TW201839005A - Novel aminoglycoside antibiotic effective for multiple drug-resistant bacteria - Google Patents

Abstract

Disclosed are: a compound represented by general formula (I), a pharmaceutically acceptable salt thereof or a solvate of the same; a medicinal composition comprising the same; use of the same for preventing or treating infectious diseases; and a method for preventing or treating infectious diseases, said method comprising using the same. The compound represented by general formula (I), which has an antibacterial activity against both of gram-positive bacteria and gram-negative bacteria, is useful for preventing or treating infectious diseases caused by these bacteria.

Description

Novel aminoglycoside antibiotics effective against multi-drug resistant bacteria

The 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 bacteria and Gram-negative bacteria in the same way as β-lactam drugs or quinolone drugs, but they do not exist in existing pharmaceutical products. I have not seen a wide range of people including drug-resistant bacteria, including these. In addition, as shown below, it also causes difficulties in development.

In recent years, cases of infection caused by methicillin-resistant Staphylococcus aureus (hereinafter referred to as "MRSA") have increased rapidly both at home and abroad, and MRSA is clinically a cause of serious infections Bacteria have become a problem, and they are beginning to review their therapeutic agents.

For xylene penicillin-resistant Staphylococcus aureus (MRSA), it has been reported that the amino group at the first position of dibekacin, which is one of the aminoglycoside antibiotics, is converted to amino hydroxybutyric acid (HABA). (S) -1-N- (4-amino-2-hydroxybutyroyl) dibekacin (arbekacin) is effective (non-patent document 1), in fact, arbekacin Since the end of 1990, it has been used as a special drug for MRSA infection in Japan.

However, it has been more than 20 years since arbekacin began to be used as a therapeutic agent for MRSA infectious diseases, and MRSA showing resistance to arbekacin has emerged, which has become a clinical problem.

In addition, recently, not only Gram-positive bacteria including MRSA, but also multi-resistant bacteria among Gram-negative bacteria such as Escherichia coli, Pneumoniae, Serratia, Acinetobacter, Pseudomonas aeruginosa, etc. Also increased. Most of these bacteria also show resistance to previous aminoglycosides, β-lactamides, and new quinolinone agents, which often cause refractory infections.

For multi-drug resistant Gram-negative bacteria such as multi-resistant E. coli or multi-resistant Acinetobacter, it has been reported that the amino group at the 1 position of sisomicin, which is one of the aminoglycoside antibiotics Hydroxybutyric acid (HABA) is acetylated and the 6'-position amine group is alkylated to give (S) -1-N- (4-amino-2-hydroxybutyroyl) -6'-N-hydroxyethyl Sistomycin (plazomicin) is effective (Patent Document 1).

However, although prazomycin has been shown to be effective against a number of multi-resistant Gram-negative bacteria, it is not effective against methylase-resistant Gram-negative bacteria. Regarding basic antibacterial activity or safety Also not enough.

Furthermore, it has been described that carbapenem-resistant Gram-negative bacteria, which are resistant to almost all aminoglycoside antibiotics by apramycin, are moderately effective (Non-Patent Document 2) . Although a compound obtained by chemically modifying the hydroxyl group at the 5-position, 6-position or 6 ”position of apramycin has been disclosed (Patent Documents 2, 3 and 4), and the 1-position of apramycin has been disclosed Or a compound obtained by chemical modification of the amine group at the 4 ”position (Patent Documents 5 and 6), but the effectiveness of all compounds against resistant bacteria has not been clearly disclosed. [Prior Technical Literature] [Patent Literature]

Patent Document 1: International Publication No. 2009/067692 Patent Document 2: Japanese Patent Laid-Open No. 57-72998 Patent Document 3: Japanese Patent Laid-Open No. 57-72999 Patent Document 4: US Patent No. 4379917 Specification Patent Document 5: US Patent No. 4424345 Specification Patent Document 6: US Patent No. 4360665 Specification [Non-Patent Document]

Non-patent literature 1: Kondo, S. et al., The Journal of Antibiotics, Vol. 26, pp. 412-415, 1973 Non-patent literature 2: J Antimicrob Chemother, Vol. 66, pp. 48-53, 2011

The object of the present invention is to provide novel antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria, in particular, it is effective against Gram-positive bacteria and Gram-negative bacteria exhibiting multi-drug resistance Aminoglycoside antibiotics.

The inventors of the present invention have vigorously explored derivatives of apramycin, which is an aminoglycoside antibiotic, and found compounds having antibacterial activity against Gram-positive bacteria and Gram-negative bacteria. In addition, it has been found that these compounds are also effective against drug-resistant bacteria such as MRSA or multi-resistant Gram-negative bacteria. The present invention is based on these findings.

That is, the present invention includes the following inventions. (1) A compound represented by general formula (I) or a pharmaceutically acceptable salt or a solvent thereof: [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group, R ² represents a hydrogen atom or a hydroxyl group, R ³ represents a hydrogen atom or a hydroxyl group, R ⁴ represents a hydrogen atom or a hydroxyl group, R ⁵ represents a hydrogen atom or a hydroxyl group, and R ⁶ represents a glycoamine Acyl, sarcosyl, N-ethylglycinyl, β-propylamine, L-isoseramine, N-formamidylglycinyl, N-formamidinyl Amido, N-methyl-L-isoseramine, or N-formamidine-L-isoseramine]. (2) The compound as described in (1) or a pharmaceutically acceptable salt or a solvent thereof, wherein R ⁶ represents N-ethylglycinyl, N-carboxamidoglycinyl, N -Formamidine sarcosinyl, N-methyl-L-isoseramine amide or N-formamidine-L-isoseramine amide. (3) The compound described in (2) or a pharmaceutically acceptable salt or a solvent thereof, wherein R ⁴ represents a hydrogen atom. (4) The compound described in (2) or (3) or a pharmaceutically acceptable salt or a solvent thereof, wherein R ⁵ represents a hydroxyl group. (5) The compound described in (1) or a pharmaceutically acceptable salt or a solvent thereof, wherein R ⁵ represents a hydrogen atom, and R ⁶ represents a glycosamino, sarcosyl, β-propylamine Acyl or L-isoseramine acyl. (6) The compound as described in (1) or a pharmaceutically acceptable salt or a solvent thereof, wherein R ² represents a hydrogen atom, and R ⁶ represents a glycosamino, sarcosyl, β-propylamine Acyl or L-isoseramine acyl. (7) The compound described in (6) or a pharmaceutically acceptable salt or a solvent thereof, wherein R ³ represents a hydrogen atom. (8) The compound as described in (1) or a pharmaceutically acceptable salt or a solvent thereof, the compound is 4 "-N- (N-formamidinoglycinyl) apuramycin, 4 ”-N- (N-formamidinosarcosinyl) apuramycin, 4” -N- (N-ethylglycinamide) apuramycin, 4 ”-N- (N -Formamidinoglycinyl) -5-epiapramycin, 5-epi-4 "-N- (N-ethylglycinyl) apramycin, 5-deoxy-4 ”-N-Glycine apramycin, 5-deoxy-4” -N-sarcosine apramycin, 5-deoxy-4 ”-N- (N-ethylglycine Amido) apramycin, 4 ”-N- (β-propylaminoamido) -5-deoxyapuramycin, 5-deoxy-4” -N- (L-isoseramide) Group) apramycin, 4 "-N- (N-formamidinoglycinyl) -5-deoxyapuramycin, 4" -N- (N-formamidinoglycinyl) ) -6-deoxy-5-epirubicin, 6-deoxy-5-epiform-4 "-N- (N-ethylglycinamide) apramycin, 3" -de Oxy-5-Table-4 "-N-Glycine Apramycin, 3" -deoxy-5-Table-4 "-N-sarcosine Apramycin, 3" -Go Oxy-5-table-4 ”-N- (L-isoseramine acetyl) apra Element, 4 ”-N- (N-methyl-L-isoseramine amide) apramycin, 5-table-4” -N- (N-methyl-L-isoseramine amide) Apramycin, 5-deoxy-4 "-N- (N-methyl-L-isoseramine amide) apramycin, 6-deoxy-5-Table-4" -N- (N-methyl-L-isoseramine amide) apramycin, 3 "-deoxy-5-epi-4" -N- (N-methyl-L-isoseramine amide) A Pramycin, 4 "-N- (N-formamidino-L-isoseramine amide) Apramycin, 4" -N- (N-formamidyl-L-isoseramine amide) ) -5-epiapramycin, 4 "-N- (N-formamidino-L-isoseramine amide) -5-deoxyapuramycin, 4" -N- (N- (Formamidinyl-L-isoseramine amide) -6-deoxy-5-epipramycin, 5,6-dideoxy-4 "-N-glycamine prasamycin, 5,6-dideoxy-4 "-N-sarcosinyl apuramycin, 5,6-dideoxy-4" -N- (L-isoseramine acetyl) apuramycin , 5,6-dideoxy-4 ”-N- (N-methyl-L-isoseramine amide) apramycin, 5,3” -ditable-4 ”-N-glycamine Apuramycin, 5,3 "-ditable-4" -N-sarcosinyl prasamycin or 5,3 "-ditable-4" -N- (L-isoseramide Gap) (9) A pharmaceutical composition comprising the compound described in any one of (1) to (8) or a pharmaceutically acceptable salt or a solvent mixture thereof. (10) The pharmaceutical composition according to (9), which is used to prevent or treat an infectious disease. (11) The pharmaceutical composition according to (10), wherein the infectious diseases are sepsis, infective endocarditis, infectious diseases in the field of dermatology, infectious diseases in the field of surgery, infectious diseases in the field of orthopedics, respiratory infections, Urinary tract infections, intestinal infections, peritonitis, meningitis, infectious diseases in the field of ophthalmology or infectious diseases in the field of otolaryngology. (12) The pharmaceutical composition according to (10) or (11), wherein the infectious disease is xylene penicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, coliform bacteria, pneumoniae or green Caused by pus bacteria. (13) The compound as described in any one of (1) to (8) or a pharmaceutically acceptable salt or a vehicle thereof, which is used for therapy. (14) The compound as described in any one of (1) to (8) or a pharmaceutically acceptable salt or a vehicle thereof for use in the prevention or treatment of infectious diseases. (15) The use of the compound described in any one of (1) to (8) or a pharmaceutically acceptable salt or vehicle thereof for the purpose of preventing or treating infectious diseases Pharmacy. (16) A method for preventing or treating an infectious disease, which comprises administering a therapeutically effective amount of the compound described in any one of (1) to (8) or a pharmaceutically acceptable salt or vehicle thereof To animals. (17) An antibacterial agent comprising the compound described in any one of (1) to (8) or a pharmaceutically acceptable salt or a solvent mixture thereof.

The compound of the present invention, or a pharmaceutically acceptable salt or a solvent thereof is advantageous in that it has a broad antibacterial spectrum from Gram-positive bacteria to Gram-negative bacteria. In addition, it is advantageous in that it has antibacterial activity against multi-drug resistant Gram-positive bacteria and Gram-negative bacteria that cannot be dealt with by existing antibiotics. In particular, it is useful in preventing or treating severe infections caused by MRSA or multi-drug resistant Gram-negative bacteria.

Hereinafter, the compound of the present invention will be specifically described.

(Aminoglycoside antibiotic) The compound of the present invention is a compound represented by the above general formula (1) or a pharmaceutically acceptable salt or a solvent thereof.

The compounds of the present invention may exist in the form of salts. Examples of the salt include pharmaceutically acceptable non-toxic salts. Specific examples of such salts include hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide; such as sulfate, nitrate, phosphate, perchlorate, Inorganic acid salt of carbonate; such as acetate, trichloroacetate, trifluoroacetate, hydroxyacetate, lactate, citrate, tartrate, oxalate, benzoate, amygdalate, butyrate , Maleate, propionate, formate, malate carboxylate; such as spermine, aspartate, glutamate, amino acid salt; such as mesylate, Sulfonates of p-toluenesulfonate, etc., as preferred examples, inorganic acid salts such as sulfates can be cited.

The compound of the present invention may exist as a vehicle. Examples of preferred solvent compounds include hydrates and ethanolates.

(Manufacturing method of aminoglycoside antibiotic) The compound of the present invention can be manufactured according to the following methods A to G, but the manufacturing method of the compound of the present invention is not limited to these.

(Method A) Method A is a method of 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 as follows. In addition, Steps A1 to A3 follow the method described in US2013 / 0165395A1.

(Step A4) Step A4 is a step of deprotecting the amine group at the 4 "position of the compound represented by formula (A3) and then deprotecting it to produce a compound represented by general formula (A4). This step is This is achieved by reacting the compound represented by formula (A3) with the active esters of various amino acid protectors in the presence of a base, followed by deprotection.

Examples of the active ester used in this step include N-hydroxyamine-based, S-alkyl, and S-phenyl-based, and N-hydroxyamine-based N-hydroxysuccinimide esters are preferred. The base is preferably triethylamine. As for the reaction temperature, any reaction is carried out at 10 ° C to 40 ° C. The reaction time is 1 to 24 hours.

The benzyloxycarbonyl group can be removed by reacting it with hydrogen in the presence of a reducing catalyst and acid. Examples of the acid used include acetic acid, trifluoroacetic acid, and hydrochloric acid, and acetic acid is preferred. Examples of the contact reduction catalyst include palladium-carbon, palladium black, palladium hydroxide, and platinum oxide. Palladium-carbon is preferred. The solvent used is not particularly limited as long as it is irrelevant to the present reaction, and it is preferably methanol, ethanol, tetrahydrofuran, dioxane, or a mixed solvent of such organic solvents and water. The reaction temperature is 10 ° C to 40 ° C, and the reaction time is usually 1 to 24 hours. The cyclic carbamate can be removed by hydrolysis using 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) Method B is to introduce epimerization at the 5-position of the compound represented by formula (B1) obtained by freeing only the 5-position hydroxyl group of apramycin. Next, the compound of the formula (B4) obtained by deprotection of the hydroxyl group and the 4 ”-position amine group is acylated and then deprotected to produce the general formula (B5) The method of the compound is shown below.

(Step B1) Step B1 is to selectively introduce a benzyl protecting group to the 6-position, 2 "-position and 3" -position hydroxyl groups of the compound represented by formula (A2) to produce a compound represented by formula (B1) step. This step is achieved by reacting the compound of formula (A2) with benzyl chloride in the presence of a base.

Examples of the solvent used in this step include pyridine, N, N-dimethylformamide, dichloromethane, chloroform, and 1,2-dichloroethane. Pyridine is preferred. Examples of the base used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, and pyridine is preferred. Regarding the reaction temperature, it is carried out at 0 ° C to 30 ° C. The reaction time is 1 to 5 hours.

(Step B2) Step B2 is a step of introducing a mesylate group to the 5-position hydroxyl group of the compound represented by the formula (B1) to produce the compound represented by the formula (B2). This step is achieved by reacting the compound of formula (B1) with mesylate in the presence of a base.

Examples of the solvent used in this step include pyridine, dichloromethane, chloroform, and 1,2-dichloroethane. Dichloromethane is preferred. Examples of the base used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, and 4-dimethylaminopyridine is preferred. Regarding the reaction temperature, it is carried out at 0 ° C to 30 ° C. The reaction time is 1 to 2 hours.

(Step B3) Step B3 is a step of inverting the 5-position of the compound represented by formula (B2) to produce the compound represented by formula (B3). The reaction is achieved by the reaction of 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, etc., preferably N, N-dimethylformamide . The reaction temperature is 80 to 100 ° C. In terms of reaction time, it is carried out in 3 to 6 hours.

(Step B4) Step B4 is to remove the acetyl group, benzyl group, and 4 ", 6" position cyclic carbamate of the compound represented by formula (B3) to produce the formula (B4) Steps of the compound. This step is achieved by reacting the compound represented by formula (B3) with an equivalent amount of 6 to 8 bases.

Examples of the solvent used in this step include aqueous 1,4-dioxane, tetrahydrofuran, methanol, and mixed solvents thereof, and preferably aqueous 1,4-dioxane. Examples of the base used include potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide, and potassium hydroxide is preferred. Regarding the reaction temperature, it is carried out at 20 ° C to 40 ° C. The reaction time is 5 to 16 hours.

(Step B5) Step B5 is a step of deprotecting the amine group at the 4 "position of the compound represented by formula (B4) and then deprotecting it to produce a compound represented by general formula (B5). This step can be The same conditions as in step A4 described above are performed.

(C method) The C method is to iodide the 5-position of the compound represented by the formula (B2) to obtain 5-deoxygen, and then deprotect the hydroxyl group and the amine group at the 4 "position. The amine group at the 4 "position of the obtained compound represented by formula (C3) is acylated and then deprotected to produce a compound represented by general formula (C4). The method is shown below.

(Step C1) Step C1 is a step of producing the compound represented by the formula (C1) by iodinating the 5-position of the compound represented by the formula (B2). This step is achieved by reacting the compound represented by formula (B2) with sodium iodide.

Examples of the solvent used in this step include acetone, N, N-dimethylformamide, tetrahydrofuran, and dioxane. N, N-dimethylformamide is preferred. As for the reaction temperature, it is carried out at 60 ° C to 120 ° C, and the reaction time is 1 to 6 hours.

(Step C2) Step C2 is a step of reducing the iodine of the compound represented by the formula (C1) to produce the compound represented by the formula (C2). This step is achieved by reacting the compound represented by formula (C1) with tributyltin hydride in the presence of 2,2'-azobis (isobutyronitrile).

Examples of the solvent used in this step include toluene, tetrahydrofuran, and dioxane, and dioxane is preferred. Regarding the reaction temperature, it is performed at 60 ° C to 100 ° C. The reaction time is 3 to 8 hours.

(Step C3) Step C3 is to remove the acetyl, benzyl and cyclic amino formates at the 4 "and 6" positions of the compound represented by formula (C2) to produce the formula (C3) Steps of the compound. This step can be performed under the same conditions as the aforementioned step B4.

(Step C4) Step C4 is a step of deprotecting the amine group at the 4 "position of the compound represented by formula (C3) and then deprotecting it to produce a compound represented by general formula (C4). This step can be The same conditions as in step A4 described above are performed.

(Method D) Method D is obtained from the compound represented by the formula (B2) through a 6,6-dehydrated intermediate to obtain 6-deoxy-5-episome, followed by deprotection of the amine group at the 4 "position The amine group at the 4 "position of the compound represented by the formula (D4) is acylated and then deprotected to produce a compound represented by the general formula (D5). The method is shown below.

(Step D1) Step D1 is the step of removing the benzyl group of the compound represented by the formula (B2) and dehydrating (epoxidizing) the 5th and 6th positions to produce the compound represented by the formula (D1) . This step is achieved by reacting the compound represented by formula (B2) with a base.

Examples of solvents used for debenzylation and dehydration include methanol, ethanol, dichloromethane, chloroform, 1,2-dichloroethane, and the like, and chloroform is preferred. Examples of the base to be used include potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide and the like, preferably sodium methoxide. Regarding the reaction temperature, it is carried out at 0 ° C to 30 ° C. The reaction time is 1 to 5 hours.

(Step D2) Step D2 is a step of cracking the epoxide of the compound represented by formula (D1) to produce the compound represented by formula (D2). This step is achieved by reacting the compound represented by 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, and dioxane, and acetone is preferred. Examples of the acidic buffer used include 5% sodium acetate and acetic acid solutions. Regarding the reaction temperature, it is performed at 60 ° C to 100 ° C. The reaction time is 1 to 6 hours.

(Step D3) Step D3 is a step of reducing the iodine of the compound represented by formula (D2) to produce the compound represented by formula (D3). This step can be performed under the same conditions as the aforementioned step C2.

(Step D4) Step D4 is the step of removing the methoxycarbonyl group at the 4 "position of the compound represented by formula (D3) to produce the compound represented by formula (D4). This step can have the same conditions as the aforementioned step B4 Implementation.

(Step D5) Step D5 is a step of deprotecting the amine group at the 4 "position of the compound represented by formula (D4) and then deprotecting it to produce a compound represented by general formula (D5). This step can be The same conditions as in step A4 described above are performed.

(Method E) Method E is to deoxidize the 3 ”hydroxyl group of the compound represented by formula (E1) obtained by freeing only the 5 and 3” hydroxyl groups of apramycin, and then carry out the 5 position Table isomerization. Next, the compound represented by the formula (E7) obtained by deprotecting the hydroxyl group and the 4 ”-position amine group is acylated and then deprotected to produce the general formula (E8) The method of the compound is shown below.

(Step E1) Step E1 is a step of selectively introducing a benzyl protecting group to the 6-position and 2 "-position hydroxyl groups of the compound represented by formula (A2) to produce the compound represented by formula (E1). This step This is achieved by reacting the compound of formula (A2) with benzyl chloride in the presence of a base.

Examples of the solvent used in this step include pyridine, N, N-dimethylformamide, dichloromethane, chloroform, and 1,2-dichloroethane. Pyridine is preferred. Examples of the base used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, and pyridine is preferred. As far as the reaction temperature is concerned, it is carried out at -15 ° C to 0 ° C. The reaction time is 0.5 to 1 hour.

(Step E2) Step E2 is a step of introducing trifluoromethanesulfonyl group to the 3 "hydroxyl group of the compound represented by formula (E1) to produce the compound represented by formula (E2). This step is performed by In the presence, the compound of formula (E1) is reacted with trifluoromethanesulfonic anhydride to achieve it.

Examples of the solvent used in this step include pyridine, dichloromethane, chloroform, and 1,2-dichloroethane. Dichloromethane is preferred. Examples of the base used include triethylamine, pyridine, 4-dimethylaminopyridine and the like, and pyridine is preferred. As far as the reaction temperature is concerned, it is carried out at -10 ° C to 10 ° C. The reaction time is 1 to 2 hours.

(Step E3) Step E3 is a step for producing the compound represented by the formula (E3) by iodinating the 3 ”position of the compound represented by the formula (E2). This step is represented by the formula (E2) The compound is reacted with sodium iodide.

Examples of the solvent used in this step include acetone, N, N-dimethylformamide, tetrahydrofuran, and dioxane. N, N-dimethylformamide is preferred. As for the reaction temperature, it is carried out at 60 ° C to 100 ° C, and the reaction time is 1 to 6 hours.

(Step E4) Step E4 is a step of reducing the iodine of the compound represented by formula (E3) to produce the compound represented by formula (E4). This step is achieved by reacting the compound represented by formula (E3) with tributyltin hydride in the presence of 2,2'-azobis (isobutyronitrile).

Examples of the solvent used in this step include toluene, tetrahydrofuran, and dioxane, and dioxane is preferred. Regarding the reaction temperature, it is performed at 60 ° C to 100 ° C. The reaction time is 3 to 8 hours.

(Step E5) Step E5 is a step of introducing a mesylate group to the 5-position hydroxyl group of the compound represented by formula (E4) to produce a compound represented by formula (E5). This step can be performed under the same conditions as the aforementioned step B2.

(Step E6) Step E6 is a step of inverting the 5-position of the compound represented by formula (E5) to produce the compound represented by formula (E6). The reaction is achieved by the reaction of the compound represented by formula (E5) with cesium acetate or sodium acetate. This step can be performed under the same conditions as the aforementioned step B3.

(Step E7) Step E7 is to remove the acetyl group, benzyl group and the 4 ", 6" position cyclic carbamate of the compound represented by formula (E6) to produce the formula (E7) Steps of the compound. This step can be performed under the same conditions as the aforementioned step B4.

(Step E8) Step E8 is a step of deprotecting the amine group at the 4 "position of the compound represented by formula (E7) and then deprotecting it to produce a compound represented by general formula (E8). This step can be The same conditions as in step A4 described above are performed.

(Method F) Method F involves N-Boc-L-isoseramine acylation of the amine group at the 4 "position of the compound represented by general formula (F). After de-boc, N-methylation and de- The method of protecting and producing the compound represented by the general formula (F5) is shown below.

(Step F1) Step F1 is to compound N-Boc-L-isoseramine amine group at the 4 "position of the compound represented by the general formula (F) to produce the compound represented by the general formula (F1) This step is achieved by reacting the compound represented by general formula (F) with the active ester of N-Boc-L-isoserine in the presence of a base.

Examples of the active ester used in this step include N-hydroxyamine-based, S-alkyl, and S-phenyl-based, and N-hydroxyamine-based N-hydroxysuccinimide esters are preferred. The base is preferably triethylamine. As for the reaction temperature, any reaction is carried out at 10 ° C to 40 ° C. The reaction time is 1 to 24 hours.

(Step F2) Step F2 is a step of removing the third butoxycarbonyl (Boc) group of the compound represented by the general formula (F1) to produce the compound represented by the general formula (F2). 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, dichloromethane, acetonitrile, acetone, and methanol, and methanol is preferred. Examples of the acid used include p-toluenesulfonic acid, methanesulfonic acid, acetic acid, and trifluoroacetic acid, and trifluoroacetic acid is preferred. The reaction temperature is usually from 0 ° C to 50 ° C. The reaction time is 1 to 5 hours.

(Step F3) Step F3 is a step of introducing a benzyl group to the amine group of the L-isoseramine amide group of the compound represented by the general formula (F2) to produce the compound represented by the general formula (F3). 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 mixed solvents thereof, preferably methanol. Regarding the reaction temperature, it is carried out at 10 ° C to 40 ° C. The reaction time is 1 to 2 hours.

(Step F4) Step F4 is a step of producing a compound represented by the general formula (F4) by methylating the benzylated amine group of the compound represented by the general formula (F3). This step is achieved by reacting formaldehyde in the presence of an acid with a compound represented by general formula (F3) and a reducing agent.

Examples of the solvent used in this step include tetrahydrofuran, dioxane, methanol, and mixed solvents of these. Examples of the reducing agent include sodium cyanoborohydride or borane-2-methylpyridine complex.

(Step F5) Step F5 is a step of deprotecting the compound represented by the general formula (F4) to produce the compound represented by the general formula (F5). This step can be carried out under the same conditions as the deprotection in step A4.

(Method G) Method G is a method for producing a compound represented by the general formula (G) by subjecting the free amine group of the compound represented by the general formula (F2) to amidinoylation and then performing deprotection. The steps are shown below.

(Step G) Step G is a step of producing a compound represented by the general formula (G) by subjecting the free amine group of the compound represented by the general formula (F2) to amidinoylation and then performing deprotection. Formamylation is achieved by reacting a compound represented by general formula (F2) with a formamylating reagent in the presence of a base, and deprotection can be performed under the same conditions as the deprotection in steps F2 and A4 described above .

Examples of the formamylating agent used in this step include 1,3-bis (third butoxycarbonyl) -2- (trifluoromethanesulfonyl) guanidine (Goodman reagent) and N, N′-di- (Third-butoxycarbonyl) thiourea, third-butyl- (Z)-((((third-butoxycarbonyl) imino) (1H-pyrazol-1-yl) methyl) aminocarbamate Etc., preferably Goodman reagent, and the base is preferably triethylamine. Any reaction is carried out at 10 ° C to 90 ° C in terms of reaction temperature. The reaction time is 1 to 24 hours.

(Method H) Method H is to convert the epoxide of the compound represented by formula (D1) into an olefin, and then to obtain the compound represented by formula (H4) obtained by deprotecting the hydroxyl group and the amine group at the 4 ”position After the amine group at the 4 "position is subjected to acylation, a method for producing a compound represented by the general formula (H5) is performed by performing deprotection and olefin reduction. The method is shown below.

(Step H1) Step H1 is a step of producing a compound represented by the formula (H1) by introducing a benzyl protecting group to the hydroxyl group at the 2 ", 3" and 6 "positions of the compound represented by the formula (D1). This step can be performed under the same conditions as the aforementioned step B1.

(Step H2) Step H2 is a step of cracking the epoxide of the compound represented by formula (H1) to produce the compound represented by formula (H2). This step can be performed under the same conditions as the aforementioned step D2.

(Step H3) Step H3 is a step of producing a compound represented by the formula (H3) by detaching the 5-position hydroxyl group of the compound represented by the formula (H2) after benzylsulfonylation and adding water. This step is achieved by reacting the compound of formula (H2) with benzylsulfonyl chloride in the presence of an alkaline solvent and adding water.

Examples of the basic solvent used for benzylation include pyridine, picolines, and lutidines, and pyridine is preferred. Regarding the reaction temperature, it is carried out at 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) Step H4 is the step of removing the benzyl acetyl group and the methoxycarbonyl group at the 4 "position of the compound represented by formula (H3) to produce the compound represented by formula (H4). The same conditions apply.

(Step H5) Step H5 is a step of deprotecting the amine group at the 4 "position of the compound represented by formula (H4) and then deprotecting it to produce a compound represented by general formula (H5). This step can be The same conditions as in step A4 described above are performed.

(Method I) The method I is to introduce a release group to the 5-position hydroxyl group of the 3 "-O-trifluoromethanesulfonate body represented by the formula (E2), and then perform isomerization of 5,3" -biepi. Next, the compound of formula (I3) obtained by deprotection of the hydroxyl group and the 4 ”-position amine group is acylated and then deprotected to produce the general formula (I4) The method of the compound is shown below.

(Step I1) Step I1 is a step of introducing a mesylate group to the 5-position hydroxyl group of the compound represented by formula (E2) to produce the compound represented by formula (I1). This step can be performed under the same conditions as the aforementioned step B2.

(Step I2) Step I2 is a step for producing the compound represented by formula (I2) by inverting the 5-position and 3 ”position of the compound represented by formula (I1). The reaction is by formula (I1) This is achieved by the reaction of the compound shown with cesium acetate or sodium acetate. This step can be carried out under the same conditions as the above step B3.

(Step I3) Step I3 is to remove the acetyl, benzyl and cyclic amino formates at the 4 "and 6" positions of the compound represented by formula (I2) to produce the formula (I3) Steps of the compound. This step can be performed under the same conditions as the aforementioned step B4.

(Step I4) Step I4 is a step of deprotecting the amine group at the 4 "position of the compound represented by formula (I3) and then deprotecting it to produce a compound represented by general formula (I4). This step can be The same conditions as in step A4 described above are performed.

The compound of the present invention and the above-mentioned compound obtained in the production process can be purified and isolated by ordinary purification operations. As the purification and separation method, for example, a liquid separation method, a distillation method, a sublimation method, a precipitation method, a crystallization method, a silica gel column chromatography method using a silica gel as a filler in a normal or reverse phase, and using Amberlite CG- 50. Dowex 50WX2 or CM-Sephadex C-25 plasma exchange resin column chromatography, column chromatography using cellulose, etc., prepared thin layer chromatography or high-speed liquid chromatography, etc. In addition, the compound obtained in the above-mentioned manufacturing step can also be suitably used in the subsequent step without performing single ion purification.

(Use of aminoglycoside antibiotics) The compound of the present invention or a pharmaceutically acceptable salt or a solvent thereof has a broad antibacterial spectrum from Gram-positive bacteria to Gram-negative bacteria among pathogenic bacteria. In addition, the compound of the present invention or a pharmaceutically acceptable salt or a vehicle thereof has excellent antibacterial activity against the causative bacteria of infections (MRSA, Staphylococcus aureus, Escherichia coli, pneumoniae, Pseudomonas aeruginosa, etc.) , Can be used as antibacterial agent.

Therefore, according to other aspects of the present invention, an antibacterial agent is provided, which comprises the compound of the present invention. Furthermore, according to another aspect of the present invention, it provides the use of the compound of the present invention or a pharmaceutically acceptable salt or a solvent thereof, which is used to manufacture an antibacterial agent.

The compound of the present invention or a pharmaceutically acceptable salt or a vehicle thereof as described above can be advantageously used as an antibacterial agent or medicine 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 infectious disease, which comprises administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or vehicle thereof to Made of human animals. The infectious diseases to be treated are preferably bacterial infectious diseases, and examples thereof include sepsis, infective endocarditis, infectious diseases in the field of dermatology, surgical infectious diseases, infectious diseases in the field of plastic surgery, respiratory infections, and urinary tract Infections, intestinal infections, peritonitis, meningitis, infectious diseases in the ophthalmological field, or infectious diseases in the otolaryngological field, preferably include skin suppurative diseases, heat wounds / surgical wound infections, pneumonia, intrabronchial infections, tuberculosis, kidney and Bangladesh Nephritis, enteritis (including food poisoning), conjunctivitis, or otitis media. Here, the animal targeted for prevention or treatment is preferably a mammal, and more preferably a human. In addition, the administration amount of the compound of the present invention or a pharmaceutically acceptable salt or a solvent thereof depends on the application method, the type of pathogenic bacteria, the patient's age, sex, weight, and severity of the disease. It is appropriate to decide that in the case of oral administration to humans, for example, each adult can administer within the range of 0.1 to 1000 mg / kg per day, and in the case of intravenous administration, the same can be within 0.01 to Administration within 100 mg / kg.

According to still another aspect of the present invention, the following invention is provided. (1) The compound of the present invention or a pharmaceutically acceptable salt or vehicle thereof is used for therapy. (2) The compound of the present invention, or a pharmaceutically acceptable salt or a vehicle thereof, is used for the prevention or treatment of an infectious disease. (3) The use of the compound of the present invention or a pharmaceutically acceptable salt or a vehicle thereof for the manufacture of a medicament for the prevention or treatment of an infectious disease. (4) The use of the compound of the present invention or a pharmaceutically acceptable salt or vehicle thereof is used for the prevention or treatment of infectious diseases.

The compound of the present invention or a pharmaceutically acceptable salt or a solvent thereof has antibacterial activity against multi-drug resistant Gram-positive bacteria and Gram-negative bacteria that existing antibiotics cannot cope with. In particular, the compound of the present invention or a pharmaceutically acceptable salt or a vehicle thereof is useful for preventing or treating severe infections caused by MRSA or multi-drug resistant Gram-negative bacteria.

The compound of the present invention or its pharmaceutically acceptable salt or its vehicle can be administered to animals in the form of a pharmaceutical composition containing pharmaceutically acceptable additives as desired. Therefore, according to another aspect of the present invention, a composition is provided, especially a pharmaceutical composition, which comprises the compound of the present invention or a pharmaceutically acceptable salt or a solvent thereof.

The pharmaceutical composition of the present invention can be administered orally or parenterally (for example, intravenous injection, intramuscular injection, subcutaneous administration, rectal administration, transdermal administration, topical ophthalmic administration, etc., depending on the type of pathogen or disease, the nature of the patient, etc.) Any of the administration routes), to all mammals including humans. Therefore, the pharmaceutical composition of the present invention can be prepared into an appropriate preparation form according to the route of administration, and as such preparation, it can be adjusted into, for example, injections, capsules, lozenges, and granules mainly used for intravenous injection, intramuscular injection, etc , Powders, pills, fine granules, syrups, oral tablets such as lozenges, ointments, eye drops, ear drops, nose drops, eye ointments, skin and mucous membrane absorbers, skin preparations, inhalation Non-oral administration of external preparations, other dry powders or atomized aerosol prescriptions, such as preparations and suppositories, is in any form of preparation.

The above formulations can use excipients, extenders, binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersants, buffers, preservatives, dissolution aids, preservatives, flavoring and deodorant , Painless agents, stabilizers and other additives are manufactured according to the usual method. Specific examples of the non-toxic additives that can be used include injections, eye drops, ear drops, and nose drops. A dissolving agent or a dissolution aid (injection for injection) that can constitute an aqueous or time-dissolving dosage form can be cited. Distilled water, 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: sodium citrate, etc .; organic alkali Sex salts: L-ionine, L-arginine, etc.), isotonicity agents (sodium chloride, glucose, glycerin, etc.), buffers (sodium chloride, benzalkonium chloride), lemon Sodium, 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, etc.) etc. In addition, eye ointments, skin and mucous membrane absorbers, and skin preparations can be suitably formulated as ointments, creams, and adhesives (white petrolatum, polyethylene glycol, glycerin, flowing paraffin, cotton cloth, etc.) ). In addition, the liquid inhalant includes pH adjusters (sodium citrate, sodium hydroxide, etc.), isotonic agents (sodium chloride, benzalkonium chloride, sodium citrate, etc.), and buffers ( Sodium chloride, benzalkonium chloride, sodium citrate, etc.), for powder inhalers, lactose and the like as a carrier can be cited. In addition, for oral administration and suppositories, excipients (lactose, D-mannitol, corn starch, crystalline cellulose, etc.), disintegrating agents (carboxymethyl cellulose, carboxymethyl cellulose Calcium, etc.), binders (hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, etc.), lubricants (magnesium stearate, talc, etc.), coating agents (shellac, hypromellose) Methyl cellulose, sugar, titanium oxide, etc.), plasticizers (glycerin, polyethylene glycol, etc.), bases (cocoa butter, polyethylene glycol, hard fat, etc.), etc.

In addition, the pharmaceutical composition of the present invention may contain, in addition to the compound of the present invention, one or more clinically useful antibacterial agents (e.g. β- Endoamide antibacterial agent (carbapenems, cephalosporin, cephamycin, penicillin), glycopeptide antibacterial agent, ansamycin (ansamycin) ) Series antibacterial agent, aminoglycoside antibacterial agent, quinolinone antibacterial agent, monobactam antibacterial agent, macrolide antibacterial agent, tetracycline antibacterial agent Antibacterial agent, chloramphenicol antibacterial agent, lincomycin antibacterial agent, streptogramin antibacterial agent, oxazolidinone antibacterial agent, frostromycin (fosfomycin), novobiocin (novobiocin), cycloserine (cycloserine), moenomycin (moenomycin, etc.), or may be administered to the organism together with the antibacterial agent. In addition, the pharmaceutical composition of the present invention may contain an efflux pump inhibitor or an existing agent in consideration of expanding or enhancing the effectiveness of resistant bacteria against Gram-negative bacteria and existing antibacterial agents Antibacterial agents decompose enzymes (β-lactamase, etc.) inhibitors, etc., or may be administered to living organisms together with these inhibitors, etc. Furthermore, the pharmaceutical composition of the present invention may be used in combination with a compound that does not possess antibacterial activity (for example, a drug used to treat complications, etc.), considering the effect of improving the treatment or prevention of infectious diseases. This aspect is also included in the present invention. [Example]

The present invention will be described in detail using examples, but the present invention is not limited to these examples.

<Example 1: Synthesis of 4 "-N- (N-formamidinoglycinyl) apuramycin (A4-a)>

Dissolve 200 mg (0.21 mmol) of the compound represented by formula (A3) in 2 ml of DMF, add 0.16 ml of triethylamine and N- (N, N′-bis (benzyloxycarbonyl)) formamidineglycine 150 mg of N-hydroxysuccinimide ester was allowed to react at room temperature for 2 hours. After the reaction was completed, it was concentrated under reduced pressure and the residue was dissolved in 1-butanol and washed with water. The organic layer was concentrated under reduced pressure, and the obtained solid was dissolved in 5.4 ml of 80% 1,4-dioxane aqueous solution, 0.5 ml of acetic acid and palladium black were added thereto, and contact reduction was carried out in a hydrogen environment at room temperature. 10 hours. After the reaction was completed, it was concentrated under reduced pressure. 1 ml of 1M potassium hydroxide aqueous solution was added to the residue, and it was made to react at room temperature for 4 hours. After the reaction was completed, 1M hydrochloric acid was added for neutralization, and purification was performed by ion exchange chromatography (CG-50) to obtain 101 mg (75%) of the title compound (A4-a).

MS (ESI) m / z: 639 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.45 (1H, q, J = 12 Hz, H-2ax) , 1.93 (1H, q, J = 12 Hz, H-3'ax), 2.23 (1H, dt, H-3'eq), 2.37 (1H, dt, H-2eq), 2.63 (3H, s, NCH ₃ ), 4.55 (1H, t, J = 2,8 Hz, H-7 '), 5.15 (1H, d, J = 8.5 Hz, H-8'), 5.39 (1H, d, J = 3.5 Hz, H-1 ') and 5.64 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 2: Synthesis of 4 "-N- (N-formamidinosarcosinyl) apuramycin (A4-b)>

Using 200 mg (0.21 mmol) of the compound represented by formula (A3) and N-hydroxysuccinimide ester 155 mg of N- (N, N′-bis (benzyloxycarbonyl)) formamidine sarcosinic acid, by and The treatment was carried out in the same manner as in Example 1 to obtain 94.6 mg (69%) of the title compound (A4-b).

MS (ESI) m / z: 653 (M + 1) ⁺ ; ¹ H NMR (DCl salt, in D ₂ O, 500 MHz): δ1.85 (1H, q, J = 13 Hz, H-2ax), 2.01 (1H, q, J = 13 Hz, H-3'ax), 2.35 (1H, dt, H-3'eq), 2.47 (1H, dt, H-2eq), 2.78 (3H, s, NCH ₃ ), 3.07 (3H, s, NCH ₃ ), 4.56 (1H, t, J = 2.3 Hz, H-7 '), 5.19 (1H, d, J = 8.5 Hz, H-8'), 5.47 (1H, d, J = 4.0 Hz, H-1 ') and 5.70 (1H, d, J = 3.5 Hz, H-1 ”).

<Example 3: Synthesis of 4 "-N- (N-ethylglycinyl) apuramycin (A4-c)>

Using 200 mg (0.21 mmol) of the compound represented by formula (A3) and 60 mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) ethylglycine, it was treated in the same manner as in Example 1. 106 mg (81%) of the title compound (A4-c) was obtained.

MS (ESI) m / z: 625 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.33 (3H, t, J = 7.3 Hz, NCH ₂ CH ₃ ), 1.45 (1H, q, J = 13 Hz, H-2ax), 1.90 (1H, q, J = 12 Hz, H-3'ax), 2.22 (1H, dt, H-3'eq), 2.37 (1H, dt, H-2eq), 2.63 (3H, s, NCH ₃ ), 2.83 (2H, q, N CH ₂ CH ₃ ), 3.57 (2H, ABq, CH ₂ (ethylglycinyl)) , 4.54 (1H, t, J = 2.5 Hz, H-7 '), 5.15 (1H, d, J = 8.5 Hz, H-8'), 5.38 (1H, d, J = 3.5 Hz, H-1 ' ) and 5.63 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 4: 6,2 ", 3"-tri-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl- 4 ”-N, 6” -O-carbonyl apramycin (B1), 6,2 ”, 3” -tri-O-benzyl-1,3,2′-para-N- (benzyloxy Carbonyl) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-5-O-methanesulfonyl apramycin (B2), 5-O-acetamide Yl-6,2 ”, 3” -tri-O-benzyl-1,3,2′-para-N- (benzyloxycarbonyl) -7′-N, 6′-O-carbonyl-4 ”- N, 6 "-O-carbonyl-5-epiapramycin (B3), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl- Synthesis of 5-epiapramycin (B4) and 4 ”-N- (N-formamidinoglycinyl) -5-epiapramycin (B5-a) ＞

<Example 4- (i): 6,2 ", 3"-tri-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'- Synthesis of O-carbonyl-4 "-N, 6" -O-carbonyl apuramycin (B1)> To a compound of formula (A2) 20.0g (20mmol) of pyridine in 100ml solution was added benzil under ice cooling Chlorine 12.5 ml (5.4 eq.) Was reacted under ice cooling for 2 hours. After the reaction was completed, water was added and concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed sequentially with 5% aq. KHSO ₄ , 5% aq. NaHCO ₃ , and brine, dried over Na ₂ SO ₄ , and concentrated under reduced pressure to obtain 25.2 g of the title compound (B1) as a pale yellow solid. (95%).

MS (ESI) m / z: 1328 (M + Na) ⁺ .

<Example 4- (ii): 6,2 ", 3" -tri-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'- Synthesis of O-carbonyl-4 ”-N, 6” -O-carbonyl-5-O-methanesulfonyl apramycin (B2)> For the title compound (B1) 22.4 of Example 4- (i) A 110 ml solution of g (17 mmol) in chloroform was added under ice-cooling 6.22 g (3 eq.) of 4-dimethylaminopyridine and 2.0 ml (1.5 eq.) of mesylate chloride, and the reaction was carried out at room temperature for 2 hours. The reaction solution was washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated sodium bicarbonate water and water in this order, and then concentrated under reduced pressure to obtain 23.1 g (98%) of the title compound (B2) as a pale yellow solid.

MS (ESI) m / z: 1406 (M + Na) ⁺ .

<Example 4- (iii): 5-O-ethoxy-6,2 ", 3"-tri-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl)- Synthesis of 7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-5-epirubicin (B3)> For the title compound of Example 4- (ii) ( B2) A solution of 6.91 g (5.0 mmol) of DMF in 35 ml was added with 3.60 g of cesium acetate, and the reaction was carried out 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 development system (CHCl ₃ : MeOH = 30: 1) to obtain 5.75 g (85%) of the title compound (B3).

MS (ESI) m / z: 1370 (M + Na) ⁺ .

<Example 4- (iv): 1,3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-epirubicin (B4) Synthesis> To a solution of 4.00 g (3.0 mmol) of 1,4-dioxane in 40 ml of the title compound (B3) of Example 4- (iii) was added 10 ml of 2M potassium hydroxide aqueous solution, and the reaction was carried out for 16 hours. After adding dry ice to the reaction solution, it was concentrated under reduced pressure and the obtained residue 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).

MS (ESI) m / z: 990 (M + Na) ⁺ .

<Example 4- (v): Synthesis of 4 "-N- (N-formamidinoglycinyl) -5-epiapramycin (B5-a)> Use example 4- (iv) The title compound (B4) 198mg (0.20mmol) and (N- (N, N'-bis (benzyloxycarbonyl)) formamidinoglycine acid N-hydroxysuccinimide ester 150mg, and the examples 1 The same method was used to obtain 83.2 mg (65%) of the title compound (B5-a).

MS (ESI) m / z: 639 (M + 1) ⁺ ; ¹ H NMR (DCl salt, in D ₂ O, 500 MHz): δ1.75 (1H, q, J = 13 Hz, H-2ax), 2.05 (1H, q, J = 12 Hz, H-3'ax), 2.38 (1H, dt, H-3'eq), 2.45 (1H, dt, H-2eq), 2.77 (3H, s, NCH ₃ ), 4.48 (1H, t, J = 2.5 Hz, H-5), 4.57 (1H, t, J = 2.3 Hz, H-7 '), 5.20 (1H, t, J = 8.5 Hz, H-8' ), 5.40 (1H, d, J = 4.0 Hz, H-1 ') and 5.47 (1H, d, J = 3.5 Hz, H-1 ”).

<Example 5: Synthesis of 5-Table-4 "-N- (N-ethylglycinyl) apuramycin (B5-b)>

Using the title compound (B4) of Example 4- (iv) 198 mg (0.20 mmol) and N- (benzyloxycarbonyl) ethylglycine of N-hydroxysuccinimide ester 60 mg, the same as in Example 1 The method was processed to obtain 102 mg (82%) of the title compound (B5-b).

MS (ESI) m / z: 625 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.35 (3H, t, J = 7.3 Hz, NCH ₂ CH ₃ ), 1.36 (1H, q, J = 13 Hz, H-2ax), 1.99 (1H, q, J = 12 Hz, H-3'ax), 2.26 (1H, dt, H-3'eq), 2.39 (1H, dt, H-2eq), 2.63 (3H, s, NCH ₃ ), 2.85 (2H, q, N CH ₂ CH ₃ ), 3.59 (2H, ABq, CH ₂ (ethylglycinyl)) , 4.51 (1H, t, J = 2.5 Hz, H-5), 4.61 (1H, t, J = 2.5 Hz, H-6 '), 5.17 (1H, d, J = 8.5 Hz, H-8') , 5.25 (1H, d, J = 3.5 Hz, H-1 ') and 5.66 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 6: 6,2 ", 3"-tri-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl- 4 "-N, 6" -O-carbonyl-5-deoxy-5-epi-5-iodoapramycin (C1), 6,2 ", 3" -tri-O-benzyl-1 , 3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-5-deoxyapuramycin ( C2), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-deoxyapuramycin (C3) and 5-deoxy- Synthesis of 4 "-N-Glycine Apramycin (C4-a) ＞

<Example 6- (i): 6,2 ", 3" -tri-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'- Synthesis of O-carbonyl-4 "-N, 6" -O-carbonyl-5-deoxy-5-epi-5-iodoapramycin (C1)> against the title compound of Example 4- (ii) (B2) A solution of 6.91 g (5.0 mmol) of DMF in 35 ml was added with 5.50 g of sodium iodide and reacted at 90 ° C for 6 hours. After ethyl acetate was added to the reaction solution and 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.

MS (ESI) m / z: 1438 (M + Na) ⁺ .

<Example 6- (ii): 6,2 ", 3"-tri-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'- Synthesis of O-carbonyl-4 "-N, 6" -O-carbonyl-5-deoxyapuramycin (C2)> The title compound (C1) of Example 6- (i) 6.00 g (4.2 mmol) ) Dissolve in 15ml of 1,4-dioxane, add 64mg of 2,2'-azobis (isobutyronitrile) (AIBN) and 3.0ml of tributyltin hydride to it at 80 ℃ under N ₂ It was reacted for 4 hours. The reaction solution was concentrated under reduced pressure, the residue was washed with diethyl ether, and then dried under reduced pressure to obtain 4.72 g (87%) of the title compound (C2) as a colorless solid.

MS (ESI) m / z: 1312 (M + Na) ⁺ .

<Example 6- (iii): 1,3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-deoxyapuramycin (C3) Synthesis> Using the title compound (C2) 4.00 g (3.1 mmol) in Example 6- (ii) in 40 ml of a solution of 1,4-dioxane and 10 ml of 2M potassium hydroxide aqueous solution. ) The same method was used to obtain 2.39 g (81%) of the title compound (C3).

MS (ESI) m / z: 974 (M + Na) ⁺ .

<Example 6- (iv): Synthesis of 5-deoxy-4 "-N-glycine apramycin (C4-a)> Use the title compound (C3) of Example 6- (iii) 170mg (0.18mmol) and 79.4mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) glycine, were treated in the same manner as in Example 1 to obtain 82.5mg of the title compound (C4-a) (80%).

MS (ESI) m / z: 581 (M + Na) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.40 (1H, q, J = 13 Hz, H-2ax) , 1.58 (1H, q, J = 12 Hz, H-5ax), 1.93 (1H, q, J = 12 Hz, H-3'ax), 2.24 (1H, dt, H-3'eq), 2.39 ( 1H, dt, H-2eq), 2.63 (1H, dt, H-5eq), 2.64 (3H, s, NCH ₃ ), 3.62 (2H, s, CH ₂ (glycamine)), 4.60 (1H, t, J = 2.5 Hz, H-6 '), 5.17 (1H, d, J = 8.5 Hz, H-8'), 5.22 (1H, d, J = 3.5 Hz, H-1 ') and 5.64 (1H , d, J = 4.0 Hz, H-1 ”).

<Example 7: Synthesis of 5-deoxy-4 "-N-sarcosinyl apuramycin (C4-b)>

Using the title compound (C3) of Example 6 (iii) 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) sarcosinic acid N-hydroxysuccinimide ester 81.5 mg, the same as in Example 1 The method was processed to obtain 76.6 mg (72%) of the title compound (C4-b).

MS (ESI) m / z: 595 (M + Na) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.40 (1H, q, J = 13 Hz, H-2ax) , 1.58 (1H, q, J = 12 Hz, H-5ax), 1.94 (1H, q, J = 12 Hz, H-3'ax), 2.24 (1H, dt, H-3'eq), 2.37 ( 1H, dt, H-2eq), 2.60 (3H, s, NCH ₃ ), 2.60 (1H, dt, H-5eq), 2.64 (3H, s, NCH ₃ ), 3.56 (2H, ABq, CH ₂ (muscle Amide)), 4.60 (1H, t, J = 2.5 Hz, H-6 '), 5.17 (1H, d, J = 8.5 Hz, H-8'), 5,22 (1H, d, J = 3.5 Hz, H-1 ') and 5.65 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 8: Synthesis of 5-deoxy-4 "-N- (N-ethylglycinyl) apuramycin (C4-c)>

Using the title compound (C3) of Example 6- (iii) 170mg (0.18mmol) and N- (benzyloxycarbonyl) -N-ethylglycine acid N-hydroxysuccinimide ester 83.4mg, by It was processed in the same manner as in Example 1 to obtain 78.4 mg (72%) of the title compound (C4-c).

MS (ESI) m / z: 609 (M + Na) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.35 (3H, t, J = 7.3 Hz, NCH ₂ CH ₃ ), 1.40 (1H, q, J = 13 Hz, H-2ax), 1.58 (1H, q, J = 12 Hz, H-5ax), 1.94 (1H, q, J = 12 Hz, H-3'ax ), 2.24 (1H, dt, H-3'eq), 2.37 (1H, dt, H-2eq), 2.60 (3H, s, NCH ₃ ), 2.64 (1H, dt, H-5eq), 2.65 (3H , s, NCH ₃ ), 2.86 (2H, q, N CH ₂ CH ₃ ), 3.59 (2H, ABq, CH ₂ (ethylglycinyl)), 4.60 (1H, t, J = 2.5 Hz, H -6 '), 5.17 (1H, d, J = 8.5 Hz, H-8'), 5.22 (1H, d, J = 3.5 Hz, H-1 ') and 5.65 (1H, d, J = 4.0 Hz, H-1 ").

<Example 9: Synthesis of 4 "-N- (β-propylamino acetyl) -5-deoxyapuramycin (C4-d)>

Using the title compound (C3) 170 mg (0.18 mmol) of Example 6- (iii) and N-hydroxysuccinimide ester 80.8 mg of N- (benzyloxycarbonyl) -β-alanine, by using Example 1 The same method was used to obtain 82.2 mg (78%) of the title compound (C4-d).

MS (ESI) m / z: 595 (M + Na) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.40 (1H, q, J = 13 Hz, H-2ax) , 1.58 (1H, q, J = 12 Hz, H-5ax), 1.94 (1H, q, J = 12 Hz, H-3'ax), 2.25 (1H, dt, H-3'eq), 2.39 ( 1H, dt, H-2eq), 2.64 (1H, dt, H-5eq), 2.65 (3H, s, NCH ₃ ), 2.70 (2H, t, J = 10 Hz, CH ₂ (β-propylamine) ), 3.15 (2H, t, CH ₂ (β-propylamine)), 4.60 (1H, t, J = 2.5 Hz, H-6 '), 5.17 (1H, d, J = 8.5 Hz, H-8 '), 5.23 (1H, d, J = 3,5 Hz, H-1') and 5.65 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 10: Synthesis of 5-deoxy-4 "-N- (L-isoseramine amide) apramycin (C4-e)>

Using the title compound (C3) of Example 6- (iii) 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) -L-isoserine N-hydroxysuccinimide ester 82.6 mg, by and Example 1 was processed in the same manner to obtain 80.8 mg (74%) of the title compound (C4-e).

MS (ESI) m / z: 611 (M + Na) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.39 (1H, q, J = 13 Hz, H-2ax) , 1.57 (1H, q, J = 12 Hz, H-5ax), 1,92 (1H, q, J = 12 Hz, H-3'ax), 2.23 (1H, dt, H-3'eq), 2.35 (1H, dt, H-2eq), 2.61 (1H, dt, H-5eq), 2.62 (3H, s, NCH ₃ ), 3.08 (1H, dd, CH ₂ (isoseramide)), 3.33 (1H, dd, CH ₂ (isoseramide)), 4.43 (1H, t, CH (isoseramine)), 4.60 (1H, t, J = 2.5 Hz, H-6 '), 5.15 (1H, d, J = 8.5 Hz, H-8 '), 5.21 (1H, d, J = 3.5 Hz, H-1') and 5.63 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 11: Synthesis of 4 "-N- (N-formamidinoglycinyl) -5-deoxyapuramycin (C4-f)>

Using the title compound (C3) 170 mg (0.18 mmol) of Example 6- (iii) and N-hydroxysuccinimide ester of N- (N, N′-bis (benzyloxycarbonyl)) formamidineglycine 125 mg, and treated in the same manner as in Example 1 to obtain 83.3 mg (75%) of the title compound (C4-f).

MS (ESI) m / z: 623 (M + Na) ⁺ ; ¹ H NMR (DCl salt, in D ₂ O, 500 MHz): δ1.46 (1H, q, J = 13 Hz, H-2ax), 1.76 (1H, q, J = 12 Hz, H-5ax), 2.00 (1H, q, J = 12 Hz, H-3'ax), 2.36 (1H, dt, H-3'eq), 2.46 (1H , dt, H-2eq), 2.67 (1H, dt, H-5eq), 2.78 (3H, s, NCH ₃ ), 4.00 (2H, s, CH ₂ (N-formamidinoglycinamide)), 4.56 (1H, t, J = 2.5 Hz, H-6 '), 5.19 (1H, d, J = 8.5 Hz, H-8'), 5.36 (1H, d, J = 3.5 Hz, H-1 ') and 5.44 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 12: 5,6-anhydro-1,3,2'-shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-Table-4 "-N-A Oxycarbonyl Apramycin (D1), 1,3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5,6-di Table-6-Iodine-4 ”-N-methoxycarbonylapuramycin (D2), 1,3,2′-para-N- (benzyloxycarbonyl) -7′-N, 6′-O- Carbonyl-6-deoxy-5-table-4 "-N-methoxycarbonylapuramycin (D3), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5-epirubicin (D4) and 4 "-N- (N-formamidinoglycinamide) -6-deoxy-5-epicarbine Synthesis of pramycin (D5-a) ＞

<Example 12- (i): 5,6-anhydro-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-Table-4 " -Synthesis of N-methoxycarbonylapuramycin (D1)> To the solution of the title compound (B2) of Example 4- (ii) 3.75 g (2.7 mmol) in 20 ml of methanol, 5 N NaOMe-methanol solution 2.7 ml was added The reaction was allowed to proceed for 1 hour at room temperature. After the reaction was completed, 1N HCl was added to the reaction solution under ice-cooling to neutralize it, followed by concentration under reduced pressure. After the residue was washed sequentially with water and isopropyl ether It was dried under reduced pressure to obtain 2.67 g (98%) of the title compound (D1) as a white solid.

MS (ESI) m / z: 1030 (M + Na) ⁺ .

<Example 12- (ii): 1,3,2'-gin-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5,6-ditable- Synthesis of 6-iodine-4 ”-N-methoxycarbonylapuramycin (D2)> Dissolve 2.52 g (2.5 mmol) of the title compound (D1) of Example 12- (i) in 14 ml of acetone and add A solution of 1.2 g of sodium iodide and 87 mg of sodium acetate in 1.7 ml of acetic acid was heated and refluxed for 6 hours. The reaction solution was concentrated and the residue obtained was added with ethyl acetate. The organic layer was washed with water and concentrated to a white solid In the form of the title compound (D2) 2.61g (92%) was obtained.

MS (ESI) m / z: 1158 (M + Na) ⁺ .

<Example 12- (iii): 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5-Table-4 "- Synthesis of N-Methoxycarbonyl Abramycin (D3) ＞

The title compound (D2) 2.50 g (2.2 mmol) of Example 12- (ii), 64 mg of AIBN and 1.5 ml of tributyltin hydride were treated by the same method as in Example 6- (ii) to obtain the title compound ( D3) 2.09g (94%).

MS (ESI) m / z: 1032 (M + Na) ⁺ .

<Example 12- (iv): 1,3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5-epiprasporium Synthesis of element (D4)> Using the title compound (D3) of Example 12- (iii), a solution of 2.00 g (2.0 mmol) of 1,4-dioxane in 20 ml and 2 ml of a 2M potassium hydroxide aqueous solution were used. 4- (iv) The same method was used to obtain 1.53 g (80%) of the title compound (D4).

MS (ESI) m / z: 974 (M + Na) ⁺ .

<Example 12- (v): Synthesis of 4 "-N- (N-formamidinoglycinyl) -6-deoxy-5-epiapramycin (D5-a)> Use example 12- (iv) of the title compound (D4) 170mg (0.18 mmol) and (N- (N, N'-bis (benzyloxycarbonyl)) formamidinoglycine acid N-hydroxysuccinimide ester 125mg, The treatment was carried out in the same manner as in Example 1 to obtain 78.7 mg (71%) of the title compound (D5-a).

MS (ESI) m / z: 623 (M + 1) ⁺ ; ¹ H NMR (DCl salt, in D ₂ O, 500 MHz): δ1.76 (1H, dt, J = 12 Hz, J = 2.5 Hz, H-6ax), 1.78 (1H, q, J = 13 Hz, H-2ax), 2.05 (1H, q, J = 12 Hz, H-3'ax), 2.28 (1H, dt, H-6eq), 2.36 (1H, dt, H-3'eq), 2.47 (1H, dt, H-2eq), 2,78 (3H, s, NCH ₃ ), 4.00 (2H, s, CH ₂ (N-formamidine Glycinamide)), 4.56 (1H, t, J = 2.5 Hz, H-6 '), 4.58 (1H, m, H-5), 5.19 (1H, d, J = 8.5 Hz, H-8' ), 5.40 (1H, d, J = 3,5 Hz, H-1 ') and 5.44 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 13: Synthesis of 6-deoxy-5-table-4 "-N- (N-ethylglycinyl) apuramycin (D5-b)>

Using the title compound (D4) of Example 12- (iv) 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) -N-ethylglycine acid N-hydroxysuccinimide ester 82.8 mg by It was processed in the same manner as in Example 1 to obtain 80.6 mg (75%) of the title compound (D5-b).

MS (ESI) m / z: 609 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.34 (3H, t, J = 7.3 Hz, NCH ₂ CH ₃ ), 1.38 (1H, q, J = 13 Hz, H-2ax), 1.63 (1H, dt, J = 13 Hz, J = 2.3 Hz, H-6ax), 1.98 (1H, q, J = 12 Hz, H-3'ax), 2.28 (1H, dt, H-2eq), 2.30 (1H, dt, H-6eq), 2.38 (1H, dt, H-3'eq), 2.64 (3H, s, NCH ₃ ), 2.85 (2H, q, N CH ₂ CH ₃ ), 3.58 (2H, ABq, CH ₂ (ethylglycinyl)), 4.58 (1H, m, H-5), 4.59 (1H, t, J = 2.5 Hz, H-6 '), 5.16 (1H, d, J = 8.5 Hz, H-8'), 5.25 (1H, d, J = 3.5 Hz, H-1 ') and 5,65 (1H , d, J = 4.0Hz, H-1 ").

<Example 14: 6,2 "-di-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4"- N, 6 ”-O-carbonyl apuramycin (E1), 6,2” -di-O-benzyl acetyl-1,3,2′-para-N- (benzyloxycarbonyl) -7′- N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-3 "-O-trifluoromethanesulfonyl apramycin (E2), 6,2" -di-O- Benzylamide-1,3,2'-ginseng-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-3 "-deoxy -3 ”-Table-3” -iodoapramycin (E3), 6,2 ”-di-O-benzylyl-1,3,2′-para-N- (benzyloxycarbonyl) -7 '-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-3 "-deoxyapuramycin (E4), 6,2" -di-O-benzyl- 1,3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-3 "-deoxy-5-O -Methanesulfonyl apramycin (E5), 5-O-acetyl-6,2 "-di-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl ) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-3 "-deoxy-5-epirubicin (E6), 1,3,2 ' -Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-3 "-deoxy-5-epipramycin (E7) and 3" -deoxy-5-epi -4 "-N-Glycine apuramycin (E8-a) Synthesis ＞

<Example 14- (i): 6,2 "-di-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl Synthesis of -4 ”-N, 6” -O-carbonyl apramycin (E1)> Using the compound represented by formula (A2) 15.0g (15mmol) and benzyl chloride 4.5ml (2.5eq.), Borrow The treatment was carried out in the same manner as in Example 4- (i) to obtain 17.1 g (95%) of the title compound (E1).

MS (ESI) m / z: 1224 (M + Na) ⁺ .

<Example 14- (ii): 6,2 "-di-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl -4 ”-N, 6” -O-carbonyl-3 ”-O-trifluoromethanesulfonyl apramycin (E2) Synthesis> Example 14- (i) title compound (E1) 16.4 A 80 ml solution of g (14 mmol) in chloroform was added 8 ml of pyridine and 3.5 ml (1.5 eq.) of trifluoromethanesulfonic anhydride under ice cooling, and the reaction was carried out at the same temperature for 1 hour. The reaction solution was washed with water, 10% aqueous potassium hydrogen sulfate solution, saturated sodium bicarbonate water and water in this order, and then concentrated under reduced pressure to obtain 16.1 g (95%) of the title compound (E2) as a pale yellow solid.

MS (ESI) m / z: 1256 (M + Na) ⁺ .

<Example 14- (iii): 6,2 "-di-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl -4 ”-N, 6” -O-Carbonyl-3 ”-deoxy-3” -Table-3 ”-iodoapramycin (E3) Synthesis> Use the title compound of Example 14- (ii) (E2) 15.5 g (12.6 mmol) and 10.3 g of sodium iodide were treated in the same manner as in Example 6- (i) to obtain 14.4 g (87%) of the title compound (E3).

MS (ESI) m / z: 1334 (M + Na) ⁺ .

<Example 14- (iv): 6,2 "-di-O-benzyl-1,3,2'-shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl -4 "-N, 6" -O-carbonyl-3 "-deoxyapuramycin (E4) synthesis> Example 14- (iii) using the title compound (E3) 14.0g (10.7 mmol), 100 mg of AIBN and 5.5 ml of tributyltin hydride were treated in the same manner as in Example 6- (ii) to obtain 9.78 g (77%) of the title compound (E4).

MS (ESI) m / z: 1208 (M + Na) ⁺ .

<Example 14- (v): 6,2 "-di-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl -4 ”-N, 6” -O-carbonyl-3 ”-deoxy-5-O-methanesulfonyl apramycin (E5) Synthesis> Use the title compound of Example 14- (iv) ( E4) 9.55 g (8.0 mmol), 4-dimethylaminopyridine 2.93 g (3 eq.) And mesylate chloride 0.95 ml (1.5 eq.) Were carried out by the same method as in Example 4- (ii) After treatment, 9.61 g (95%) of the title compound (E5) was obtained.

MS (ESI) m / z: 1286 (M + Na) ⁺ .

<Example 14- (vi): 5-O-aceto-6,2 "-di-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'- Synthesis of N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-3 "-deoxy-5-epirubicin (E6)> Use Example 14- (v) The title compound (E5) 9.42 g (7.5 mmol) and cesium acetate 4.60 g were treated in the same manner as in Example 4- (iii) to obtain 6.75 g (73%) of the title compound (E6).

MS (ESI) m / z: 1250 (M + Na) ⁺ .

<Example 14- (vii): 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-3 "-deoxy-5-epiapura Synthesis of erythromycin (E7)> Using the title compound (E6) of Example 14- (vi) in 6.54 g (5.3 mmol) in 60 ml of 1,4-dioxane and 15 ml of 2M aqueous potassium hydroxide solution Example 4- (iv) was treated in the same manner to obtain 3.85 g (83%) of the title compound (E7).

MS (ESI) m / z: 974 (M + Na) ⁺ .

<Example 14- (viii): Synthesis of 3 "-deoxy-5-table-4" -N-glycinyl apuramycin (E8-a)> Use example 14- (vii) 170 mg (0.18 mmol) of the title compound (E7) and 76.2 mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) glycine acid were treated in the same manner as in Example 1 to obtain the title compound (E8) -a) 77.9 mg (75%).

MS (ESI) m / z: 581 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500MHz): δ1.33 (1H, q, J = 13 Hz, H-2ax), 1.97 (1H, q, J = 12 Hz, H-3'ax), 2.14 (1H, q, J = 12 Hz, H-3 ”ax), 2.23 (1H, dt, H-2eq), 2.29 (1H , dt, H-3 ”eq), 2.37 (1H, dt, H-3'eq), 2.65 (3H, s, NCH ₃ ), 3.55 (2H, s, CH ₂ (glycamine)), 4.50 (1H, t, J = 2.5 Hz, H-5), 4.58 (1H, t, J = 2.5 Hz, H-6 '), 5.19 (1H, d, J = 8.5 Hz, H-8'), 5.24 (1H, d, J = 3.5 Hz, H-1 ') and 5.55 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 15: Synthesis of 3 "-deoxy-5-epi-4" -N-sarcosyl apramycin (E8-b)>

Using the title compound (E7) of Example 14- (vii) 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) sarcosinic acid N-hydroxysuccinimide ester 82.0 mg, the same as in Example 1 The method was processed to obtain 78.1 mg (74%) of the title compound (E8-b).

MS (ESI) m / z: 595 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500MHz): δ1.34 (1H, q, J = 13 Hz, H-2ax), 1.97 (1H, q, J = 12 Hz, H-3'ax), 2.14 (1H, q, J = 12 Hz, H-3 ”ax), 2.24 (1H, dt, H-2eq), 2.29 (1H , dt, H-3 ”eq), 2.37 (1H, dt, H-3'eq), 2.55 (3H, s, NCH ₃ (sarcosinyl)), 2.65 (3H, s, NCH ₃ ), 3.49 (2H, s, CH ₂ (sarcosinyl)), 4.50 (1H, t, J = 2.5 Hz, H-5), 4.58 (1H, t, J = 2.5 Hz, H-6 '), 5.20 ( 1H, d, J = 8.5 Hz, H-8 '), 5.24 (1H, d, J = 3.5 Hz, H-1') and 5.54 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 16: Synthesis of 3 "-deoxy-5-table-4" -N- (L-isoseramine amide) apramycin (E8-c)>

Using the title compound (E7) of Example 14- (vii) 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) -L-isoserine N-hydroxysuccinimide ester 82.6 mg, by and implementation Example 1 was processed in the same manner as above to obtain 75.9 mg (70%) of the title compound (E8-c).

MS (ESI) m / z: 611 (M + 1) ⁺ ; δ1.34 (1H, q, J = 13 Hz, H-2ax), 1.97 (1H, q, J = 12 Hz, H-3'ax ), 2.20 ~ 2.28 (3H, q, J = 12 Hz, H-3 ”ax, H-3” eq and H-2eq), 2.37 (1H, dt, H-3'eq), 2.63 (3H, s , NCH ₃ ), 3.03 and 3.23 (each 1H, dd, CH ₂ (isoseramide)), 4.37 (1H, t, CH (isoseramine)), 4.50 (1H, t, J = 2.5 Hz, H-5), 4.60 (1H, t, J = 2.5 Hz, H-6 '), 5.19 (1H, d, J = 8.5 Hz, H-8'), 5.24 (1H, d, J = 3.5 Hz, H-1 ') and 5.53 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 17: 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7'-N, 6'-O-carbonyl apuramycin (F1-a), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "-N -(L-Iserine Aminoyl) Apramycin (F2-a), 4 "-N- (N-Benzyl-L-Iserine Aminoyl) -1,3,2'-ginseng- N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonylapuramycin (F3-a), 4 "-N- (N-benzyl-N-methyl-L-isose Aminyl) -1,3,2'-ginseng-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl apuramycin (F4-a) and 4 "-N- ( Synthesis of N-methyl-L-isoseramine amide) apuramycin (F5-a) ＞

<Example 17- (i): 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7 Synthesis of '-N, 6'-O-carbonyl apuramycin (F1-a)> 360 mg (0.38 mmol) of the compound represented by formula (A3) was dissolved in 2 ml of DMF, and 0.16 ml of triethylamine was added 180 mg of N-hydroxysuccinimide ester of N-third butoxycarbonyl-L-isoserine was reacted at room temperature for 2 hours. After adding 28% ammonia water to the reaction solution, it was concentrated under reduced pressure. The residue was dissolved in 1-butanol, washed with water, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a development system (CHCl ₃ : MeOH = 10: 1). 355 mg (81%) of the title compound (F1-a) was obtained.

MS (ESI) m / z: 1177 (M + Na) ⁺ .

<Example 17- (ii): 1,3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4 "-N- (L-isoseramide) ) The synthesis of apramycin (F2-a)> Dissolve the title compound (F1-a) 350mg (0.30mmol) of Example 17- (i) in 1ml of 90% TFA-MeOH solution at room temperature The reaction was allowed to proceed for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with isopropyl ether to obtain 352 g of the title compound (F2-a) as a colorless solid (99% for TFA salt).

MS (ESI) m / z: 1077 (M + Na) ⁺ .

<Example 17- (iii): 4 "-N- (N-benzyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) -7'-N , Synthesis of 6'-O-carbonyl apuramycin (F3-a)> For the title compound (F2-a) of Example 17- (ii), a solution of 150 mg (0.13 mmol in terms of TFA salt) in 3 ml of methanol 0.5 ml of triethylamine and 0.2 ml of benzaldehyde were added, and after stirring at room temperature for 2 hours, 100 mg of NaBH _{4 was} added, and the reaction was carried out at room temperature for 10 minutes. The reaction solution was concentrated under reduced pressure and the residue obtained was The sequence was washed with water and isopropyl ether to obtain 144 mg (97%) of the title compound (F3-a) as a colorless solid.

MS (ESI) m / z: 1168 (M + Na) ⁺ .

<Example 17- (iv): 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) Synthesis of -7'-N, 6'-O-carbonyl apuramycin (F4-a)> For the title compound (F3-a) of Example 17- (iii), 140 mg (0.12 mmol) of 10% acetic acid -Add 2ml of 37% formalin aqueous solution and 10mg of NaBH ₃ CN to 2ml of methanol solution, and react at room temperature for 3 hours. After the reaction is completed, concentrate under reduced pressure and wash the obtained residue with water, followed by drying , The title compound (F4-a) 134 mg (95%) was obtained as a colorless solid.

MS (ESI) m / z: 1181 (M + Na) ⁺ .

<Example 17- (v): Synthesis of 4 "-N- (N-methyl-L-isoseramine amide) apuramycin (F5-a)> for example 17- (iv) The title compound (F4-a) 140 mg (0.12 mmol) in 80% 1,4-dioxane water 2.2 ml solution was added 0.1 ml of acetic acid and palladium black, and contact reduction was carried out in a hydrogen environment at room temperature for 10 hours. After the reaction was completed Concentrate under reduced pressure. To the residue, add 1 ml of 1M potassium hydroxide aqueous solution and react at room temperature for 4 hours. After the reaction is complete, add 1M hydrochloric acid to neutralize, concentrate, and convert the obtained residue by ion exchange Chromatography (CG50) refine | purified, and 56.5 mg (74%) of the title compound (F5-a) was obtained.

MS (ESI) m / z: 641 (M + 1) ⁺ ; 1H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.58 (1H, q, J = 12 Hz, H-2ax), 1.94 (1H, q, J = 12 Hz, H-3'ax), 2.25 (1H, dt, H-3'eq), 2.40 (1H, dt, H-2eq), 2.62 (3H, s, NCH ₃ (N-methylisoseramide)), 2.65 (3H, s, NCH ₃ ), 2.96 and 3.12 (each 1H, dd, CH ₂ (N-methylisoseramide)), 4.57 (1H , dd, CH (N-methylisoseramine amide)), 5.17 (1H, d, H-8 '), 5.42 (1H, d, H-1') and 5.66 (1H, d, H-1 ").

<Example 18: 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7'-N, 6'-O-carbonyl-5-epirubicin (F1-b), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl- 5-Table-4 ”-N- (L-isoseramine acetyl) apuramycin (F2-b), 4” -N- (N-benzyl-L-isoseramine amide) -1 , 3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-epipramycin (F3-b), 4 "-N- (N- Benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-epichloropeptide Synthesis of pramycin (F4-b) and 5-epi-4 "-N- (N-methyl-L-isoseramine amide) apramycin (F5-b) ＞

<Example 18- (i): 1,3,2'-gin-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramide amide) -7 Synthesis of '-N, 6'-O-carbonyl-5-epipramycin (F1-b)> Using the compound represented by formula (B4) 355mg (0.37mmol), triethylamine 0.16ml and N -180 mg of N-hydroxysuccinimide ester of the third butoxycarbonyl-L-isoserine, was treated by the same method as in Example 17- (i) to obtain 340 mg of the title compound (F1-b) ( 81%).

MS (ESI) m / z: 1177 (M + Na) ⁺ .

<Example 18- (ii): 1,3,2'-gin-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-Table-4 "-N- (L- Synthesis of Isoseminamide) Apramycin (F2-b)> Using the title compound (F1-b) 330mg (0.29mmol) of Example 18- (i), and Example 17- (ii ) The same method was used to obtain 331 g of colorless solid of the title compound (F2-b) (98% in terms of TFA salt).

MS (ESI) m / z: 1077 (M + Na) ⁺ .

<Example 18- (iii): 4 "-N- (N-benzyl-L-isoseramine amide) -1,3,2'-shen-N- (benzyloxycarbonyl) -7'-N , Synthesis of 6'-O-carbonyl-5-epipramycin (F3-b)> Use the title compound (F2-b) of Example 18- (ii) 150 mg (0.13 mmol in terms of TFA salt) , 0.2 ml of benzaldehyde and 100 mg of NaBH ₄ were treated in the same manner as in Example 17- (iii) to obtain 139 mg (93%) of the title compound (F3-b).

MS (ESI) m / z: 1168 (M + Na) ⁺ .

<Example 18- (iv): 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) Synthesis of -7'-N, 6'-O-carbonyl-5-epirubicin (F4-b)> Using title compound (F3-b) 130mg (0.11 mmol) of Example 18- (iii) 2ml of 10% acetic acid-methanol solution, 0.1ml of 37% formalin solution and 10mg of NaBH ₃ CN were treated by the same method as in Example 17- (iv) to obtain the title compound (F4-b) 125mg (95% ).

MS (ESI) m / z: 1181 (M + Na) ⁺ .

<Example 18- (v): Synthesis of 5-Table-4 "-N- (N-methyl-L-isoseramine amide) apramycin (F5-b)> Use Example 18- The title compound (F4-b) (iv) 120 mg (0.088 mmol) was treated in the same manner as in Example 17- (v) to obtain the title compound (F5-b) 46.8 mg (83%).

MS (ESI) m / z: 641 (M + 1) ⁺ ; 1H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.36 (1H, q, J = 12 Hz, H-2ax), 2.00 (1H, q, J = 12 Hz, H-3'ax), 2.26 (1H, dt, H-3'eq), 2.40 (1H, dt, H-2eq), 2.62 (3H, s, NCH ₃ (N-methylisoseramide)), 2.64 (3H, s, NCH ₃ ), 3.05 and 3.13 (each 1H, dd, CH ₂ (N-methylisoseramide)), 4.57 (1H , dd, CH ((N-Methylisoseramide)), 4.63 (1H, t, J = 2.3 Hz, H-5), 4.63 (1H, t, H-6 '), 5.17 (1H, d, H-8 '), 5.26 (1H, d, H-1') and 5.66 (1H, d, H-1 ”).

<Example 19: 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7'-N, 6'-O-carbonyl-5-deoxyapuramycin (F1-c), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl -5-deoxy-4 ”-N- (L-isoseramine amide) apramycin (F2-c), 4” -N- (N-benzyl-L-isoseramine amide) -1,3,2'-ginseng-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-deoxyapuramycin (F3-c), 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5 -Synthesis of deoxyapramycin (F4-c) and 5-deoxy-4 "-N- (N-methyl-L-isoseramine acetyl) apuramycin (F5-a) ＞

<Example 19- (i): 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7 Synthesis of '-N, 6'-O-carbonyl-5-deoxyapuramycin (F1-c)> using the compound represented by formula (C4) 351mg (0.37mmol), triethylamine 0.16ml and 180 mg of N-hydroxysuccinimide ester of N-third butoxycarbonyl-L-isoserine was treated by the same method as in Example 17- (i) to obtain 321 mg of the title compound (F1-c) (76%).

MS (ESI) m / z: 1161 (M + Na) ⁺ .

<Example 19- (ii): 1,3,2'-gin-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-deoxy-4 "-N- (L -Synthesis of Isoseminamide) Apramycin (F2-c)> Using the title compound (F1-c) 315 mg (0.28 mmol) of Example 19- (i), and Example 17- ( ii) The same method was used to obtain 311 mg (98% in terms of TFA salt) of the title compound (F2-c) as a colorless solid.

MS (ESI) m / z: 1061 (M + Na) ⁺ .

<Example 19- (iii): 4 "-N- (N-benzyl-L-isoseramine amide) -1,3,2'-shen-N- (benzyloxycarbonyl) -7'-N , Synthesis of 6'-O-carbonyl-5-deoxyapuramycin (F3-c)> Using the title compound (F2-c) of Example 19- (ii) 142 mg (0.12 mmol in terms of TFA salt) ), 0.2 ml of benzaldehyde and 100 mg of NaBH ₄ were treated by the same method as in Example 17- (iii) to obtain 115 mg (83%) of the title compound (F3-c).

MS (ESI) m / z: 1151 (M + Na) ⁺ .

<Example 19- (iv): 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) Synthesis of -7'-N, 6'-O-carbonyl-5-deoxyapuramycin (F4-c)> Using the title compound (F3-c) 111mg (0.098 mmol of Example 19- (iii) ) Of 10% acetic acid-methanol solution 2ml, 37% formalin aqueous solution 0.1ml and NaBH ₃ CN 10mg, treated in the same manner as in Example 17- (iv) to obtain the title compound (F4-c) 102mg (92 %).

MS (ESI) m / z: 1165 (M + Na) ⁺ .

<Example 19- (v): Synthesis of 5-deoxy-4 "-N- (N-methyl-L-isoseramine amide) apramycin (F5-a)> Use Example 19 -(iv) 98.4 mg (0.086 mmol) of the title compound (F4-c) was treated in the same manner as in Example 17- (v) to obtain 44.4 mg (83%) of the title compound (F5-c).

MS (ESI) m / z: 625 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.39 (1H, q, J = 13 Hz, H-2ax) , 1.57 (1H, q, J = 12 Hz, H-5ax), 1.93 (1H, q, J = 12 Hz, H-3'ax), 2.24 (1H, dt, H-3'eq), 2.36 ( 1H, dt, H-2eq), 2.60 (3H, s, NCH ₃ (N-methylisoseramine amide)), 2.62 (3H, s, NCH ₃ ), 2.63 (1H, dt, H-5eq) , 3.03 and 3.12 (each 1H, dd, CH ₂ (N-methylisoseramide)), 4.55 (1H, dd, CH (N-methylisoseramide)), 4.61 (1H, t , J = 2.5 Hz, H-6 '), 5.15 (1H, d, J = 8.5 Hz, H-8'), 5.22 (1H, d, J = 3.5 Hz, H-1 ') and 5.64 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 20: 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7'-N, 6'-O-carbonyl-6-deoxy-5-epiapramycin (F1-d), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6 ' -O-carbonyl-6-deoxy-5-table-4 "-N- (L-isoseramine acetyl) apuramycin (F2-d), 4" -N- (N-benzyl- L-isoseramine acetyl) -1,3,2'-shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5-epipramol (F3-d), 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) -7 '-N, 6'-O-carbonyl-6-deoxy-5-epipramycin (F4-d) and 6-deoxy-5-epi-4 "-N- (N-methyl- Synthesis of L-isoseramine acetyl group) apuramycin (F5-d) ＞

<Example 20- (i): 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7 Synthesis of '-N, 6'-O-carbonyl-6-deoxy-5-epiapramycin (F1-d)> Using the compound represented by formula (D4) 355mg (0.37mmol), triethyl 0.16 ml of amine and 180 mg of N-hydroxysuccinimide ester of N-third butoxycarbonyl-L-isoserine were treated by the same method as in Example 17- (i) to obtain the title compound (F1 -d) 313 mg (74%).

MS (ESI) m / z: 1161 (M + Na) ⁺ .

<Example 20- (ii): 1,3,2'-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5-Table-4 "- Synthesis of N- (L-isoseramine acetyl) apuramycin (F2-d)> Using the title compound (F1-d) 305 mg (0.27 mmol) of Example 20- (i), and carrying out Example 17- (ii) was treated in the same manner to obtain 298 mg of the title compound (F2-d) as a colorless solid (97% in terms of TFA salt).

MS (ESI) m / z: 1061 (M + Na) ⁺ .

<Example 20- (iii): 4 "-N- (N-benzyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) -7'-N , 6'-O-carbonyl-6-deoxy-5-epiapramycin (F3-d) synthesis> Use the title compound of Example 20- (ii) (F2-d) 140mg (as TFA salt In terms of 0.12 mmol), benzaldehyde 0.2 ml and NaBH ₄ 100 mg, the same procedure as in Example 17- (iii) was performed to obtain 108 mg (80%) of the title compound (F3-d).

MS (ESI) m / z: 1151 (M + Na) ⁺ .

<Example 20- (iv): 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) Synthesis of -7'-N, 6'-O-carbonyl-6-deoxy-5-epiapramycin (F4-d)> Using the title compound (F3-d) of Example 20- (iii) 100 mg (0.089 mmol) of 10% acetic acid-methanol solution 2 ml, 37% formalin aqueous solution 0.1 ml and NaBH ₃ CN 10 mg were treated by the same method as in Example 17- (iv) to obtain the title compound (F4-d ) 97.6 mg (96%).

MS (ESI) m / z: 1165 (M + Na) ⁺ .

<Example 20- (v): Synthesis of 6-deoxy-5-Table-4 "-N- (N-methyl-L-isoseramine amide) apramycin (F5-d)> Using the title compound (F4-d) 95.0 mg (0.083 mmol) of Example 20- (iv) and the same procedure as in Example 17- (v), 42.1 mg of the title compound (F5-d) was obtained ( 81%).

MS (ESI) m / z: 625 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.38 (1H, q, J = 13 Hz, H-2ax) , 1.63 (1H, dt, J = 13 Hz, J = 2.3 Hz, H-6ax), 1,98 (1H, q, J = 12 Hz, H-3'ax), 2.28 (1H, dt, H- 2eq), 2.30 (1H, dt, H-6eq), 2.38 (1H, dt, H-3'eq), 2.60 (3H, s, NCH ₃ (N-methylisoseramine amide)), 2.63 ( 3H, s, NCH ₃ ), 3.04 and 3.11 (each 1H, dd, CH ₂ (N-methylisoseramide amide)), 4.56 (1H, dd, CH (N-methylisoseramine amide) ), 4.58 (1H, m, H-5), 4.61 (1H, t, H-6 '), 5.15 (1H, d, H-8'), 5.25 (1H, d, H-1 ') and 5.65 (1H, d, H-1 ").

<Example 21: 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7'-N, 6'-O-carbonyl-3 "-deoxy-5-epirubicin (F1-e), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6 '-O-Carbonyl-3 "-deoxy-5-table-4" -N- (L-isoseramine amide) apuramycin (F2-e), 4 "-N- (N-benzyl -L-isoseramine amide) -1,3,2'-shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-3 "-deoxy-5-epoxy Pramycin (F3-e), 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) ) -7'-N, 6'-O-carbonyl-3 "-deoxy-5-epiapramycin (F4-e) and 3" -deoxy-5-epiform-4 "-N- ( Synthesis of N-Methyl-L-Iserine Aminoyl) Apramycin (F5-e) ＞

<Example 21- (i): 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramide amide) -7 Synthesis of '-N, 6'-O-carbonyl-3 "-deoxy-5-epiapramycin (F1-e)> 322 mg (0.34 mmol), triethyl compound using the compound represented by formula (E7) 0.14 ml of amine and 165 mg of N-hydroxysuccinimide ester of N-third butoxycarbonyl-L-isoserine were treated by the same method as in Example 17- (i) to obtain the title compound ( F1-e) 303 mg (78%).

MS (ESI) m / z: 1161 (M + Na) ⁺ .

<Example 21- (ii): 1,3,2'-gin-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-3 "-deoxy-5-Table-4" -N- (L-isoseramine acetyl) apuramycin (F2-e) synthesis> using the title compound of Example 21- (i) (F1-e) 295mg (0.26 mmol), by Example 17- (ii) was treated in the same manner to obtain 286 mg of the title compound (F2-e) as a colorless solid (95% in terms of TFA salt).

MS (ESI) m / z: 1061 (M + Na) ⁺ .

<Example 21- (iii): 4 "-N- (N-benzyl-L-isoseramine amide) -1,3,2'-shen-N- (benzyloxycarbonyl) -7'-N , 6'-O-Carbonyl-3 "-deoxy-5-epiapramycin (F3-e) Synthesis> Using the title compound (F2-e) 130mg (as for TFA) of Example 21- (ii) As for the salt, 0.11 mmol), benzaldehyde 0.2 ml, and NaBH ₄ 100 mg were treated in the same manner as in Example 17- (iii) to obtain 100 mg (81%) of the title compound (F3-e).

MS (ESI) m / z: 1151 (M + Na) ⁺ .

<Example 21- (iv): 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) Synthesis of -7'-N, 6'-O-carbonyl-3 "-deoxy-5-epirubicin (F4-e)> Using the title compound (F3-e) of Example 21- (iii) ) 95.6mg (0.085mmol) of 10% acetic acid-methanol solution 2ml, 37% formalin aqueous solution 0.1ml and NaBH ₃ CN 10mg, treated by the same method as in Example 17- (iv) to obtain the title compound (F4 -e) 93.6 mg (96%).

MS (ESI) m / z: 1165 (M + Na) ⁺ .

<Example 21- (v): Synthesis of 3 "-deoxy-5-table-4" -N- (N-methyl-L-isoseramine acetyl) apramycin (F5-e) > Using the title compound (F4-e) 95.0 mg (0.083 mmol) of Example 21- (iv) and treating it in the same manner as in Example 17- (v) to obtain the title compound (F5-e) 40.6 mg (78%).

MS (ESI) m / z: 625 (M + 1) ⁺ ; δ1.34 (1H, q, J = 13 Hz, H-2ax), 1.98 (1H, q, J = 12 Hz, H-3'ax ), 2.20 ~ 2.28 (3H, q, J = 12 Hz, H-3 ”ax, H-3” eq and H-2eq), 2.37 (1H, dt, H-3'eq), 2.58 (3H, s , NCH ₃ (N-methylisoseramide amide)), 2.64 (3H, s, NCH ₃ ), 2.98 and 3.07 (each 1H, dd, CH ₂ (N-methylisoseramide amide)), 4.47 ~ 4.53 (2H, m, CH (N-methylisoseramide) and H-5), 4.60 (1H, t, J = 2.5 Hz, H-6 '), 5.19 (1H, d, J = 8.5 Hz, H-8 '), 5.24 (1H, d, J = 3.5 Hz, H-1') and 5.54 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 22: Synthesis of 4 "-N- (N-formamidine-L-isoseramine amide) apramycin (Ga)>

150mg (0.14mmol) of the title compound (F2-a) of Example 17- (ii) was dissolved in 3ml of a mixture of chloroform: methanol (10: 1), and 0.16ml of triethylamine and 1,3-bis ( 100 mg of third butoxycarbonyl) -2- (trifluoromethanesulfonyl) guanidine (Goodman reagent) and allowed to react at room temperature for 3 hours. After the reaction was completed, the reaction solution was washed with water and concentrated under reduced pressure. The residue was dissolved in 3 ml of 90% TFA-MeOH solution, and the reaction was carried out at room temperature for 1 hour, followed by concentration under reduced pressure. The residue was dissolved in 3 ml of 50% 1,4-dioxane-water, 0.5 ml of acetic acid and palladium black were added thereto, and contact reduction was performed in a hydrogen environment at room temperature for 10 hours. After the reaction was completed, it was neutralized with NH ₄ OH, and after filtration, it was concentrated under reduced pressure. The residue was dissolved in 1 ml of water, and 1 ml of a 2M potassium hydroxide aqueous solution was added and reacted for 6 hours. After the reaction solution was neutralized by adding 1N HCl, it was purified by ion exchange chromatography (CG5O) to obtain 65.1 mg (70%) of the title compound (Ga).

MS (ESI) m / z: 669 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.48 (1H, q, J = 12 Hz, H-2ax) , 1.94 (1H, q, J = 12 Hz, H-3'ax), 2.25 (1H, dt, H-3'eq), 2.40 (1H, dt, H-2eq), 2.65 (3H, s, NCH ₃ ), 4.59 (1H, t, H-6 '), 5.17 (1H, d, H-8'), 5.42 (1H, d, H-1 ') and 5.66 (1H, d, H-1 ”) .

<Example 23: Synthesis of 4 "-N- (N-formamidine-L-isoseramine amide) -5-epiapramycin (Gb)>

Using the title compound (F2-b) of Example 18- (ii) 150 mg (0.14 mmol) and 1,3-bis (third butoxycarbonyl) -2- (trifluoromethanesulfonyl) guanidine (Goodman reagent) 100 mg was treated in the same manner as in Example 22 to obtain 66.8 mg (71%) of the title compound (Gb).

MS (ESI) m / z: 669 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.36 (1H, q, J = 12 Hz, H-2ax) , 2.00 (1H, q, J = 12 Hz, H-3'ax), 2.26 (1H, dt, H-3'eq), 2.40 (1H, dt, H-2eq), 2.65 (3H, s, NCH ₃ ), 4.53 (1H, t, J = 2.8 Hz, H-5), 4.63 (1H, t, H-6 '), 5.17 (1H, d, H-8'), 5.26 (1H, d, H -1 ') and 5.66 (1H, d, H-1 ”).

<Example 24: Synthesis of 4 "-N- (N-formamidine-L-isoseramine amide) -5-deoxyapuramycin (Gc)>

Using the title compound (F2-c) of Example 19- (ii) 125 mg (0.12 mmol) and 1,3-bis (third butoxycarbonyl) -2- (trifluoromethanesulfonyl) guanidine (Goodman reagent) 100 mg was treated in the same manner as in Example 22 to obtain 55.6 mg (71%) of the title compound (Gc).

MS (ESI) m / z: 653 (M + 1) ⁺ ; ¹ H NMR (DCl salt, in D ₂ O, 500 MHz): δ1.45 (1H, q, J = 13 Hz, H-2ax), 1.76 (1H, q, J = 12 Hz, H-5ax), 2.02 (1H, q, J = 12 Hz, H-3'ax), 2.36 (1H, dt, H-3'eq), 2.46 (1H , dt, H-2eq), 2.68 (1H, dt, H-5eq), 2.78 (3H, s, NCH ₃ ), 4.35 (1H, dd, CH (isoseramide)), 4.57 (1H, t , J = 2.5 Hz, H-6 '), 5.19 (1H, d, J = 8.5 Hz, H-8'), 5.36 (1H, d, J = 3.5 Hz, H-1 ') and 5.44 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 25: Synthesis of 4 "-N- (N-formamidino-L-isoseramine amide) -6-deoxy-5-epirubicin (Gd)>

Using the title compound (F2-d) of Example 20- (ii) 113 mg (0.11 mmol) and 1,3-bis (third butoxycarbonyl) -2- (trifluoromethanesulfonyl) guanidine (Goodman reagent) 100 mg was treated in the same manner as in Example 22 to obtain 50.1 mg (70%) of the title compound (Gd).

MS (ESI) m / z: 653 (M + 1) ⁺ ; ¹ H NMR (DCl salt, in D ₂ O, 500 MHz): δ1.76 (1H, dt, J = 12 Hz, J = 2.5 Hz, H-6ax), 1.78 (1H, q, J = 13 Hz, H-2ax), 2.05 (1H, q, J = 12 Hz, H-3'ax), 2.29 (1H, dt, H-6eq), 2.38 (1H, dt, H-3'eq), 2.47 (1H, dt, H-2eq), 2.78 (3H, s, NCH ₃ ), 3.50 and 3.54 (each 1H, dd, CH ₂ (isoseramide) Base)), 4.35 (1H, q, CH (isoseramide)), 4.57 (1H, t, J = 2.5 Hz, H-6 '), 4.59 (1H, m, H-5), 5.19 ( 1H, d, J = 8.5 Hz, H-8 '), 5.41 (1H, d, J = 3.5 Hz, H-1') and 5.44 (1H, d, J = 4.0 Hz, H-1 ").

<Example 26: 5,6-anhydro-2 ", 3", 6 "-tri-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5-Table-4 "-N-methoxycarbonylapuramycin (H1), 2", 3 ", 6" -tri-O-benzylyl-1,3,2 '-Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-6-deoxy-5,6-ditable-6-iodine-4 "-N-methoxycarbonyl arp Laramycin (H2), 2 ", 3", 6 "-tri-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O -Carbonyl-5,6-dideoxy-5-ene bridge-4 "-N-methoxycarbonylapuramycin (H3), ginseng-N- (benzyloxycarbonyl) -7'-N, 6 ' -O-carbonyl-5,6-dideoxy-5-ene bridge apuramycin (H4) and 5,6-dideoxy-4 "-N-glycinyl apuramycin (H5 -a) Synthesis ＞

<Example 26- (i): 5,6-anhydro-2 ", 3", 6 "-tri-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7 Synthesis of '-N, 6'-O-carbonyl-5-Table-4 "-N-methoxycarbonylapuramycin (H1)> use the title compound (D1) 5.00g of Example 12- (i) (5 mmol) and benzyl chloride 2.3 ml (4 eq.) Were treated in the same manner as in Example 4- (i) to obtain 6.39 g (97%) of the title compound (H1).

MS (ESI) m / z: 1342 (M + Na) ⁺ .

<Example 26- (ii): 2 ", 3", 6 "-tri-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6 ' -O-carbonyl-6-deoxy-5,6-ditable-6-iodine-4 "-N-methoxycarbonylapuramycin (H2) Synthesis> Use the title of Example 26- (i) 6.25 g (4.7 mmol) of the compound (H1) was treated by the same method as in Example 12- (ii) to obtain 6.31 g (93%) of the title compound (H2).

MS (ESI) m / z: 1470 (M + Na) ⁺ .

<Example 26- (iii): 2 ", 3", 6 "-tri-O-benzylyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6 ' -O-carbonyl-5,6-dideoxy-5-ene bridge-4 "-N-methoxycarbonylapuramycin (H3) Synthesis> For the title compound of Example 26- (ii) (H2 ) A solution of 6.20 g (4.28 mmol) of pyridine in 30 ml was added 1.21 g of benzosulfonyl chloride at -10 to 0 ° C, and the reaction was carried out at the same temperature for 1 hour. Next, 2 ml of water was added to the reaction liquid, and heated at 80 ° C for 2 hours. The reaction solution was concentrated, water was added to the residue, and the resulting precipitate was filtered, which was purified by silica gel column chromatography using a developing system (CHCl ₃ : MeOH = 30: 1) to obtain the title compound (H3) 4.78g (86%).

MS (ESI) m / z: 1327 (M + Na) ⁺ .

<Example 26- (iv): 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,6-dideoxy-5-ene bridge Synthesis of Apramycin (H4)> To the title compound (H3) of Example 26- (iii), a solution of 4.70 g (3.6 mmol) of 1,4-dioxane in 50 ml was added to 9 ml of a 2M potassium hydroxide aqueous solution. The title compound (H4) 2.85 g (83%) was obtained by the process similar to Example 4- (iv).

MS (ESI) m / z: 956 (M + Na) ⁺ .

<Example 26- (v): Synthesis of 5,6-dideoxy-4 "-N-glycine apramycin (H5-a)> Use the title compound of Example 26- (iv) (H4) 170 mg (0.18 mmol) and 76.2 mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) glycine acid, and treated in the same manner as in Example 1 to obtain the title compound (H5-a ) 76.6 mg (75%).

MS (ESI) m / z: 565 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.30-1.53 (3H, m, H-2ax, -6ax and -5ax), 1.89 (1H, q, J = 12 Hz, H-3'ax), 2.06-2.13 (1H, m, H-6eq), 2.17-2.23 (1H, m, H-5eq), 2.28- 2.38 (2H, m, H-3'eq and H-2eq), 2.60 (3H, s, NCH ₃ ), 3.57 (2H, s, CH ₂ (glycinyl)), 4.56 (1H, t, J = 2.5 Hz, H-6 '), 5.12 (1H, d, J = 8.5 Hz, H-8'), 5.18 (1H, d, J = 3.5 Hz, H-1 ') and 5.61 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 27: Synthesis of 5,6-dideoxy-4 "-N-sarcosine apramycin (H5-b)>

170 mg (0.18 mmol) of the title compound (H4) of Example 26- (iv) and 82.0 mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) sarcosinic acid were used, as in Example 1. The method was processed to obtain 74.1 mg (71%) of the title compound (H5-b).

MS (ESI) m / z: 579 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.27-1.54 (3H, m, H-2ax, -6ax and -5ax), 1.88 (1H, q, J = 12 Hz, H-3'ax), 2.06-2.13 (1H, m, H-6eq), 2.17-2.23 (1H, m, H-5eq), 2.28- 2.38 (2H, m, H-3'eq and H-2eq), 2.53 (3H, s, NCH ₃ ), 2.59 (3H, s, NCH ₃ ), 3.55 (2H, ABq, CH ₂ (sarcosinyl )), 4.55 (1H, t, J = 2.5 Hz, H-6 '), 5.11 (1H, d, J = 8.5 Hz, H-8'), 5.17 (1H, d, J = 3.5 Hz, H- 1 ') and 5,60 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 28: Synthesis of 5,6-dideoxy-4 "-N- (L-isoseramine amide) apramycin (H5-c)>

Using the title compound (H4) of Example 26- (iv) 170 mg (0.18 mmol) and N- (benzyloxycarbonyl) -L-isoserine N-hydroxysuccinimide ester 82.6 mg, by and implementation Example 1 was treated in the same manner to obtain 76.2 mg (71%) of the title compound (H5-c).

MS (ESI) m / z: 595 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1,29-1.55 (3H, m, H-2ax, -6ax and -5ax), 1.89 (1H, q, J = 12 Hz, H-3'ax), 2.07-2.14 (1H, m, H-6eq), 2.17-2.23 (1H, m, H-5eq), 2.28- 2.38 (2H, m, H-3'eq and H-2eq), 2.59 (3H, s, NCH ₃ ), 3.06 and 3.18 (each 1H, dd, CH ₂ (isoseramide)), 4.40 (1H , t, CH (isoseramide)), 4.58 (1H, t, J = 2.5 Hz, H-6 '), 5.12 (1H, d, J = 8.5 Hz, H-8'), 5.19 (1H , d, J = 3.5 Hz, H-1 ') and 5,61 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 29: 1,3,2'-Shen-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7'-N, 6'-O-carbonyl-5,6-dideoxy-5-ene bridge aspramycin (H4-a), 1,3,2'-para-N- (benzyloxycarbonyl) -7'- N, 6'-O-carbonyl-5,6-dideoxy-5-ene bridge-4 "-N- (L-isoseramine amide) apramycin (H4-b), 4"- N- (N-benzyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,6- Dideoxy-5-ene bridge apuramycin (H4-c), 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2 ' -Shen-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,6-dideoxy-5-ene bridge apramycin (H4-d) and 5,6- Synthesis of dideoxy-4 ”-N- (N-methyl-L-isoseramine amide) apuramycin (H5-d) ＞

<Example 29- (i): 1,3,2'-gin-N- (benzyloxycarbonyl) -4 "-N- (N-third butoxycarbonyl-L-isoseramine amide) -7 Synthesis of '-N, 6'-O-carbonyl-5,6-dideoxy-5-ene bridge apramycin (H4-a)> Use the title compound (H4) of Example 26- (iv) 340 mg (0.37 mmol), 0.16 ml of triethylamine and 170 mg of N-hydroxysuccinimide ester of N-third butoxycarbonyl-L-isoserine, by the same method as in Example 17- (i) The method was processed to obtain 331 mg (80%) of the title compound (H4-a).

MS (ESI) m / z: 1145 (M + Na) ⁺ .

<Example 29- (ii): 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,6-dideoxy-5-ene bridge -4 "-N- (L-isoseramine acetyl) apuramycin (H4-b) synthesis> using the title compound (H4-a) 330 mg (0.29 mmol) of Example 29- (i), By treating in the same manner as in Example 17- (ii), 321 mg (98% in terms of TFA salt) of the title compound (H4-b) was obtained as a colorless solid.

MS (ESI) m / z: 1043 (M + Na) ⁺ .

<Example 29- (iii): 4 "-N- (N-benzyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) -7'-N , Synthesis of 6'-O-carbonyl-5,6-dideoxy-5-ene bridge apuramycin (H4-c)> Use the title compound (H4-b) 300mg of Example 29- (ii) (TFA salt 0.26 mmol), benzaldehyde 0.4 ml, and NaBH ₄ 150 mg were treated in the same manner as in Example 17- (iii) to obtain 225 mg (78%) of the title compound (H4-c).

MS (ESI) m / z: 1133 (M + Na) ⁺ .

<Example 29- (iv): 4 "-N- (N-benzyl-N-methyl-L-isoseramine amide) -1,3,2'-para-N- (benzyloxycarbonyl) Synthesis of -7'-N, 6'-O-carbonyl-5,6-dideoxy-5-ene bridge aspramycin (H4-d)> Using the title compound of Example 29- (iii) ( H4-c) 220 mg (0.2 mmol) of 3% 10% acetic acid-methanol solution, 0.15 ml of 37% formalin aqueous solution and 15 mg of NaBH ₃ CN, and treated by the same method as in Example 17- (iv) to obtain the title compound (H4-d) 222 mg (95%).

MS (ESI) m / z: 1147 (M + Na) ⁺ .

<Example 29- (v): Synthesis of 5,6-dideoxy-4 "-N- (N-methyl-L-isoseramine amide) apramycin (H5-d)> used Example 29- (iv) of the title compound (H4-d) 220 mg (0.20 mmol) was treated by the same method as in Example 17- (v) to obtain the title compound (H5-d) 77.8 mg (64% ).

MS (ESI) m / z: 609 (M + 1) ⁺ ; 1H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.25-1.57 (3H, m, H-2ax, -6ax and- 5ax), 1.90 (1H, q, J = 12 Hz, H-3'ax), 2.08-2.15 (1H, m, H-6eq), 2.17-2.25 (1H, m, H-5eq), 2.31-2.42 (2H, m, H-3'eq and H-2eq), 2.59 (3H, s, NCH ₃ ), 2.58 (3H, s, NCH ₃ (N-methylisoseramide amide)), 2.61 (3H , s, NCH ₃ ), 3.08 and 3.18 (each 1H, dd, CH ₂ (N-methylisoseramide amide)), 4.54 (1H, dd, CH (N-methylisoseramine amide)) , 4.59 (1H, t, J = 2.5 Hz, H-6 '), 5.13 (1H, d, J = 8.5 Hz, H-8'), 5.20 (1H, d, J = 3.5 Hz, H-1 ' ) and 5.63 (1H, d, J = 4.0 Hz, H-1 ”).

<Example 30: 6,2 "-di-O-benzyl yl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4"- N, 6 ”-O-carbonyl-5-O-methylsulfonyl-3” -O-trifluoromethanesulfonyl apramycin (I1), 5,3 ”-di-O-acetoyl -6,2 "-Di-O-benzyl -1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-4" -N, 6 " -O-carbonyl-5,3 "-diepiapramycin (I2), 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl- Synthesis of 5,3 ”-Diepirubicin (I3) and 5,3” -Diepirubin-4 ”-N-Glycinamipramine (I4-a) ＞

<Example 30- (i): 6,2 "-di-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl -4 "-N, 6" -O-carbonyl-5-O-methylsulfonyl-3 "-O-trifluoromethanesulfonyl apramycin (I1) Synthesis> Use Example 14- ( ii) The title compound (E2) 2.68 g (2.0 mmol), 4-dimethylaminopyridine 733 mg (3 eq.) and mesylate 0.24 ml (1.5 eq.), and the example 4- (ii ) The same method was used to obtain 2.82 g (quantitative) of the title compound (I1).

MS (ESI) m / z: 1434 (M + Na) ⁺ .

<Example 30- (ii): 5,3 "-di-O-acetoyl-6,2" -di-O-benzyl-1,3,2'-para-N- (benzyloxycarbonyl ) -7'-N, 6'-O-carbonyl-4 "-N, 6" -O-carbonyl-5,3 "-diepiapramycin (I2) Synthesis> Use Example 30- ( The title compound (I1) 2.75 g (1.9 mmol) and cesium acetate 1.60 g of i) were treated in the same manner as in Example 4- (iii) to obtain 2.15 g (88%) of the title compound (I2).

MS (ESI) m / z: 1309 (M + Na) ⁺ .

<Example 30- (iii): 1,3,2'-para-N- (benzyloxycarbonyl) -7'-N, 6'-O-carbonyl-5,3 "-diprapamycin Synthesis of (I3)> Using the title compound (I2) of Example 30- (ii) in 2.00 g (1.55 mmol) of a solution of 20 ml of 1,4-dioxane and 5 ml of a 2M potassium hydroxide aqueous solution, by using Example 4 -(iv) The same method was used to obtain 1.45 g (75%) of the title compound (I3).

MS (ESI) m / z: 990 (M + Na) ⁺ .

<Example 30- (iv): Synthesis of 5,3 "-Ditable-4" -N-Glycine apuramycin (I4-a)> Use the title compound of Example 30- (iii) (I3) 175 mg (0.18 mmol) and 76.2 mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) glycine acid were treated in the same manner as in Example 1 to obtain the title compound (I4-a ) 76.5 mg (71%).

MS (ESI) m / z: 597 (M + 1) ⁺ ; 1H NMR (25% ND ₃ -D ₂ O, 500MHz): δ1.32 (1H, q, H-2ax), 1.96 (1H, q, J = 12 Hz, H-3'ax), 2.22 (1H, dt, H-3'eq), 2.36 (1H, dt, H-2eq), 2.61 (3H, s, NCH ₃ ), 3.59 (2H, s, CH ₂ (glycinyl)), 4.03 (1H, t, J = 2.5 Hz, H-3 ”), 4.48 (1H, t, J = 2.5 Hz, H-5), 4.57 (1H, t , J = 2.3 Hz, H-7 '), 5.13 (1H, d, J = 8.5 Hz, H-8'), 5.22 (1H, d, J = 4.0 Hz, H-1 ') and 5.62 (1H, d, J = 3.5 Hz, H-1 ”).

<Example 31: Synthesis of 5,3 "-Ditable-4" -N-sarcosinamide apuramycin (I4-b)>

175 mg (0.18 mmol) of the title compound (I3) of Example 30- (iii) and 82.0 mg of N-hydroxysuccinimide ester of N- (benzyloxycarbonyl) sarcosinic acid were used, as in Example 1. The method was processed to obtain 77.2 mg (70%) of the title compound (I4-b).

MS (ESI) m / z: 611 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.32 (1H, q, H-2ax), 1.96 (1H, q, J = 12 Hz, H-3'ax), 2.22 (1H, dt, H-3'eq), 2.36 (1H, dt, H-2eq), 2.56 (3H, s, NCH ₃ ), 2.61 ( 3H, s, NCH ₃ ), 3.50 (2H, ABq, CH ₂ (sarcosinyl)), 4.04 (1H, t, J = 2.5 Hz, H-3 ”), 4.49 (1H, t, J = 2.5 Hz, H-5), 4.57 (1H, t, J = 2.3 Hz, H-7 '), 5.14 (1H, d, J = 8.5 Hz, H-8'), 5.22 (1H, d, J = 4.0 Hz, H-1 ') and 5.63 (1H, d, J = 3.5 Hz, H-1 ”).

<Example 32: Synthesis of 5,3 "-Ditable-4" -N- (L-isoseramine-yl) apuramycin (I4-c)>

Using the title compound (I3) of Example 30- (iii) 175 mg (0.18 mmol) and N- (benzyloxycarbonyl) -L-isoserine N-hydroxysuccinimide ester 82.6 mg, by and implementation Example 1 was treated in the same manner to obtain 80.2 mg (71%) of the title compound (I4-c).

MS (ESI) m / z: 627 (M + 1) ⁺ ; ¹ H NMR (25% ND ₃ -D ₂ O, 500 MHz): δ1.29 (1H, q, H-2ax), 1.90 (1H, q, J = 12 Hz, H-3'ax), 2.19 (1H, dt, H-3'eq), 2.32 (1H, dt, H-2eq), 2.56 (3H, s, NCH ₃ ), 3.03 and 3.14 (each 1H, dd, CH ₂ (isoseramide)), 4.00 (1H, t, J = 2.5 Hz, H-3 ”), 4.37 (1H, t, CH (isoseramine)) , 4.45 (1H, t, J = 2.5 Hz, H-5), 4.55 (1H, t, J = 2.3 Hz, H-7 '), 5.09 (1H, d, J = 8.5 Hz, H-8') , 5.19 (1H, d, J = 4.0 Hz, H-1 ') and 5.59 (1H, d, J = 3.5 Hz, H-1 ”).

<Test Example 1> (Antibacterial activity) For the compounds described in the representative examples of the novel aminoglycoside antibiotics of the present invention, the minimum developmental inhibition of various tested bacteria was determined by the cold plate dilution method according to the Japanese Chemical Therapy Society Concentration (MIC, μg / mL). The results are shown in Tables 1 to 3.

The results of Tables 1 to 3 show that the compound of the present invention has antibacterial activity against both Gram-positive bacteria and Gram-negative bacteria. In addition, it has been exemplified that the compounds of the present invention show resistance to arbekacin (ABK), amikacin (AMK) and gentamicin (GM), which are existing antibiotics Or low-susceptibility S. aureus, pneumoniae, Acinetobacter, Serratia and Pseudomonas aeruginosa resistant or low-susceptibility strains also have strong antibacterial properties.

Claims (17)

A compound represented by general formula (I) or a pharmaceutically acceptable salt or a solvent thereof: [In the formula, R ¹ represents a hydrogen atom or a hydroxyl group, R ² represents a hydrogen atom or a hydroxyl group, R ³ represents a hydrogen atom or a hydroxyl group, R ⁴ represents a hydrogen atom or a hydroxyl group, R ⁵ represents a hydrogen atom or a hydroxyl group, and R ⁶ represents a glycoamine Acyl, sarcosyl, N-ethylglycinyl, β-propylamine, L-isoseramine, N-formamidylglycinyl, N-formamidinyl Amido, N-methyl-L-isoseramine, or N-formamidine-L-isoseramine]. For example, the compound of claim 1, or a pharmaceutically acceptable salt or a solvent thereof, wherein R ⁶ represents N-ethylglycinyl, N-carboxamidoglycinyl, N-methyl Aminoyl sarcosinyl, N-methyl-L-isoseramine amide or N-formamidine-L-isoseramine amide. For example, the compound of claim 2 or its pharmaceutically acceptable salt or its solvent, wherein R ⁴ represents a hydrogen atom. For example, the compound of claim 2 or 3, or a pharmaceutically acceptable salt or a solvent thereof, wherein R ⁵ represents a hydroxyl group. For example, the compound of claim 1, or a pharmaceutically acceptable salt or a solvent thereof, wherein R ⁵ represents a hydrogen atom, and R ⁶ represents a glycinyl group, a sarcosinyl group, and a β-propylamine group Or L-isoseramine amide. For example, the compound of claim 1, or a pharmaceutically acceptable salt or a solvent thereof, wherein R ² represents a hydrogen atom, and R ⁶ represents a glycosamino, sarcosinyl, or β-propylaminoamide Or L-isoseramine amide. For example, the compound of claim 6, or a pharmaceutically acceptable salt or a solvent thereof, wherein R ³ represents a hydrogen atom. For example, if the compound of the first patent application or its pharmaceutically acceptable salt or its solvent, the compound is 4 "-N- (N-formamidinoglycinyl) apuramycin, 4" -N- (N-formamidinosarcosaminyl) apuramycin, 4 ”-N- (N-ethylglycinamide) apuramycin, 4” -N- (N-A (Amidinoglycinamide) -5-epiapramycin, 5-epi-4 ”-N- (N-ethylglycinamide) apuramycin, 5-deoxy-4”- N-Glycine-based apuramycin, 5-deoxy-4 "-N-sarcosine-based apuramycin, 5-deoxy-4" -N- (N-ethylglycine amide Base) apuramycin, 4 ”-N- (β-propylamine amide) -5-deoxyapuramycin, 5-deoxy-4” -N- (L-isoseramine amide) Apramycin, 4 ”-N- (N-formamidinoglycinyl) -5-deoxyapuramycin, 4” -N- (N-formamidinoglycinyl)- 6-deoxy-5-epirubicin, 6-deoxy-5-epiform-4 "-N- (N-ethylglycinyl) apramycin, 3" -deoxy- 5-Table-4 ”-N-Glycine Apramycin, 3” -deoxy-5-Table-4 ”-N- Sarcosinyl apuramycin, 3 ”-deoxy-5-table-4” -N- (L-isoseramine acetyl) apramycin, 4 ”-N- (N-methyl -L-isoseramine amide) apuramycin, 5-Table-4 "-N- (N-methyl-L-isoseramine amide) apramycin, 5-deoxy-4 ”-N- (N-methyl-L-isoseramine amide) apramycin, 6-deoxy-5-table-4” -N- (N-methyl-L-isoseramine amide Group) apuramycin, 3 ”-deoxy-5-table-4” -N- (N-methyl-L-isoseramine acetyl) apuramycin, 4 ”-N- (N -Formamidinyl-L-isoseramine amide) apuramycin, 4 ”-N- (N-formamidine-L-isoseramine amide) -5-epiapramycin, 4 ”-N- (N-formamidino-L-isoseramine amide) -5-deoxyapuramycin, 4” -N- (N-formamidine-L-isoseramine amide) -6-deoxy-5-epiapramycin, 5,6-dideoxy-4 "-N-glycamine apramycin, 5,6-dideoxy-4" -N -Sarcosinyl apuramycin, 5,6-dideoxy-4 "-N- (L-isoseramine acetyl) apuramycin, 5,6-dideoxy-4"- N- (N-methyl-L-isoseramine amide) apramycin, 5,3 ”-DiTable-4” -N-Glycine Apramycin, 5,3 ”-DiTable-4” -N-sarcosine Apramycin or 5,3 ” -Ditable-4 "-N- (L-isoseramine amide) apramycin. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or a solvent mixture thereof. For example, the pharmaceutical composition of claim 9 is used to prevent or treat infectious diseases. For example, the pharmaceutical composition according to item 10 of the patent application, wherein the infectious diseases are sepsis, infective endocarditis, dermatological infections, surgical infections, orthopedic infections, respiratory infections, urinary tract Infectious diseases, intestinal infections, peritonitis, meningitis, infectious diseases in the field of ophthalmology or infectious diseases in the field of otolaryngology. For example, a pharmaceutical composition according to claim 10 or 11, wherein the aforementioned infection is caused by xylene penicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus aureus, coliform bacteria, pneumoniae, or Pseudomonas aeruginosa . For example, the compound according to any one of the items 1 to 8 of the patent application, or a pharmaceutically acceptable salt or a vehicle thereof, is used in therapy. For example, the compound of any one of items 1 to 8 of the patent application, or a pharmaceutically acceptable salt or a vehicle thereof, is used for the prevention or treatment of infectious diseases. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or a solvent thereof for the manufacture of a medicament for the prevention or treatment of an infectious disease. A method for preventing or treating infectious diseases, which comprises administering to a animal a therapeutically effective amount of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or a vehicle thereof . An antibacterial agent comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt or a solvent mixture thereof.