Substance of novel siderophore-type antifungal agent (compound) and use of same

Abstract

The present invention provides a compound of general formula (II) or a solvate thereof, an antifungal agent containing the same, or a method for treating a fungal disease using these. R1 represents a C6-10 cycloalkyl C1-3 alkyl group, and M represents a group 8 or group 13 element.

Description

Novel siderophore-type antifungal agent (compound) and its use

[0001] The present invention provides novel siderophore-type cyclic peptide compounds, antifungal agents comprising the compounds, and methods of treating fungal diseases using the compounds.

[0002] Fungi infect humans, animals, plants, and other organisms, causing a variety of diseases. For example, fungi can cause superficial mycoses in keratinized tissues such as the stratum corneum of the human skin, nails, and hair, as well as mucosal epithelia in the oral cavity and other tissues. They can also cause deep dermatomycoses in skin tissues located deep beneath the body surface, and deep mycoses in deep tissues such as the esophagus, internal organs, and brain. The main pathogenic fungi that infect humans and cause deep mycoses include Candida, Cryptococcus, and Aspergillus. The main superficial mycoses include Candida, which infects the skin, oral cavity, and vagina, and Trichophyton, which infects the skin of the hands and feet. To date, considerable effort has been made to develop antifungal agents, but compared to the development of antibacterial chemotherapeutic agents, few compounds have been used in clinical practice. In particular, deep mycoses have become more common in recent years, and the drugs used to treat these diseases are extremely limited in terms of antibacterial spectrum, efficacy, safety, and other factors. Furthermore, fluconazole, which is widely used among these antifungal agents, has low susceptibility to, for example, Candida glabrata, Candida tropicalis, and Candida krusei, and resistant strains have also emerged. Therefore, a new antifungal agent that overcomes these problems is eagerly awaited.

[0003]

[0004] As part of their search for compounds with antifungal activity, a research group at Astellas conducted extensive research on naturally occurring microorganisms and discovered the fungus Acremonium persicinum, which produces a cyclic compound with good antifungal activity and may be useful as an antifungal agent. From the culture medium, they isolated a novel siderophore-type antifungal agent, ASP2397(I), and found that the cyclic compound or its salts have good antifungal activity, particularly as a preventive or therapeutic agent for deep mycoses (Patent Documents 1, 2, and Non-Patent Document 1). This compound was licensed from Astellas to Vical, Inc., USA, and underwent phase 1 (PI) testing for the treatment of deep Aspergillus infections. As a result, it received FDA fast track designation and progressed to phase 2 (PI2), but is currently suspended.

[0005] WO2009113660A1 "Microorganisms producing cyclic compounds" (published September 17, 2009) WO2009113661A1 "Cyclic compounds and salts thereof" (published September 17, 2009)

[0006] J. Antibiot 2017 Jan;70(1):45-51.

[0007] The problem to be solved by the present invention is to provide a siderophore-type compound having antifungal activity and uses thereof.

[0008] The present inventors have conducted extensive studies of the structure-activity relationship between the metal chelating moiety and the other three amino acid residues of Compound (I) with this unique structure. As a result, it was found that modifying the benzene ring of D-Phe would result in an amino acid substitution, but that the activity could be enhanced by converting leucine. They then focused on this area. They discovered that the novel compound of the present invention, in which the amino acid in the cyclic compound (natural product) of Formula (I) is replaced with a non-natural amino acid, exhibits even greater activity than ASP2397 in the treatment of fungal infections, particularly deep fungal infections, and thus completed the present invention.

[0009] In one embodiment of the present invention, there is provided a compound or solvate of general formula (II): Here, R １ is C ６～１０ Cycloalkyl C １～３ an alkyl group; and M represents an element of Group 8 or 13.

[0010] In one embodiment of the present invention, preferably, R １ But C ６～１０ Compound (II) is provided, which is a cycloalkylmethyl group.

[0011] In one embodiment of the present invention, more preferably, R １ is substituted by cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl or 2-adamantyl １～３ The compound (II) is selected from the group consisting of alkyl groups.

[0012] In one embodiment of the present invention, even more preferably, R １ is selected from the group consisting of cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl or 2-adamantylmethyl.

[0013] In one embodiment of the present invention, M represents an element of Group 8 or Group 13, preferably iron (Fe) or ruthenium (Ru) of Group 8, or aluminum (Al) or gallium (Ga) of Group 13. More preferably, the present invention provides a compound (II) in which M represents Fe, a compound (II) in which M represents Al, a compound (II) in which M represents Ga, or a compound (II) in which M represents Ru.

[0014] In one embodiment of the present invention, most preferably, compound (II) is selected from the following:

[0015]

[0016]

[0017]

[0018]

[0019] In one embodiment of the present invention, it is most preferred that compound (II) is selected from compounds (IVf), (IVa), (IVg), (Vf), (Va), (Vg), (VIf), (VIa) and (VIg).

[0020] In another embodiment of the present invention, there is provided a compound of general formula (III) or a solvate thereof. Here, R １ is C ６～１０ Cycloalkyl C １～３ Indicates an alkyl group.

[0021] In one embodiment of the present invention, preferably, R １ But C ６～１０ Compound (III) is provided, which is a cycloalkylmethyl group.

[0022] In one embodiment of the present invention, more preferably, R １ is substituted by cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl or 2-adamantyl １～３ The compound (III) is selected from the group consisting of alkyl groups.

[0023] In one embodiment of the present invention, even more preferably, R １ is selected from the group consisting of cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl or 2-adamantylmethyl.

[0024] In yet another embodiment of the present invention, there is provided an antifungal agent comprising a compound of the above general formula (II) or a solvate thereof. Here, R １ and M has the same meaning as defined above.

[0025] In one embodiment of the present invention, there is also provided a method for treating fungal diseases using a compound of general formula (II) or a solvate thereof. Here, R １ and M have the same meanings as defined above. In one embodiment of the present invention, there is provided a compound of general formula (II) or a solvate thereof for use in treating fungal diseases. In one embodiment of the present invention, there is provided use of a compound of general formula (II) or a solvate thereof for the manufacture of an antifungal agent.

[0026] The compounds of the general formula (II) of the present invention have excellent antifungal activity.

[0027] FIG. 1 shows LC-MS data for the cyclized product (22). FIG. 1 shows LC-MS data for the cyclized product (22). FIG. 2 shows NMR data for the cyclized product (22). FIG. 3 shows HPLC data for the deprotected product (23) at the end of the reaction. FIG. 4 shows HPLC data for the crude product of complex (24). FIG. 5 shows LC-MS data for the crude product of complex (24). FIG. 5 shows LC-MS data for the crude product of complex (24). FIG. 6 shows NMR data for the crude product of complex (24). FIG. 7 shows HPLC data for the complex (24) after purification. FIG. 8 shows LC-MS data for the complex (24) after purification. FIG. 8 shows LC-MS data for the complex (24) after purification. FIG. 9 shows NMR data for the complex (24) after purification. FIG. 10 shows the antifungal activity evaluation of compound IVa (Al chelate), compound IVg (Ga chelate), and compound IVf (Fe chelate). FIG. 11 shows proton NMR data for compound 23 (metal-free form). FIG. 12 shows proton NMR data for complex IVg (23+Ga). FIG. 13 shows proton NMR data for the cyclized form of compound (231). FIG. 14 shows proton NMR data for the metal-free form of compound (232). FIG. 15 shows proton NMR data for complex (Va) (232+Al). FIG. 16 shows proton NMR data for complex (Vg) (232+Ga). FIG. 17 shows proton NMR data for the cyclized form of compound (234). FIG. 18 shows proton NMR data for the metal-free form of compound (235). Figure 19 shows proton NMR data for complex (VIa) (235+Al). Figure 20 shows proton NMR data for complex (VIg) (235+Ga). Figure 21 shows proton NMR data for the cyclized form of compound (247). Figure 22 shows proton NMR data for the metal-free form of compound (248). Figure 23 shows the antifungal activity evaluation of Al chelates of compounds 232 and 235. Figure 24 shows the antifungal activity evaluation of an Al, Ga, and Fe chelate of compound 232. Figure 25 shows the antifungal activity evaluation of an Al, Ga, and Fe chelate of compound 235. Figure 26 shows the results of preparing an Al, Ga, and Fe chelate of compound 248 and comparing its activity with that of ASP2397.

[0028] "C ６～１０ Cycloalkyl C１～３ "C" of "Alkyl group" ６～１０ "Cycloalkyl," as used herein, refers to mono- or polycyclic saturated hydrocarbon rings (including spiro compounds) containing the indicated number of carbon atoms, and includes cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl, and 2-adamantyl.

[0029] R １ "C" as defined in ６～１０ Cycloalkyl C １～３ "C" of "Alkyl group" １～３ The term "alkyl group" refers to a straight or branched chain alkyl group having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, or isopropyl.

[0030] "C ６～１０ Cycloalkyl C １～３ As the "alkyl group", preferably, R １ But C ６～１０ R is a cycloalkylmethyl group, and more preferably １ is substituted by cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl or 2-adamantyl １～３ alkyl group, and even more preferably R １ is cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl or 2-adamantylmethyl.

[0031] The term "solvate" refers to a form of a compound that is associated with a solvent, usually by solvation. This physical association involves hydrogen bonding. Solvents include water, ethanol, acetic acid, and the like. The compounds of the present invention may be prepared, for example, in crystalline form, and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.

[0032] Examples of fungi against which the compound of the present invention is effective include species of the genus Candida such as Candida albicans, Candida glabrata, Candida krusei, and Candida tropicalis; species of the genus Cryptococcus such as Cryptococcus neoformans; species of the genus Aspergillus such as Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger; species of the genus Pneumocystis carinii; species of the genus Rhizopus; species of the genus Absidia; The genus Histoplasma, such as Histoplasma capsulatum, the genus Coccidioides, such as Coccidioides immitis, the genus Blastomyces, the genus Paracoccidioides, such as Paracoccidioides brasiliensis, the genus Penicillium, the genus Pseudallescheria, the genus Sporothrix, dematiaceous fungi, the genus Trichophyton, the genus Microsporum, the genus Epidermophyton, the genus Malassezia, Fonsecaea genus, Fusarium genus, Paecillomyces genus, Trichosporon cutaneumExamples of the yeast include the genus Trichosporon, such as Trichosporon cutaneum, the genus Hyalophora, the genus Cladosporium, the genus Saccharomyces cerevisiae, and the genus Schizosaccharomyces, such as Schizosaccharomyces pombe (fission yeast).

[0033] In particular, the compounds of the present invention exhibited high activity against any of the following fungi: Schizosaccharomyces, Cryptococcus neoformans (ATCC 32045), Aspergillus fumigatus (IFM 40835, IFM 40836), Aspergillus niger (NBRC 105649), Candida glabrata (ATCC MYA-2950), and Candida parapsilosis (ATCC 22019).

[0034] The iron chelate and aluminum chelate, especially the iron chelate of compound IVf and the aluminum chelate of compound IVa, showed excellent activity against the above-mentioned bacteria.

[0035] Diseases caused by these pathogens include visceral mycoses (deep mycoses) such as candidiasis, cryptococcosis, and aspergillus (filamentous mycosis), and more specifically, fungemia, respiratory mycosis, digestive mycosis, urinary tract mycosis, and fungal meningitis; deep cutaneous mycoses such as sporotrichosis, chromomycosis (black mycosis), and mycetoma; and superficial mycoses such as common tinea pedis, tinea profunda, refractory tinea pedis, tinea unguium, tinea versicolor, cutaneous candidiasis, and oral candidiasis.

[0036] The administration method, dosage, and frequency of administration of the pharmaceutical of the present invention are not particularly limited and can be appropriately selected depending on various conditions such as the type of pathogenic fungus, the age, weight, symptoms, etc. For adults, the pharmaceutical can usually be administered orally or parenterally (by injection, drip infusion, etc.) at a dose of 0.001 to 100 mg / kg, preferably 0.01 to 100 mg / kg, daily in one or several divided doses.

[0037] The compounds of the present invention or solvates thereof can be used to produce therapeutic agents for infectious diseases by, for example, blending them and adding additives as needed according to a conventional formulation method.

[0038] The dosage form of the antifungal agent containing the compound of the present invention may be, for example, tablets, powders, granules, or capsules, or solutions, syrups, elixirs, or oily or aqueous suspensions, etc., as oral preparations. For injections, stabilizers, preservatives, or solubilizers may be used in the formulation. A solution that may contain these additives may be placed in a container and then freeze-dried or otherwise prepared as a solid preparation for immediate use. Examples of topical preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, and sprays. Solid preparations may contain pharmaceutically acceptable additives, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants, etc., selected and mixed as needed to form a formulation. Liquid preparations include solutions, suspensions, emulsions, etc., and may contain additives such as suspending agents and emulsifiers.

[0039] Methods for administering the compound of the present invention or a solvate thereof to animals include orally administering the compound directly or by mixing it in feed, or orally administering the compound in a solution, or by adding the solution to drinking water or feed, or by injection.

[0040] General manufacturing method

[0041] 1. Test method

[0042] (1) HPLC HPLC was performed using reverse phase chromatography, for example, as follows: Detector: ultraviolet absorption spectrophotometer (measurement wavelength: 220 nm) Column: Mightysil RP-18 GP 5 μm, 4.6 mm i.d. × 150 mm Column temperature: set temperature 40°C Mobile phase: 0.5% aqueous ammonium dihydrogen phosphate / MeCN = 70:30 Flow rate: 1.0 mL / min

[0043] (2) １ H NMR １ H NMR was measured using, for example, the following: Type: Bruker Ascend 400 Spectrometer: Bruker Fourier 400 Probe: Bruker BBO (5 mmφ)

[0044] (3) LC-MS LC-MS was performed, for example, as follows: MS detector: Waters Micromass ZQ HPLC: Waters 2695 Separations Module UV detector: Waters 2998 Photodiode Array Detect Ionization mode: ESI+

[0045] 2. List of Abbreviations ●Fmoc-Asn(Trt)-Alko-PEG Resin: N-α-(9-fluorenylmethoxycarbonyl)-N-γ-trityl-L-asparagine p-methoxybenzyl alcohol polyethylene glycol resin ●Fmoc-N-δ-acetyl-N-δ-(benzyloxy)-L-ornithine-OH: N-α-(9-fluorenylmethoxycarbonyl)-N-δ-acetyl-N-δ-(benzyloxy)-L-ornithine ●Fmoc-Cha-OH: N-α-(9-fluorenylmethoxycarbonyl)-β-cyclohexyl-L-alanine ●Fmoc-D-Phe-OH: N-α-(9-fluorenylmethoxycarbonyl)-D-phenylalanine ●HATU: O-(7-Aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DIEA: N,N-diisopropylethylamine, DMF: N,N-dimethylformamide, TFA: 2,2,2,2-trifluoroacetic acid, TIPS: triisopropylsilane, MALDI-TOF MASS: Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometry

[0046] 3. Synthesis scheme

[0047] (1) Scheme for synthesis of linear peptides

[0048] (1-1) Overview of Synthesis The linear peptides disclosed herein can be easily produced according to general chemical synthesis methods, for example, either conventional solid-phase synthesis or liquid-phase synthesis.

[0049] As described below, any linear peptide can be produced by a conventional peptide synthesis method, such as the solid-phase method. For example, the reaction is carried out by a conventional peptide synthesis method, such as the azide method, active esterification method, mixed acid anhydride method, or condensation method.

[0050] The azide method involves reacting an amino acid or its ester with hydrazine in an inert solvent at about room temperature to produce an amino acid hydrazine, which is then reacted with a nitrite compound to convert it into an azide compound, followed by treatment with an amine compound. Examples of the nitrite compound used include alkali metal nitrites such as sodium nitrite, and alkyl nitrites such as isoamyl nitrite. Examples of the inert solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethyl sulfoxide, and pyrrolidones such as N-methylpyrrolidone. One of the two reactions in this step is usually carried out in a reaction solution, with the reaction temperature being −50 to 0° C. in the first step and −10 to 10° C. in the second step. The reaction times are 5 minutes to 1 hour in the first step and 10 hours to 5 days in the second step.

[0051] The active esterification method is carried out by reacting an amino acid with an active esterifying agent in a solvent to produce an active ester, which is then reacted with an amine compound. The solvent to be used is not particularly limited as long as it is inert, and examples thereof include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as ether and tetrahydrofuran, and amides such as dimethylformamide and dimethylacetamide.

[0052] Examples of the active esterifying agent to be used include N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, and N-hydroxy-5-norbornene-2,3-dicarboximide; diimidazole compounds such as 1,1'-oxalyldiimidazole and N,N'-carbonyldiimidazole; disulfide compounds such as 2,2'-dipyridyldisulfide; succinic acid compounds such as N,N'-disuccinimidyl carbonate; and N,N'-bis(2-oxo-3-oxazolidinyl)phosphine. phosphinic chloride compounds such as benzotriazolyl chloride; and oxalate compounds such as N,N'-disuccinimidyl oxalate (DSO), N,N'-diphthalimido oxalate (DPO), N,N'-bis(norbornenylsuccinimidyl) oxalate (BNO), 1,1'-bis(benzotriazolyl) oxalate (BBTO), 1,1'-bis(6-chlorobenzotriazolyl) oxalate (BCTO), and 1,1'-bis(6-trifluoromethylbenzotriazolyl) oxalate (BTBO).

[0053] The activated esterification reaction can be carried out using, for example, azodicarboxylate di-lower alkyl-triphenylphosphines such as azodicarboxylate diethyl-triphenylphosphine, N-lower alkyl-5-arylisoxazolium-3'-sulfonates such as N-ethyl-5-phenylisoxazolium-3'-sulfonate, N',N'-dicycloalkylcarbodiimides such as N',N'-dicyclohexylcarbodiimide (DCC), diheteroaryl diselenides such as di-2-pyridyl diselenide, triarylphosphines such as triphenylphosphine, arylsulfonyl triazolides such as p-nitrobenzenesulfonyl triazolide, and 2-halo-1-lower alkylpyridinium iodide. The reaction is preferably carried out in the presence of a condensing agent such as a halide and a diarylphosphoryl azide such as diphenylphosphoryl azide (DPPA), an imidazole derivative such as N,N'-carbodiimidazole (CDI), a benzotriazole derivative such as 1-hydroxybenzotriazole (HOBT), a dicarboximide derivative such as N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), or a carbodiimide derivative such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDAPC). The reaction temperature is −10 to 25° C. for the active esterification reaction and around room temperature for the reaction of the active ester compound with the amine. The reaction time is 30 minutes to 10 hours for both reactions.

[0054] The mixed acid anhydride method involves preparing a mixed acid anhydride of an amino acid and then reacting it with an amine. The reaction to prepare the mixed acid anhydride is accomplished by reacting the amino acid with a lower alkyl halide carbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate, or a di-lower alkyl cyanophosphate such as diethyl cyanophosphate, in an inert solvent (e.g., ethers such as ether and tetrahydrofuran, or amides such as dimethylformamide and dimethylacetamide). The reaction is preferably carried out in the presence of an organic amine such as triethylamine or N-methylmorpholine, at a reaction temperature of −10 to 25° C. for a reaction time of 30 minutes to 5 hours. The reaction of the mixed acid anhydride with an amine is preferably carried out in an inert solvent (e.g., ethers such as ether and tetrahydrofuran, or amides such as dimethylformamide and dimethylacetamide) in the presence of the organic amine, at a reaction temperature of 0° C. to room temperature for a reaction time of 1 to 24 hours.

[0055] The condensation method is carried out by directly reacting an amino acid with an amine in the presence of the condensing agent, in the same manner as in the reaction for producing the activated ester.

[0056] In peptide synthesis, if the desired peptide has a functional group, the functional group can be protected in the reaction according to a standard method, if desired, and can also be removed, if desired, before carrying out the first step described below.

[0057] In particular, solid-phase synthesis using Boc (t-butoxycarbonyl) or Fmoc (9-fluorenylmethoxycarbonyl) as the amino-protecting group is preferred. The linear peptides disclosed herein can be synthesized using a commercially available peptide synthesizer by solid-phase synthesis according to B. Dorner et al., Novabiochem Solid-Phase Synthesis Handbook (Merck), standard methods, and the manufacturer's instructions, to synthesize peptide chains having the desired amino acid sequence and modified portions (e.g., C-terminal amidation).

[0058] The solid phase resin used for synthesis is Alko-PEG resin, which is made by bonding polyethylene glycol to polystyrene. The Fmoc amino acids are elongated one residue at a time using a condensing agent. HATU is used as the condensing agent, and 20% piperidine in DMF is used for deprotection of the Fmoc group. DMF is also used as the reaction and resin washing solvent.

[0059] After the synthesis was completed, the peptide was treated with TFA containing a scavenger to remove the peptide from the resin and the protecting groups of the amino acid residue side chains. The TFA was then removed by evaporation under reduced pressure, and the peptide was converted to the hydrochloride salt. Ethyl ether was added to precipitate the free peptide, which was then recovered by filtration and freeze-dried to obtain a solid powder of the crude peptide (hydrochloride salt).

[0060] (1-2) Synthesis of the precursor linear peptide (Compound 11) Because the C-terminal amino acid of this sequence is an asparagine residue, a solid-phase synthesis resin to which an asparagine residue had been immobilized was used. Specifically, 0.33 mmol of Fmoc-Asn(Trt)-PEG resin (amount of amino acid supported on resin: 0.23 mmol / g) was used as the solid-phase support, and the synthesis was carried out according to the following procedure.

[0061] The sequence of the target peptide is H ２ N-Cha-D-Phe-Orn-Orn-Orn-Asn-COOH (Orn: N-δ-acetyl-N-δ-(benzoyl)-L-ornithine, Cha: cyclohexylalanine), and the peptide chain was elongated by sequentially condensing amino acids from the C-terminus toward the N-terminus.

[0062]

[0063] *The Fmoc amino acids used were as follows: Fmoc-Cha-OH: purchased from Ark Pharma through Namiki Shoji, CAS number 135673-97-1, Fmoc-D-Phe-OH: generally available for purchase, CAS number 6123-10-6, Fmoc-N-δ-acetyl-N-δ-(benzyloxy)-L-ornithine-OH: purchased from Sundia through Namiki Shoji, synthesized, CAS number 2209864-45-7. *Coupling of each amino acid was performed in the following composition ratio. (Fmoc amino acid was used in an amount of 4 equivalents relative to the resin) Fmoc amino acid (mmol): HATU (mmol): DIEA (mmol): DMF (mL) = 1.32:1.32:2.64:9 Only the special Orn residue was used in the following composition ratio (Fmoc special Orn was used in an amount of 2 equivalents relative to the resin) Fmoc special Orn (mmol): HATU (mmol): DIEA (mmol): DMF (mL) = 0.66:0.66:1.32:4.

[0064] Other R １ The amino acids corresponding to the groups (for example, cycloheptylalanine, cyclooctylalanine, cyclononylalanine, cyclodecylalanine, 1-adamantylalanine, 2-adamantylalanine) were introduced into the linear peptide according to the method described above.

[0065] Cycloheptylalanine and cyclooctylalanine themselves are commercially available, but 1-adamantylalanine can be produced from 1-adamantylacetaldehyde in accordance with Overkleeft, et al., Chem. Commun., 2016, vol. 52, 4064-4067. Other amino acids (e.g., cycloheptylalanine, cyclooctylalanine, cyclononylalanine, cyclodecylalanine, 2-adamantylalanine) can also be synthesized using the corresponding acetaldehyde as a starting material in accordance with Overkleeft, et al., Chem. Commun., 2016, vol. 52, 4064-4067.

[0066] After the synthesis was completed, 0.33 mmol of the solid-phase resin was added with a scavenger mixture of thioanisole (mL): m-cresol (mL): TIPS (mL): TFA (mL) = 5.4:1.5:0.9:39, and the mixture was stirred for 1.5 hours to remove the resin and deprotect the peptide (cleavage procedure). After cleavage, the cleavage solution was recovered by filtration, the TFA was removed by evaporation under reduced pressure, and an appropriate amount of 4N hydrochloric acid / ethyl acetate was added and mixed well. Ethyl ether was then added, and the precipitate was collected by filtration to obtain 335 mg of the desired crude peptide (hydrochloride salt) in a crude yield of 81%.

[0067] This was subjected to mass spectrometry using a MALDI-TOF / MS (Shimadzu Biotech Axima Assurance). Mass (measured value): 1220.60. Consistency with the theoretical mass value of the target peptide (1219.503) was confirmed.

[0068] (2) Cyclization reaction scheme

[0069] In the above formula, R １ and M have the same meaning as defined above. The starting compound (11) of the compound of the present invention can be produced according to the above explanation (1).

[0070] Step 1: In this step, linear peptide (11) is cyclized by intramolecular amidation of the carboxylic acid and amino groups in the molecule, similar to step (1), to produce compound (12). Prior to treatment with an amine in the presence of a base, the carboxylic acid must first be activated, a process typically performed by converting the -OH group of the acid into a good leaving group. Suitable methods for activating the carboxyl group include, but are not limited to, the formation of acid halides, acyl azides, mixed acid anhydrides, activated esters, and the like. Acid halides can be prepared by treating carboxylic acids with halogen sources such as, but not limited to, thionyl chloride, oxalyl chloride, phosphorus pentachloride, triphosgene, cyanuric fluoride, cyanuric chloride, BoP-Cl, PyBroP, and the like, in an aprotic solvent. Mixed acid anhydrides can be prepared using reagents such as, but not limited to, pivaloyl chloride and EEDQ in an aprotic solvent. Suitable coupling reagents used in the process of amidation via activated esters include, but are not limited to, carbodiimides such as DCC, DIC, and EDAC; uronium salts such as HATU, TATU, HBTU, TBTU, and TDBTU; and phosphonium salts such as PyBoP, BoP, and DEPBT, with uronium salts being preferred, and HATU being more preferred. These coupling reagents can be used as stand-alone activators or in the presence of additives such as HOAt and HOBt, but are not limited to these. Other suitable amidation coupling reagents that operate via a different mechanism of carboxyl group activation include, but are not limited to, DPPA, T3P®, CDI, Mukaiyama's reagent, and the like. Activation can also be achieved using solid-supported versions of the above coupling reagents, such as, but not limited to, PS-CDI, PS-EDC, and PS-BoP. Suitable bases used in the amidation process include, but are not limited to, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, TEA, DIEA, DBU, DBN, DABCO, etc. Preferably, DIEA is used.A more complete discussion of the amidation can be found in Valeur, E. et al. (Chem. Soc. Rev. (2009), 38, 606). The reaction is typically carried out by dissolving the linear peptide (11) or a suitable salt thereof in an inert solvent such as DMF, adding a solvent solution of an activating agent such as HATU, typically at room temperature under a nitrogen stream, and then adding a base such as diisopropylethylamine dropwise under cooling.

[0071] Step 2: In Step 2, the remaining hydroxylamide protecting group of compound (12) prepared in Step 1 is removed by conventional methods to produce compound (13). While the removal of the protecting group varies depending on the type, it is generally carried out by methods well known in the art, as follows. Conditions for hydrogenation reactions in the presence of a catalyst (based on a report from Kobe Natural Products) showed that in the removal of aralkyl or aralkyloxycarbonyl groups by catalytic reduction, an increase in by-products, presumably hydrogenolysis-induced dehydration, was observed with increasing reaction time, for example, in the debenzylation reaction to obtain the target compound of this reaction. Pressurization, heating, and increasing the amount of catalyst had little effect on the reaction. Optimizing the reaction solvent (specifically, adding water to the reaction system) to shorten the reaction time and suppressing by-products by reducing catalyst activity were effective. After the reaction is complete, the target compound (13) is collected from the reaction mixture by conventional methods. However, in this step, the reaction is confirmed to be complete and the product is used in the next step, Step 3, without purification.

[0072] Step 3 Step 3 is a step in which compound (13) obtained in step 2 is chelated with aluminum, gallium, iron, or ruthenium to produce compound (14). When producing an aluminum chelate, for example, a Milli-Q aqueous solution of potassium aluminum sulfate dodecahydrate or aluminum chloride is added at room temperature and stirred for 30 minutes to 6 hours, and then Milli-Q water is added and stirred for a while, followed by solid-phase extraction with OASIS HLB and distillation of the solvent under reduced pressure to obtain compound (14).

[0073] When producing an iron chelate, ferric chloride or ferric sulfate hydrate was added to chelate the same as for aluminum. When producing a gallium chelate, gallium chloride or gallium sulfate hydrate was added to chelate the same as for aluminum. When producing a ruthenium chelate, ruthenium chloride was added to chelate the same.

[0074] After completion of the reaction, compound (14) is collected from the reaction mixture by a conventional method. If necessary, the target compound obtained can be separated and purified by conventional methods, such as recrystallization, reprecipitation, or methods commonly used for separating and purifying organic compounds, such as solid-phase extraction and reverse-phase column chromatography (preferably high-performance liquid chromatography), in combination with an appropriate eluent.

[0075] In fact, in the case of the aluminum chelate, the concentrated residue was dissolved in Milli-Q water, freeze-dried, and then purified by solid-phase extraction and reverse-phase column chromatography to obtain compound (14) as a white solid.

[0076] Example

[0077] Example 1 (Compound II (R １ = cyclohexylmethyl; M = Al) = preparation of compound (24)

[0078] (1) Cyclization process

[0079] To a solution of the hydrochloride salt of the linear peptide (21: 1.3400 g, 1,067 μmol; obtained by solid-phase synthesis with an HPLC purity of 72.9% (220 nm). The amount of reagent charged (equivalents) was calculated based on the purity and content of this product as 100% without converting to HPLC purity.) in DMF (1,004.06 g) was added a solution of HATU (527.4 mg, 1,387 μmol; obtained from Watanabe Chemical Industry Co., Ltd.) in DMF (28.55 g) at room temperature under a nitrogen stream. Diisopropylethylamine (Tokyo Chemical Industry: 560 μL, 3,206 μmol) was added dropwise under cooling (-16°C) in an ice / methanol bath. After stirring at the same temperature for 1 hour, the mixture was warmed to room temperature and the solvent was evaporated under reduced pressure in a 45°C water bath. The resulting residue was purified by reverse phase chromatography (Biotage Isolera, SNAP Ultra C18 60 g, 0.05% TFA aq. / MeCN = 90:10 → 0:100) to give the cyclized product (22) as a white solid (0.79 g, LC purity 97.5% (220 nm), yield 61%). For physical data, see Figure 1: LC-MS data of cyclized product (22) and Figure 2: NMR data of cyclized product (22).

[0080] (2) Deprotection (compound III (R １ = cyclohexylmethyl) = preparation of compound (23)

[0081]

[0082] The cyclized product (22: 0.79 g, 658 μmol) obtained in (1) above was dissolved in methanol (15.80 g), and Milli-Q water (12.63 g) and 10% Pd / C PE (manufactured by N.E. CHEMCAT, 50% wet, 144.7 mg) were added successively at room temperature. The mixture was stirred under slight hydrogen pressure (balloon) for 2 hours, and the reaction endpoint of compound (23) was confirmed.

[0083] For physical data, see Figure 3: HPLC data at the end of the reaction of the deprotected product (23). The catalyst was removed by filtration through Celite, and methanol (246.22 g) and Milli-Q water (318.52 g) were added, followed by subjecting the crude product to the next reaction.

[0084] (3) Complexation step (compound II(R １(M = cyclohexylmethyl; M = Al) = Preparation of Compound (24)) To the above solution, a solution of potassium aluminum sulfate dodecahydrate (obtained from Kanto Chemical: 0.79 g, 1,665 μmol) in Milli-Q water (30.05 g) was added at room temperature and stirred for 1 hour. Milli-Q water (1.9 L) was added, and after stirring for a while, solid-phase extraction was performed with OASIS HLB 6 g / 35 cc, and the solvent was evaporated under reduced pressure. The concentrated residue was dissolved in Milli-Q water and lyophilized to obtain crude Compound (24) as a pale yellow solid (559.3 mg, HPLC purity 93.8% (220 nm), two-step yield 88%). For physical data, see Figure 4. HPLC data of the crude product of Complex (24), Figure 5. LC-MS data of the crude product of Complex (24), and Figure 6. NMR data of the crude product of Complex (24).

[0085] (4) Reverse-Phase Purification Step The crude compound (24) (554.3 mg) described above was subjected to reverse-phase purification (Biotage Isolera, SNAP Ultra C18 120 g, 0.05% TFA aq. / MeCN=90:10→0:100) and solid-phase extraction with OASIS HLB 6 g / 35 cc. The fraction with an HPLC purity of 94% (220 nm) or more was then combined with compound (24′) (51.7 mg, HPLC purity of 95% (220 nm)) obtained in the previous study, and the solvent was distilled off under reduced pressure. The concentrated residue was dissolved in Milli-Q water and lyophilized to obtain compound (24) as a white solid (462.7 mg, HPLC purity 98.4% (220 nm). The physical data are shown in Figure 7. HPLC data of complex (24) after purification, Figure 8. LC-MS data of complex (24) after purification, and Figure 9. １ H NMR data, see (NMR: structural support, LC-MS: structural support).

[0086] Antifungal action

[0087] Antifungal Activity Measurement Method Antifungal activity measurements against the test bacteria shown in the table below were performed using the broth microdilution method (Kume Hikaru and Yamazaki Toshikazu, Clinical and Microbiology, Vol. 21, No. 5, pp. 573-580, 1994) based on the Clinical and Laboratory Standards Institute (CLSI) standard methods (1) and (2). (1) CLSI-M27: Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard -4th Edition. 2017. (2) CLSI-M38: Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standard -3rd Edition. 2017.

[0088] In in vitro antibacterial activity tests, the derivatives of the present invention, especially (IVa, 24), showed more significant activity than the reference compound ASP2397.

[0089] Antifungal Activity Evaluation Using Compound IVa (Al Chelate, 24), Compound IVg (Ga Chelate), and Compound IVf (Fe Chelate) The antifungal activity of Compound IVa (Al Chelate), IVg (Ga Chelate), and Compound IVf (Fe Chelate) was evaluated using the fission yeast (Schizosaccharomyces pombe) JY1 strain. S. pombe JY1 was cultured overnight at 30°C in YE(Ade) medium (5 g yeast extract, 20 g glucose, 15 mg adenine sulfate / 1 L) to prepare a pre-culture medium. 1 mL of the pre-culture medium was added to 3 mL of YE(Ade) medium, followed by a 2-hour recovery culture at 30°C. The turbidity was then measured using an absorption spectrometer, and the solution was adjusted with YE (Ade) medium to a calculated OD600 of 0.05 to prepare a test bacterial solution.

[0090] Compound IVa (Al chelate, 24), compound IVg (Ga chelate), and compound IVf (Fe chelate) were prepared by dissolving 23 in a 50% DMSO aqueous solution and 1.5 equivalents of AlCl before adding them to the test bacterial solution. ３ , GaCl ３ , or FeCl ３ For activity evaluation, a 96-well plate was used, 100 μL of the test bacterial solution was dispensed per well, and the culture was performed at 30°C for 18 to 24 hours with shaking at 200 rpm, after which the OD600 was measured using a plate reader to determine the MIC (minimum effective concentration).

[0091] The MIC of ASP2397 against S. pombe JY1 was 0.28 μM, whereas compound IVa (Al chelate) (in FIG. 10, "Compound 23 + Al"), compound IVg (Ga chelate) (in FIG. 10, "Compound 23 + Ga"), and compound IVf (Fe chelate) (in FIG. 10, "Compound 23 + Fe") all showed comparable activity, with an MIC value of 0.04 μM.

[0092] The concentration of AlCl used in preparing each metal chelate was ３ , GaCl ３ , and FeCl ３ It was also confirmed that it did not exhibit antifungal activity.

[0093] The compounds of the present invention exhibited high activity against all of the fungi of the genus Schizosaccharomyces (fission yeast (Schizosaccharomyces pombe)), Aspergillus fumigatus, and Candida glabrata. In particular, compound IVa (aluminum chelate, 24) and compound IVf (iron chelate) exhibited excellent activity.

[0094] Example 2: Preparation of Compound Va,232+Al (R1=cycloheptylmethyl; M=Al)

[0095] (1) Cyclization Step: Under a nitrogen stream, a solution of the hydrochloride salt of the linear peptide (230: 98.6 mg, 80.0 μmol; obtained by solid-phase synthesis with an HPLC purity of 61.0% (220 nm). The amount (equivalent) of the reagents charged was calculated based on the purity and content of this product as 100%, without converting to HPLC purity.) in DMF (75.52 g) was added with a solution of HATU (45.6 mg, 120 μmol; obtained from Watanabe Chemical Industry Co., Ltd.) in DMF (0.94 g) at room temperature, and diisopropylethylamine (Tokyo Chemical Industry: 41.8 μL, 240 μmol) was added dropwise while cooling on ice. After stirring at the same temperature for 1 hour, the mixture was warmed to room temperature and the solvent was evaporated under reduced pressure in a 45°C water bath. The resulting residue was purified by silica gel chromatography (Merck Millipore, Silica gel 60 (0.040-0.063 mm) 15 ml, chloroform / methanol=4:1), and the solvent was distilled off under reduced pressure to obtain a concentrated residue (126.8 mg) containing the cyclized product (231).

[0096] (2) Deprotection: The concentrated residue (126.8 mg) containing the cyclized product (231) obtained in (1) above was dissolved in methanol (7.92 g), 10% Pd / C (Wako Pure Chemical Industries, wet, 40.0 mg) was added, and the mixture was stirred for 16 hours under slight hydrogen pressure (balloon). The catalyst was removed, the solvent was evaporated under reduced pressure, and the mixture was purified by reverse-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ×250 mm, Milli-Q water / 0.1% TFA MeCN = 0 min 64:36 → 6 min 60:40 → 6.5 min 10:90 → 7 min 10:90 → 7.5 min 64:36 → 12 min 64:36, 4 mL / min), and the solvent was evaporated under reduced pressure. Milli-Q water was added to the concentrated residue to dissolve it, and the solution was lyophilized to obtain compound (232) as a white solid (30.8 mg, yield from compound 230: 41%).

[0097] (3) Complexation step (preparation of compound Va, 232 + Al (R1 = cycloheptylmethyl; M = Al)) A solution of aluminum chloride hexahydrate (obtained from Wako Pure Chemical Industries, Ltd.: 3.8 mg, 15.8 μmol) in Milli-Q water (400.0 mg) was added to a DMF (94.4 mg) solution of 232 (10 mg, 10.6 μmol) obtained in (2) above at room temperature and mixed thoroughly. The resulting solution was purified by reversed-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ × 250 mm Milli-Q water / MeCN = 0 min 63:37 → 6 min 30:70 → 6.5 min 63:37 → 11 min). After the mixture was evaporated at a rate of 63:37 (4 ml / min), the solvent was removed by evaporation under reduced pressure. The concentrated residue was dissolved in Milli-Q water and lyophilized to obtain compound (Va,232+Al) as a white solid (5.4 mg, yield 53%).

[0098] Example 3: Production of compound Vg, 232+Ga (R1 = cycloheptylmethyl; M = Ga) A step of obtaining 232+Ga using the compound (232) as a raw material.

[0099] To a solution of compound (232) (10 mg, 10.6 μmol) obtained in Example 2(2) in DMF (94.4 mg), a solution of gallium chloride (obtained from Tokyo Chemical Industry: 2.8 mg, 15.8 μmol) in Milli-Q water (400.0 mg) was added at room temperature and mixed thoroughly. The resulting solution was purified by reverse-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ x 250 mm Milli-Q water / MeCN = 0 min 63:37 → 6 min 30:70 → 6.5 min 63:37 → 11 min 63:37, 4 ml / min), and the solvent was then distilled off under reduced pressure. The concentrated residue was dissolved in Milli-Q water and lyophilized to obtain compound (Vg, 232 + Ga) as a white solid (7.1 mg, yield 66%).

[0100] Example 4: Preparation of Compound VIa, 235 + Al (R1 = cyclooctylmethyl; M = Al)

[0101] (1) Cyclization Step: Under a nitrogen stream, a solution of the hydrochloride salt of the linear peptide (233: 99.7 mg, 80.0 μmol; obtained by solid-phase synthesis with an HPLC purity of 64.0% (220 nm). The amount (equivalent) of the reagents charged was calculated based on the purity and content of this product as 100%, without converting to HPLC purity.) in DMF (75.52 g) was added with a solution of HATU (36.5 mg, 96 μmol; obtained from Watanabe Chemical Industry Co., Ltd.) in DMF (0.94 g) at room temperature, and diisopropylethylamine (Tokyo Chemical Industry: 41.8 μL, 240 μmol) was added dropwise while cooling on ice. After stirring at the same temperature for 1 hour, the mixture was warmed to room temperature and the solvent was evaporated under reduced pressure in a 45°C water bath. The resulting residue was purified by reverse-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ×250 mm, 0.1% TFA aq. / 0.1% TFA MeCN = 0 min 60:40 → 5 min 10:90 → 6 min 60:40 → 10 min 60:40, 4 mL / min), and the solvent was removed under reduced pressure. The concentrated residue was dissolved in Milli-Q water and lyophilized to give cyclized product (234) as a white solid (45.6 mg, yield 46%).

[0102] The cyclized product (234: 45.6 mg, 37.1 μmol) obtained in (1) above was dissolved in acetic acid (10.5 g), 10% Pd / C (Wako Pure Chemical Industries, wet, 40.0 mg) was added, and the mixture was stirred for 16 hours under slight hydrogen pressure (balloon). After removing the catalyst and evaporating the solvent under reduced pressure, the mixture was purified by reverse-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ×250 mm Milli-Q water / 0.1% TFA MeCN = 0 min 63:37 → 6 min 59:41 → 6.5 min 20:80 → 7 min 63:37 → 12 min 63:37, 4 mL / min), and the solvent was evaporated under reduced pressure. Milli-Q water was added to the concentrated residue to dissolve it, and the solution was lyophilized to obtain compound (235) as a white solid (26.5 mg, yield 74%).

[0103] (3) Complexation step (preparation of compound VIa, 235 + Al (R1 = cyclooctylmethyl; M = Al)) A solution of aluminum chloride hexahydrate (obtained from Wako Pure Chemical Industries, Ltd.: 3.8 mg, 15.6 μmol) in Milli-Q water (400.0 mg) was added to a DMF (94.4 mg) solution of compound (235) (10 mg, 10.4 μmol) obtained in (2) above at room temperature and thoroughly mixed. The resulting solution was purified by reversed-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ × 250 mm Milli-Q water / MeCN = 0 min 60:40 → 5 min 15:85 → 5.5 min 60:40 → 10 min). After the mixture was diluted with water (60:40, 4 ml / min), the solvent was removed by evaporation under reduced pressure. The concentrated residue was dissolved in Milli-Q water and lyophilized to obtain Compound (VIa, 235+Al) as a white solid (6.5 mg, yield 64%).

[0104] Example 5: Preparation of compound VIg, 235+Ga (R1 = cyclooctylmethyl; M = Ga) A process for obtaining 235+Ga using compound (235) as a raw material.

[0105] To a solution of compound (235) (13 mg, 15.6 μmol) obtained in (2) above in DMF (94.4 mg), a solution of gallium chloride (obtained from Tokyo Chemical Industry: 8.2 mg, 46.8 μmol) in Milli-Q water (400.0 mg) was added at room temperature and mixed thoroughly. The resulting solution was purified by reverse-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ x 250 mm Milli-Q water / MeCN = 0 min 63:37 → 6 min 30:70 → 6.5 min 63:37 → 11 min 63:37, 4 ml / min), and the solvent was then distilled off under reduced pressure. The concentrated residue was dissolved in Milli-Q water and lyophilized to obtain compound (VIg, 235 + Ga) as a white solid (11.5 mg, yield 72%).

[0106] Example 6: 1-Adamantyl derivative

[0107] (1) Cyclization Step: Step for Obtaining 247 (R1 = 1-Adamantylmethyl) Under a nitrogen stream, a solution of the hydrochloride salt of the linear peptide (246: 203.4 mg, 160.0 μmol; a compound obtained by solid-phase synthesis with an HPLC purity of 68.6% (220 nm). The amount (equivalent) of the reagents charged was calculated based on the purity and content of this product as 100% without converting to HPLC purity.) in DMF (151.04 g) was added with a solution of HATU (73.0 mg, 192 μmol; obtained from Watanabe Chemical Industry Co., Ltd.) in DMF (1.88 g) at room temperature, and diisopropylethylamine (Tokyo Chemical Industry: 83.6 μL, 480 μmol) was added dropwise while cooling on ice. After stirring at the same temperature for 1 hour, the mixture was warmed to room temperature and the solvent was evaporated under reduced pressure in a 45°C water bath. The resulting residue was purified by reverse-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ×250 mm, 0.1% TFA aq. / 0.1% TFA MeCN = 0 min 25:75 → 6 min 15:85 → 6.5 min 25:75 → 12 min 25:75, 4 mL / min), and the solvent was evaporated under reduced pressure. The concentrated residue was lyophilized to give cyclized product (247) as a white solid (85.0 mg, yield 42%).

[0108] (2) Deprotection Step to Obtain 248 (R1 = 1-adamantylmethyl) The cyclized product (247: 81.2 mg, 64.8 μmol) obtained in (1) above was dissolved in acetic acid (10.5 g), 10% Pd / C (Wako Pure Chemical Industries, wet, 40.0 mg) was added, and the mixture was stirred for 16 hours under slight hydrogen pressure (balloon). After removing the catalyst and evaporating the solvent under reduced pressure, the mixture was purified by reverse-phase HPLC (Senshu Pak PEGASIL ODS SP100 10Φ × 250 mm, Milli-Q water / 0.1% TFA MeCN = 0 min 60:40 → 6 min 58:42 → 6.5 min 20:80 → 7 min 60:40 → 12 min 60:40, 4 mL / min), and the solvent was evaporated under reduced pressure. Milli-Q water was added to the concentrated residue to dissolve it, and the solution was lyophilized to obtain compound (248) as a white solid (54.4 mg, yield 85%).

[0109] The instrumental data of the produced compounds are shown in the table below. The following measuring equipment was used: HR-MS Synapt G2 (Waters) hybrid quadrupole time-of-flight tandem mass spectrometer Proton NMR JNM-ECZ600R (JEOL) SuperCOOL prove 5 mm, NM-Z15070TTH5SC (JEOL)

[0110]

[0111] The antifungal activity of each of the above compounds was measured using the same method as in Example 1, "Antifungal Activity Evaluation Using Compound IVa (Al Chelate, 24), Compound IVg (Ga Chelate), and Compound IVf (Fe Chelate)." Figure 23 shows the antifungal activity evaluation of the Al chelates of Compounds 232 and 235. Figure 24 shows the results of comparing the activity of the Al, Ga, and Fe chelates of Compound 232 with ASP2397. Figure 25 shows the results of comparing the activity of the Al, Ga, and Fe chelates of Compound 235 with ASP2397. An Al, Ga, and Fe chelate was prepared in situ from Compound 248, and the activity was compared with ASP2397. Figure 26 shows the results. Each compound was confirmed to exhibit excellent antifungal activity.

[0112] The antifungal activity of Compound 124 + Al (Compound (IVa, 24)), Compound 232 + Al (Compound Va), and ASP2397 was measured by the same method as in the "Antifungal Activity Measurement Method" in Example 1. Table 4 shows the MIC values ​​against drug-resistant Aspergillus (closely related strains Aspergillus felis, Aspergillus lentulus, and three species of A. fumigatus). Table 5 shows the MIC values ​​against Candida (three species of C. parapsilosis, C. glabrata, and C. auris, and their respective drug-resistant strains). Each compound was confirmed to exhibit excellent antifungal activity.

[0113]

[0114]

Claims

1. A compound of formula (II) or a solvate thereof: 【Chemistry 1】 Where: R １ is C ６～１０ Cycloalkyl C １～３ is an alkyl group, M represents an element of Group 8 or Group 13.

2. R １ But, C ６～１０ 2. The compound of claim 1, or a solvate thereof, which is a cycloalkylmethyl group.

3. R １ is substituted with cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl or 2-adamantyl; １～３ 2. The compound of claim 1, or a solvate thereof, selected from the group consisting of alkyl groups.

4. R １ The compound according to claim 1, or a solvate thereof, wherein is selected from the group consisting of cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl, or 2-adamantylmethyl.

5. 2. The compound according to claim 1, or a solvate thereof, wherein M is an element of Group 8 or Group 13.

6. 6. The compound according to claim 5, or a solvate thereof, wherein M is iron (Fe), aluminum (Al), gallium (Ga) or ruthenium (Ru).

7. 2. The compound of claim 1, selected from: 【Chemistry 2】 【Chemistry 3】 【Chemistry 4】 【Chemistry 5】 【Chemistry 6】

8. A compound of formula (III) or a solvate thereof: 【Chemistry 7】 Where: R １ is C ６～１０ Cycloalkyl C １～３ Indicates an alkyl group.

9. R １ The compound according to claim 8, or a solvate thereof, wherein is selected from the group consisting of cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl, or 2-adamantylmethyl.

10. An antifungal agent comprising a compound of general formula (II) or a solvate thereof according to any one of claims 1 to 7.

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