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WO2018139599A1 - Nouvel antibiotique aminoglycoside efficace pour de multiples bactéries résistantes aux médicaments - Google Patents

Nouvel antibiotique aminoglycoside efficace pour de multiples bactéries résistantes aux médicaments Download PDF

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Publication number
WO2018139599A1
WO2018139599A1 PCT/JP2018/002544 JP2018002544W WO2018139599A1 WO 2018139599 A1 WO2018139599 A1 WO 2018139599A1 JP 2018002544 W JP2018002544 W JP 2018002544W WO 2018139599 A1 WO2018139599 A1 WO 2018139599A1
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Prior art keywords
isoceryl
group
apramycin
deoxy
pharmaceutically acceptable
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PCT/JP2018/002544
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English (en)
Japanese (ja)
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英二郎 梅村
高橋　良昭
井田　孝志
雅之 五十嵐
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公益財団法人 微生物化学研究会
Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社
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Publication of WO2018139599A1 publication Critical patent/WO2018139599A1/fr

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H5/00—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium
    • C07H5/04—Compounds containing saccharide radicals in which the hetero bonds to oxygen have been replaced by the same number of hetero bonds to halogen, nitrogen, sulfur, selenium, or tellurium to nitrogen
    • C07H5/06—Aminosugars
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel aminoglycoside antibiotic and a pharmaceutical composition containing the aminoglycoside antibiotic.
  • Aminoglycoside antibiotics are antibiotics that have antibacterial activity against both gram-positive and gram-negative bacteria, as well as ⁇ -lactam and quinolone drugs, but those that cover these and other resistant bacteria already exist. It has not been found in other pharmaceuticals, and as shown below, it has been difficult to develop.
  • MRSA methicillin-resistant Staphylococcus aureus
  • MRSA methicillin-resistant Staphylococcus aureus
  • HABA aminohydroxybutyric acid
  • S aminohydroxybutyric acid
  • arbekacin (4-Amino-2-hydroxybutyryl) dibekacin
  • Non-Patent Document 1 arbekacin has been used in Japan as a specific drug for MRSA infection since the end of 1990. Yes.
  • multidrug-resistant bacteria are increasing not only in Gram-positive bacteria such as MRSA, but also in Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae, Serratia, Acinetobacter, and Pseudomonas aeruginosa. Many of these bacteria are also resistant to conventional aminoglycosides, ⁇ -lactams and new quinolones, which often cause refractory infections.
  • the amino group at the 1-position of sisomicin is aminohydroxybutyric acid (HABA).
  • HABA aminohydroxybutyric acid
  • S -1-N- (4-amino-2-hydroxybutyryl) -6′-N-hydroxyethylsisomicin (prazomicin), which is acylated and alkylated at the 6′-position amino group, is effective (Patent Document 1).
  • prazomicin is effective against a part of multidrug-resistant gram-negative bacteria, it is ineffective for resistant gram-negative bacteria that produce methylase and is not sufficient in terms of basic antibacterial activity and safety.
  • Non-patent Document 2 A compound in which the hydroxyl group at position 5, 6 or 6 ′′ of apramycin is chemically modified is disclosed (Patent Documents 2, 3 and 4), and the amino group at position 1 or 4 ′′ of apramycin is chemically modified. Although compounds have been disclosed (Patent Documents 5 and 6), none of the compounds has clearly disclosed the effectiveness against resistant bacteria.
  • An object of the present invention is to provide a novel aminoglycoside antibiotic having antibacterial activity against both gram-positive and gram-negative bacteria, and particularly effective against gram-positive and gram-negative bacteria exhibiting multidrug resistance. To do.
  • the present inventors have eagerly searched for a derivative of apramycin, which is a kind of aminoglycoside antibiotic, and found a compound having antibacterial activity against gram-positive bacteria and gram-negative bacteria. These compounds were also found to be effective against resistant bacteria such as MRSA and multidrug resistant gram-negative bacteria.
  • the present invention is based on these findings.
  • the present invention includes the following inventions.
  • R 6 represents an N-ethylglycyl group, an N-amidinoglycyl group, an N-amidinosarcosyl group, an N-methyl-L-isoceryl group, or an N-amidino-L-isoceryl group Or a pharmaceutically acceptable salt or solvate thereof.
  • R 4 represents a hydrogen atom.
  • R 5 represents a hydroxyl group, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (8), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the infection is sepsis, infective endocarditis, dermatological infection, surgical infection, orthopedic infection, respiratory infection, urinary tract infection, intestinal infection, peritonitis, marrow
  • the pharmaceutical composition according to (10), wherein the composition is membrane inflammation, ophthalmic area infection, or otolaryngological infection.
  • the compound according to any one of (1) to (8), or a pharmaceutically acceptable salt thereof, or a solvate thereof for the manufacture of a medicament for the prevention or treatment of infectious diseases Use of things.
  • a method for preventing or treating an infection comprising a therapeutically effective amount of the compound according to any one of (1) to (8), or a pharmaceutically acceptable salt thereof, or a solvent thereof Administering a Japanese product to an animal.
  • An antibacterial agent comprising the compound according to any one of (1) to (8), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound of the present invention is advantageous in that it has a broad antibacterial spectrum from gram positive bacteria to gram negative bacteria. It is also advantageous in that it has antibacterial activity against multidrug-resistant gram-positive and gram-negative bacteria that cannot be dealt with by existing antibiotics. In particular, it is advantageous in that it is useful for the prevention or treatment of serious infections caused by MRSA, multidrug resistant gram-negative bacteria, and the like.
  • the compound of the present invention is a compound represented by the above general formula (I), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the compound of the present invention can exist as a salt.
  • the salt include pharmaceutically acceptable non-toxic salts.
  • Specific examples of such salts include hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, sulfate, nitrate, phosphate and perchloric acid.
  • Inorganic acid salts such as salt, carbonate, acetate, trichloroacetate, trifluoroacetate, hydroxyacetate, lactate, citrate, tartrate, oxalate, benzoate, mandelate, butyric acid Of amino acid salts such as salt, maleate, propionate, formate, malate, arginate, aspartate, glutamate, methanesulfonate, paratoluenesulfonate
  • sulfonates include inorganic acid salts such as sulfates.
  • the compounds of the present invention can exist as solvates.
  • Preferred solvates include hydrates and ethanol solvates.
  • the compound of the present invention can be produced according to the following methods AG, but the method for producing the compound of the present invention is not limited thereto.
  • Method A is a method for producing a compound represented by the general formula (A4) by introducing a substituent at the 4 ′′ position of apramycin, followed by deprotection, and the steps are shown below.
  • the steps A1 to A3 were in accordance with the method described in US2013 / 0165395A1.
  • Step A4 is a process for producing a compound represented by the general formula (A4) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by the formula (A3). This step is achieved by reacting the compound represented by the formula (A3) with an active ester of various amino acid protected forms in the presence of a base, followed by deprotection.
  • the active ester used in this step includes N-hydroxyamine, S-alkyl, S-phenyl, and the like, preferably N-hydroxyamine N-hydroxysuccinimide ester.
  • the base is preferably triethylamine.
  • the reaction temperature is 10 ° C to 40 ° C.
  • the reaction time is 1 to 24 hours.
  • the benzyloxycarbonyl group can be removed by reacting with hydrogen in the presence of a catalytic reduction catalyst and an acid.
  • a catalytic reduction catalyst and an acid examples include acetic acid, trifluoroacetic acid, hydrochloric acid and the like, and acetic acid is preferable.
  • the catalytic reduction catalyst include palladium-carbon, palladium black, palladium hydroxide, platinum oxide and the like, preferably palladium-carbon.
  • the solvent to be used is not particularly limited as long as it does not participate in this reaction, but methanol, ethanol, tetrahydrofuran, dioxane, or a mixed solvent of these organic solvents and water is preferable.
  • the reaction temperature is 10 ° C.
  • Cyclic carbamate can be removed by hydrolysis with a base.
  • Examples of the base include sodium hydroxide and potassium hydroxide.
  • the reaction temperature is 20 ° C. to 110 ° C., and the reaction time is usually 0.5 to 48 hours.
  • Method B epimerization occurs after the introduction of a leaving group at the 5-position of the compound represented by formula (B1) in which only the 5-position hydroxyl group of apramycin is released.
  • the compound represented by the general formula (B5) is deprotected. It is a manufacturing method, and the method is as shown below.
  • Step B1 is a step of selectively introducing a benzoyl protecting group into the 6-position, 2 ′′ -position and 3 ′′ -position hydroxyl group of a compound represented by the formula (A2) to produce a compound represented by the formula (B1). It is a manufacturing process. This step is achieved by reacting the compound of formula (A2) with benzoyl chloride in the presence of a base.
  • Examples of the solvent used in this step include pyridine, N, N-dimethylformamide, methylene chloride, chloroform, 1,2-dichloroethane, and preferably pyridine.
  • Examples of the base to be used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, preferably pyridine.
  • the reaction temperature is 0 ° C to 30 ° C.
  • the reaction time is 1 to 5 hours.
  • Step B2 is a process for producing a compound represented by formula (B2) by introducing a methanesulfonyl group into the 5-position hydroxyl group of a compound represented by formula (B1). This step is achieved by reacting the compound of formula (B1) with methanesulfonyl chloride in the presence of a base.
  • Examples of the solvent used in this step include pyridine, methylene chloride, chloroform, 1,2-dichloroethane, and preferably methylene chloride.
  • Examples of the base used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, and 4-dimethylaminopyridine is preferable.
  • the reaction temperature is 0 ° C to 30 ° C.
  • the reaction time is 1 to 2 hours.
  • Step B3 is a process for producing a compound represented by formula (B3) by inverting the 5-position of the compound represented by formula (B2). The reaction is achieved by reacting the compound represented by formula (B2) with cesium acetate or sodium acetate.
  • Examples of the solvent used in this step include dioxane, N, N-dimethylformamide, 1,2-dimethoxyethane, and preferably N, N-dimethylformamide.
  • the reaction temperature is 80 ° C to 100 ° C.
  • the reaction time is 3 to 6 hours.
  • Step B4 removes the acetyl group, benzoyl group and cyclic carbamate at the 4 ′′ and 6 ′′ positions of the compound represented by formula (B3) to produce a compound represented by formula (B4). It is a process. This step is achieved by reacting the compound represented by the formula (B3) with 6 to 8 equivalents of a base.
  • Examples of the solvent used in this step include water-containing 1,4-dioxane, tetrahydrofuran, methanol and a mixed solvent thereof, and preferably water-containing 1,4-dioxane.
  • Examples of the base to be used include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide and the like, preferably potassium hydroxide.
  • the reaction temperature is 20 to 40 ° C.
  • the reaction time is 5 to 16 hours.
  • Step B5 is a process for producing a compound represented by the general formula (B5) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by the formula (B4). This step can be performed under the same conditions as in the aforementioned step A4.
  • Method C is a formula obtained by iodination of the 5-position of the compound represented by formula (B2), followed by reduction to obtain a 5-deoxy form, and then deprotection of the hydroxyl group and the amino group at the 4 ′′ position ( This is a method for producing a compound represented by the general formula (C4) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by C3), and the method is as shown below. .
  • Step C1 is a process for producing a compound represented by formula (C1) by iodination at the 5-position of a compound represented by formula (B2). This step is achieved by reacting the compound represented by the formula (B2) with sodium iodide.
  • Examples of the solvent used in this step include acetone, N, N-dimethylformamide, tetrahydrofuran and dioxane, and N, N-dimethylformamide is preferable.
  • the reaction temperature is 60 ° C to 120 ° C, and the reaction time is 1 to 6 hours.
  • Step C2 is a process for producing a compound represented by formula (C2) by reducing iodo of a compound represented by formula (C1). This step is achieved by reacting the compound represented by the formula (C1) with tributyltin hydride in the presence of 2,2′-azobis (isobutyronitrile).
  • Examples of the solvent used in this step include toluene, tetrahydrofuran, dioxane and the like, preferably dioxane.
  • the reaction temperature is 60 ° C to 100 ° C.
  • the reaction time is 3 to 8 hours.
  • Step C3 removes the acetyl group, benzoyl group and cyclic carbamate at the 4 ′′ and 6 ′′ positions of the compound represented by formula (C2) to produce a compound represented by formula (C3). It is a process. This step can be performed under the same conditions as in the aforementioned B4 step.
  • Step C4 is a process for producing a compound represented by the general formula (C4) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by the formula (C3). This step can be performed under the same conditions as in the aforementioned step A4.
  • Method D is a formula obtained by obtaining a 6-deoxy-5-epi form from a compound represented by formula (B2) via a 5,6-anhydro intermediate and then deprotecting the amino group at the 4 ′′ position.
  • This is a method for producing a compound represented by the general formula (D5) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by (D4), and the method is as shown below. is there.
  • Step D1 the benzoyl group of the compound represented by formula (B2) is removed and at the same time the 5-position and 6-position are anhydrolated (epoxidized) to produce a compound represented by formula (D1). It is a process. This step is achieved by reacting the compound represented by formula (B2) with a base.
  • Examples of the solvent used for debenzoylation and anhydrolysis include methanol, ethanol, methylene chloride, chloroform, 1,2-dichloroethane, and preferably chloroform.
  • Examples of the base used include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, tert-butoxypotassium and the like, and preferably sodium methoxide.
  • the reaction temperature is 0 ° C to 30 ° C.
  • the reaction time is 1 to 5 hours.
  • Step D2 is a process for producing a compound represented by formula (D2) by cleaving an epoxide of a compound represented by formula (D1). This step is achieved by reacting the compound represented by the formula (D1) with sodium iodide in the presence of an acidic buffer.
  • Examples of the solvent used in this step include acetone, N, N-dimethylformamide, tetrahydrofuran, dioxane and the like, preferably acetone.
  • Examples of the acidic buffer used include 5% sodium acetate solution.
  • the reaction temperature is 60 ° C to 100 ° C.
  • the reaction time is 1 to 6 hours.
  • Step D3 is a process for producing a compound represented by formula (D3) by reducing iodo of a compound represented by formula (D2). This step can be performed under the same conditions as in step C2.
  • Step D4 is a process for removing the methoxycarbonyl group at position 4 ′′ of the compound represented by formula (D3) to produce a compound represented by formula (D4). It can carry out on the conditions similar to B4 process.
  • Step D5 is a process for producing a compound represented by the general formula (D5) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by the formula (D4). This step can be performed under the same conditions as in the aforementioned step A4.
  • Method E deoxylates the 3 ′′ hydroxyl group of the compound represented by the formula (E1) in which only the 5th and 3 ′′ hydroxyl groups of apramycin are released, and then epithelizes the 5th position.
  • the compound represented by the general formula (E8) is deprotected after acylating the 4 ′′ -position amino group of the compound represented by the formula (E7) obtained by deprotecting the hydroxyl group and the 4 ′′ -position amino group.
  • the method is as follows.
  • Step E1 is a step of producing a compound represented by the formula (E1) by selectively introducing benzoyl protecting groups into the 6-position and 2 ′′ -position hydroxyl groups of the compound represented by the formula (A2). This step is achieved by reacting the compound of formula (A2) with benzoyl chloride in the presence of a base.
  • Examples of the solvent used in this step include pyridine, N, N-dimethylformamide, methylene chloride, chloroform, 1,2-dichloroethane, and preferably pyridine.
  • Examples of the base to be used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, preferably pyridine.
  • the reaction temperature is ⁇ 15 ° C. to 0 ° C.
  • the reaction time is 0.5 to 1 hour.
  • Step E2 is a step for producing a compound represented by formula (E2) by introducing a trifluoromethanesulfonyl group into the 3 ′′ -position hydroxyl group of a compound represented by formula (E1). This is achieved by reacting the compound of formula (E1) with trifluoromethanesulfonic anhydride in the presence of a base.
  • Examples of the solvent used in this step include pyridine, methylene chloride, chloroform, 1,2-dichloroethane, and preferably methylene chloride.
  • Examples of the base to be used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, preferably pyridine.
  • the reaction temperature is ⁇ 10 ° C. to 10 ° C.
  • the reaction time is 1 to 2 hours.
  • Step E3 is a step in which the compound represented by formula (E3) is produced by iodination at the 3 ′′ position of the compound represented by formula (E2). This step is represented by formula (E2). This is accomplished by reacting the represented compound with sodium iodide.
  • Examples of the solvent used in this step include acetone, N, N-dimethylformamide, tetrahydrofuran and dioxane, and N, N-dimethylformamide is preferable.
  • the reaction temperature is 60 to 100 ° C., and the reaction time is 1 to 6 hours.
  • Step E4 is a process for producing a compound represented by formula (E4) by reducing iodo of a compound represented by formula (E3). This step is achieved by reacting the compound represented by the formula (E3) with tributyltin hydride in the presence of 2,2′-azobis (isobutyronitrile).
  • Examples of the solvent used in this step include toluene, tetrahydrofuran, dioxane and the like, preferably dioxane.
  • the reaction temperature is 60 ° C to 100 ° C.
  • the reaction time is 3 to 8 hours.
  • Step E5 is a process for producing a compound represented by formula (E5) by introducing a methanesulfonyl group into the 5-position hydroxyl group of a compound represented by formula (E4). This step can be performed under the same conditions as in the aforementioned step B2.
  • Step E6 is a process for producing a compound represented by formula (E6) by inverting the 5-position of the compound represented by formula (E5).
  • the reaction is achieved by reacting the compound represented by formula (E5) with cesium acetate or sodium acetate. This step can be performed under the same conditions as in step B3 described above.
  • Step E7 removes the acetyl group, benzoyl group and cyclic carbamate at the 4 ′′ and 6 ′′ positions of the compound represented by formula (E6) to produce the compound represented by formula (E7). It is a process. This step can be performed under the same conditions as in the aforementioned B4 step.
  • Step E8 is a process for the preparation of a compound represented by the general formula (E8) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by the formula (E7). This step can be performed under the same conditions as in the aforementioned step A4.
  • Method F the amino group at the 4 ′′ position of the compound represented by the general formula (F) is N-Boc-L-isocerylated. After de-Boc, N-methylation and deprotection are carried out. ), And the method is as shown below.
  • Step F1 is a process for producing a compound represented by the general formula (F1) by N-Boc-L-isocerylation of the amino group at the 4 ′′ position of the compound represented by the general formula (F). This step is achieved by reacting the compound represented by formula (F) with an active ester of N-Boc-L-isoserine in the presence of a base.
  • the active ester used in this step includes N-hydroxyamine, S-alkyl, S-phenyl, and the like, preferably N-hydroxyamine N-hydroxysuccinimide ester.
  • the base is preferably triethylamine.
  • the reaction temperature is 10 ° C to 40 ° C.
  • the reaction time is 1 to 24 hours.
  • Step F2 is a process for producing a compound represented by the general formula (F2) by removing the t-butoxycarbonyl (Boc) group of the compound represented by the general formula (F1). This step is achieved by reacting the compound represented by the general formula (F1) with an acid.
  • Examples of the solvent used in this step include ethyl acetate, methylene chloride, acetonitrile, acetone, methanol, etc., preferably methanol.
  • Examples of the acid used include p-toluenesulfonic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid and the like, and trifluoroacetic acid is preferable.
  • the reaction temperature is usually 0 ° C to 50 ° C.
  • the reaction time is 1 to 5 hours.
  • Step F3 is a process for producing a compound represented by the general formula (F3) by introducing a benzyl group into the amino group of the L-isoceryl group of the compound represented by the general formula (F2). This step is achieved by reacting benzaldehyde and sodium borohydride in the presence of a base.
  • Examples of the solvent used in this step include methanol, tetrahydrofuran, dioxane and a mixed solvent thereof, preferably methanol.
  • the reaction temperature is 10 ° C to 40 ° C.
  • the reaction time is 1 to 2 hours.
  • Step F4 is a process for producing a compound represented by general formula (F4) by methylating a benzylated amino group of a compound represented by general formula (F3). This step is achieved by reacting the compound represented by formula (F3) with a reducing reagent in the presence of acid with formaldehyde.
  • Examples of the solvent used in this step include tetrahydrofuran, dioxane, methanol, and mixed solvents thereof.
  • Examples of the reducing reagent include sodium cyanoborohydride and borane-2-methylpyridine complex.
  • Step F5 is a process for producing a compound represented by general formula (F5) by deprotecting the compound represented by general formula (F4). This step can be performed under the same conditions as the deprotection in the aforementioned step A4.
  • Method G is a method for producing a compound represented by the general formula (G) by deprotecting the free amino group of the compound represented by the general formula (F2) after amidination, and the process is as follows. As shown below.
  • Step G is a step for producing a compound represented by the general formula (G) by amidinating a free amino group of the compound represented by the general formula (F2), followed by deprotection. Amidination is achieved by reacting the compound represented by formula (F2) with an amidinating reagent in the presence of a base. Deprotection is carried out under the same conditions as the deprotection in the aforementioned F2 step and A4 step. It can be carried out.
  • the amidinating agents used in this step include 1,3-bis (tert-butoxycarbonyl) -2- (trifluoromethanesulfonyl) guanidine (Goodman reagent), N, N′-di- (t-butoxycarbonyl) thio And urea, t-butyl- (Z)-(((t-butoxycarbonyl) imino) (1H-pyrazol-1-yl) methyl) carbamate, and the like, preferably Goodman's reagent, and the base is preferably triethylamine .
  • the reaction temperature is 10 ° C to 90 ° C.
  • the reaction time is 1 to 24 hours.
  • Method H the epoxide of the compound represented by the formula (D1) is converted to an olefin, and then the 4 ′′ position of the compound represented by the formula (H4) obtained by deprotecting the hydroxyl group and the amino group at the 4 ′′ position.
  • This is a method for producing a compound represented by the general formula (H5) by deprotecting and reducing the olefin after acylation of the amino group, and the method is as shown below.
  • Step H1 is a step of producing a compound represented by the formula (H1) by introducing a benzoyl protecting group into the 2 ′′ -position, 3 ′′ -position and 6 ′′ -position hydroxyl group of the compound represented by the formula (D1). This step can be carried out under the same conditions as in the aforementioned B1 step.
  • Step H2 is a process for producing a compound represented by formula (H2) by cleaving an epoxide of a compound represented by formula (H1). This step can be performed under the same conditions as in the aforementioned step D2.
  • Step H3 is a process for producing a compound represented by formula (H3) by benzylsulfonylation of the 5-position hydroxyl group of a compound represented by formula (H2), followed by addition of water and elimination reaction. is there. This step is achieved by reacting the compound of formula (H2) with benzylsulfonyl chloride in the presence of a basic solvent and then adding water.
  • Examples of the basic solvent used in the benzylsulfonylation include pyridine, picolines, lutidines, and preferably pyridine.
  • the reaction temperature is 0 ° C to 30 ° C.
  • the reaction time is 0.5 to 2 hours.
  • the reaction temperature after adding water is 40 ° C to 90 ° C.
  • the reaction time is 1 to 5 hours.
  • Step H4 is a process for producing a compound represented by formula (H4) by removing a benzoyl group and a 4 ′′ -position methoxycarbonyl group of a compound represented by formula (H3). Can be performed under the same conditions as in the aforementioned B4 step.
  • Step H5 is a process for producing a compound represented by the general formula (H5) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by the formula (H4). This step can be performed under the same conditions as in the aforementioned step A4.
  • Method I a leaving group is introduced into the 5-position hydroxyl group of the 3 ′′ -O-triflate represented by the formula (E2), and then 5,3 ′′ -diepilation occurs.
  • the compound represented by the general formula (I4) is obtained by acylating the 4 ′′ -position amino group of the compound represented by the formula (I3) obtained by deprotection of the hydroxyl group and the 4 ′′ -position amino group,
  • the method is as follows.
  • Step I1 is a step for producing a compound represented by formula (I1) by introducing a methanesulfonyl group into the 5-position hydroxyl group of a compound represented by formula (E2). This step can be performed under the same conditions as in the aforementioned step B2.
  • Step I2 is a step for producing a compound represented by formula (I2) by inverting the 5-position and 3 ′′ -position of a compound represented by formula (I1).
  • the reaction is represented by formula (I1).
  • a reaction of cesium acetate or sodium acetate which can be carried out under the same conditions as in Step B3 described above.
  • Step I3 removes the acetyl group, benzoyl group and cyclic carbamates at positions 4 ′′ and 6 ′′ of the compound represented by formula (I2) to produce a compound represented by formula (I3). It is a process. This step can be performed under the same conditions as in the aforementioned B4 step.
  • Step I4 is a process for producing a compound represented by the general formula (I4) by acylating and deprotecting the 4 ′′ -position amino group of the compound represented by the formula (I3). This step can be performed under the same conditions as in the aforementioned step A4.
  • the compound of the present invention and the above-mentioned compound obtained in the production process thereof can be purified and isolated by ordinary purification operations.
  • the purification / isolation method include a liquid separation operation method, a distillation method, a sublimation method, a precipitation method, a crystallization method, a silica gel column chromatography method using normal phase or reverse phase silica gel as a packing material, Amberlite CG-50, Dowex 50WX2.
  • a column chromatography method using an ion exchange resin such as CM-Sephadex C-25, a column chromatography method using cellulose or the like, a preparative thin layer chromatography method, or a high performance liquid chromatography method can be used.
  • the compound obtained in the above-mentioned manufacturing process can also be used for a subsequent process suitably, without performing isolation and purification.
  • the compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof have a broad antibacterial spectrum from gram positive bacteria to gram negative bacteria among pathogenic bacteria.
  • the compound of the present invention, or a pharmaceutically acceptable salt thereof, or a solvate thereof is against infectious disease-causing bacteria (MRSA, Staphylococcus aureus, Escherichia coli, Neisseria pneumoniae, Pseudomonas aeruginosa, etc.) It has excellent antibacterial activity and can therefore be used as an antibacterial agent.
  • MRSA infectious disease-causing bacteria
  • an antibacterial agent comprising the compound of the present invention. Furthermore, according to another aspect of the present invention, there is provided the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof, for the manufacture of an antibacterial agent.
  • the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof can be advantageously used as an antibacterial agent or a medicament in the prevention or treatment of infectious diseases. Therefore, according to another aspect of the present invention, there is provided a method for preventing or treating an infection, comprising a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof. Is provided to animals, including humans.
  • the infection to be treated is preferably a bacterial infection, such as sepsis, infective endocarditis, dermatological infection, surgical infection, orthopedic infection, respiratory infection, urine Include urinary tract infection, intestinal infection, peritonitis, meningitis, ophthalmological infection, or otolaryngological infection, preferably cutaneous purulent disease, burn / secondary wound infection, pneumonia, intrabronchial Infectious diseases, tuberculosis, pyelonephritis, enteritis (including food poisoning), conjunctivitis, otitis media and the like can be mentioned.
  • the animal to be prevented or treated is preferably a mammal, more preferably a human.
  • the dose of the compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof depends on the usage, type of pathogen, patient age, sex, body weight, disease severity, etc. As determined appropriately by those skilled in the art, in the case of oral administration to humans, for example, 0.1 to 1000 mg / kg per day for an adult, and 0.01 to 100 mg / kg in the case of intravenous administration. Can be administered.
  • the compounds of the present invention, or pharmaceutically acceptable salts or solvates thereof have antibacterial activity against multidrug resistant Gram-positive and Gram-negative bacteria that cannot be addressed by existing antibiotics. ing.
  • the compounds of the present invention, or pharmaceutically acceptable salts thereof, or solvates thereof are particularly useful for the prevention or treatment of serious infections caused by MRSA, multidrug resistant gram-negative bacteria, and the like.
  • compositions in particular a pharmaceutical composition, comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • the pharmaceutical composition of the present invention can be used orally or parenterally (eg, intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration, topical ocular administration, transocular administration, depending on the type of pathogen or disease, the nature of the patient, etc. It can be administered to all mammals including humans by any route of administration (pulmonary administration). Therefore, the pharmaceutical composition of the present invention can be made into a suitable preparation form according to the administration route. Examples of such preparation include injections, capsules, tablets, mainly used for intravenous injection, intramuscular injection, etc.
  • the above formulations are excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants, buffers, preservatives, solubilizers, preservatives, flavoring agents, It can be produced by conventional methods using additives such as soothing agents and stabilizers.
  • additives such as soothing agents and stabilizers.
  • non-toxic additives include injections, eye drops, ear drops, and nasal drops, which are soluble or soluble that can form aqueous or use-soluble dosage forms.
  • Adjuvants distilled water for injection, physiological saline, ethanol, glycerin, propylene glycol, corn oil, sesame oil, etc.
  • pH adjusters inorganic acid addition salts: trisodium orthophosphate, sodium bicarbonate, etc., organic acid salts: citrate Sodium salt, organic basic salts: L-lysine, L-arginine, etc.
  • isotonic agents sodium chloride, glucose, glycerin, etc.
  • buffering agents sodium chloride, benzalkonium chloride, sodium citrate, etc.
  • Surfactants sorbitan monooleate, polysorbate 80, etc.
  • dispersants D-mannitol, etc.
  • stabilizers antioxidants: ascorbic acid, sodium sulfite
  • sodium metabisulfite etc.
  • chelating agents citric acid, tartaric acid
  • Suitable formulation components white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.
  • suitable formulation components white petrolatum, macrogol, glycerin, liquid paraffin, cotton cloth, etc.
  • pH adjusters sodium citrate, sodium hydroxide, etc.
  • isotonic agents sodium chloride, benzalkonium chloride, sodium citrate, etc.
  • buffers sodium chloride, Benzalkonium chloride, sodium citrate, etc.
  • powder inhalants include lactose as a carrier.
  • excipients lactose, D-mannitol, corn starch, crystalline cellulose, etc.
  • disintegrants carboxymethylcellulose calcium, etc.
  • binders hydroxypropylcellulose, Hydroxypropylmethylcellulose, polyvinylpyrrolidone, etc.
  • lubricants magnesium stearate, talc, etc.
  • coating agents shellac, hydroxypropylmethylcellulose, sucrose, titanium oxide, etc.
  • plasticizers glycerin, polyethylene glycol, etc.
  • substrates cocoa) Fat, polyethylene glycol, hard fat, etc.
  • the pharmaceutical composition of the present invention in view of enhancing the effect of treating or preventing infectious diseases, includes one or more clinically useful antibacterial agents (for example, ⁇ -lactam antibacterial agents (carbapenems, cephalosporins, cephamycins, penicillins), glycopeptide antibacterial agents, ansamycin antibacterial agents, aminoglycoside antibacterial agents, quinolone antibacterial agents, monobactam antibacterial agents, Macrolide antibacterial agent, tetracycline antibacterial agent, chloramphenicol antibacterial agent, lincomycin antibacterial agent, streptogramin antibacterial agent, oxazolidinone antibacterial agent, fosfomycins, novobiocins, cycloserines, moenomycins, etc.) Or may be administered to a living body together with the antibacterial agent.
  • ⁇ -lactam antibacterial agents carbapenems, cephalosporins, cephamycins, penicillins
  • glycopeptide antibacterial agents for example, ⁇ -
  • the pharmaceutical composition of the present invention can be used to expand or improve the effectiveness of Gram-negative bacteria and existing antibacterial agents against resistant bacteria, so that drug efflux pump inhibitors and existing antibacterial agent-degrading enzymes ( ⁇ -lactamase etc.) may be contained or administered to a living body together with these inhibitors and the like.
  • the pharmaceutical composition of the present invention can be used in combination with a compound having no antibacterial activity (for example, a drug for treating complications) in consideration of enhancing the effect of treatment or prevention of infectious diseases.
  • the present invention includes such an embodiment.
  • Example 4 6,2 ", 3" -tri-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "- N, 6 "-O-carbonylapramycin (B1), 6,2", 3 "-tri-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6′-O-carbonyl-4 ′′ -N, 6 ′′ -O-carbonyl-5-O-mesylapramycin (B2), 5-O-acetyl-6,2 ′′, 3 ′′ -tri-O-benzoyl- 1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-4 ′′ -N, 6 ′′ -O-carbonyl-5-epiapramycin (B3), 1,3,2'-tris-N- (benzyloxycarbon
  • Example 4- (i): 6,2 ′′, 3 ′′ -tri-O-benzoyl-1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl Synthesis of -4 "-N, 6" -O-carbonylapramycin (B1) 20.0 g (20 mmol) of the compound represented by the formula (A2) in 100 ml of pyridine and 12.5 ml of benzoyl chloride under ice-cooling (5.4 eq.) was added and allowed to react for 2 hours under ice cooling. After completion of the reaction, water was added and concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was 5% aq. KHSO 4 , 5% aq. The extract was washed successively with NaHCO 3 and brine, dried over Na 2 SO 4 and concentrated under reduced pressure to give 25.2 g (95%) of the title compound (B1) as a pale yellow solid.
  • B1 a solution of 22.4 g (17 mmol) of the title compound (B1) of Example 4- (i) in 110 ml of chloroform Under ice-cooling, 6.22 g (3 eq.) Of 4-dimethylaminopyridine and 2.0 ml (1.5 eq.) Of mesyl chloride were added and reacted at room temperature for 2 hours.
  • reaction mixture was washed successively with water, 10% aqueous potassium bisulfate solution, saturated aqueous sodium hydrogen carbonate and water, and concentrated under reduced pressure to give 23.1 g (98%) of the title compound (B2) as a pale yellow solid.
  • Example 4- (iii): 5-O-acetyl-6,2 ", 3"-tri-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, Synthesis of 6′-O-carbonyl-4 ′′ -N, 6 ′′ -O-carbonyl-5- epiapramycin ( B3) 6.91 g (5.0 mmol) of the title compound (B2) of Example 4- (ii) ) was added to a 35 ml solution of DMF, and 3.60 g of cesium acetate was added and reacted at 80 ° C. for 3 hours. Ethyl acetate was added to the reaction solution, washed with water, and the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a developing system (CHCl 3 : MeOH 30: 1) to obtain 5.75 g (85%) of the title compound (B3).
  • B4 Example 4
  • 10 ml of 2M aqueous potassium hydroxide solution was added and reacted for 16 hours.
  • the residue obtained by concentration under reduced pressure was dissolved in 1-butanol and washed with water.
  • the organic layer was concentrated under reduced pressure to obtain 2.24 g (77%) of the title compound (B4).
  • Example 4- (iv) 198 mg (0.20 mmol) of the title compound (B4) and N- (benzyloxycarbonyl) ethylglycine N-hydroxysuccinimide ester 60 mg were used and treated in the same manner as in Example 1. This gave 102 mg (82%) of the title compound (B5-b).
  • Example 6 6,2 ", 3" -Tri-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "- N, 6 "-O-carbonyl-5-deoxy-5-epi-5-iodopramycin (C1), 6,2", 3 "-tri-O-benzoyl-1,3,2'-tris-N -(Benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-5-deoxyapramycin (C2), 1,3,2'-tris-N Synthesis of-(benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-deoxyapramycin (C3) and 5-deoxy-4 "-N-glycylapramycin (C4-a)
  • Example 6- (i): 6,2 ′′, 3 ′′ -tri-O-benzoyl-1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl Synthesis of -4 "-N, 6" -O-carbonyl-5-deoxy-5-epi-5- iodopramycin ( C1) 6.91 g (5) of the title compound (B2) of Example 4- (ii) 0.0 mmol) in 35 ml of DMF was added 5.50 g of sodium iodide and reacted at 90 ° C. for 6 hours. Ethyl acetate was added to the reaction mixture, and the mixture was washed twice with water. The organic layer was concentrated under reduced pressure to obtain 6.66 g (94%) of the title compound (C1) as a white solid.
  • AIBN 2,2′-azobis (isobutyronit
  • Example 6 Using the title compound (C3) of 170- (iii) in 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) - ⁇ -alanine N-hydroxysuccinimide ester in 80.8 mg, the same as in Example 1 Treatment by method gave 82.2 mg (78%) of the title compound (C4-d).
  • Example 6 Using 170 mg (0.18 mmol) of the title compound (C3) of Example 6- (iii) and 125 mg of N- (N, N′-bis (benzyloxycarbonyl)) amidinoglycine N-hydroxysuccinimide ester In the same manner as in Example 1, 83.3 mg (75%) of the title compound (C4-f) was obtained.
  • Example 12 5,6-Anhydro-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-epi-4 "-N-methoxycarbonyl Apramycin (D1), 1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-6-deoxy-5,6-diepi-6-iodo-4 "-N-methoxycarbonylapramycin (D2), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5-epi-4 "-N-methoxycarbonylapramycin (D3), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5-epiapramycin (D4) and 4 " Synthesis of —N- (N-ami
  • Example 12- (i): 5,6-anhydro-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-epi-4 "- Synthesis of N-methoxycarbonylapramycin (D1)
  • Example 12- (ii) The title compound (D2) of Example 12- (ii) was treated in the same manner as in Example 6- (ii) using 2.50 g (2.2 mmol) of AIBN, 64 mg of AIBN and 1.5 ml of tributyltin hydride. 2.09 g (94%) of D3) was obtained.
  • Example 14 6,2 "-Di-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4" -N, 6 "-O-carbonylapramycin (E1), 6,2" -di-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl -4 "-N, 6" -O-carbonyl-3 "-O-trifluoromethanesulfonylapramycin (E2), 6,2" -di-O-benzoyl-1,3,2'-tris-N- ( Benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-3 "-deoxy-3” -epi-3 "-iodopramycin (E3), 6 , 2 "-Di-O-
  • Example 4 was conducted using 15.0 g (15 mmol) of the compound represented by the formula (A2) and 4.5 ml (2.5 eq.) Of benzoyl chloride. Treatment in the same manner as in (i) gave 17.1 g (95%) of the title compound (E1).
  • Example 14- Using (vii) the title compound (E7) 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) -L-isoserine N-hydroxysuccinimide ester 82.6 mg, the same as in Example 1 Treatment by method gave 75.9 mg (70%) of the title compound (E8-c).
  • Example 17 1,3,2'-Tris-N- (benzyloxycarbonyl) -4 "-N- (N-tert-butoxycarbonyl-L-isoceryl) -7'-N, 6'-O-carbonyl Apramycin (F1-a), 1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-4 ′′ -N- (L-isoceryl) apramycin ( F2-a), 4 ′′ -N- (N-benzyl-L-isoceryl) -1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonylapramycin (F3-a), 4 ′′ -N- (N-benzyl-N-methyl-L-isoceryl) -1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′- O-carbonylapramycin (F
  • the title compound (F3-a) of Example 17- (iii) was dissolved in 2 ml of a 140 mg (0.12 mmol) 10% acetic acid-methanol solution with a 37% formalin aqueous solution.
  • Example 18 1,3,2'-Tris-N- (benzyloxycarbonyl) -4 "-N- (N-tert-butoxycarbonyl-L-isoceryl) -7'-N, 6'-O-carbonyl -5-epiapramycin (F1-b), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-epi-4 "-N- (L-isoceryl) apramycin (F2-b), 4 ′′ -N- (N-benzyl-L-isoceryl) -1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-5-epiapramycin (F3-b), 4 ′′ -N- (N-benzyl-N-methyl-L-isoceryl) -1,3,2′-tris-N- (benzyl Oxycarbonyl) -7
  • the title compound (F1-b) of Example 18- (i) was treated with 330 mg (0.29 mmol) in the same manner as in Example 17- (ii). 331 g (98% as TFA salt) of the title compound (F2-b) was obtained as a colorless solid.
  • Title compound of Example 18- (iv) (F4-b) was treated in the same manner as in Example 17- (v) to give 46.8 mg (83%) of the title compound (F5-b).
  • Example 19 1,3,2'-Tris-N- (benzyloxycarbonyl) -4 "-N- (N-tert-butoxycarbonyl-L-isoceryl) -7'-N, 6'-O-carbonyl -5-deoxyapramycin (F1-c), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-deoxy-4 "-N- (L-isoceryl) apramycin (F2-c), 4 ′′ -N- (N-benzyl-L-isoceryl) -1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-5-deoxyapramycin (F3-c), 4 ′′ -N- (N-benzyl-N-methyl-L-isoceryl) -1,3,2′-tris-N- (benzyl Oxycarbonyl) -7'-N
  • the title compound (F1-c) of Example 19- (i) was treated with 315 mg (0.28 mmol) in the same manner as in Example 17- (ii). 311 mg (98% as TFA salt) of the title compound (F2-c) was obtained as a colorless solid.
  • the title compound (F2-c) of Example 19- (ii) 142 mg (0.12 mmol as TFA salt), benzaldehyde 0.2 ml and NaBH 4 100 mg were used.
  • Treatment in a similar manner to Example 17- (iii) gave 115 mg (83%) of the title compound (F3-c).
  • Title compound of Example 19- (iv) (F4-c) was used in the same manner as in Example 17- (v) to give 44.4 mg (83%) of the title compound (F5-c).
  • Example 20 1,3,2'-Tris-N- (benzyloxycarbonyl) -4 "-N- (N-tert-butoxycarbonyl-L-isoceryl) -7'-N, 6'-O-carbonyl -6-deoxy-5-epiapramycin (F1-d), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5 -Epi-4 "-N- (L-isoceryl) apramycin (F2-d), 4" -N- (N-benzyl-L-isoceryl) -1,3,2'-tris-N- (benzyloxy Carbonyl) -7′-N, 6′-O-carbonyl-6-deoxy-5-epiapramycin (F3-d), 4 ′′ -N- (N-benzyl-N-methyl-L-isoceryl) -1 , 3,2'-Tris-N
  • the title compound of Example 20- (iv) The product was treated in the same manner as in Example 17- (v) using 95.0 mg (0.083 mmol) of F4-d) to obtain 42.1 mg (81%) of the title compound (F5-d).
  • Example 21 1,3,2'-Tris-N- (benzyloxycarbonyl) -4 "-N- (N-tert-butoxycarbonyl-L-isoceryl) -7'-N, 6'-O-carbonyl -3 "-deoxy-5-epiapramycin (F1-e), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-3" -deoxy -5-epi-4 "-N- (L-isoceryl) apramycin (F2-e), 4" -N- (N-benzyl-L-isoceryl) -1,3,2'-tris-N- ( Benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-3 "-deoxy-5-epiapramycin (F3-e), 4" -N- (N-benzyl-N-methyl-L-isoceryl) ) -1,3,2′
  • Example 26 5,6-Anhydro-2 ′′, 3 ′′, 6 ′′ -tri-O-benzoyl-1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′- O-carbonyl-5-epi-4 "-N-methoxycarbonylapramycin (H1), 2", 3 ", 6" -tri-O-benzoyl-1,3,2'-tris-N- (benzyloxy Carbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5,6-diepi-6-iodo-4 "-N-methoxycarbonylapramycin (H2), 2", 3 ", 6” -Tri-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,6-dideoxy-5-eno-4 "-N -Methoxycarbonylapramycin (H3), Tris-
  • 26- (title compound iii) (1,4-dioxane 50ml solution 2M aqueous potassium hydroxide solution 9ml of 4.70 g (3.6 mmol) of H3) was added, example 4-(iv) To give 2.85 g (83%) of the title compound (H4).
  • Example 1 The same as Example 1 using 170 mg (0.18 mmol) of the title compound (H4) of Example 26- (iv) and 82.6 mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) -L-isoserine Treatment by method gave 76.2 mg (71%) of the title compound (H5-c).
  • Example 29 1,3,2'-Tris-N- (benzyloxycarbonyl) -4 "-N- (N-tert-butoxycarbonyl-L-isoceryl) -7'-N, 6'-O-carbonyl -5,6-dideoxy-5-enoapramycin (H4-a), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,6 -Dideoxy-5-eno-4 "-N- (L-isoceryl) apramycin (H4-b), 4" -N- (N-benzyl-L-isoceryl) -1,3,2'-Tris-N -(Benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,6-dideoxy-5-enoapramycin (H4-c), 4 "-N- (N-benzyl-N-methyl- L-isoceryl) -1,3,2′
  • the title compound of Example 29- (iv) (H4- Using 220 mg (0.20 mmol) of d) and treating in the same manner as in Example 17- (v), 77.8 mg (64%) of the title compound (H5-d) was obtained.
  • Example 30 6,2 "-di-O-benzoyl-1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4" -N, 6 "-O-carbonyl-5-O-mesyl-3" -O-trifluoromethanesulfonylapramycin (I1), 5,3 "-di-O-acetyl-6,2" -di-O-benzoyl-1, 3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-4 ′′ -N, 6 ′′ -O-carbonyl-5,3 ′′ -diepipramycin (I2 ), 1,3,2'-tris-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,3 "-diepiramycin (I3) and 5,3" -diepi Of -4 "-N-glyc
  • Example 30- (i): 6,2 ′′ -di-O-benzoyl-1,3,2′-tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-4 ′′ Synthesis of —N, 6 ′′ -O-carbonyl-5-O-mesyl-3 ′′ -O-trifluoromethanesulfonylapramycin (I1) 2.68 g (2) of the title compound (E2) of Example 14- (ii) 0.0mmol), 733 mg (3 eq.) Of 4-dimethylaminopyridine and 0.24 ml (1.5 eq.) Of mesyl chloride in the same manner as in Example 4- (ii) to give the title compound (I1) 2.82 g (quantitative) was obtained.
  • Example 30- (ii): 5,3 ′′ -di-O-acetyl-6,2 ′′ -di-O-benzoyl-1,3,2′-tris-N- (benzyloxycarbonyl) -7′- Synthesis of N, 6′-O-carbonyl-4 ′′ -N, 6 ′′ -O-carbonyl-5,3 ′′ -diepiprapramycin (I2) 2 of the title compound (I1) of Example 30- (i) .75 g (1.9 mmol) and cesium acetate 1.60 g were used and treated in the same manner as in Example 4- (iii) to obtain 2.15 g (88%) of the title compound (I2).
  • Example 30- (iii): 1,3,2′-Tris-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-5,3 ′′ -diepiapramycin (I3) Similar to Example 4- (iv), using 2.00 g (1.55 mmol) of the title compound (I2) of Synthesis Example 30- (ii) in 20 ml of 1,4-dioxane and 5 ml of 2M aqueous potassium hydroxide. To give 1.45 g (75%) of the title compound (I3).
  • Example 30- (iv): Synthesis of 5,3 ′′ -diepi-4 ′′ -N-glycylapramycin (I4-a) 175 mg ( 0.18 mmol ) of the title compound (I3) of Example 30- (iii) ) And 76.2 mg of N- (benzyloxycarbonyl) glycine N-hydroxysuccinimide ester and treated in the same manner as in Example 1 to obtain 76.5 mg (71%) of the title compound (I4-a). It was.
  • Test example 1 Antibacterial Activity Regarding the compounds described in the Examples in the novel aminoglycoside antibiotics of the present invention, the minimum inhibitory concentration (MIC, ⁇ g / mL) against various test bacteria was measured by the agar plate dilution method according to the Japanese Society of Chemotherapy did. The results are shown in Tables 1 to 3.
  • Tables 1 to 3 show that the compound of the present invention has antibacterial activity against both gram-positive and gram-negative bacteria.
  • the compounds of the present invention are resistant to, or less sensitive to, the existing antibiotics arbekacin (ABK), amikacin (AMK) and gentamicin (GM). It was demonstrated to have strong antibacterial activity against resistant strains of Pseudomonas aeruginosa or low-susceptibility strains.

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Abstract

L'invention concerne : un composé représenté par la formule générale (I), un sel pharmaceutiquement acceptable ou un solvate de celui-ci ; une composition médicinale le comprenant ; l'utilisation dudit composé pour la prévention ou le traitement de maladies infectieuses ; et un procédé de prévention ou de traitement de maladies infectieuses, le procédé comprenant l'utilisation dudit composé. Le composé représenté par la formule générale (I) possède une activité antibactérienne à la fois contre les bactéries à gram-positif et les bactéries à gram-négatif, et est par conséquent utile pour la prévention ou le traitement de maladies infectieuses induites par ces bactéries.
PCT/JP2018/002544 2017-01-27 2018-01-26 Nouvel antibiotique aminoglycoside efficace pour de multiples bactéries résistantes aux médicaments WO2018139599A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019230863A1 (fr) * 2018-05-31 2019-12-05 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Procédé de production d'une substance antibiotique aminoglycoside efficace pour des bactéries multirésistantes aux médicaments
CN116462721A (zh) * 2023-04-18 2023-07-21 江南大学 抗菌性氨基糖苷衍生物

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Publication number Priority date Publication date Assignee Title
US4360665A (en) * 1981-12-24 1982-11-23 Eli Lilly And Company 4"-N-(Substituted)-apramycin antibiotic derivatives and intermediates therefor
JP2013537177A (ja) * 2010-09-13 2013-09-30 ユニバーシティ・オブ・チューリッヒ 細菌感染性疾患の処置
WO2017018528A1 (fr) * 2015-07-30 2017-02-02 公益財団法人 微生物化学研究会 Nouvel antibiotique aminoglycosidique efficace contre les bactéries résistantes à plusieurs médicaments

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US4360665A (en) * 1981-12-24 1982-11-23 Eli Lilly And Company 4"-N-(Substituted)-apramycin antibiotic derivatives and intermediates therefor
JP2013537177A (ja) * 2010-09-13 2013-09-30 ユニバーシティ・オブ・チューリッヒ 細菌感染性疾患の処置
WO2017018528A1 (fr) * 2015-07-30 2017-02-02 公益財団法人 微生物化学研究会 Nouvel antibiotique aminoglycosidique efficace contre les bactéries résistantes à plusieurs médicaments

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Title
KUWAHARA,R. ET AL.: "Synthesis of 2''-acylamido derivatives of 2' ' -amino-5, 2' ' -dideoxy-5-epi-5-fluorodibekacin and a study on the structures of 5-fluorinated dibekacin analogs by 13C NMR", CARBOHYDRATE RESEARCH, vol. 299, no. 4, 1997, pages 271 - 279, XP 004085849 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019230863A1 (fr) * 2018-05-31 2019-12-05 Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 Procédé de production d'une substance antibiotique aminoglycoside efficace pour des bactéries multirésistantes aux médicaments
CN116462721A (zh) * 2023-04-18 2023-07-21 江南大学 抗菌性氨基糖苷衍生物
CN116462721B (zh) * 2023-04-18 2024-02-02 江南大学 抗菌性氨基糖苷衍生物

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