WO2022215745A1 - Substance d'un nouvel agent antifongique de type sidérophore (composé) et son utilisation - Google Patents

Substance d'un nouvel agent antifongique de type sidérophore (composé) et son utilisation Download PDF

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WO2022215745A1
WO2022215745A1 PCT/JP2022/017337 JP2022017337W WO2022215745A1 WO 2022215745 A1 WO2022215745 A1 WO 2022215745A1 JP 2022017337 W JP2022017337 W JP 2022017337W WO 2022215745 A1 WO2022215745 A1 WO 2022215745A1
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compound
group
added
solvate
chelate
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稔 吉田
知成 平塚
憲和 西野
博治 知花
隆 梅山
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国立研究開発法人理化学研究所
国立大学法人千葉大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms

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  • the present invention provides novel siderophore-type cyclic peptide compounds, antifungal agents containing the compounds, and methods of treating fungal diseases using the compounds.
  • deep skin fungi also occur in skin tissues located deep from the surface of the body.
  • deep-seated mycosis in deep tissues such as the esophagus, internal organs, and brain.
  • Candida, Cryptococcus, Aspergillus, etc. are known as the main pathogenic fungi that infect humans and cause deep mycoses.
  • Superficial mycoses infect the skin, oral cavity, vagina, etc.
  • Candida which infects the skin of the hands and feet
  • Trichophyton Trichophyton.
  • antifungal agents great efforts have been made to develop antifungal agents, but compared to the development of antibacterial chemotherapeutic agents, fewer compounds have entered the clinical arena.
  • deep-seated mycosis has been increasing, and the drugs used for this treatment are very few in terms of antibacterial spectrum, efficacy, safety, etc., and have a high degree of satisfaction.
  • fluconazole which is frequently used among these anti-deep fungal agents, has low sensitivity to, for example, Candida glabrata, Candida tropicalis, Candida krusei, etc., and resistant strains have also emerged. . Therefore, novel antifungal agents that overcome these problems are eagerly awaited.
  • An object of the present invention is to provide a siderophore-type compound having antifungal activity and uses thereof.
  • the present inventors diligently studied the structure-activity relationship of the metal chelate portion and three other amino acid residues of compound (I) having this unique structure. It is possible to modify the benzene ring, but since the possibility of enhancing the activity was found in the conversion of leucine, we focused on it. Then, the novel compound of the present invention, in which the amino acid of the cyclic compound (natural product) of formula (I) is substituted with a non-natural amino acid, is more effective than ASP2397 in the application to fungal infections, particularly deep fungal infections. The present invention was completed based on the discovery that further improvement in activity and the like was demonstrated.
  • R 1 is a C 6-10 cycloalkyl C 1-3 alkyl group
  • M represents a Group 8 or Group 13 element.
  • Compound (II) is provided, wherein R 1 is a C 6-10 cycloalkylmethyl group.
  • R 1 is selected from the group consisting of C 1-3 alkyl groups substituted with cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl or 2-adamantyl.
  • R 1 is selected from the group consisting of cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl or 2-adamantylmethyl.
  • M represents an element of group 8 or 13, preferably M is iron (Fe) or ruthenium (Ru) of group 8 or aluminum of group 13 (Al) or gallium (Ga). More preferably M is Compound (II) representing Fe, compound (II) representing Al, Compound (II) representing Ga, or Compound (II) representing Ru, I will provide a.
  • compound (II) most preferably provides a compound selected from:
  • compound (II) is compound (IVf), (IVa), (IVg), (Vf), (Va), (Vg), (VIf), (VIa) ) and (VIg).
  • R 1 represents a C 6-10 cycloalkyl C 1-3 alkyl group.
  • R 1 is selected from the group consisting of C 1-3 alkyl groups substituted with cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl or 2-adamantyl.
  • R 1 is selected from the group consisting of cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl or 2-adamantylmethyl.
  • an antifungal agent comprising the compound of general formula (II) or a solvate thereof.
  • R 1 and M have the same meanings as above.
  • a method for treating fungal diseases using compounds of general formula (II) or their solvates is provided.
  • R 1 and M have the same meanings as above.
  • a compound of general formula (II) or a solvate thereof for use in the treatment of fungal diseases is also provided in one embodiment of the present invention.
  • the compound of general formula (II) of the present invention has excellent antifungal activity.
  • FIG. 1 shows LC-MS data for the cyclized form (22).
  • FIG. 1 shows LC-MS data for the cyclized form (22).
  • FIG. 2 shows NMR data for the cyclized form (22).
  • FIG. 3 shows HPLC data at the end of the reaction for the deprotected form (23).
  • 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 after purification of complex (24).
  • FIG. 8 shows LC-MS data after purification of complex (24).
  • FIG. 8 shows LC-MS data after purification of complex (24).
  • FIG. 8 shows LC-MS data after purification of complex (24).
  • FIG. 8 shows LC-MS data after purification of complex (24).
  • FIG. 8 shows
  • FIG. 9 shows the NMR data after purification of complex (24).
  • 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 of compound 23 (metal-free form).
  • FIG. 12 shows proton NMR data for complex IVg(23+Ga).
  • FIG. 13 shows proton NMR data of compound (231) cyclized form.
  • FIG. 14 shows proton NMR data of compound (232) metal-free form.
  • 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 of compound (234) cyclized form.
  • FIG. 18 shows proton NMR data of compound (235) metal-free form.
  • FIG. 19 shows proton NMR data for complex (VIa) (235+Al).
  • FIG. 20 shows proton NMR data for complex (VIg) (235+Ga).
  • FIG. 21 shows proton NMR data of compound (247) cyclized form.
  • FIG. 22 shows proton NMR data of compound (248) metal-free form.
  • FIG. 23 shows the antifungal activity evaluation of Al chelates of compounds 232 and 235.
  • FIG. 24 shows the antifungal activity evaluation of Al, Ga, Fe chelates of compound 232.
  • FIG. 25 shows the antifungal activity evaluation of Al, Ga, Fe chelates of compound 235.
  • FIG. 26 shows the results of preparing an Al, Ga, and Fe chelate form of compound 248 and comparing the activity with ASP2397.
  • C 6-10 cycloalkyl of “C 6-10 cycloalkyl C 1-3 alkyl group”, as used herein, is a monocyclic ring containing the indicated number of carbon atoms or Refers to polycyclic saturated hydrocarbon rings (including spiro compounds), including cyclohexyl, cycloheptyl, bicyclo[2.2.1]heptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl and 2-adamantyl.
  • the “C 1-3 alkyl group” of the “C 6-10 cycloalkyl C 1-3 alkyl group” defined for R 1 means, for example, a C 1-3 alkyl group such as methyl, ethyl, n-propyl and isopropyl. represents a straight or branched chain alkyl group.
  • R 1 is a C 6-10 cycloalkylmethyl group, more preferably R 1 is a C 1-3 alkyl group substituted with cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, 1-adamantyl or 2-adamantyl, even more preferably R 1 is cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl, cyclodecylmethyl, 1-adamantyl or 2-adamantylmethyl.
  • solvate refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association involves hydrogen bonding.
  • Solvents include water, ethanol, acetic acid, and the like.
  • the compounds of the invention may, for example, be prepared 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 in the crystal lattice of the crystalline solid.
  • Candida genus species such as Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Genus Cryptococcus such as Cryptococcus neoformans, Aspergillus genus such as Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Pneumocystis carinii, Rhizopus (Rhizopus) genus, genus Absidia, Genus Histoplasma such as Histoplasma capsulatum, Genus Coccidioides such as Coccidioides immitis, Blastomyces genus, Genus Paracoccidioides such as Paracoccidioides brasiliensis, Penicillium genus, Genus Pseudallescheria, Sporothrix genus, black fungus (dematiaceous fungi), genus Trichophyton, Microsporum genus, Epiderm
  • the compounds of the present invention are useful for the genus 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).
  • the iron chelate and the aluminum chelate especially the iron chelate of compound IVf and the aluminum chelate of compound IVa, exhibited excellent activity against the above bacteria.
  • Viscosis Deep mycosis
  • candidiasis such as candidiasis, cryptococcosis, and aspergillus (mycosis)
  • mycosis specifically fungemia, respiratory mycosis, Gastrointestinal mycosis, urinary tract mycosis, fungal meningitis, etc.
  • Deep cutaneous mycosis such as sporotrichosis, chromomycosis (black mycosis), mycetoma, etc.
  • superficial mycosis includes usual type tinea, deep tinea, intractable tinea, tinea unguium, tinea versicolor, cutaneous candidiasis, oral candidiasis and the like.
  • the administration method, dosage, and frequency of administration of the pharmaceutical of the present invention are not particularly limited, and can be appropriately selected according to various conditions such as the type of pathogenic fungi and the patient's age, weight, and symptoms. Usually, for adults, 0.001 to 100 mg/kg, preferably 0.01 to 100 mg/kg, once or several times per day by oral or parenteral (injection, infusion, etc.) administration. Can be administered in divided doses.
  • a therapeutic agent for infectious diseases can be produced from the compounds of the present invention or their solvates, for example, by conventional formulation methods such as blending them and appropriately adding additives as necessary.
  • the dosage form of the antifungal agent of the compound of the present invention includes, for example, tablets, powders, granules, or capsules, or solutions, syrups, elixirs, or oily or aqueous suspensions as oral preparations. can be mentioned.
  • stabilizers, preservatives, or solubilizing agents may be used in the formulation.
  • External preparations include solutions, suspensions, emulsions, ointments, gels, creams, lotions, sprays, and the like.
  • Solid preparations may contain pharmaceutically acceptable additives together with the compounds of the present invention or their solvates, such as fillers, extenders, binders, disintegrants, dissolving agents, Accelerators, wetting agents, lubricants and the like can be selected and mixed as required to form a formulation.
  • pharmaceutically acceptable additives such as fillers, extenders, binders, disintegrants, dissolving agents, Accelerators, wetting agents, lubricants and the like can be selected and mixed as required to form a formulation.
  • liquid formulations include solutions, suspensions, emulsions, and the like, and additives such as suspending agents and emulsifying agents can be included.
  • Methods of administering the compounds of the present invention or their solvates to animals include a method of orally administering them directly or by mixing them in feed, or a method of making a solution and then adding it directly or into drinking water or feed. Examples include a method of orally administering the drug through an injection, a method of administering it by injection, and the like.
  • HPLC HPLC was performed using reverse phase chromatography, for example, as follows.
  • Detector UV absorption photometer (measurement wavelength: 220 nm)
  • Column Mightysil RP-18 GP 5 ⁇ m, 4.6 mm i. d ⁇ 150mm
  • linear peptides disclosed herein can be easily produced according to general chemical synthesis methods. For example, either a conventionally known solid-phase synthesis method or a liquid-phase synthesis method may be employed.
  • reaction is carried out according to a common peptide synthesis method, such as the azide method, active esterification method, mixed acid anhydride method or condensation method.
  • the amino acid hydrazine produced by reacting an amino acid or its ester with hydrazine in an inert solvent at around room temperature is reacted with a nitrite compound, converted to an azide compound, and then treated with an amine compound.
  • a nitrite compound may include, for example, alkali metal nitrites such as sodium nitrite or alkyl nitrite compounds such as isoamyl nitrite.
  • alkali metal nitrites such as sodium nitrite or alkyl nitrite compounds such as isoamyl nitrite.
  • inert solvents used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and pyrrolidones such as N-methylpyrrolidone.
  • the two reactions in this step are usually carried out one in a reaction solution, the reaction temperature is -50 to 0 ° C. in the first stage and -10 to 10 ° C. in the second stage, and the reaction time is 5 minutes to 1 hour, followed by 10 hours to 5 days.
  • the active esterification method is carried out by reacting an amino acid with an active esterification agent in a solvent to produce an active ester, and then reacting it with an amine compound.
  • the solvent to be used is not particularly limited as long as it is inert. Examples include halogenated hydrocarbons such as methylene chloride and chloroform, ethers such as ether and tetrahydrofuran, dimethylformamide and dimethylacetamide. Amides may be mentioned.
  • Active esterification agents used include, for example, N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide; Diimidazole compounds such as 1'-oxalyldiimidazole and N,N'-carbonyldiimidazole; disulfide compounds such as 2,2'-dipyridyldisulfide; N,N'- succinic acid compounds such as disuccinimidyl carbonate; phosphinic chloride compounds such as N,N'-bis(2-oxo-3-oxazolidinyl)phosphinic chloride; N,N'- disuccinimidyl oxalate (DSO), N,N'-diphthalimide oxalate (DPO), N,N'-bis(norbornenylsuccinimidyl) oxalate (BNO), 1,1 '-bis (benzotri
  • the active esterification reaction is for example, azodicarboxylic acid di-lower alkyl-triphenylphosphine such as diethyl-triphenylphosphine azodicarboxylate, N-lower alkyl such as N-ethyl-5-phenylisoxazolium-3′-sulfonate -5-arylisoxazolium-3'-sulfonates, N',N'-dicycloalkylcarbodiimides such as N',N'-dicyclohexylcarbodiimide (DCC), di-2-pyridyldisele diheteroaryldiselenides such as nido, triarylphosphines such as triphenylphosphine, arylsulfonyltriazolides such as p-nitrobenzenesulfonyltriazolide, 2-chloro-1-methylpyridinium iodide.
  • 2-halo-1-lower alkylpyridinium halides such as and diarylphosphorylazides such as diphenylphosphorylazide (DPPA), imidazole derivatives such as N,N'-carbodiimidazole (CDI), 1-hydroxybenzotriazole (HOBT), dicarboximide derivatives such as N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ( It is preferably carried out in the presence of a condensing agent such as a carbodiimide derivative such as EDAPC).
  • the reaction temperature is ⁇ 10 to 25° C. for the active esterification reaction, and around room temperature for the reaction between the active ester compound and the amine, and the reaction time is 30 minutes to 10 hours for both reactions.
  • the mixed anhydride method is carried out by preparing mixed anhydrides of amino acids and then reacting them with amines. Reactions to produce mixed acid anhydrides can be carried out in an inert solvent (e.g., ether, ethers such as tetrahydrofuran, amides such as dimethylformamide, dimethylacetamide) using a lower carbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate. This is accomplished by reacting the amino acid with an alkyl halide or a di-lower alkyl cyanophosphate such as diethylcyanophosphate.
  • an inert solvent e.g., ether, ethers such as tetrahydrofuran, amides such as dimethylformamide, dimethylacetamide
  • a lower carbonate such as ethyl chlorocarbonate or isobutyl chlorocarbonate.
  • 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 anhydride and the amine is preferably carried out in an inert solvent (e.g., ether, ethers such as tetrahydrofuran, amides such as dimethylformamide, dimethylacetamide) in the presence of the organic amine.
  • the reaction temperature is 0° C. to room temperature, and the reaction time is 1 hour to 24 hours.
  • the condensation method is carried out by directly reacting an amino acid and an amine in the presence of the condensing agent. This reaction is carried out in the same manner as the reaction for producing the active ester.
  • the functional group is protected in the reaction according to the usual method, and if desired, it is removed before performing the first step below. be able to.
  • a solid-phase synthesis method using Boc (t-butoxycarbonyl) or Fmoc (9-fluorenylmethoxycarbonyl) as an amino-protecting group is suitable.
  • the linear peptides disclosed herein can be prepared by B. et al. using a commercially available peptide synthesizer. Dorner et al. A peptide chain having a desired amino acid sequence and a modified (C-terminal amidation, etc.) portion can be synthesized by a solid-phase synthesis method according to the solid-phase synthesis handbook (Merck), standard methods, and product instruction manuals. .
  • Alko-PEG resin in which polyethylene glycol is bound to polystyrene, is used as a solid-phase resin for synthesis, and each Fmoc amino acid residue is subjected to an elongation reaction using a condensing agent.
  • HATU is used as a condensing agent in this case, and 20% piperidine in DMF is used for deprotection of the Fmoc group.
  • DMF is used as a solvent for all reactions and resin washing.
  • the synthesized peptide is cleaved from the resin and treated with TFA containing a scavenger to deprotect the protecting group of the side chain of the amino acid residue. After addition of ethyl ether, the free peptide was recovered by precipitation and filtration, and freeze-dried to obtain a solid powder (hydrochloride) of the unpurified peptide.
  • the sequence of the target peptide is H 2 N-Cha-D-Phe-Orn-Orn-Orn-Asn-COOH (Orn: N- ⁇ -acetyl-N- ⁇ -(benzoyl)-L-ornithine, Cha: cyclohexylalanine ), and the peptide chain was elongated by sequentially condensing amino acids from the C-terminus to the N-terminus.
  • Fmoc amino acids used are as follows. ⁇ Fmoc-Cha-OH: purchased from Ark Pharma through Namiki Shoji, CAS number 135673-97-1, - Fmoc-D-Phe-OH: commercially available. CAS number 6123-10-6, ⁇ Fmoc-N- ⁇ -acetyl-N- ⁇ -(benzyloxy)-L-ornithine-OH: purchased synthesized by Sundia through Namiki Shoji, CAS number 2209864-45-7. * Coupling of each amino acid was performed at the following compositional ratio.
  • Fmoc amino acid (mmol): HATU (mmol): DIEA (mmol): DMF (mL) 1.32: 1.32: 2.64: 9 Only special Orn residues were carried out at the following compositional ratios.
  • Fmoc special Orn uses 2 equivalents to resin
  • Fmoc Special Orn (mmol): HATU (mmol): DIEA (mmol): DMF (mL) 0.66:0.66:1.32:4.
  • Amino acids corresponding to other R 1 groups can be added to the chain peptide according to the methods described above. introduced to
  • 1-adamantylalanine is available from Overkleeft, et al, Chem. Commun. , 2016, vol. 52, 4064-4067. According to, can be produced from 1-adamantyl acetaldehyde, other amino acids (e.g., cycloheptylalanine, cyclooctylalanine, cyclononylalanine, cyclodecylalanine, 2-adamantylalanine) can also be produced from the corresponding acetaldehyde form as a raw material , Overkleeft, et al, Chem. Commun. , 2016, vol. 52, 4064-4067. can be synthesized according to
  • the cutting solution is collected by filtration, TFA is distilled off under reduced pressure, an appropriate amount of 4N-hydrochloric acid/ethyl acetate is added and mixed well, then ethyl ether is added and the precipitate is collected by filtration to obtain the unpurified peptide of interest. 335 mg, crude yield 81% (hydrochloride form) were obtained.
  • R 1 and M have the same meanings as above.
  • the starting compound (11) of the compound of the present invention can be produced according to the above description (1).
  • the linear peptide (11) is subjected to intramolecular amidation of the carboxylic acid and amino group in the molecule in the same manner as in (1) above, and the cyclized compound (12) is obtained. It is a manufacturing process. It is necessary to first activate the carboxylic acid in the presence of a base, in a process that normally occurs by converting the -OH of the acid to a good leaving group before treatment with the amine. Suitable methods for activation of the carboxy group include, but are not limited to, formation of acid halides, acyl azides, mixed anhydrides, activated esters, and the like.
  • Acid halides include, but are not limited to, halogen sources such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, triphosgene, cyanuric fluoride, cyanuric chloride, BoP-Cl, PyBroP, etc., with a carboxylic acid in an aprotic solvent. It can be prepared by processing in Mixed anhydrides can be prepared using reagents such as, but not limited to, pivaloyl chloride, EEDQ in aprotic solvents.
  • Suitable coupling reagents for use in the process of amidation via active esters include, but are not limited to, carbodiimides such as DCC, DIC, EDAC, uroniums such as HATU, TATU, HBTU, TBTU, TDBTU. salts, phosphonium salts such as PyBoP, BoP, DEPBT, preferably uronium salts, more preferably HATU.
  • carbodiimides such as DCC, DIC, EDAC
  • uroniums such as HATU, TATU, HBTU, TBTU, TDBTU. salts, phosphonium salts such as PyBoP, BoP, DEPBT, preferably uronium salts, more preferably HATU.
  • phosphonium salts such as PyBoP, BoP, DEPBT, preferably uronium salts, more preferably HATU.
  • additives such as, but not limited to, HOAt, HOBt.
  • amidating coupling reagents that act by different mechanisms of carboxyl group activation include, but are not limited to, DPPA, T3P®, CDI, Mukaiyama's reagent, and the like. Activation can also be performed by using solid supported versions of the above binding reagents such as, but not limited to, PS-CDI, PS-EDC, PS-BoP, and the like.
  • 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, and the like. DIEA is preferred. A more complete discussion of amidation can be found in Valeur, E.; (Chem. Soc.
  • the reaction can be carried out by dissolving the linear peptide (11) or an appropriate salt thereof in an inert solvent such as DMF, and adding an active compound such as HATU under a stream of nitrogen at room temperature. A solvent solution of the agent is added, followed by dropwise addition of a base such as, for example, diisopropylethylamine under cooling.
  • a base such as, for example, diisopropylethylamine under cooling.
  • the 2nd step is a method for preparing compound (13) by removing the remaining protective group of hydroxylamide of compound (12) prepared in step 1 by a conventional method.
  • the removal of the protecting group varies depending on the type, but is generally carried out as follows by methods well known in the art. Investigation of conditions for hydrogenation reaction in the presence of a catalyst (created from a report by Kobe Natural Products) In the removal of aralkyl groups or aralkyloxycarbonyl groups by catalytic reduction, as the reaction time is extended, In the preparative debenzylation reaction, an increase in by-products presumed to be hydrodehydrated was observed.
  • the target compound (13) of this reaction is collected from the reaction mixture according to a conventional method. be done.
  • the third step is to chelate the compound (13) produced in the second step with aluminum, gallium, iron or ruthenium to produce the compound (14).
  • aluminum, gallium, iron or ruthenium In the case of producing an aluminum chelate, at room temperature, for example, milli-Q aqueous solution of potassium aluminum sulfate dodecahydrate or aluminum chloride is added, and after stirring for 30 minutes to 6 hours, milli-Q water is added and stirred for a while. , OASIS HLB, and the solvent was distilled off under reduced pressure to obtain compound (14).
  • iron chloride or iron sulfate hydrate was added and chelated similarly to aluminum.
  • gallium chloride or gallium sulfate hydrate was added and chelated in the same manner as aluminum.
  • ruthenium chelate ruthenium chloride was added for chelation.
  • compound (14) of this reaction is collected from the reaction mixture according to a conventional method.
  • the target compound obtained is subjected to a conventional method such as recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds such as solid phase extraction, reverse phase column chromatography ( Preferably, it is high performance liquid chromatography.) can be appropriately combined and eluted with an appropriate eluent for separation and purification.
  • Hydrochloride salt of linear peptide (21:1.3400 g, 1,067 ⁇ mol) under a nitrogen stream: A compound with HPLC purity of 72.9% (220 nm) was obtained by solid-phase synthesis. Conversion by HPLC purity was not performed.
  • HATU (527.4 mg, 1,387 ⁇ mol; Watanabe Chemical Industry Co., Ltd.) was added to a DMF (1004.06 g) solution of , at room temperature. ) was added, and diisopropylethylamine (Tokyo Kasei: 560 ⁇ L, 3,206 ⁇ mol) was added dropwise under cooling ( ⁇ 16° C.) in an ice+methanol bath.
  • the cyclized product (22: 0.79 g, 658 ⁇ mol) obtained in (1) above was dissolved in methanol (15.80 g) and stirred at room temperature with Milli-Q water (12.63 g) and 10% Pd/C. PE (manufactured by NE CHEMCAT, 50% wet, 144.7 mg) was sequentially added and stirred for 2 hours under slight pressure of hydrogen (balloon) to confirm the reaction end point of compound (23).
  • Antifungal activity measurement method The antifungal activity against the test bacteria shown in the table below was measured using a microdilution method (Kumemitsu, Yamazaki Toshikazu, Clinical and Microorganisms, Vol. 21, No. 5, pp. 573-580, 1994).
  • CLSI-M27 Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Approved Standard-4th Edition. 2017.
  • CLSI-M38 Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi; Approved Standard-3rd Edition. 2017.
  • the derivatives of the invention in particular (IVa, 24), showed significantly more activity than the control compound ASP2397.
  • Compound IVa Al chelate, 24
  • Compound IVg Ga chelate
  • Compound IVf Fe chelate
  • Activity evaluation uses a 96-well plate, dispenses 100 ⁇ L of test bacterial solution per well, cultures with shaking at 200 rpm at 30 ° C. for 18 to 24 hours, and then measures OD600 with a plate reader. MIC (minimum effective concentration) was determined.
  • the compounds of the present invention exhibited high activity against any of the fungi of the genus Schizosaccharomyces (fission yeast (Schizosaccharomyces pombe)), Aspergillus fumigatus, and Candida glabrata.
  • compound IVa aluminum chelate, 24
  • compound IVf iron chelate
  • Example 2 The antifungal activity of each compound described above was evaluated in the same manner as in Example 1, "Evaluation of antifungal activity using compound IVa (Al chelate, 24), compound IVg (Ga chelate), and compound IVf (Fe chelate)." It was measured by the method of Antifungal activity evaluation of Al chelates of compounds 232 and 235 is shown in FIG.
  • FIG. 24 shows the results of comparing the activity of the Al, Ga, Fe chelate form of compound 232 with that of ASP2397.
  • FIG. 25 shows the results of comparing the activity of the Al, Ga, Fe chelate form of compound 235 with that of ASP2397.
  • Al, Ga, and Fe chelates were prepared in situ from compound 248, and the results of comparing the activity with ASP2397 are shown in FIG. It was confirmed that each compound exhibited excellent antifungal activity.
  • Compound 124+Al (compounds (IVa, 24)), compound 232+Al (compound Va), and ASP2397 were measured for antifungal activity in the same manner as in Example 1 "antifungal activity measurement method".
  • Table 4 shows the MIC values against drug-resistant Aspergillus (closely related strains Aspergillus felis, Aspergillus lentulus, and A. fumigatus).
  • Table 5 shows the MIC values for the genus Candida (three species of C. parapsilosis, C. glabrata, and C. auris and their respective drug-resistant strains). It was confirmed that each compound exhibited excellent antifungal activity.

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Abstract

La présente invention concerne un composé de formule générale (II) ou un solvate de celui-ci, un agent antifongique le contenant, ou un procédé de traitement d'une maladie fongique à l'aide de ceux-ci. R1 représente un groupe alkyle en C1-3 cycloalkyle en C6-10 et M représente un élément du groupe 8 ou du groupe 13.
PCT/JP2022/017337 2021-04-08 2022-04-08 Substance d'un nouvel agent antifongique de type sidérophore (composé) et son utilisation WO2022215745A1 (fr)

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WO2009113661A1 (fr) * 2008-03-14 2009-09-17 アステラス製薬株式会社 Composé cyclique et son sel

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Publication number Priority date Publication date Assignee Title
WO2009113661A1 (fr) * 2008-03-14 2009-09-17 アステラス製薬株式会社 Composé cyclique et son sel

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Title
ASAI YOSHIKI, HIRATSUKA TOMOSHIGE, UEDA MIYU, KAWAMURA YUMI, ASAMIZU SHUMPEI, ONAKA HIROYASU, ARIOKA MANABU, NISHIMURA SHINICHI, Y: "Differential Biosynthesis and Roles of Two Ferrichrome-Type Siderophores, ASP2397/AS2488053 and Ferricrocin, in Acremonium persicinum", ACS CHEMICAL BIOLOGY, vol. 17, no. 1, 21 January 2022 (2022-01-21), pages 207 - 216, XP055975193, ISSN: 1554-8929, DOI: 10.1021/acschembio.1c00867 *
BUTLER, M.S. ; BUSS, A.D.: "Natural products - The future scaffolds for novel antibiotics?", BIOCHEMICAL PHARMACOLOGY, ELSEVIER, US, vol. 71, no. 7, 30 March 2006 (2006-03-30), US , pages 919 - 929, XP027905234, ISSN: 0006-2952 *
DUSHIN RUSSELL G., WANG TING-ZHONG, SUM PHAIK-ENG, HE HAIYIN, SUTHERLAND ALAN G., ASHCROFT JOSEPH S., GRAZIANI EDMUND I., KOEHN FR: "Hydrophobic Acetal and Ketal Derivatives of Mannopeptimycin-α and Desmethylhexahydromannopeptimycin-α: Semisynthetic Glycopeptides with Potent Activity Against Gram-Positive Bacteria", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 47, no. 14, 1 July 2004 (2004-07-01), US , pages 3487 - 3490, XP055975191, ISSN: 0022-2623, DOI: 10.1021/jm049765y *
NAKAMURA IKUKO; YOSHIMURA SEIJI; MASAKI TERUHISA; TAKASE SHIGEHIRO; OHSUMI KEISUKE; HASHIMOTO MICHIZANE; FURUKAWA SHIGETADA; FUJIE: "ASP2397: a novel antifungal agent produced by Acremonium persicinum MF-347833", THE JOURNAL OF ANTIBIOTICS, NATURE PUBLISHING GROUP UK, LONDON, vol. 70, no. 1, 7 September 2016 (2016-09-07), London, pages 45 - 51, XP037651174, ISSN: 0021-8820, DOI: 10.1038/ja.2016.107 *

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