein R ^{6 to} R ¹⁰ are the same or different and represent OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyl. Oxy group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, Represents a carbamoyl group, provided that two or three adjacent groups of R ^{6 to} R ¹⁰ are OH, and two adjacent groups of R ^{1 to} R ⁵ together form a methylenedioxy group. Also good.
R ^d represents a hydrogen atom or a cyano group. R ^e represents a hydrogen atom or a methyl group.
* Indicates a bond with an NH group. ) Is represented. ]
Or a physiologically acceptable salt thereof. The following formula (IA):
[Wherein R ^{1 to} R ⁵ are the same or different and represent OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyl. Oxy group, alkoxyalkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, A carbamoyl group is shown. However, two or three adjacent groups among R ^{1 to} R ⁵ are OH, and two adjacent groups of R ^{1 to} R ⁵ may be combined to form a methylenedioxy group.
R ^{6 to} R ¹⁰ are the same or different and are OH, SH, hydrogen atom, halogen atom, alkyl group, aryl group, aralkyl group, cycloalkyl group, alkoxy group, alkylthio group, aryloxy group, aralkyloxy group, alkoxy Alkyl group, alkoxycarbonyl group, CN, NO ₂ , CF ₃ , C ₂ F ₅ , acetyl group, amino group, mono- or di-substituted amino group, mono- or di-substituted carbamoyl group, acylamino group, acyloxy group, carbamoyl group . However, two or three adjacent groups of R ^{6 to} R ¹⁰ are OH, and two adjacent groups of R ^{1 to} R ⁵ may be combined to form a methylenedioxy group.
R ^a and R ^b are the same or different and each represents a hydrogen atom or a methyl group. R ^c represents a hydrogen atom or OH. R ^d represents a hydrogen atom or a cyano group. R ^e represents a hydrogen atom or a methyl group.
* 1 and * 2 represent asymmetric carbon atoms, and may have any configuration of D and L.
Y represents COOH, CN, CHO, CH ₂ OH, an alkoxymethyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group, a mono- or di-substituted carbamoyl group. ]
The compound of Claim 1 represented by these, or its physiologically acceptable salt. An aminopeptidase A inhibitor comprising the compound according to claim 1 or 2. An iron chelator agent comprising the compound according to claim 1 or 2. A pharmaceutical composition comprising the compound according to claim 1 or 2 and a pharmaceutical carrier. The pharmaceutical composition according to claim 5, which is a preventive or therapeutic agent for cancer. The pharmaceutical composition according to claim 5, which is a therapeutic agent for chronic iron overload.