Novel antibiotic and method for producing the same

Abstract

To provide a novel compound with antibacterial activity against drug-resistant nontuberculous mycobacteria, and a method for producing the same.SOLUTION: The invention provides a compound represented by the formula in the figure, or a salt thereof. (In the formula, one of X1 and X2 represents a group represented by -A-B-D, while the other represents -OH; A is a sugar chain derived from a pentose, hexose, or a polymer of one of them; B is an optionally substituted divalent hydrocarbon group; and D is -N3 or an optionally substituted triazolyl group.)SELECTED DRAWING: Figure 3

Description

[Technical field]

[0001] The present invention relates to a novel antibiotic and a method for producing the same, and more particularly to a novel azithromycin derivative and a method for producing the same. [Background technology]

[0002] Nontuberculous mycobacteria (NTM), along with Mycobacterium tuberculosis and Mycobacterium leprae, are classified as a type of acid-fast bacillus (mycobacterium). NTM includes more than 190 types of bacteria and inhabits the environment, such as soil, water, and animals, including livestock. NTM infect humans (1) through the respiratory system via inhalation, (2) through the digestive system via water or food, or (3) through broken skin or wounds, causing lesions in the lungs, lymph nodes, skin, bones, and joints. The most common organ infected is the lung, and lung infection caused by NTM is called pulmonary nontuberculous mycobacterial disease (pulmonary NTM disease). Until now, pulmonary NTM disease was said to be likely to occur in people with tuberculosis or lung disease, or in people with weakened immune systems. However, the incidence of pulmonary NTM disease has recently increased among people with no lung disease and normal immune systems, it requires a long treatment period, there is a high probability of recurrence, and the incidence rate is increasing worldwide, making it a serious problem that needs to be solved.

[0003] In Japan, Mycobacterium avium and Mycobacterium intracellulare account for approximately 90% of NTM species causing pulmonary NTM disease, and M. avium and M. intracellulare are collectively called Mycobacterium avium complex (MAC). Mycobacterium kansaii accounts for approximately 4% and Mycobacterium abscessus for approximately 3%. Pulmonary infection caused by MAC is called pulmonary MAC disease, and pulmonary infection caused by Mycobacterium abscessus is called pulmonary abscessus disease. In Japan, the incidence of pulmonary MAC disease and pulmonary abscessus disease has been increasing in recent years.

[0004] Currently, the typical treatment for pulmonary NTM infection involves the combined administration of three drugs, the macrolide antibiotics azithromycin (or clarithromycin), ethambutol, and rifampicin, with azithromycin (or clarithromycin) being an important drug in treatment. However, drug-resistant NTM has emerged in recent years, and there is a strong demand for the development of new therapeutic drugs that are effective against resistant bacteria.

[0005] Non-Patent Document 1 reports that gepotidacin, a triazaacenaaptylene topoisomerase inhibitor, exhibits antibacterial activity against drug-resistant NTM.

[0006] Non-Patent Document 2 reports that tetracycline-like antibiotics odacycline and eravacycline exhibit antibacterial activity against drug-resistant NTM.

[0007] Non-Patent Document 3 reports that telithromycin, a ketolide antibiotic similar to macrolide antibiotics, interacts with domain II of Escherichia coli 23r RNA. However, the mode of interaction with NTM is unknown. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Antimicrob. Agents Chemother. 2022, 66, e00564-22 [Non-Patent Document 2] Antimicrob. Agents Chemother. 2019, 24, e00470-19 [Non-Patent Document 3] Proc. Natl. Acad. Sci. USA 2010, 107, 17152-17157 Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a novel compound having antibacterial activity against drug-resistant nontuberculous mycobacteria, and a method for producing the same. [Means for solving the problem]

[0010] The present invention encompasses the embodiments described below.

[0011] Section 1. A compound represented by the following formula (1), or a salt thereof:

[0012] [ka]

[0013] (In the formula, one of X1 and X2 is a group represented by -ABD, and the other is -OH, A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group, D is -N3 or an optionally substituted triazolyl group.

[0014] Section 2. Item 13. An antibacterial agent comprising the compound or salt thereof according to item 1 as an active ingredient.

[0015] Section 3. Item 3. The antibacterial agent according to Item 2, which is an antibacterial agent against drug-resistant nontuberculous mycobacteria.

[0016] Section 4. Item 13. A composition comprising the compound or a salt thereof according to item 1.

[0017] Section 5. Item 5. The composition according to item 4, which is an antibacterial composition.

[0018] Section 6. Item 5. The composition according to item 4, which is a pharmaceutical composition.

[0019] Section 7. A compound represented by formula (5).

[0020] [ka]

[0021] (In the formula, one of Y1 and Y2 is a group represented by -FG-N3, and the other is -OH, F is a sugar chain derived from a pentose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, a hexose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, or a polymer of either of these; G is an optionally substituted divalent hydrocarbon group. Section 8. A method for producing a compound represented by formula (1a), comprising removing a silyl protecting group and / or a benzyl protecting group in a compound represented by the following formula (5) to convert it to a hydroxyl group:

[0022] [ka]

[0023] (In the formula, one of Y1 and Y2 is a group represented by -FG-N3, and the other is -OH, F is a sugar chain derived from a pentose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, a hexose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, or a polymer of either of these; G is an optionally substituted divalent hydrocarbon group.

[0024] [ka]

[0025] (In the formula, one of X1 and X2 is a group represented by -ABD, and the other is -OH, A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group, D is -N3. Section 9. A method for producing a compound represented by the following formula (1b):

[0026] [ka]

[0027] (In formula (1a), one of X1 and X2 is a group represented by -ABD, and the other is -OH, A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group, D is -N3.

[0028] [ka]

[0029] (In formula (1b), one of X1 and X2 is a group represented by -ABD, and the other is -OH, A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group, D is an optionally substituted triazolyl group. [Brief description of the drawings]

[0030] [Figure 1] Schematic diagram of the mechanism of action of macrolide antibiotics. [Diagram 2] Schematic diagram of the resistance mechanism of NTM to macrolide antibiotics. [Diagram 3] (A) Telithromycin derivatives with a substituent at the 11th position, (B) Schematic diagram showing the state in which the telithromycin derivative in Figure 3(A) binds to domain II of E. coli 23S rRNA, (C) Crystal structure of the E. coli ribosome (PDB:3OAT, Proc. Natl. Acad. Sci. USA 2010, 107, 17152-17157.), (D) An example of a novel azithromycin derivative. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0031] As used herein, the singular forms "a," "an," and "the" are intended to include both the singular and the plural unless otherwise expressly stated herein or clearly contradictory in context.

[0032] In this specification, the term "comprise" is a concept that encompasses "consist essentially of" and "consist only of."

[0033] In the numerical ranges described in stages in this specification, the upper or lower limit of a certain numerical range can be arbitrarily combined with the upper or lower limit of another numerical range. In addition, in the numerical ranges described in this specification, the upper or lower limit of the numerical range may be replaced with a value shown in an example or a value that can be unambiguously derived from an example. Furthermore, in this specification, a numerical value connected with "~" means a numerical range that includes the numerical values ​​before and after "~" as the lower and upper limits.

[0034] As used herein, macrolide antibiotics refer to antibiotics that inhibit bacterial protein synthesis and have a 12-, 14-, 15-, or 16-membered lactone ring (macrolide ring) to which a neutral sugar or an amino sugar is bound.

[0035] In this specification, unless otherwise specified, examples of the "substituent" include a halogen atom, a hydroxyl group, a cyano group, a nitro group, an alkyl group, a hydroxyalkyl group, a halogenoalkyl group, a cycloalkyl group, a hydroxycycloalkyl group, a cycloalkyl-alkyl group, an aralkyl group, an alkenyl group, an alkynyl group, an alkoxy group, a halogenoalkoxy group, a cycloalkoxy group, a cycloalkyl-alkoxy group, an alkyl sulfoxide, an aryl sulfoxide, a sulfo group, an alkylthio group, a cycloalkyl-alkylthio group, an amino group, a mono- or dialkylamino group, a dialkylamino-alkyl group, a cycloalkylamino group, a cycloalkyl-alkylamino group, an acyl group, an acyloxy group, an oxo group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group which may have an unsaturated hydrocarbon ring group as a substituent, a saturated or unsaturated heterocyclic group, an unsaturated hydrocarbon ring group such as an aromatic hydrocarbon group, a saturated heterocyclic oxy group, etc. When a substituent is present, the number thereof is typically 1, 2, or 3.

[0036] In this specification, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like, and is preferably a fluorine atom, a chlorine atom, or a bromine atom.

[0037] In this specification, the alkyl group is preferably an alkyl group having 1 to 6 carbon atoms.

[0038] In this specification, a hydroxyalkyl group preferably has one hydroxyl group and has 1 to 4 carbon atoms.

[0039] In this specification, the halogenoalkyl group is preferably a halogenoalkyl group having 1 to 7 halogen atoms and 1 to 6 carbon atoms.

[0040] In this specification, a cycloalkyl group is a cycloalkyl group having 3 to 7 carbon atoms.

[0041] In this specification, the hydroxycycloalkyl group preferably has one or more hydroxyl groups and has 3 to 7 carbon atoms.

[0042] In this specification, a cycloalkyl-alkyl group is preferably an alkyl group having 1 to 4 carbon atoms substituted with a cycloalkyl group having 3 to 7 carbon atoms.

[0043] In this specification, the aralkyl group is preferably an aralkyl group having 7 to 13 carbon atoms.

[0044] In this specification, the alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms.

[0045] In this specification, the alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms.

[0046] In this specification, the alkoxy group is preferably an alkoxy group having 1 to 6 carbon atoms.

[0047] In this specification, the halogenoalkoxy group is preferably an alkoxy group having 1 to 7 halogen atoms and 1 to 4 carbon atoms.

[0048] In this specification, the cycloalkoxy group is preferably a cycloalkoxy group having 7 to 13 carbon atoms.

[0049] In this specification, the cycloalkyl-alkoxy group is preferably an alkoxy group having 1 to 4 carbon atoms substituted with a cycloalkyl having 3 to 7 carbon atoms.

[0050] In this specification, the alkyl sulfoxide group is preferably an alkyl sulfoxide group having 1 to 6 carbon atoms.

[0051] In this specification, the aryl sulfoxide group is preferably a sulfoxide group having an aryl group having 6 to 13 carbon atoms.

[0052] In this specification, the alkylthio group is preferably an alkylthio group having 1 to 6 carbon atoms.

[0053] In this specification, the cycloalkyl-alkylthio group is preferably an alkylthio group having 1 to 4 carbon atoms substituted with a cycloalkyl having 3 to 7 carbon atoms.

[0054] In this specification, a monoalkylamino group is an amino group mono-substituted with an alkyl group preferably having 1 to 6 carbon atoms.

[0055] In this specification, a dialkylamino group is preferably an amino group di-substituted with the same or different alkyl groups having 1 to 6 carbon atoms.

[0056] In this specification, a dialkylamino-alkyl group is an alkyl group substituted with a dialkylamino, and preferably an alkyl group having 1 to 4 carbon atoms substituted with a dialkylamino.

[0057] In this specification, the cycloalkylamino group is an amino group having one or two cycloalkyl groups preferably having 3 to 7 carbon atoms.

[0058] In this specification, the cycloalkyl-alkylamino group is preferably an alkylamino group having 1 to 4 carbon atoms substituted with a cycloalkyl having 3 to 7 carbon atoms.

[0059] In the present specification, the acyl group refers to an alkylcarbonyl group or an arylcarbonyl group. The alkylcarbonyl group is preferably a carbonyl group having an alkyl group with 1 to 6 carbon atoms. The arylcarbonyl group is preferably a carbonyl group having an aryl group with 6 to 13 carbon atoms.

[0060] In the present specification, the acyloxy group refers to an alkylcarbonyloxy group or an arylcarbonyloxy group. The alkylcarbonyloxy group is preferably a carbonyloxy group having an alkyl group with 1 to 6 carbon atoms. The arylcarbonyloxy group is preferably a carbonyloxy group having an aryl group with 6 to 13 carbon atoms.

[0061] In this specification, the alkoxycarbonyl group is preferably a carbonyl group having an alkoxy group having 1 to 6 carbon atoms.

[0062] In this specification, the aralkyloxycarbonyl group is preferably an oxycarbonyl group having an aralkyl having 7 to 13 carbon atoms.

[0063] In this specification, the unsaturated heterocyclic group refers to a monocyclic or polycyclic, fully unsaturated or partially unsaturated heterocyclic group having at least one heteroatom (preferably 1 to 3) selected from a nitrogen atom, an oxygen atom, and a sulfur atom.

[0064] In this specification, the unsaturated hydrocarbon ring group is preferably a hydrocarbon ring group having 5 to 14 carbon atoms, consisting of a single ring or multiple rings, which has at least one unsaturated bond (for example, 1 to 8 unsaturated bonds), and more preferably an aromatic hydrocarbon group having 6 to 14 carbon atoms, or a monocyclic or bicyclic unsaturated hydrocarbon ring group having 5 to 14 carbon atoms.

[0065] In this specification, the saturated heterocyclic oxy group is a saturated heterocyclic oxy group having a heteroatom selected from a nitrogen atom, an oxygen atom, and a sulfur atom, and is preferably a saturated heterocyclic oxy group having 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom.

[0066] Azithromycin (AZM) is a macrolide antibiotic that has an antibacterial effect by inhibiting bacterial protein synthesis and is widely used as a treatment for pneumonia, gonorrhea, and pulmonary nontuberculous mycobacterial disease (NTM pulmonary disease) (J. Periodontol. 1997, 68, 1206-1209).

[0067] [ka]

[0068] Pulmonary NTM disease (Front. Microbiol.2022, 13, 1044515) is becoming more prevalent worldwide, and there are few effective treatments. Furthermore, the emergence of drug-resistant NTM has necessitated the development of new treatments.

[0069] Figure 1 is a schematic diagram of the mechanism of action of macrolide antibiotics (Antimicrob. Agents Chemother. 2010, 54, 4961-4970). Bacterial ribosome 1 has two particles, a large one and a small one, the 50S subunit and the 30S subunit, and the 23S rRNA 2 of the 50S subunit is a component of the peptide tunnel 6 (sometimes called the ribosomal tunnel). Based on the genetic codon of mRNA 3, the amino acid 5 of tRNA 4 is linked, and the genetic information of mRNA 2 is transcribed into a polypeptide consisting of the amino acid 5 linked. Polypeptides with 50 or more amino acids are usually called proteins. The synthesized protein is exported out of the ribosome 1 through the peptide tunnel 6. Macrolide antibiotics 7 bind to the 23S rRNA 2 of the 50S subunit of ribosome 1 and inhibit the export of the protein.

[0070] Figure 2 is a schematic diagram of the resistance mechanism of NTM to macrolide antibiotics. 23S rRNA 2 is composed of approximately 3000 nucleotides and is classified into six domains, I to VI. Of these, existing macrolide antibiotics 7 block the peptide tunnel 6 by binding to domain V, but drug-resistant bacteria are thought to acquire macrolide resistance through mutations in domain V (Front. Microbiol. 2022, 13, 1044515).

[0071] Based on the report that a telithromycin derivative with a substituent introduced at the 11th position of telithromycin (TLM) formed a new bond with domain II of 23S rRNA of Escherichia coli (Proc. Natl. Acad. Sci. USA 2010, 107, 17152-17157.) (Fig. 3(A)-(C)), the present inventors synthesized a new azithromycin derivative with a substituent introduced at the 11th position of azithromycin (Fig. 3(D)). The newly synthesized compound had improved antibacterial activity against drug-resistant NTM compared to azithromycin.

[0072] In one aspect of the present invention, there is provided a compound represented by the following formula (1), or a salt thereof:

[0073] [ka]

[0074] In the formula, one of X1 and X2 is a group represented by -ABD, and the other is -OH. A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group, D is -N3 or an optionally substituted triazolyl group.

[0075] The compound represented by formula (1) is a glycoside macrolide having a 15-membered ring lactone and can be considered as a derivative of azithromycin. The compound represented by formula (1) has an azide group or an optionally substituted triazolyl group at the 11th position of the 15-membered ring via a sugar chain and a phenyl group or an alkyl group, and thus has antibacterial activity against drug-resistant nontuberculous mycobacteria.

[0076] When A is a sugar chain derived from a pentose or a polymer thereof, the pentose is preferably arabinofuranose or ribose. When A is a sugar chain derived from a polymer of pentose, the pentose is preferably polymerized with adjacent pentoses by condensation of the hydroxyl groups bonded to the 1st and 4th carbons.

[0077] When A is a sugar chain derived from a hexose or a polymer thereof, the hexose is preferably glucose, galactose, mannose, rhamnose, or fucose. When A is a sugar chain derived from a polymer of hexose, the hexose is preferably polymerized with an adjacent hexose by condensation of the hydroxyl groups bonded to the 1- and 4-carbons.

[0078] The pentose or hexose constituting A may be one type or two or more types.

[0079] The hydrogen and / or hydroxyl groups bonded to the carbon skeleton of the pentose or hexose constituting A may be further substituted with an amino group or the like.

[0080] When A is a polymer derived from a pentose or a hexose, the degree of polymerization of the pentose or hexose is preferably 1-3.

[0081] In some embodiments, X1 is a group represented by -ABD and X2 is -OH.

[0082] In some embodiments, X2 is a group represented by -ABD, and X1 is -OH.

[0083] In some embodiments, A is of formula (2) or (3):

[0084] [ka]

[0085] In formula (2), m is 1 to 3; R 5 and R 6 one of which is hydrogen and the other is -OH; R 7 and R 8 one of which is hydrogen and the other is -OH; R 9 is hydrogen or -CHOH.

[0086] In formula (3), n is 1 to 3; R 10 and R 11 one of which is hydrogen and the other is -OH; R 12 and R 13 One of them is hydrogen and the other is -OH.

[0087] B may be a saturated or unsaturated hydrocarbon group.

[0088] B is preferably a substituted or unsubstituted alkylphenyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted alkyl group. The alkylphenyl group is a phenyl group substituted with an alkyl group. The alkyl group may be linear or branched, and preferably has 1 to 6 carbon atoms.

[0089] In some embodiments, B is an unsubstituted alkylphenyl group, an unsubstituted phenyl group, or an unsubstituted alkyl group. When B is substituted, the substituents may be any of the substituents defined herein.

[0090] In some embodiments, D is -N3. In some embodiments, D is an unsubstituted or substituted triazolyl group. The triazolyl group may be a 1,2,3-triazolyl group or a 1,2,4-triazolyl group. When D is substituted, the substituent may be any of the substituents defined herein. Particularly preferred substituents include alkylamino groups (e.g., -CH2-NH2), dialkylamino-alkyl groups (e.g., -CH2-N(CH2)2), aminophenyl groups, pyridyl groups, and the like.

[0091] The salt of the compound represented by formula (1) means a salt commonly used in the field of organic chemistry, such as a base addition salt at the carboxyl group when the compound has a carboxyl group, or an acid addition salt at the amino group or basic heterocyclic group when the compound has an amino group or basic heterocyclic group. The salt of the compound represented by formula (1) is preferably a pharma- ceutically acceptable salt.

[0092] Examples of the base for the base addition salt include alkali metals such as sodium and potassium, and alkaline earth metals such as magnesium.

[0093] Examples of the acid for the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, glutamic acid, and aspartic acid.

[0094] When the compound represented by formula (1) has isomers such as optical isomers, stereoisomers, rotational isomers, tautomers, etc., all isomers and mixtures thereof are included in the compound of the present invention unless otherwise specified. These isomers can be obtained as single compounds by known synthesis and separation methods (concentration, solvent extraction, column chromatography, recrystallization, etc.).

[0095] The compound represented by formula (1) or a salt thereof may be in the form of a crystal, and whether the crystal form is a single crystal or a polymorphic mixture, it is included in the compound represented by formula (1) or a salt thereof. The crystal can be produced by crystallization using a crystallization method known per se. The compound represented by formula (1) or a salt thereof may be in the form of a solvate (e.g., a hydrate, etc.) or a non-solvate, and both are included in the compound of the present invention or a salt thereof. Isotopes (e.g., 3 H, 14 C. 35 S, 125 Compounds labeled with, for example, I are also included in the compound represented by formula (1) or a salt thereof.

[0096] In one aspect of the present invention, there is provided an antibacterial agent comprising a compound represented by formula (1) or a salt thereof as an active ingredient.

[0097] Since the compound represented by formula (1) or a salt thereof has an antibacterial effect against drug-resistant nontuberculous mycobacteria, such an antibacterial agent also has an antibacterial effect against drug-resistant nontuberculous mycobacteria.

[0098] In one embodiment, the drug-resistant non-tuberculous mycobacteria are M. avium, M. intracellulare, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium complex (MAC) (M. avium and M. intracellulare), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M. terraecomplex, M. haemophilum, M. genavense, M. asiaticum, M. The drug-resistant nontuberculous mycobacteria are preferably resistant to macrolide antibiotics, including azithromycin. In a further embodiment, the drug-resistant nontuberculous mycobacteria are resistant to the drug and M. intracellulare.

[0099] In some embodiments, the compound represented by formula (1) or a salt thereof has an antibacterial activity against nontuberculous mycobacteria that are not drug-resistant. In one embodiment, the non-tuberculous mycobacteria include M. avium, M. intracellulare, M. avium subsp. hominissuis (MAH), M. abscessus, M. chelonae, M. bolletii, M. kansasii, M. ulcerans, M. avium complex (MAC) (M. avium and M. intracellulare), M. conspicuum, M. kansasii, M. peregrinum, M. immunogenum, M. xenopi, M. marinum, M. malmoense, M. marinum, M. mucogenicum, M. nonchromogenicum, M. scrofulaceum, M. simiae, M. smegmatis, M. szulgai, M. terrae, M. terraecomplex, M. haemophilum, M. genavense, M. asiaticum, M. shimoidei, M. gordonae, M. nonchromogenicum, M. triplex, M. lentiflavum, M. celatum, M. fortuitum, M. fortuitum complex (M. fortuitum and M. chelonae) or combinations thereof.

[0100] In some embodiments, the antibacterial activity of the compound represented by formula (1) or a salt thereof is greater than the antibacterial activity of azithromycin.

[0101] The antibacterial agent according to the embodiment of the present invention may contain only the compound represented by formula (1) or a salt thereof as an active ingredient, or the antibacterial agent according to the embodiment of the present invention may further contain an antibacterial agent other than the compound represented by formula (1) or a salt thereof (sometimes simply referred to as "other antibacterial agents" in the present specification) as long as the antibacterial activity of the compound represented by formula (1) or a salt thereof is not impaired. The other antibacterial agents may be used alone or in combination of two or more kinds.

[0102] The use and mode of the antibacterial agent of the embodiment of the present invention are not particularly limited as long as it is for the purpose of antibacterial action against bacteria. For example, it may be used as an antibacterial agent as it is, or may be incorporated into various compositions (pharmaceutical compositions, cosmetic compositions, food compositions, medical cleaning compositions, tableware disinfecting and cleaning compositions, oral compositions, surface antibacterial compositions, etc.).

[0103] The antibacterial agent according to an embodiment of the present invention preferably contains the compound represented by formula (1) or a salt thereof in an effective amount, or in an amount such that the concentration is equal to or higher than the minimum inhibitory concentration (MIC).

[0104] According to the above-mentioned use and aspect, the antibacterial agent of the embodiment of the present invention can be a composition containing an additive. Examples of additives include bases, carriers, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, lubricants, thickeners, moisturizers, colorants, fragrances, chelating agents, rust inhibitors, metal corrosion inhibitors, antifoaming agents, rust inhibitors, extreme pressure additives, metal corrosion inhibitors, antifoaming agents, dyes, etc. It is preferable to select and use pharma- ceutically acceptable components among these additives according to the purpose of use. The antibacterial agent of the embodiment of the present invention can be prepared and used in an appropriate form (tablets, pills, powders, liquids, injections, suspensions, emulsions, powders, granules, capsules, etc.) by a conventional method according to the purpose of use.

[0105] The content of the compound represented by formula (1) or a salt thereof in the antibacterial agent according to the embodiment of the present invention is not particularly limited as long as the antibacterial action is exhibited, and may be, for example, 0.0001% by weight or more, preferably 0.0005 to 1% by weight, and more preferably 0.001 to 0.1% by weight.

[0106] When the antibacterial agent according to an embodiment of the present invention is used for medical purposes, or when it is incorporated into a pharmaceutical composition for use, the administration method, dosage, etc. are appropriately selected depending on the content of the compound represented by formula (1) or a salt thereof, the content of other antibacterial agents, the dosage form, the age and weight of the subject to be administered, etc.

[0107] Next, a method for producing the compound represented by formula (1) will be described.

[0108] In one embodiment of the present invention, a compound represented by formula (1a), which is one of the compounds represented by the following formula (1), is produced by removing a silyl protecting group and / or a benzyl protecting group in a compound represented by formula (5) to form a hydroxyl group.

[0109] [ka]

[0110] (In the formula, one of X1 and X2 is a group represented by -ABD, and the other is -OH, A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group, D is -N3.

[0111] [ka]

[0112] (In the formula, one of Y1 and Y2 is a group represented by -FG-N3, and the other is -OH, F is a sugar chain derived from a pentose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, a hexose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, or a polymer of either of these; G is an optionally substituted divalent hydrocarbon group.

[0113] F is a sugar chain derived from a pentose in which at least a portion of the hydroxyl groups is substituted with a silyl protecting group and / or a benzyl protecting group, a hexose in which at least a portion of the hydroxyl groups is substituted with a silyl protecting group and / or a benzyl protecting group, or a polymer of either of these.

[0114] When F is a pentose sugar having at least some of its hydroxyl groups substituted with silyl protecting groups and / or benzyl protecting groups, some or all of the hydroxyl groups of the pentose sugar may be substituted with silyl protecting groups, some or all of the hydroxyl groups may be substituted with benzyl protecting groups, or some of the hydroxyl groups may be substituted with silyl protecting groups and some of the hydroxyl groups may be substituted with benzyl protecting groups.

[0115] When F is a hexose sugar having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, some or all of the hydroxyl groups of the hexose sugar may be substituted with a silyl protecting group, some or all of the hydroxyl groups may be substituted with a benzyl protecting group, or some of the hydroxyl groups may be substituted with a silyl protecting group and some of the hydroxyl groups may be substituted with a benzyl protecting group.

[0116] When F is a sugar chain derived from a pentose or a polymer thereof, the pentose is preferably arabinofuranose or ribose. When F is a sugar chain derived from a polymer of pentose, the pentose is preferably polymerized with adjacent pentoses by condensation of the hydroxyl groups bonded to the 1st and 4th carbons.

[0117] When F is a sugar chain derived from a hexose or a polymer thereof, the hexose is preferably glucose, galactose, mannose, rhamnose, or fucose. When F is a sugar chain derived from a polymer of hexose, the hexose is preferably polymerized with an adjacent hexose by condensation of the hydroxyl groups bonded to the 1- and 4-carbons.

[0118] The pentose or hexose constituting F may be one type or two or more types.

[0119] The hydrogen and / or hydroxyl groups bonded to the carbon skeleton of the pentose or hexose constituting F may be further substituted with an amino group or the like.

[0120] When F is a polymer derived from a pentose or a hexose, the degree of polymerization of the pentose or hexose is preferably 1-3.

[0121] As the silyl protecting group, a silyl protecting group for protecting a primary alcohol, such as tert-butyldimethylsilyl (TBS), triisopropylsilyl (TIPS), or tert-butyldiphenylsilyl (TBDPS), can be used.

[0122] As the benzyl protecting group, benzyl groups that protect primary alcohols, including 4-methylbenzyl group (-CH2-Ph-CH3) and 4-methoxybenzyl (-CH2-Ph-OCH3), can be used.

[0123] In some embodiments, F is of formula (6) or (7):

[0124] [ka]

[0125] In formula (6), m is 1 to 3; R 5 and R 6 One of them is hydrogen and the other is -OP roc (P roc is a silyl or benzyl protecting group; R 7 and R 8 One of them is hydrogen and the other is -OP roc (P roc is a silyl or benzyl protecting group; R 9 is hydrogen or -CH2O-P roc (P roc is a silyl or benzyl protecting group.

[0126] In formula (7), n is 1 to 3; R 10 and R 11 One of them is hydrogen and the other is -OP roc (P roc is a silyl or benzyl protecting group; R 12 and R 13 One of them is hydrogen and the other is -OP roc (P roc is a silyl or benzyl protecting group.

[0127] G may be a saturated or unsaturated hydrocarbon group.

[0128] G is preferably a substituted or unsubstituted alkylphenyl group, a substituted or unsubstituted phenyl group, or a substituted or unsubstituted alkyl group. The alkylphenyl group is a phenyl group substituted with an alkyl group. The alkyl group may be linear or branched, and preferably has 1 to 6 carbon atoms.

[0129] In some embodiments, G is an unsubstituted alkylphenyl group, an unsubstituted phenyl group, or an unsubstituted alkyl group. When G is substituted, the substituents can be any of the substituents defined herein.

[0130] The compound represented by formula (5) can be obtained by reacting azithromycin with an azide compound (specifically, an azide compound in which a sugar chain derived from a pentose, a hexose, or a polymer thereof is linked to a -G-N3 group (G is an optionally substituted divalent hydrocarbon group) via an ether bond) in the presence of an arylboronic acid (e.g., 4-nitrophenylboronic acid).

[0131] F is a sugar chain derived from a pentose in which at least a portion of the hydroxyl groups is substituted with a silyl protecting group and / or a benzyl protecting group, a hexose in which at least a portion of the hydroxyl groups is substituted with a silyl protecting group and / or a benzyl protecting group, or a polymer of either of these.

[0132] In one embodiment of the present invention, a compound represented by formula (1b), which is one of the compounds represented by formula (1), is produced by reacting a compound represented by formula (1a) with an alkyne and an azide. A method for producing a triazole compound by reacting an alkyne with an azide is known as an azide-click reaction, and the compound represented by formula (1b) can also be produced using the azide-click reaction. The azide-click reaction can be preferably carried out in the presence of a copper catalyst. The azide is preferably an organic azide having a structure of R1R2R3C-N3 (R is hydrogen or a substituent). The alkyne is preferably an alkyne having 1 to 6 carbon atoms which may be substituted. When the alkyne has a substituent, examples of the substituent include an alkyl group, a hydroxyalkyl group, a halogenoalkyl group, a cycloalkyl group, a hydroxycycloalkyl group, a cycloalkyl-alkyl group, an aralkyl group, an alkenyl group, a cycloalkyl-alkoxy group, an alkylthio group, a cycloalkyl-alkylthio group, an amino group, a mono- or dialkylamino group, a dialkylamino-alkyl group, a cycloalkylamino group, a cycloalkyl-alkylamino group, an acyl group, an acyloxy group, a carboxyl group, an alkoxycarbonyl group, an aralkyloxycarbonyl group, a carbamoyl group which may have an unsaturated hydrocarbon ring group as a substituent, a saturated or unsaturated heterocyclic group, an unsaturated hydrocarbon ring group such as an aromatic hydrocarbon group, and a saturated heterocyclic oxy group.

[0133] [ka]

[0134] (In formula (1b), one of X1 and X2 is a group represented by -ABD, and the other is -OH, A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group, D is an optionally substituted triazolyl group. The triazolyl group of D may be a 1,2,3-triazolyl group or a 1,2,4-triazolyl group. When D is substituted, the substituent may be any of the substituents defined herein. Particularly preferred substituents include alkylamino groups (e.g., -CH2-NH2), dialkylamino-alkyl groups (e.g., -CH2-N(CH2)2), aminophenyl groups, pyridyl groups, and the like.

[0135] The disclosures of all patent applications and publications cited herein are hereby incorporated by reference in their entireties.

[0136] The following examples are intended for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Unless otherwise specified, reagents are commercially available or are obtained or prepared according to conventional techniques or procedures known in the art. EXAMPLES

[0137] Example 1 Synthesis of azithromycin derivatives In the following, unless otherwise specified, a liquid represented as A / B refers to a mixed solution of A and B. THF refers to tetrahydrofuran, and TBAF refers to tetrabutylammonium fluoride.

[0138] (1) Synthesis of compound KK01

[0139] [ka]

[0140] To a solution of azithromycin (1.0 eq.) and p-nitrophenylboronic acid (0.2 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) was added 3,4,6-tri-O-benzyl-1,2-anhydro-d-glucose (2.0 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) at room temperature under argon atmosphere. The reaction mixture was stirred at the same room temperature for 24 h and quenched by adding 0.05 M aqueous NaBO3 solution. To the resulting mixture was added saturated aqueous NaHCO3 solution. The aqueous layer was extracted with acetic acid ethanol, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. Purification of the residue by flash silica gel column chromatography gave the protected KK01 (86% yield).

[0141] Compound Protected KK01: White solid; mp 117-118 o C; 11H NMR (400 MHz, CDCl3) δ 7.35 - 7.15 (15H, m), 5.26 (1H, d, J = 3.6 Hz), 5.19 (1H, d, J = 6.4 Hz), 4.90 (1H, ABq, J = 11.6 Hz), 4.89 (1H, d, J = 5.6 Hz), 4.81 (2H, dd, J = 10.8 Hz, 11.2), 4.64 (1H, d, J = 12.0 Hz), 4.52 (1H, d, J = 10.8 Hz), 4.41 (1H, d, J = 7.2 Hz), 4.12 - 4.08 (1H, m), 3.96 (1H, d, J = 8.8 Hz), 3.79 - 3.77 (3H, m), 3.74 - 3.53 (5H, m), 3.28 (3H, s), 3.00 (1H, d), 2.75 (1H, dd, J = 6.4, 7.2 Hz), 2.33 (6H, s), 2.17 (3H, s), 2.05 - 2.00 (3H,m), 1.77 - 1.61 (4H, m), 1.53 - 1.49 (1H, dd, J = 4.4, 14.8 Hz), 1.33 - 1.22 (19H, m), 1.14 (3H, s, H - 22), 1.09 (3H, d, J = 7.2 Hz), 1.01 (3H, d, J = 6.4 Hz), 0.96 (3H, d, J = 5.6 Hz), 0.90 (3H, t, J = 7.2 Hz); HRMS (ESI - TOF) m / z 1180.7045 (C 65 H 100 N2O 17 [M + H] + calculated value 1180.7022).

[0142]

Chem.

[0143] A solution of the protected KK01 (1.0 eq.) in dry acetic acid / ethanol / methanol (volume ratio 3 / 1) (= 3 / 1) and formic acid was stirred under hydrogen atmosphere (7 atm) at room temperature for 4 h in the presence of 20% Pd(OH)2 / C. After returning to normal pressure from ambient pressure, the reaction mixture was filtered through a disposable membrane filter (DISMIC-13cp) and the filtrate was concentrated under vacuum. Anion exchange resin (Amberlite) was added to the water / methanol solution of the crude product at room temperature. The mixture was stirred at the same room temperature for 1 h, filtered and concentrated under vacuum. Purification of the residue by reversed-phase silica gel column chromatography gave KK01 (yield 97%).

[0144] Compound KK01: White solid; melting point 110-111 °C; 1H NMR (500 MHz, CD3OD) d 5.42 (1H, d, J = 4.0 Hz), 5.27 (1H, d, J = 10.0 Hz), 4.90 (1H), 4.49 (1H, d, J = 7.0 Hz), 4.32 (1H, d, J = 6.5 Hz), 4.20 (1H, dq, J= 6.0, 9.5 Hz), 3.77-3.62 (8H, m), 3.50 (1H, dd, J = 4.0, 9.5 Hz), 3.34 (3H, s), 3.26 (1H, dd, J = 7.0, 10.5 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.89-2.84 (2H, m), 2.70 (1H, dt, J = 4.0, 11.0 Hz), 2.47-2.38 (2H, m), 2.34 (6H, s), 2.25 (3H, s), 2.10-2.02 (2H, m), 1.96 (1H, br-s), 1.85 (1H, m), 1.76-1.70 (2H, m), 1.63 (1H, m), 1.57 (1H, dd, J = 5.0, 15.0 Hz), 1.44 (1H, br-d, J = 8.0 Hz), 1.32-1.19 (19H, m), 1.11 (3H, d, J = 7.5 Hz), 1.08 (3H, d, J = 6.5 Hz), 0.95 (3H, d, J = 6.5 Hz), 0.88 (3H, t, J = 7.5 Hz); HRMS (ESI-TOF) m / z911.5715 (C 44 H 83 N2O 17 [M+H] + The calculated value is 911.5686).

[0145] (2) Synthesis of compound KK02

[0146]

change

[0147] To a solution of azithromycin (1.0 eq.) and p-nitrophenylboronic acid (0.2 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) was added 3,4,6-tri-O-benzyl-1,2-anhydro-D-galactose (2.0 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) at room temperature under argon atmosphere. The reaction mixture was stirred for 24 h at the same room temperature and quenched by adding 0.05 M aqueous NaBO3 solution. To the resulting mixture was added saturated aqueous NaHCO3 solution. The aqueous layer was extracted with acetic acid ethanol, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. Purification of the residue by flash silica gel column chromatography gave the protected KK02 (79% yield).

[0148] Compound Protected KK02: White solid; mp 119-120 o C; 1H NMR (400 MHz, CDCl3) d 7.35-7.25 (15H, m), 5.32 (1H, d, J = 3.6 Hz), 5.18 (1H, d, J = 8.0 Hz), 4.86 (2H, m), 4.74 (1H, ABq, J = 11.2 Hz), 4.58 (2H, ABq, J = 11.2 Hz), 4.46-4.41 (3H, m), 4.30-4.22 (2H, m), 4.12-4.08 (3H, m), 3.77-3.57 (6H, m), 3.48-3.46 (1H, m), 3.35 (1H, m), 3.27 (3H, s), 3.01 (1H, d, J = 9.2 Hz), 2.77-2.72 (3H, m), 2.43 (6H, s), 2.33 (1H, d, J = 15.2 Hz), 2.11 (3H, s), 2.04-1.98 (3H, m), 1.85-1.50 (4H, m), 1.32-1.22 (21H, m), 1.14 (3H, s), 1.06 (3H, d, J = 7.2 Hz), 1.00 (3H, d, J = 6.4 Hz), 0.96 (3H, d, J= 4.8 Hz), 0.89 (3H, t, J = 7.2, 7.6 Hz); HRMS (ESI-TOF) m / z1180.7039 (C 65 H 100 N2O 17 [M+H] + The calculated value is 1180.7022).

[0149]

change

[0150] A solution of protected KK02 (1.0 eq.) in dry acetic acid / ethanol / methanol (volume ratio 3 / 1) (= 3 / 1) and formic acid was stirred under hydrogen atmosphere (7 atm) at room temperature for 4 h in the presence of 20% Pd(OH)2 / C. After returning to normal pressure from ambient pressure, the reaction mixture was filtered through a disposable membrane filter (DISMIC-13cp) and the filtrate was concentrated under vacuum. Anion exchange resin (Amberlite) was added to the water / methanol solution of the crude product at room temperature. The mixture was stirred at the same room temperature for 1 h, filtered and concentrated under vacuum. Purification of the residue by reversed-phase silica gel column chromatography gave KK02 (yield 94%).

[0151] Compound KK02: White solid; melting point 120-121 °C; 1H NMR (500 MHz, CD3OD) d5.41 (1H, d, J = 4.0 Hz), 5.29 (1H, d, J = 9.0 Hz), 4.90 (1H), 4.49 (1H, d, J = 7.0 Hz), 4.32 (1H, d, J = 6.5 Hz), 4.20 (1H, dq, J= 6.5, 9.5 Hz), 3.98 (1H, dd, J = 6.5, 6.5 Hz), 3.94 (1H, br-d, J= 3.5 Hz), 3.91 (1H, dd, J = 4.0, 10.0 Hz), 3.75 (1H, dd, J = 3.5, 10.0 Hz), 3.71-3.64 (5H, m), 3.33 (3H, s), 3.26 (1H, dd, J = 7.5, 10.5 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.89-2.83 (2H, m), 2.71 (1H, dt, J = 4.0, 11.0 Hz), 2.47-2.39 (2H, m), 2.34 (6H, s), 2.25 (3H, s), 2.10-2.02 (2H, m), 1.95 (1H, br-s), 1.86 (1H, m), 1.76-1.73 (2H, m), 1.64 (1H, m), 1.58 (1H, dd, J = 5.0, 15.5 Hz), 1.38 (1H, br-d, J= 10.5 Hz), 1.32-1.19 (19H, m), 1.11 (3H, d, J = 7.5 Hz), 1.08 (3H, d, J= 7.0 Hz), 0.95 (3H, d, J = 6.5 Hz), 0.89 (3H, t, J = 7.5 Hz); HRMS (ESI-TOF) m / z 911.5708 (C 44 H 83 N2O 17 [M+H] + The calculated value is 911.5686).

[0152] (3) Synthesis of compound KK03

[0153]

change

[0154] To a solution of azithromycin (1.0 eq.) and p-nitrophenylboronic acid (0.2 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) was added 3,4,6-tri-O-benzyl-1,2-anhydro-D-mannose (3.0 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) at room temperature under argon atmosphere. The reaction mixture was stirred for 24 h at the same room temperature and quenched by adding 0.05 M aqueous NaBO3 solution. To the resulting mixture was added saturated aqueous NaHCO3 solution. The aqueous layer was extracted with acetic acid ethanol, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. Purification of the residue by flash silica gel column chromatography gave the protected KK03 (51% yield).

[0155] Compound Protected KK03: Colorless form; 1H NMR (400 MHz, CDCl3) d 7.37-7.19 (15H, m), 5.17-5.14 (2H, m), 4.85 (1H, ABq, J = 11.2 Hz), 4.72-4.58 (4H, ABq, J = 11.2, 11.6, 9.6, 11.2 Hz), 4.54-4.47 (3H, ABq, J = 11.6, 11.2, 7.2 Hz), 4.31-4.26 (2H, m), 4.03-4.00 (1H, m), 3.94-3.85 (2H, m), 3.78-3.65 (5H, m), 3.58 (1H, d, J= 5.6 Hz), 3.33 (3H, s), 3.30-3.25 (1H, m), 2.98 (1H, t, J = 8.0, 8.8 Hz), 2.77-2.57 (3H, m), 2.36 (3H, s), 2.30 (6H, s), 2.16-1.74 (9H, m), 1.59 (1H, dd, J = 5.2, 15.2 Hz), 1.45-1.41 (1H, m), 1.31-1.14 (30H, m), 1.02 (3H, d, J = 7.2 Hz), 0.91 (3H, d, J = 6.8 Hz), 0.88 (3H, d, J= 7.2 Hz), 0.79 (3H, t, J = 7.2, 7.6 Hz); HRMS (ESI-TOF) m / z1180.7059 (C 65 H 100 N2O 17 [M+H] + The calculated value is 1180.7022).

[0156]

change

[0157] A solution of the protected KK03 (1.0 eq.) in dry acetic acid / ethanol / methanol (volume ratio 3 / 1) (= 3 / 1) and formic acid was stirred under hydrogen atmosphere (7 atm) at room temperature for 4 h in the presence of 20% Pd(OH)2 / C. After returning to normal pressure from ambient pressure, the reaction mixture was filtered through a disposable membrane filter (DISMIC-13cp) and the filtrate was concentrated in vacuum. Anion exchange resin (Amberlite) was added to the water / methanol solution of the crude product at room temperature. The mixture was stirred at the same room temperature for 1 h, filtered and concentrated in vacuum. Purification of the residue by reversed-phase silica gel column chromatography gave KK03 (yield 91%).

[0158] Compound KK03: White solid; melting point 120-121 °C; 1H NMR (500 MHz, CD3OD) d 5.41 (1H, dd, J = 3.0, 9.5 Hz), 5.09 (1H, d, J = 5.0 Hz), 4.71 (1H, br-s), 4.52 (1H, d, J = 7.5 Hz), 4.28 (1H, dd, J = 2.0, 4.0 Hz), 4.21 (1H, dq, J = 6.0, 9.5 Hz), 4.07 (1H, d, J = 2.5 Hz), 3.91 (1H, dd, J = 3.0, 12.0 Hz), 3.89 (1H, m), 3.82 (1H, dd, J = 3.5, 11.5 Hz), 3.74 (1H, m), 3.71 (1H, dd, J = 9.5, 9.5 Hz), 3.66 (1H, d, J = 7.0 Hz), 3.54 (1H, dd, J = 3.0, 9.5 Hz), 3.42 (1H, dt, J = 3.0, 10.0 Hz), 3.37 (3H, s), 3.25 (1H, dd, J = 7.0, 10.0 Hz), 3.04 (1H, d, J = 9.5 Hz), 2.89 (1H, dd, J= 6.0, 13.5 Hz), 2.78 (1H, dq, J = 4.0, 7.5 Hz), 2.72 (1H, dt, J = 4.0, 11.0 Hz), 2.58 (1H, d, J = 10.5 Hz), 2.43 (1H, d, J = 15.0 Hz), 2.35 (6H, s), 2.30 (3H, s), 2.18 (1H, dd, J = 11.5, 11.5 Hz), 2.05 (1H, m), 2.00 (1H, m), 1.93 (1H, m), 1.77-1.74 (2H, m), 1.58 (1H, dd, J= 5.0, 15.0 Hz), 1.49 (1H, m), 1.38 (1H, dd, J = 9.0, 15.0 Hz), 1.31-1.14 (22H, m), 1.05 (3H, d, J = 7.5 Hz), 0.93-0.90 (6H, m); HRMS (ESI-TOF) m / z 911.5710 (C 44 H 83 N2O 17[M+H] + Calculated value of 911.5686).

[0159] (4) Synthesis of compound KK04

[0160] [ka]

[0161] To a solution of azithromycin (1.0 eq.) and p-nitrophenylboronic acid (0.2 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio), 3,4-di-O-benzyl-1,2-anhydro-L-fucose (2.0 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) was added. The reaction mixture was stirred at the same room temperature for 24 h and quenched by adding 0.05 M aqueous NaBO3. To the resulting mixture was added saturated aqueous NaHCO3. The aqueous layer was extracted with acetic acid ethanol, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. Purification of the residue by flash silica gel column chromatography afforded the protected KK04 (93% yield).

[0162] Compound Protected KK04: Colorless form; 11H NMR (400 MHz, CDCl3) δ 7.42 - 7.26 (10H, m), 5.04 (1H, d, J = 4.4 Hz), 4.98 (1H, ABq, J = 11.6 Hz), 4.92 (1H, d, J = 4.4 Hz), 4.90 (1H, ABq, J = 12.4 Hz), 4.75 (1H, ABq, J = 12.4 Hz), 4.67 (1H, ABq, J = 11.6 Hz), 4.43 (1H, d, J = 7.6 Hz), 4.39 (1H, br-s), 4.21 (1H, dd, J = 7.6, 10.4 Hz), 4.04 - 3.90 (3H, m), 3.75 - 3.48 (5H, m), 3.34 (3H, s), 3.28 - 3.22 (1H, m), 3.02 (1H, t, J = 7.6, 9.2 Hz), 2.63 - 2.58 (2H, m), 2.34 (6H, s), 2.22 (3H, s), 2.06 - 1.98 (2H, m), 1.90 - 1.82 (2H, m), 1.54 (1H, dd, J = 4.0, 14.4 Hz), 1.42 (3H, d, J = 6.4 Hz), 1.36 (3H, s), 1.31 (3H, d, 4.0 Hz), 1.26 - 1.21 (9H, m), 1.16 (6H, m), 1.12 (3H, s), 1.05 (6H, d, J = 5.6 Hz), 1.00 (3H, 7.2 Hz), 0.93 (3H, t, J = 7.2, 7.6 Hz); HRMS (ESI-TOF) m / z 1074.6623 (C 58 H 94 N2O 16 [M + H] + calculated value 1074.6603).

[0163]

Chem.

[0164] A solution of the protected KK04 (1.0 eq.) in dry acetic acid / ethanol / methanol (volume ratio 3 / 1) (= 3 / 1) and formic acid was stirred under hydrogen atmosphere (7 atm) at room temperature for 4 h in the presence of 20% Pd(OH)2 / C. After returning to normal pressure from ambient pressure, the reaction mixture was filtered through a disposable membrane filter (DISMIC-13cp) and the filtrate was concentrated under vacuum. Anion exchange resin (Amberlite) was added to the water / methanol solution of the crude product at room temperature. The mixture was stirred at the same room temperature for 1 h, filtered and concentrated under vacuum. Purification of the residue by reversed-phase silica gel column chromatography gave KK04 (yield 87%).

[0165] Compound KK04: White solid; melting point 104-105 °C; 1H NMR (500 MHz, CD3OD) d 5.19 (1H, dd, J = 3.5, 8.0 Hz), 4.99 (1H, d, J = 5.0 Hz), 4.95 (1H, d, J = 3.5 Hz), 4.51 (1H, d, J = 7.0 Hz), 4.33 (1H, br-s), 4.22 (1H, dd, J = 7.0, 13.5 Hz), 4.18 (1H, dq, J = 6.0, 9.5 Hz), 3.83-3.79 (3H, m), 3.73-3.65 (3H, m), 3.36 (3H, s), 3.24 (1H, dd, J= 7.0, 10.5 Hz), 3.03 (1H, d, J = 10.0 Hz), 2.77-2.69 (3H, m,), 2.58 (1H, dd, J= 6.0, 12.0 Hz), 2.41 (1H, d, J = 15.0 Hz), 2.34 (6H, s), 2.33 (3H, s), 2.17 (1H, dd), 2.04 (1H, m), 1.97-1.89 (2H, m), 1.74 (1H, dd, J = 2.0, 10.5 Hz), 1.56 (1H, dd, J= 5.0, 15.0 Hz), 1.52-1.40 (3H, m), 1.32-1.16 (22H, m), 1.07 (3H, d, J = 7.5 Hz), 1.02 (3H, d, J = 6.5 Hz), 0.94 (3H, t, J = 7.5 Hz); HRMS (ESI-TOF) m / z895.5761 (C 44 H 83 N2O 16 [M+H] + The calculated value is 895.5737).

[0166] (5) Synthesis of compound KK05

[0167]

change

[0168] To a solution of azithromycin (1.0 eq.) and p-nitrophenylboronic acid (0.2 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) was added 3,4-di-O-benzyl-1,2-anhydro-L-rhamnose (2.0 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) at room temperature under argon atmosphere. The reaction mixture was stirred at the same room temperature for 24 h and quenched by adding 0.05 M aqueous NaBO3. To the resulting mixture was added saturated aqueous NaHCO3. The aqueous layer was extracted with acetic acid ethanol, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. Purification of the residue by flash silica gel column chromatography gave the protected KK05 (82% yield).

[0169] Compound Protected KK05: White solid; mp 134-135 o C; 11H NMR (400 MHz, CDCl3) δ 7.40 - 7.20 (10H, m), 5.01 - 4.98 (2H, m), 4.86 (1H, ABq, J = 11.2 Hz), 4.80 (1H, ABq, J = 11.6 Hz), 4.63 (1H, ABq, J = 12.4 Hz), 4.58 - 4.54 (3H, m), 4.40 (1H, d, J = 7.6 Hz), 4.30 (1H, br-s), 4.00 - 3.94 (1H, m), 3.90 (1H, br-s), 3.73 - 3.56 (3H, m), 3.48 - 3.42 (1H, m), 3.36 - 3.33 (1H, m), 3.31 (3H, s), 3.28 - 3.23 (1H, m), 2.84 - 2.76 (2H, m), 2.69 (1H, dd, J = 2.8, 10.8 Hz), 2.47 - 2.44 (1H, m), 2.32 (6H, s), 2.30 (3H, s), 2.18 - 1.92 (5H, m), 1.72 - 1.68 (2H, m), 1.52 - 1.40 (1H, dd, J = 4.0, 14.4 Hz), 1.26 - 1.13 (27H, m), 1.02 (3H, J = 8.0 Hz), 0.91 - 0.87 (6H, m); HRMS (ESI-TOF) m / z 1074.6619 (C 58 H 94 N2O 16 [M+H] + calcd for 1074.6603).

[0170]

Chem.

[0171] A solution of the protected KK05 (1.0 eq.) in dry acetic acid / ethanol / methanol (volume ratio 3 / 1) (= 3 / 1) and formic acid was stirred under hydrogen atmosphere (7 atm) at room temperature for 4 h in the presence of 20% Pd(OH)2 / C. After returning to normal pressure from ambient pressure, the reaction mixture was filtered through a disposable membrane filter (DISMIC-13cp) and the filtrate was concentrated under vacuum. Anion exchange resin (Amberlite) was added to the water / methanol solution of the crude product at room temperature. The mixture was stirred at the same room temperature for 1 h, filtered and concentrated under vacuum. Purification of the residue by reversed-phase silica gel column chromatography gave KK05 (yield 82%).

[0172] Compound KK05: White solid; melting point 111-112 °C; 11H NMR (500 MHz, CD3OD) δ 5.05 (1H, d, J = 4.5 Hz), 5.01 (1H, dd, J = 2.5, 10.0 Hz, H-13), 4.46 (1H, d, J = 7.5 Hz), 4.43 (1H, s), 4.35 (1H, br-s), 4.21 (1H, dq, J = 6.5, 9.5 Hz), 4.19 (1H, d, J = 3.5 Hz), 3.91 (1H, br-s), 3.72 (1H, m), 3.64 (1H, d, J = 7.5 Hz), 3.53 - 3.47 (2H, m), 3.37 (3H, s), 3.27 (1H, dd, J = 9.5, 9.5 Hz), 3.25 (1H, dd, J = 7.5, 10.0 Hz), 3.03 (1H, d, J = 10.0 Hz), 2.82 (1H, dd, J = 7.0, 14.0 Hz), 2.74 (1H, dq, J = 3.5, 7.0 Hz), 2.68 (1H, dt, J = 4.0, 11.0 Hz), 2.45 (1H, d, J = 15.5 Hz), 2.34 (1H, m), 2.34 (6H, s), 2.31 (3H, s), 2.22 (1H, dd, J = 11.0, 11.0 Hz), 2.12 (1H, m), 2.05 (1H, m), 1.90 (1H, m), 1.75 - 1.68 (2H, m), 1.57 (1H, dd, J = 5.0, 15.0 Hz), 1.49 (1H, m), 1.35 (1H, br-d, J = 12.5 Hz), 1.30 - 1.25 (12H, m), 1.20 - 1.17 (10H, m), 1.06 (3H, d, J = 7.5 Hz), 0.93 (3H, d, J = 6.5 Hz), 0.88 (3H, t, J = 7.5 Hz); 1 HRMS (ESI-TOF) m / z 895.5750 (C 44 H 83 N2O 16 [M+H] + calcd for 895.5737).

[0173] (6) Synthesis of compound KK06

[0174] [ka]

[0175] A solution of azithromycin (1.0 eq.) and p-nitrophenylboronic acid (0.2 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio) was added with 4-Op-azidobenzyl-3,6-di-O-triisopropylsilyl-1,2-anhydro-D-glucose (2.0 eq.) in dry CH3CN / DMSO (3 / 1 volume ratio). The reaction mixture was stirred at the same room temperature for 24 h and quenched by adding 0.05 M aqueous NaBO3 (0.2 eq.). The resulting mixture was added with saturated aqueous NaHCO3. The aqueous layer was extracted with acetic acid ethanol, and the combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuum. Purification of the residue by flash silica gel column chromatography gave the protected KK06 (89% yield).

[0176] Compound KK06: Yellow foam; 1H NMR (400 MHz, CD3OD) d 7.34-7.31 (2H, m), 7.04-7.02 (2H, m), 5.21 (1H, d, J = 8.8 Hz), 5.11 (1H, d, J = 3.6 Hz), 4.86 and 4.76 (2H, ABq, J = 12.0 Hz), 4.85 (1H), 4.52 (1H, d, J = 7.6 Hz), 4.42 (1H, d, J = 7.2 Hz), 4.21 (1H, dq, J = 6.4, 9.2 Hz), 4.16 (1H, dd, J= 9.2, 9.2 Hz), 3.93 (1H, dd, J = 3.2, 11.6 Hz), 3.87-3.79 (3H, m), 3.71-3.65 (2H, m), 3.48 (1H, dd, J = 9.2, 9.2 Hz), 3.44 (1H, dd, J = 3.2, 9.6 Hz), 3.33 (3H, s), 3.28 (1H, m), 3.03 (1H, d, J = 9.6 Hz), 2.87-2.78 (3H, m), 2.45-2.40 (2H, m), 2.40 (6H, s), 2.23 (3H, s), 2.08-1.99 (4H, m), 1.84-1.66 (3H, m), 1.57 (1H, dd, J = 4.4, 15.2 Hz), 1.32-1.30 (10H, m), 1.24-1.03 (58H, m), 0.97 (3H, d, J = 6.0 Hz), 0.91 (3H, t, J = 6.8 Hz); HRMS (ESI-TOF) m / z1354.8839 (C 69 H 128 N5O 17 Si2[M+H] + The calculated value is 1354.8838).

[0177] (7) Synthesis of compound KK07

[0178]

change

[0179] To a solution of KK06 (1.0 eq.) in tetrahydrofuran was added a solution of 1.0 M TBAF in THF (10 eq.) at room temperature under argon atmosphere. The reaction mixture was stirred for 18 h at 40° C. and then concentrated in vacuo. Purification of the residue by flash silica gel column chromatography afforded KK07 (yield 70%).

[0180] Compound KK07: yellow solid; 1H NMR (500 MHz, CD3OD) d 7.42-7.40 (2H, m), 7.06-7.03 (2H, m), 5.41 (1H, d, J = 3.5 Hz), 5.27 (1H, d, J = 10.0 Hz), 4.93 and 4.64 (2H, ABq, J = 11.0 Hz), 4.90 (1H), 4.49 (1H, d, J = 7.0 Hz), 4.32 (1H, d, J = 6.5 Hz), 4.20 (1H, dq J = 6.0, 9.0 Hz), 3.80 (1H, dd, J = 9.5, 9.5 Hz), 3.78-3.64 (6H, m), 3.53 (1H, dd, J = 4.0, 9.5 Hz), 3.36 (1H, dd, J = 9.5, 9.5 Hz), 3.34 (3H, s), 3.26 (1H, dd, J = 7.0, 10.0 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.89-2.84 (2H, m), 2.71 (1H, dt, J = 4.0, 11.0 Hz), 2.47-2.41 (2H, m), 2.34 (6H, s), 2.23 (3H, s), 2.09-2.01 (2H, m), 1.95 (1H, br-s), 1.85 (1H, m), δ 5.17 (5.17 ± 0.13 Hz) 1.54 (2H, m), 1.76-1.71 (2H, m), 1.64 (1H, m), 1.57 (1H, dd, J = 4.5, 15.0 Hz), 1.41 (1H, br-d, J = 14.5 Hz), 1.32-1.19 (19H, m), 1.11 (3H, d, J = 7.5 Hz), 1.05 (3H, d, J = 6.5 Hz), 0.94 (3H, d, J = 6.5 Hz), 0.89 (3H, t, J = 7.0 Hz); HRMS (ESI-TOF) m / z 1042.6176 (calcd. for C51H88N5O17 [M+H]+ 1042.6175).

[0181] (8) Synthesis of compound KK08

[0182]

change

[0183] To a solution of KK07 (1.0 eq.) in THF was added propargylamine (4.4 eq.) at room temperature under argon atmosphere. The reaction mixture was stirred for 5 min at the same room temperature, and an aqueous solution of CuSO4·5H2O (4.0 eq.) and Na-Asc (1.0 eq.) was added to the reaction mixture. After stirring for 18 h, the reaction mixture was purified by flash silica gel column chromatography to give KK08 (yield 85%).

[0184] Compound KK08: yellow solid; melting point 150-151 °C; 1H NMR (500 MHz, CD3OD) d 8.39 (1H, s), 7.83-7.81 (2H, m), 7.61-7.60 (2H, m), 5.43 (1H, d, J = 3.5 Hz), 5.28 (1H, d, J = 10.5 Hz), 5.05 and 4.76 (2H, ABq, J = 11.5 Hz), 4.90 (1H), 4.50 (1H, d, J = 7.0 Hz), 4.32 (1H, d, J = 6.5 Hz), 4.20 (1H, dq, J = 6.0, 9.5 Hz), 3.98 (2H, s), 3.84 (1H, dd, J = 9.5, 9.5 Hz), 3.81 (1H, m), 3.73-3.64 (5H, m), 3.55 (1H, dd, J = 4.0, 9.5 Hz), 3.42 (1H, dd, J = 9.5, 9.5 Hz), 3.34 (3H, s), 3.27 (1H, dd, J = 7.5, 10.0 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.88-2.85 (2H, m), 2.75 (1H, dt, J = 4.0, 11.0 Hz), 2.44-2.41 (2H, m), 2.37 (6H, s), 2.25 (3H, s), 2.11-2.02 (2H, m), 1.96 (1H, br-s), 1.86 (1H, m), 1.77-1.70 (2H, m), 1.64 (1H, m), 1.58 (1H, dd, J = 4.5, 15.0 Hz), 1.42 (1H, br-d, J = 15.5Hz), 1.32-1.19 (19H, m), 1.11 (3H, d, J = 7.5 Hz), 1.07 (3H, d, J = 7.0 Hz), 0.95 (3H, d, J = 7.0 Hz), 0.89 (3H, t, J = 7.0 Hz); HRMS (ESI-TOF) m / z 1097.6582 (calculated value of C54H93N6O17 [M+H]+ 1097.6592).

[0185] (9) Synthesis of compound KK09

[0186] [ka]

[0187] To a solution of KK07 (1.0 eq.) in THF was added N,N-dimethylpropargylamine (4.4 eq.) at room temperature under argon atmosphere. The reaction mixture was stirred for 5 min at the same room temperature, and an aqueous solution of CuSO4·5H2O (4.0 eq.) and Na-Asc (1.0 eq.) was added to the reaction mixture. After stirring for 18 h, the reaction mixture was purified by flash silica gel column chromatography to give KK09 (yield 94%).

[0188] Compound KK09: yellow solid; melting point 152-153 °C; 1H NMR (500 MHz, CD3OD) d 8.46 (1H, s), 7.84-7.83 (2H, m), 7.62-7.60 (2H, m), 5.42 (1H, d, J = 3.5 Hz), 5.28 (1H, d, J = 9.5 Hz, 5.05 and 4.76 (2H, ABq, J = 11.5 Hz), 4.90 (1H), 4.49 (1H, d, J = 7.5 Hz), 4.32 (1H, d, J = 6.0 Hz), 4.20 (1H, dq, J = 6.0 Hz , J = 9.5 Hz), 3.84 (1H, dd, J = 9.5, 9.5 Hz), 3.81 (1H, m), 3.72-3.64 (7H, m), 3.55 (1H, dd, J = 4.0, 9.5 Hz), 3.42 (1H, dd, J = 9.5, 9.5 Hz), 3.34 (3H, s), 3.27 (1H, dd, J = 7.5, 10.5 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.88-2.85 (2H, m), 2.72 (1H, dt, J = 3.5, 11.0 Hz), 2.48-2.41 (2H, m), 2.35 (6H, s), 2.33 (6H, s), 2.24 (3H, s), 2.10-2.02 (2H, m), 1.95 (1H, br-s), 1.86 (1H, m), 1.77-1.71 (2H, m), 1.64 (1H, m), 1.58 (1H, dd, J = 4.5, 15.0 Hz), 1.42 (1H, br-d, J = 12.0 Hz), 1.32-1.20 (19H, m), 1.11 (3H, d, J = 7.0 Hz), 1.07 (3H, d, J = 6.5 Hz), 0.95 (3H, d, J = 6.5 Hz), 0.89 (3H, t, J = 7.0 Hz); HRMS (ESI-TOF) m / z 1125.6939 (calculated value of C56H97N6O17 [M+H]+ 1125.6905).

[0189] (10) Synthesis of compound KK10

[0190] [ka]

[0191] To a solution of KK07 (1.0 eq.) in methanol was added 3-ethynylaniline (2.0 eq.) at room temperature under argon atmosphere. The reaction mixture was stirred for 5 hours at the same room temperature. TBTA (1.0 eq.) and [Cu(MeCN)4]PF6 (1.0 eq.) were added to the reaction mixture. After stirring for 15 hours, the residue was purified by flash silica gel column chromatography to give KK10 (yield 88%).

[0192] Compound KK10: yellow solid; melting point 170-171 °C; 1H NMR (500 MHz, CD3OD) d 8.80 (1H, s), 7.90-7.88 (2H, m), 7.63-7.62 (2H, m), 7.28 (1H, br-s), 7.23-7.18 (2H, m), 6.75 (1H, dt, J = 2.0, 7.0 Hz), 5.42 (1H, d, J = 3.5 Hz), 5.28 (1H, d, J = 10.0 Hz), 5.06 and 4.77 (2H, ABq, J = 12.0 Hz), 4.90 (1H,), 4.49 (1H, d, J = 7.0 Hz), 4.32 (1H, d, J = 6.5 Hz), 4.20 (1H, dq, J = 6.0, 9.5 Hz), 3.85 (1H, dd, J = 9.5, 9.5 Hz), 3.82 (1H, m), 3.75-3.63 (5H, m), 3.56 (1H, dd, J = 4.0, 9.5 Hz), 3.43 (1H, dd, J = 9.5, 9.5 Hz,), 3.33 (3H, s), 3.26 (1H, dd, J = 7.0, 10.0 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.89-2.85 (2H, m), 2.71 (1H, dt, J = 4.0, 11.0 Hz), 2.47-2.41 (2H, m), 2.34 (6H, s), 2.24 (3H, s), 2.09-2.02 (2H, m), 1.95 (1H, br-s), 1.86 (1H, m), 1.75-1.72 (2H, m), 1.64 (1H, m), 1.57 (1H, dd, J = 4.5, 15.0 Hz), 1.41 (1H, br-d, J = 10.0 Hz), 1.32-1.20 (19H, m), 1.11 (3H, d, J = 7.0 Hz), 1.07 (3H, d, J = 6.5 Hz), 0.94 (3H, d, J = 6.5 Hz), 0.89 (3H, t, J = 7.5 Hz); HRMS (ESI-TOF) m / z 1159.6785 (calcd. for C59H95N6O17 [M+H]+ 1159.6748).

[0193] (11) Synthesis of compound KK11

[0194] [ka]

[0195] To a solution of KK07 (1.0 eq.) in methanol was added 3-ethynylpyridine (2.0 eq.) at room temperature under argon atmosphere. The reaction mixture was stirred for 5 hours at the same room temperature. TBTA (1.0 eq.) and [Cu(MeCN)4]PF6 (1.0 eq.) were added to the reaction mixture. After stirring for 15 hours, the residue was purified by flash silica gel column chromatography to give KK11 (yield 99%).

[0196] Compound KK11: yellow solid; melting point 164 - 165 °C; 1H NMR (500 MHz, CD3OD) δ 9.12 (1H, br-s), 9.09 (1H, s), 8.56 (1H, br-d, J = 5.0 Hz), 8.39 (1H, br-d, J = 8.0 Hz), 7.92 - 7.90 (2H, m), 7.65 - 7.63 (2H, m), 7.57 (1H, dd, J = 5.0, 8.0 Hz), 5.43 (1H, d, J = 4.0 Hz), 5.28 (1H, d, J = 9.5 Hz), 5.07 and 4.78 (2H, ABq, J = 12.0 Hz), 4.89 (1H), 4.49 (1H, d, J = 7.0 Hz), 4.32 (1H, d, J = 6.0 Hz), 4.20 (1H, dq, J = 6.0, 9.5 Hz), 3.85 (1H, dd, J = 9.5, 9.5 Hz), 3.82 (1H, m), 3.74 - 3.64 (5H, m), 3.56 (1H, dd, J = 4.0, 9.5 Hz), 3.44 (1H, dd, J = 9.5, 9.5 Hz), 3.34 (3H, s), 3.27 (1H, dd, J = 7.5, 10.0 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.88 - 2.85 (2H, m), 2.72 (1H, dt, J = 3.5, 11.0 Hz), 2.44 - 2.41 (2H, m), 2.35 (6H, s), 2.25 (3H, s), 2.09 - 2.03 (2H, m), 1.95 (1H, br-s), 1.87 (1H, m), 1.76 - 1.72 (2H, m), 1.64 (1H, m), 1.58 (1H, dd, J = 4.5, 15.0 Hz), 1.41 (1H, br-d, J = 13.0 Hz), 1.32 - 1.20 (19H, m), 1.11 (3H, d, J = 7.0 Hz), 1.07 (3H, d, J = 6.5 Hz), 0.94 (3H, d, J = 6.5 Hz), 0.89 (3H, t, J = 7.5 Hz); HRMS (ESI-TOF) m / z 1145.6616 (calculated for C59H95N6O17 [M+H]+ 1145.6592).

[0197] (12) Synthesis of compound KK12

[0198] [ka]

[0199] To a solution of KK07 (1.0 eq.) in methanol was added 4-ethynylaniline (2.0 eq.) at room temperature under argon atmosphere. The reaction mixture was stirred for 5 hours at the same room temperature. TBTA (1.0 eq.) and [Cu(MeCN)4]PF6 (1.0 eq.) were added to the reaction mixture. After stirring for 15 hours, the residue was purified by flash silica gel column chromatography to give KK12 (yield 99%).

[0200] Compound KK12: yellow solid; melting point 186-187 °C; 1H NMR (500 MHz, CD3OD) d 8.71 (1H, s), 7.89-7.87 (2H, m), 7.66-7.61 (4H, m), 6.81-6.78 (2H, m), 5.42 (1H, d, J = 3.5 Hz), 5.28 (1H, d, J = 9.5 Hz), 5.05 and 4.77 (2H, ABq, J = 11.5 Hz), 4.89 (1H), 4.49 (1H, d, J = 7.5 Hz), 4.32 (1H, d, J = 6.5 Hz), 4.20 (1H, dq, J = 6.5, 9.5 Hz), 3.85 (1H, dd, J = 9.5, 9.5 Hz), 3.82 (1H, m), 3.75-3.64 (5H, m), 3.56 (1H, dd, J = 4.0, 9.5 Hz), 3.43 (1H, dd, J = 9.5, 9.5 Hz), 3.33 (3H, s), 3.26 (1H, dd, J = 7.5, 10.0 Hz), 3.03 (1H, d, J = 9.5 Hz), 2.89-2.82 (2H, m), 2.72 (1H, dt, J = 3.5, 11.0 Hz), 2.47-2.41 (2H, m), 2.34 (6H, s), 2.24 (3H, s), 2.09-2.02 (2H, m), 1.95 (1H, br-s), 1.86 (1H, m), 1.75-1.71 (2H, m), 1.64 (1H, m), 1.57 (1H, dd, J = 4.5, 15.0 Hz), 1.41 (1H, br-d, J = 12.0 Hz), 1.32-1.20 (19H, m), 1.11 (3H, d, J = 7.0 Hz), 1.07 (3H, d, J = 6.5 Hz), 0.94 (3H, d, J = 6.0 Hz), 0.89 (3H, t, J = 7.5 Hz); HRMS (ESI-TOF) m / z 1159.6763 (calculated value of C59H95N6O17 [M+H]+ 1159.6748).

[0201] (13) Synthesis of compound KK13

[0202] [ka]

[0203] To a solution of KK07 (1.0 eq.) in methanol was added 4-ethynylpyridine (2.0 eq.) at room temperature under argon atmosphere. The reaction mixture was stirred for 5 hours at the same room temperature. TBTA (1.0 eq.) and [Cu(MeCN)4]PF6 (1.0 eq.) were added to the reaction mixture. After stirring for 15 hours, the residue was purified by flash silica gel column chromatography to give KK13 (yield 93%).

[0204] Compound KK13: yellow solid; melting point 171-172 °C; 1H NMR (500 MHz, CD3OD) d 9.19 (1H, s), 8.64 (2H, br-s), 7.99-7.98 (2H, m), 7.92-7.91 (2H, m), 7.65-7.64 (2H, m), 5.43 (1H, d, J = 3.5 Hz), 5.28 (1H, d, J = 10.5 Hz), 5.07 and 4.78 (2H, ABq, J = 11.5 Hz), 4.90 (1H), 4.49 (1H, d, J = 7.0 Hz), 4.32 (1H, d, J = 6.5 Hz), 4.20 (1H, dq, J = 6.0, 9.5 Hz), 3.85 (1H, dd, J = 9.5, 9.5 Hz), 3.82 (1H, m), 3.76-3.64 (5H, m), 3.56 (1H, dd, J = 4.0, 10.0 Hz), 3.44 (1H, dd, J = 9.5, 9.5 Hz), 3.34 (3H, s), 3.26 (1H, dd, J = 7.5, 10.0 Hz), 3.03 (1H, d, J = 10.0 Hz), 2.90-2.84 (2H, m), 2.72 (1H, dt, J = 4.0, 11.0 Hz), 2.48-2.41 (2H, m), 2.35 (6H, s), 2.24 (3H, s), 2.09-2.02 (2H, m), 1.95 (1H, br-s), 1.86 (1H, m), 1.76-1.71 (2H, m), 1.64 (1H, m), 1.57 (1H, dd, J = 4.5, 15.0 Hz), 1.42 (1H, br-d, J = 12.5 Hz), 1.32-1.20 (19H, m, 1.11 (3H, d, J = 7.0 Hz), 1.07 (3H, d, J = 7.0 Hz), 0.94 (3H, d, J = 6.5 Hz), 0.89 (3H, t, J = 7.5 Hz); HRMS (ESI-TOF) m / z 1145.6621 (calculated value of C58H93N6O17 [M+H]+ 1145.6592).

[0205] Example 2 Antibacterial activity evaluation The antibacterial activity of the compounds KK01 to KK13 prepared in Example 1 was tested. The antibacterial activity of azithromycin was also evaluated. All of the tested bacteria were nontuberculous acid-fast bacteria, Mycobacterium avium ATCC25291 and Mycobacterium intracellilare JCM6384 were non-drug resistant bacteria, and Mycobacterium avium B-1657 and Mycobacterium intracellilare B-1639 were macrolide resistant bacteria.

[0206] ATCC 25291 was obtained from the American Type Culture Collection (ATCC), and JCM6384 was obtained from the RIKEN BioResource Research Center. B-1657 and B-1639 were selected as resistant single colonies by culturing ATCC 25291 and JCM6384, respectively, on agar medium containing erythromycin. To confirm the genotype, the rrl gene encoding 23S rRNA was amplified by PCR using the genomic DNA of these strains as a template and two primers, 5_23S_MAC (sequence 5'-ATCGAGAGCCGATGAAGG) and 3_23S_MAC (sequence 5'-TTCCAGGTCTGGCCTATCG). The PCR fragments obtained were subjected to Sanger sequencing using 3_23S_MAC as a primer, and it was confirmed that B-1657 and B-1639 had the A to C mutation at positions 2059 and 2058 (E. coli numbering) of the rrl gene, respectively.

[0207] Antibacterial tests were performed using the broth microdilution method. The liquid medium used was Middlebrook 7H9 broth adjusted to pH 7.4 and supplemented with Middlebrook ADC Enrichment. Each test bacterium was inoculated into this at 100,000 cfu / ml and dispensed into a microplate. Azithromycin and azithromycin derivatives were added to each well in a two-fold dilution series and incubated at 37 degrees Celsius. After 14 days, the growth of the test bacterium was evaluated by visually checking the increase in turbidity of the culture medium, and the minimum concentration (MIC) that inhibits the growth of the test bacterium was used as an index of the antibacterial activity of each drug.

[0208] Table 1 shows the results of the antibacterial test.

[0209] Compounds KK07 to KK13 showed higher antibacterial activity than azithromycin against drug-resistant bacteria M. avium B-1657. Compound KK13 also showed antibacterial activity against M. intracellilare B-1639.

[0210] Furthermore, compounds KK07 to KK13 also exhibited antibacterial activity against M. avium ATCC25291 and M. intracellilare JCM6384, and the antibacterial activity of compounds KK07, KK11, and KK13 against M. avium ATCC25291 and M. intracellilare JCM6384 was higher than that of azithromycin.

[0211] Compounds KK01 to KK05 showed antibacterial activity against M. avium ATCC25291 and M. intracellilare JCM6384, although the activity was weaker than that of azithromycin. Compound KK06 showed weak antibacterial activity against both M. avium ATCC25291 and M. intracellilare JCM6384. Compounds KK01 to KK06 did not have antibacterial activity against drug-resistant bacteria, except for compound KK04, which showed weak antibacterial activity against M. avium B-1657.

[0212]

Table 1

Claims

1. A compound represented by the following formula (1), or a salt thereof: 【Chemistry 1】 (In the formula, X １ and X ２ one of the above is a group represented by -AB-D, and the other is -OH; A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group; D is -N ３ or an optionally substituted triazolyl group.

2. 13. An antibacterial agent comprising the compound or salt thereof according to claim 1 as an active ingredient.

3. The antibacterial agent according to claim 2, which is an antibacterial agent against drug-resistant nontuberculous mycobacteria.

4. A composition comprising the compound of claim 1 or a salt thereof.

5. The composition of claim 4 which is an antibacterial composition.

6. The composition of claim 4 which is a pharmaceutical composition.

7. A compound represented by formula (5). 【Chemistry 2】 (In the formula, Y １ and Y ２ Either one of -F-G-N ３ and the other is —OH; F is a sugar chain derived from a pentose having at least a portion of its hydroxyl groups substituted with a silyl protecting group or a benzyl protecting group, a hexose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, or a polymer of either of these; G is an optionally substituted divalent hydrocarbon group.

8. A method for producing a compound represented by formula (1a), comprising removing a silyl protecting group and / or a benzyl protecting group in a compound represented by the following formula (5) to convert it into a hydroxyl group: 【Chemistry 3】 (In the formula, Y １ and Y ２ Either one of -F-G-N ３ and the other is —OH; F is a sugar chain derived from a pentose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, a hexose having at least a portion of its hydroxyl groups substituted with a silyl protecting group and / or a benzyl protecting group, or a polymer of either of these; G is an optionally substituted divalent hydrocarbon group. 【Chemistry 4】 (In the formula, X １ and X ２ one of the above is a group represented by -AB-D, and the other is -OH; A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group; D is -N ３ It is.)

9. A method for producing a compound represented by formula (1b): 【Chemistry 5】 (In formula (1a), X １ and X ２ one of the above is a group represented by -AB-D, and the other is -OH; A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group; D is -N ３ It is.) 【Chemistry 6】 (In formula (1b), X １ and X ２ one of the above is a group represented by -AB-D, and the other is -OH; A is a sugar chain derived from a pentose, a hexose, or a polymer thereof; B is an optionally substituted divalent hydrocarbon group; D is an optionally substituted triazolyl group.

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