JPS6331478B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to novel aminoglycoside derivatives and salts thereof. More particularly, the present invention relates to novel aminoglycoside derivatives and salts thereof having antiviral and immunostimulatory activities, processes for their production, and pharmaceutical compositions containing them. That is, one object of the present invention is to provide novel aminoglycoside derivatives useful as preventive and therapeutic agents for pathogenic microbial infections. Another object of this invention is to provide a method for producing aminoglycoside derivatives. Yet another object of the invention is to provide pharmaceutical compositions containing aminoglycoside derivatives. The novel aminoglycoside derivative that is the object of this invention can be represented by the following general formula. [In the formula, at least one of R ¹ , R ² , R ³ and R ⁴ is higher alkanoylamino, higher alkenoylamino, which may each have a suitable substituent;
Higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others are amino or acylamino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ means hydroxy or phosphonooxy respectively]. According to this invention, the novel aminoglycoside derivative () can be produced, for example, by the method described below. Manufacturing method 1 [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as before, R ⁴ _a is acylamino, R ⁴ _b is amino, and at least one of R ¹ , R ² and R ³ is an appropriate Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a substituent, and others are amino or acylamino. each meaning]. Manufacturing method 2 [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as before, R ¹ _a is acylamino, R ¹ _b is amino, and at least one of R ² , R ³ and R ⁴ is an appropriate Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkanoylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a substituent, and others are amino or acylamino. each meaning]. Manufacturing method 3 [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as before, R ² _a is acylamino, R ² _b is amino, and at least one of R ¹ , R ³ and R ⁴ is an appropriate Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a substituent, and others are amino or acylamino. each meaning]. Manufacturing method 4 [In the formula, R ¹ _b , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ¹ is a higher alkanoylamino or higher alkenoyl which each may have an appropriate substituent. amino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ² , R ³ and R ⁴ each mean amino or acylamino]. Manufacturing method 5 [In the formula, R ² _b , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ² is a higher alkanoylamino or higher alkenoyl which each may have an appropriate substituent. amino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ² , R ³ and R ⁴ each mean amino or acylamino]. Manufacturing method 6 [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, R ³ _b is amino, R ³ is higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ¹ , R ² and R ⁴ each mean amino or acylamino]. Manufacturing method 7 [In the formula, R ⁴ _b , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ⁴ is a higher alkanoylamino or higher alkenoyl which each may have an appropriate substituent. amino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ¹ , R ² and R ³ each mean amino or acylamino]. Manufacturing method 8 [In the formula, R ¹ _b , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ¹ _a ′ is a higher alkanoylamino, higher acylamino, excluding alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino and higher alkylthiocarbonylamino, at least one of R ² , R ³ and R ⁴ is each substituted with a suitable substituent; higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, and others mean amino or acylamino]. Manufacturing method 9 [In the formula, R ² _b , R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ² _a ′ is a higher alkanoylamino, higher acylamino, excluding alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino and higher alkylthiocarbonylamino, at least one of R ¹ , R ³ and R ⁴ is each substituted with a suitable substituent; higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, and others mean amino or acylamino]. Manufacturing method 10 [In the formula, R ⁵ _a , R ⁶ _a , R ⁷ _a , R ⁸ _a , R ⁹ _a and R ¹⁰ _a are each acyloxy, and at least one of R ¹ , R ² , R ³ and R ⁴ is an appropriate substituted Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a group, and others mean amino or acylamino, respectively. do〕. Manufacturing method 11 [In the formula, R ⁵ _a , R ⁶ _a , R ⁷ _a , R ⁸ _a and R ⁹ _a have the same meanings as before, R ¹⁰ _c is protected phosphonooxy, R ¹ , R ² , R ³ and At least one of R ⁴ may each have a suitable substituent: higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino, or higher alkylthiocarbonyl "amino" and "other" mean amino or acylamino, respectively]. Among the raw material compounds of this invention, compound (b),
(d), (f), (h), (m') and (
q) is a new compound and can be produced by the method below. Manufacturing method A (wherein R ¹ _a , R ¹ _b , R ⁵ , R ⁶ and R ⁷ each have the same meaning as before, and R ² , R ³ and R ⁴ each mean amino or acylamino). Manufacturing method B (In the formula, R ² _a , R ² _b , R ⁵ , R ⁶ and R ⁷ each have the same meaning as before, and R ¹ , R ³ and R ⁴ each mean amino or acylamino). Manufacturing method C (In the formula, R ³ _b , R ⁵ , R ⁶ and R ⁷ each have the same meaning as before, R ³ _a means acylamino, and R ¹ , R ² and R ⁴ each mean amino or acylamino). Manufacturing method D (In the formula, R ⁴ _a , R ⁴ _b , R ⁵ , R ⁶ and R ⁷ each have the same meaning as before, and R ¹ , R ² and R ³ each mean amino or acylamino). Manufacturing method E (In the formula, R ¹ _a , R ¹ _b , R ⁵ , R ⁶ and R ⁷ each have the same meaning as before, and R ² , R ³ and R ⁴ each mean amino or acylamino). Manufacturing method F (In the formula, R ² _a , R ² _b , R ⁵ , R ⁶ and R ⁷ each have the same meaning as before, and R ¹ , R ³ and R ⁴ each mean amino or acylamino]. Production method G (wherein R ³ _a , R ³ _b , R ⁵ , R ⁶ and R ⁷ each have the same meaning as before, and R ¹ , R ² and R ⁴ each mean amino or acylamino). Manufacturing method H (In the formula, R ⁵ _a , R ⁶ _a , R ⁷ _a , R ⁸ _a , R ⁹ _a and R ¹⁰ _a each have the same meaning as before, and R ¹ , R ² , R ³ and R ⁴ are each amino or acylamino). Manufacturing method I [In the formula, R ¹ _a , R ¹ _b , R ⁵ _a , R ⁶ _a , R ⁷ _a , R ⁸ _a , R ⁹ _a and
R ¹⁰ _a each has the same meaning as before, R ¹ is higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy ( lower) alkanoylamino or higher alkylthiocarbonylamino, R ² , R ³ and R ⁴ each mean amino or acylamino]. Manufacturing method J [In the formula, R ⁵ _a , R ⁶ _a , R ⁷ _a , R ⁸ _a and R ⁹ _a have the same meanings as before, R ¹⁰ _b is alk(lower) alkoxy, R ¹⁰ _c is protected phosphonooxy , higher ^{alkanoylamino ,} higher ^{alkenoylamino} , higher alkoxycarbonylamino, higher alkylaminocarbonylamino ^, higher Alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others mean amino or acylamino, respectively]. Suitable pharmaceutically acceptable salts of the aminoglycoside derivatives () are the conventional salts, such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, carbonates, phosphates, acetates, fumars. Examples include organic or inorganic acid addition salts such as acid salts, maleates, tartrates, methanesulfonates, benzenesulfonates, toluenesulfonates, and the like. Preferred examples and explanations of various definitions in the foregoing and following descriptions of this specification will now be described in detail. "Lower" shall mean 1 to 6 carbon atoms unless otherwise specified. Suitable "acyl" moieties for "acylamino" and "acyloxy" include carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl and aliphatic acyl substituted with an aromatic or heterocyclic group. Examples of aliphatic acyl include formyl, acetyl, propionyl, butyryl, isobutyryl,
Lower alkanoyl such as valeryl, isovaleryl, pivaloyl, hexanoyl, lower alkanesulfonyl such as mesyl, ethanesulfonyl, propanesulfonyl, lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tertiary butoxycarbonyl, Examples include lower alkenoyl such as acryloyl, methacryloyl, crotonoyl, saturated or unsaturated acyclic or cyclic acyl such as ( _C3 - _C7 )-cycloalkanecarbonyl such as cyclohexanecarbonyl. Examples of the aromatic acyl include aroyl such as benzoyl, toluoyl, and xyloyl, and allenesulfonyl such as benzenesulfonyl and tosyl. Examples of the heterocyclic acyl include heterocyclic carbonyl such as furoyl, thenoyl, nicotinoyl, isonicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl. As aliphatic acyl substituted with an aromatic group,
For example, phenyl (lower) such as phenylacetyl, phenylpropionyl, phenylhexanoyl, etc.
Alkanoyl includes, for example, phenyl (lower) alkoxycarbonyl such as benzyloxycarbonyl and phenethyloxycarbonyl, and phenoxy (lower) alkanoyl such as phenoxyacetyl and phenoxypropionyl. As aliphatic acyl substituted with a heterocyclic group,
Examples include thienyl acetyl, imidazolylacetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thienylpropionyl, thiadiazolylpropionyl, and the like. These acyl groups may further include hydroxy, amino, carboxy, lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogen such as chlorine, bromine,
Iodine, fluorine, lower alkoxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentyloxy, hexyloxy, lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, pentylthio, hexylthio, nitro, acylamino , aryloxy such as benzyloxy, tolyloxy, lower alkanoyloxy such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, etc. Preferred acyls having such substituents include mono(or di- or tri)halo(lower)alkanoyl such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc. , amino(lower)alkanoyl such as glycyl, aminopropionyl, diaminobutyryl, phenyl(lower)alkoxycarbonylamino(lower)alkanoyl such as benzyloxycarbonylglycyl, phenyl(lower)alkoxycarbonylcarbamoyl, e.g. benzyloxycarbonylcarbamoyl , phenyl(lower)alkoxy(lower)alkanoyl such as benzyloxyacetyl, benzyloxypropionyl, carboxy(lower)alkanoyl such as carboxyacetyl, carboxypropionyl, hydroxy(lower)alkanoyl such as glycoloyl, hydroxypropionyl, hydroxybutyryl, etc. Examples include alkanoyl. Suitable "higher alkanoyl" moieties in "higher alkanoylamino" include octanoyl, nonanoyl, decanoyl, undecanoyl,
lauroyl, myristoyl, pentadecanoyl,
those having 8 or more carbon atoms, such as palmitoyl, heptadecanoyl, stearoyl, icosanoyl, docosanoyl, tetracosanoyl, etc.;
Preferably, those having 8 to 24 carbon atoms are mentioned. "Higher alkoxycarbonylamino" and "higher alkoxy (lower) alkanoylamino"
Suitable "higher alkoxy" moieties include octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy, tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy,
Included are those having 8 or more carbon atoms, preferably 12 to 20 carbon atoms, such as octadecyloxy, nonadecyloxy, and the like. Suitable "higher alkyl" moieties in "higher alkylaminocarbonylamino" and "higher alkylthiocarbonylamino" include octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, etc. Examples include those having 8 or more carbon atoms, preferably 14 to 18 carbon atoms. Suitable "lower alkanoyl" moieties in "higher alkoxy (lower) alkanoylamino" include those exemplified in the explanation of "acyl" above. Suitable "higher alkenoyl moieties" in "higher alkenoylamino" include octenoyl,
Decenoyl, dodecenoyl, tetradecenoyl,
Examples include those having 8 or more carbon atoms, preferably 20 to 24 carbon atoms, such as hexadecenoyl, octadecenoyl, icosenoyl, docosenoyl, tetracosenoyl and the like. "Suitable examples of higher alkoxy (lower) alkanoyl include octyloxyacetyl, dodecyloxyacetyl, tridecyloxyacetyl,
10 to 17 carbon atoms, such as tetradecyloxyacetyl
carbon atoms, preferably 14 to 16 carbon atoms. The above-mentioned "higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino,
"Higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino" means lower alkyl such as methyl, ethyl, propyl, butyl, pentyl, hexyl, hydroxy, such as formyloxy, acetoxy, propionyloxy,
Lower alkanoyloxy such as butyryloxy, higher alkanoyloxy such as lauroyloxy, etc. may have 1 to 3 suitable substituents; Preferred examples of "lower alkyl-higher alkenoylamino, hydroxy-higher alkanoylamino, lower alkyl-higher alkoxycarbonylamino" or (lower or higher ) Alkanoyloxy-higher alkanoylamino. Suitable "al(lower)alkoxy" is
Examples include benzyloxy, phenethyloxy, trityloxy and the like. Suitable "protected phosphonooxy" includes esterified phosphonooxy, such as methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, tertiary butyl ester, Examples include lower alkyl esters such as bentyl ester, tertiary pentyl ester, hexyl ester, and aryl esters such as phenyl ester, tolyl ester, xylyl ester, mesityl ester, cumenyl ester, and the like. The method for producing the target compound and raw material compound of this invention will be explained in detail below. Production method 1 Compound (b) or a salt thereof is a compound (b) or a salt thereof.
It can be produced by subjecting a) or a salt thereof to a deacylation reaction. This deacylation reaction can be carried out by hydrolysis, reduction, deacylation using a Lewis acid, reacting compound (a) with an iminohalogenating agent, then an iminoetherifying agent, and optionally hydrolyzing the product. This is carried out by conventional methods such as deacylation. Suitable iminohalogenating agents include, for example, phosphorus halides such as phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, and phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, and phosgene. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature. Suitable iminoetherifying agents to be reacted with the reaction product thus obtained include alcohols, metal alkoxides, and the like. Suitable alcohols include, for example, methoxy, ethoxy,
Alkanols optionally substituted with alkoxy such as propoxy, isopropoxy, butoxy, etc., such as methanol, ethanol, propanol, isopropanol, butanol, tertiary butanol,
Examples include 1,3-butanediol. Suitable metal alkoxides include, for example, alkali metal alkoxides such as sodium alkoxide and potassium alkoxide, and alkaline earth metal alkoxides such as calcium alkoxide and barium alkoxide. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature. The product thus obtained is optionally subjected to hydrolysis. Hydrolysis can be easily carried out by pouring the reaction mixture obtained above into water. For example, an acid such as dilute hydrochloric acid or acetic acid may be added. The reaction temperature is not particularly limited and may be selected appropriately depending on the type of protecting group for the amino group and the type of the above-mentioned elimination method, but preferably under cooling, at room temperature, or under mild conditions with slightly elevated temperature. This reaction takes place. Hydrolysis includes methods using acids or bases. These methods may be selected depending on the type of acyl group to be eliminated. Suitable acids include organic or inorganic acids such as formic acid, trifluoroacetic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, and the like. The acid suitable for this reaction can be selected depending on the type of acyl group to be eliminated. When the elimination reaction is carried out using an acid, the reaction can be carried out in the presence or absence of a solvent. Suitable solvents include organic solvents, water or mixtures thereof. When trifluoroacetic acid is used, the deacylation reaction is preferably carried out in the presence of anisole. Examples of suitable bases include alkali metal hydroxides such as sodium hydroxide and potassium hydroxide; alkaline earth metal hydroxides such as magnesium hydroxide and calcium hydroxide; and alkaline earth metal hydroxides such as sodium carbonate and potassium carbonate. Alkali metal carbonates, e.g. alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate, alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, alkali metal acetates such as sodium acetate, potassium acetate, e.g. Alkaline earth metal phosphates such as magnesium phosphate and calcium phosphate; inorganic bases such as alkali metal hydrogen phosphates such as disodium hydrogen phosphate and dipotassium hydrogen phosphate; trialkylamines such as trimethylamine and triethylamine; picoline; N-methylpyrrolidine, N-methylmorpholine, 1,5
-Diazabicyclo[4,3,0]non-5-ene, 1,4-diazabicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]undecene-5, and the like. Hydrolysis with a base is often carried out in water or a hydrophilic organic solvent or a mixture thereof. Examples of reduction methods include reduction with an alkali metal borohydride such as sodium borohydride, catalytic reduction using a conventional catalyst, and the like. The reaction temperature is not particularly limited, and the reaction is usually carried out in a range of cooling to heating. In this deacylation reaction, the acylamino groups of R ¹ , R ² , R ³ and R ⁵ may be similarly deacylated during the reaction or during the post-treatment of this reaction; is included within the scope of. Furthermore, in this deacylation reaction, lower or higher alkenoylamino, acyloxy, acylamino substituted with acylamino and acylamino substituted with aryloxy group were substituted with corresponding lower or higher alkanoylamino, hydroxyamino, respectively. Changes to acylamino and hydroxy-substituted acylamino during the reaction or post-processing of this process are also included within the scope. Production method 2 The target compound (d) or a salt thereof can be produced by subjecting the compound (c) or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as Production Method 1. In this elimination reaction, R ² , R ³ , R ⁴ and R ⁵
The acylamino group of may also be deacylated during the reaction or during work-up of the reaction, which is also included within the scope of the reaction. Production method 3 The target compound (f) or a salt thereof can be produced by subjecting the compound (e) or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as Production Method 1. In this deacylation reaction, the acylamino groups of R ¹ , R ³ , R ⁴ and R ⁵ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case, it is within the scope of this reaction. included in. Production method 4 The target compound (g) or a salt thereof can be produced by reacting the compound (b) or a reactive derivative at an amino group or a salt thereof with an acylating agent. Suitable reactive derivatives of the amino group of compound (b) include silyl derivatives produced by the reaction of compound (b) with silyl compounds such as bis(trimethylsilyl)acetamide, mono(trimethylsilyl)acetamide, etc. Can be mentioned. Suitable salts of compound (b) include organic acid salts such as, for example, acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, or, for example, hydrochloride, hydrobromide, sulfate. and acid addition salts such as inorganic acid salts such as phosphates. Suitable acylating agents are conventional and have the formula: R
-OH() (in the formula, R means the above-mentioned acyl)
or a reactive derivative thereof in the carboxy group, or a salt thereof. Suitable salts of the compound () include, for example, metal salts such as sodium salts, potassium salts, calcium salts, and magnesium salts; ammonium salts; and organic amine salts such as triethylamine salts and dicyclohexylamine salts. Suitable reactive derivatives for the carboxy group of compound () include acid halides, acid anhydrides,
Examples include activated amides and activated esters.
Preferred examples are acid chlorides; acid azides; substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid;
dialkyl phosphites, sulfites, thiosulfates, sulfates, alkyl carbonates, aliphatic carboxylic acids such as pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or trichloroacetic acid or aromatic carboxylic acids such as benzoic acid. mixed acid anhydrides with acids; symmetrical acid anhydrides; activated amides with imidazoles, 4-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles; or e.g. cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl [(CH ₃ ) ₂ ⁺ _N = CH−]
ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesyl phenyl ester, phenyl azophenyl ester, phenyl thio ester, p -nitrophenyl thioester, p-cresyl thioester, carboxymethyl thioester, pyranyl ester,
Activated esters such as pyridyl esters, piperidyl esters, 8-quinolylthioesters, or e.g. N,N-dimethylhydroxylamine, 1
Examples include esters with N-hydroxy compounds such as -hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-6-chloro-1H-benzotriazole. These reactive derivatives can be arbitrarily selected from the above compounds depending on the type of compound () to be used. The reaction is carried out, for example, with an alkali metal such as sodium,
Alkaline earth metals such as calcium, alkali metal or alkaline earth metal hydrides such as sodium hydride, calcium hydride, alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, calcium hydroxide, etc. metal hydroxides, e.g. alkali metal or alkaline earth metal carbonates or bicarbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate;
Alkoxides of alkali metals or alkaline earth metals such as sodium ethoxide, lithium methoxide, magnesium methoxide, trialkylamines such as triethylamine, pyridine, 1,5-diazabicyclo[3,4,
0] nonene-5,1,5-diazabicyclo[5,
The reaction is preferably carried out in the presence of an organic or inorganic base such as a bicyclodiaza compound such as 4,0]undecene-5. When the acylating agent is used in the free acid form, for example N,N'-carbonyldiimidazole, N,
N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,
N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide, N-ethyl-N'-(3
-dimethylaminopropyl) carbodiimide, N,N-carbonyldi(2-methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloro ethylene,
Trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus compounds such as phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, 2
-ethyl-7-hydroxybenzisoxazolium salt, 2-ethyl-5-(m-sulfophenyl)
Isoxazolium hydroxide, (chloromethylene)dimethylammonium chloride, 2,2,
4,4,6,6-hexachloro-1,3,5,
Condensing agents such as 2,4,6-triazatriphosphorine, 1-benzenesulfonyloxy-6-chloro-1H-benzotriazole, p-toluenesulfonyl chloride, isopropoxybenzenesulfonyl chloride, or triphenylphosphine and e.g. the presence of mixed condensing agents, such as combinations with carbon tetrahalides such as carbon tetrachloride, carbon tetrabromide, or so-called Vilsmeier reagents, such as complex salts of N,N-dimethylformamide with phosphoryl chloride, phosgene or thionyl chloride; It is preferable to carry out the reaction of this production method below. The reaction is usually performed using chemicals that adversely affect the reaction, such as water, acetone, dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, pyridine, N-methylmorpholine, N-methylpyrrolidine, etc. It is carried out in customary solvents or mixtures thereof that do not cause any oxidation. The reaction temperature is not particularly limited, and the reaction can be carried out in a temperature range from cooling to heating. In this acylation reaction, the amino groups of R ² , R ³ , R ⁴ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in this case also within the scope of this reaction. included in. Production method 5 The target compound (h) or a salt thereof can be produced by reacting the compound (d) or its reactive derivative at an amino group or a salt thereof with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ³ , R ⁴ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is included within. Production method 6 The target compound (i) or a salt thereof can be produced by reacting compound (f) or a reactive derivative thereof at an amino group or a salt thereof with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ² , R ⁴ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production Method 7 The target compound (j) or a salt thereof can be produced by reacting the compound (h) or its reactive derivative at an amino group or a salt thereof with an acylating agent. This reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ² , R ³ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method 8 The target compound (l) or its salt can be produced by reacting compound (k) or its reactive derivative at the amino group or its salt with an acylating agent. This reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ² , R ³ , R ⁴ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method 9 The target compound (n) or its salt can be produced by reacting compound (m) or its reactive derivative at the amino group or its salt with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ³ , R ⁴ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method 10 The target compound (o) or a salt thereof can be produced by subjecting the compound (m') or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as in Production Method 1. In this deacylation reaction, the acylamino groups of R ¹ , R ² , R ³ and R ⁴ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method 11 The target compound (p) or a salt thereof can be produced by subjecting the compound (q) or a salt thereof to an elimination reaction of the phosphono-protecting group. The reaction can be carried out in the same manner as the base hydrolysis method in Production Method 1. In this reaction, the acylamino groups of R ¹ , R ² , R ³ and R ⁴ may be similarly deacylated during the reaction or during the work-up of this reaction, but in that case also within the scope of this reaction. Included. Production method A The target compound (b) or a salt thereof can be produced by subjecting the compound (a) or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as in Production Method 1. In this deacylation reaction, the acylamino groups of R ² , R ³ , R ⁴ and R ⁵ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method B The target compound (d) or a salt thereof can be produced by subjecting the compound (c) or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as in Production Method 1. In this deacylation reaction, the acylaminos of R ¹ , R ³ , R ⁴ and R ⁵ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case also within the scope of this reaction. included in Production method C The target compound (f) or a salt thereof can be produced by subjecting the compound (e) or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as in Production Method 1. In this deacylation reaction, the acylamino groups of R ¹ , R ² , R ⁴ and R ⁵ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method D The target compound (h) or a salt thereof can be produced by subjecting the compound (g) or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as in Production Method 1. In this deacylation reaction, the acylamino groups of R ¹ , R ² , R ³ and R ⁵ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method E The target compound (a) or a salt thereof can be produced by reacting the compound (b) or a reactive derivative thereof at an amino group or a salt thereof with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this deacylation reaction, the amino groups of R ² , R ³ , R ⁴ and R ⁵ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method F The target compound (c) or a salt thereof can be produced by reacting the compound (d) or a reactive derivative thereof at an amino group or a salt thereof with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ³ , R ⁴ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production Method G The target compound (e) or a salt thereof can be produced by reacting the compound (f) or its reactive derivative at an amino group or its salt with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ² , R ⁴ and R ⁵ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method H The target compound (j) or a salt thereof can be produced by reacting compound (i) or a reactive derivative thereof at an amino group or a salt thereof with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ₂ , R ³ and R ⁴ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method (1) The target compound (l) or a salt thereof can be produced by subjecting compound (k) or a salt thereof to a deacylation reaction. The reaction can be carried out in the same manner as in Production Method 1. In this deacylation reaction, the acylamino groups of R ¹ , R ² , R ³ and R ⁴ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in this case also the scope of this reaction is contained within. Production method (2) The target compound (m) or its salt can be produced by reacting compound (l) or its reactive derivative at an amino group or its salt with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, R ² , R ³ and R ⁴
The amino groups of may likewise be acylated during the reaction or during work-up of the reaction, which are also encompassed within the scope of the reaction. Production method J-(1) The target compound (n) or a salt thereof can be produced by subjecting the compound (o) or a salt thereof to a reaction for introducing a hydroxy protecting group. Suitable hydroxy-protecting group introducing agents are inertial introducing agents, and compounds that can be represented by the formula: Ra-OH (a), where Ra means a (lower) alkyl such as benzyl, trityl, etc. or a reactive derivative thereof or a salt thereof at the hydroxy group. The reaction can be carried out under the same conditions as in Production Method 4. Production method J-(2) The target compound (o) or a salt thereof can be produced by reacting the compound (n) or a salt thereof with an acylating agent. The reaction can be carried out in the same manner as Production Method 4. In this acylation reaction, the amino groups of R ¹ , R ² , R ³ and R ⁴ may be similarly acylated during the reaction or during the post-treatment of this reaction, but in that case, the scope of this reaction is contained within. Production method J-(3) The target compound (p) or a salt thereof can be produced by subjecting the compound (o) or a salt thereof to an elimination reaction of the hydroxy protecting group. The reaction can be carried out in the same manner as the acid hydrolysis method in Production Method 1. In this reaction, the acylamino groups of R ¹ , R ² , R ³ and R ⁴ may be similarly deacylated during the reaction or during the post-treatment of this reaction, but in that case also within the scope of this reaction. Included. Production method J-(4) The target compound (q) or a salt thereof can be produced by subjecting the compound (p) or a salt thereof to a reaction for introducing a protected phosphono group. Suitable introduction agents to be used in this introduction reaction include diphenyl chlorophosphorus salts and the like. The reaction is usually performed using chemicals that adversely affect the reaction, such as water, acetone, dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, dichloromethane, chloroform, pyridine, N-methylmorpholine, N-methylpyrrolidine, etc. It is carried out in customary solvents or mixtures thereof that do not cause any oxidation. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling, room temperature, or heating. The target compound () and its salts may be further treated with urea, sugars such as α-cyclodextrin, β-cyclodextrin, γ-cyclodextrin, etc. to form a complex with the above compound. are also included within the scope of this invention. The target compound () and its salts have antiviral activity and immunostimulatory activity, and are therefore useful as antiviral agents for humans, animals, and plants, and as preventive agents for pathogenic microbial infections. For prophylactic or therapeutic purposes, the object compound of the present invention () and pharmaceutically acceptable salts thereof can be prepared using organic or inorganic compounds suitable for oral administration, parenteral administration, and external use, containing the above-mentioned compound as an active ingredient.
They are used in the form of conventional pharmaceutical formulations containing them in admixture with pharmaceutically acceptable carriers such as solid or liquid excipients. Pharmaceutical formulations may be in solid form, such as tablets, dragees, ointments, granules, powders, capsules, or liquid forms, such as solutions, suspensions, syrups, emulsions, lemonades, and the like. If necessary, adjuvants, stabilizers, wetting agents, and others such as lactose, magnesium stearate, terra alba, sucrose, corn starch, talc, stearic acid, gelatin, agar, pectin, peanut oil, and olive oil may be added to the above formulation. , cocoa butter, ethylene glycol, etc., may also be included. The dosage of the compound () or its pharmaceutically acceptable salt varies depending on the age and condition of the patient, the type of disease, and the type of the compound () or pharmaceutically acceptable salt thereof to be applied. Generally, the preferred dose for a patient of Compound () or a pharmaceutically acceptable salt thereof is 0.1
Selected in the range of ~100mg/Kg/day. The present invention will be explained below with reference to manufacturing agents and examples. In the examples, the position numbers of carbon atoms in the aminoglycoside derivatives shall follow the position numbers of kanamycin A and kanamycin B as shown below.

【formula】

[Formula] In order to demonstrate the usefulness of the target compound, the antiviral activity and cytotoxicity of representative compounds of this invention are shown below. Assays were performed in confluent Vero cell cultures in multiwell trays (96 wells). Cell cultures were in Eagle's minimal medium (MEM) supplemented with 5% fetal bovine serum (FBS).
They grew inside and fused together. (1) Anti-HSV (herpes simplex virus) activity (A) Test method The medium was changed to 0.5% FBS-MEM. Cell cultures were inoculated with approximately 100 TCID ₅₀ HSV-I Miyama strains, immediately after which test compounds at various concentration levels were added and incubated for 2 days at 37°C in a humidified atmosphere of 5% _CO2 and 95% air. .
Four wells were used for each concentration. 5 of these
% trifluoroacetic acid and stained with 0.1% crystal violet. Virus CPE
was observed under a microscope (40x magnification). Antiviral activity is defined as ID ₅₀ (50% inhibitory dose), i.e. virus
It was expressed as the compound concentration required to reduce viral CPE by 50% (in wells) when CPE reached completion (100% cell destruction) in control virus-infected cell cultures. (B) Test compound (1) 1-N-palmitoyl-3″-N-propionylkanamycin A dihydrochloride. (2) 3″-N-palmitoyl-1-N-trifluoroacetylkanamycin A dihydrochloride . (3) 1-N-n-hexadecyloxycarbonyl-3''-N-trifluoroacetylkanamycin A dihydrochloride. (4) 3-N-palmitoyl-3''-N-trifluoroacetylkanamycin A dihydrochloride Hydrochloride. (5) 1-N-n-icosanoyl-3″-N-trifluoroacetylkanamycin A dihydrochloride. (C) Test results

(2) Cytotoxicity (A) Test Method In a parallel study to the antiviral assay on confluent Vero cell cultures (uninfected), the compounds were tested for their effects on cells of normal morphology. Cytotoxicity was expressed as the lowest drug concentration that disrupted the cell monolayer. (B) Test compound (1) 1-N-palmitoyl-3″-N-propionylkanamycin A dihydrochloride. (2) 3″-N-palmitoyl-1-N-trifluoroacetylkanamycin A dihydrochloride . (3) 1-N-n-hexadecyloxycarbonyl-3″-N-trifluoroacetylkanamycin A dihydrochloride. (4) 1-N-n-icosanoyl-3″-N-trifluoroacetylkanamycin A・Dihydrochloride. (C) Test results

【table】 Manufacturing example 1 3,6'-bis-N-benzyloxycarbonyl
-3″-N-trifluoroacetylkanamycin A
(1.4 g) of tetrahydrofuran (40 ml) and water
(10ml) of benzyloxycarboxylic acid.
Nil chloride (0.28 ml) was added to triethyl chloride under ice cooling.
Add dropwise to the mixture while maintaining pH 8 to 8.5 with
Stir at the same temperature for 1 hour. Concentrate the reaction mixture under reduced pressure
do. The residual solid was dissolved in diethyl ether (50 ml) and
Wash twice with water and water (50 ml), air dry,
1,3,6'-tris-N-benzyloxycarbo
Nyl-3″-N-trifluoroacetyl kanamaysi
Obtain A (1.45 g). Melting point >260℃ (decomposition) IR (Nujiyor): 1680, 1645, 1520, 1270,
1150, 1030cm^-1 NMR (DMSO−d₆, δ): 4.98, 7.28 (15H, s) Manufacturing example 2 According to the method of Production Example 1, the following compound is obtained. 1,6'-bis-N-benzyloxycarbonyl
-3-N-tertiary butoxycarbonyl-3″-N-
Trifluoroacetylkanamycin A. IR (nujiyor): 1700, 1680, 1520cm^-1 NMR (DMSO−d₆, δ): 1.37 (9H, s), 7.33
(10H, s) Manufacturing example 3 1,3,6'-tris-N-benzyloxycarl
Bonyl-3″-N-trifluoroacetylkanamai
Syn A (1.4 g) in N,N-dimethylformamide
(20ml) and concentrated ammonia water (20ml) mixture
The solution is stirred at room temperature for 6 hours. Even more concentrated ammonia
Add water (10ml) to this solution and stir the mixture at the same temperature.
Stir for an additional 3 hours. The reaction mixture was diluted with diethyl ethyl ethyl ether.
Add dropwise to solution (150 ml) under stirring. generate
Take the precipitate and add diethyl ether (20ml) and
Wash twice with water (20 ml), air dry,
6'-Tris-N-benzyloxycarbonylkana
Obtain Mycin A (700 mg). Manufacturing example 4 (a) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-trifluoroacetyl kanamaysi
of tetrahydrofuran (48 ml)) and
In a mixture solution with water (12 ml), 2-tert.
Xycarbonyloxyimino-2-phenyla
Setonitrile (1.04g) and triethylamine
(0.59ml) at room temperature, and the mixture was heated at the same temperature for 2 hours.
Stir for an hour. Then 2-tertiary butoxylic
Bonylimino-2-phenylacetonitrile
(1.04g) and triethylamine (0.59ml)
was added to this solution and the mixture was stirred at room temperature overnight.
Ru. Concentrate the solution under reduced pressure to obtain a residue under reduced pressure at room temperature.
Dry to give 3,6'-bis-N-benzyloxy
Carbonyl-1-N-tert-butoxycarbonyl
Ru-3″-N-trifluoroacetyl kanamaysi
Obtain A as a crude solid (12 g). (b) 3,6'-bis-N-benzyloxycarbonyl
Ru-1-N-tertiary butoxycarbonyl-3″-
N-trifluoroacetylkanamycin A (crude
product, 12 g) of N,N-dimethylformamide
(50ml) and concentrated ammonia water (25ml)
Stir the solution overnight at room temperature. Add concentrated anhydride to this solution.
Add Monia water (15ml) and stir at room temperature for 4 hours.
Ru. Add concentrated ammonia water (15ml) to this solution.
and stirred at the same temperature for 4 hours. Dilute this solution
Pour into ethyl ether (500ml) to produce
Remove the precipitate and add diethyl ether (100ml).
and water (100ml). Precipitate phosphorus pentoxide
to give 3,6'-bis-N-benne.
Zyloxycarbonyl-1-N-tertiary butoxy
Cycarbonylkanamycin A (2.50g) as a solid
get as. Melting point 246-247℃ IR (Nuzhiyor): 3320, 1685, 1670 (sh) 1650
(sh), 1520, 1270, 1145, 1065, 1050cm^-1 NMR (DMSO−d₆, δ): 1.36 (9H, s) Manufacturing example 5 (1) Add phosphorus oxychloride (0.56ml) to dimethylforma.
Mido (0.47ml) and tetrahydrofuran (0.9ml)
and the suspension at -5 to 0°C for 10 minutes.
Stir for a while. Add tetrahydrofuran to the above suspension.
(9 ml), then N-(benzyloxycarbonyl)
) Glycine (981 mg) was stirred at -5 to 0°C.
Add to. Stir this mixture for 30 minutes at the same temperature.
Prepare an activated acid solution. 3,6'-bis-N-
benzyloxycarbonyl-1-N-tertiary butyl
Toxicarbonylkanamycin A (2g)
Mixture of trahydrofuran (60ml) and water (15ml)
Add the activated acid solution obtained above to the compound solution,
Maintain pH between 8 and 9 with triethylamine
Drip. Stir the reaction mixture for 30 minutes at the same temperature.
Ru. The reaction mixture is concentrated under reduced pressure. solid produced
and then sequentially add 1N hydrochloric acid and diethyl ether.
(90ml) and water until the pH of the washing solution shows 7.
further diluted with diethyl ether (10 ml) and isochloride.
Clean with a mixture of propyl alcohol (10ml)
3,6'-bis-N-benzyl
xycarbonyl-3″-N-[N-(benzyloxycarbonyl
cyclocarbonyl)glycyl]-1-N-tertiary butyl
Toxicarbonylkanamycin A (1.91g)
Obtained as a solid. Melting point 148~150℃ IR (Nujiyor): 3300, 1680, 1520, 1260,
1150, 1040cm^-1 NMR (DMSO−d₆, δ): 1.35 (9H, s) (2) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-tert-butoxycarbonylkanama
Isin A (2g) in tetrahydrofuran (40ml)
and water (10 ml), add acetyl chloride to the solution.
Lido (0.22g) was added to triethyl alcohol at room temperature while stirring.
Add it dropwise while maintaining the pH between 8 and 8.5.
This solution is stirred at the same temperature for 1 hour. The sediment produced
Collect the precipitate and sequentially dilute the precipitate with diethyl ether.
(20 ml) and water (60 ml) three times. Shen
Air-dry the membrane and extract 3″-N-acetyl-3,6′-bi
Su-N-benzyloxycarbonyl-1-N-
Tertiary-butoxycarbonylkanamycin A
(1.86 g) is obtained as a solid. Melting point>236℃ (decomposition) IR (Nujiyor): 1680, 1510, 1500, 1140,
1030cm^-1 NMR (DMSO−d₆, δ): 1.85 (3H, s) Manufacturing example 6 The following compound was prepared according to the method of Production Example 5(1) and 5(2).
get something (1) 3″-N-benzyloxyacetyl-3,6′-
Bis-N-benzyloxycarbonyl-1-N
-Tertiary butoxycarbonylkanamycin A. IR (nujiyor): 1680, 1520cm^-1 NMR (DMSO−d₆, δ): 1.37 (1H, s), 4.57
(2H, s), 7.27 (5H, s), 7.30 (5H, s),
7.33 (5H, s) (2) 3,6′,3″-tris-N-benzyloxyca
Rubonyl-1'-N-tertiary butoxycarbonyl
Kanamycin A. Melting point>239℃ (decomposition) IR (Nujiyor): 3320, 1690, 1520, 1300,
1150, 1070, 1040cm^-1 NMR (DMSO−d₆, δ): 1.35 (9H, s), 5.00
(6H, s), 7.31 (10H, s) Manufacturing example 7 3,6,′,3″-tris-N-benzyloxy
Carbonyl-1-N-tertiary butoxycarbonyl
Kanamycin A (1g) and anisole (3ml)
and trifluoroacetic acid (10ml) on ice.
Stir for 30 minutes in the cold. Concentrate the solution under reduced pressure to obtain a residue.
get. Add diethyl ether (50ml) to this residue.
pour. Take the formed precipitate and dilute it with diethyl ether.
Wash 3 times with (30 ml). The precipitate is then placed under reduced pressure.
Dry with phosphorous pentoxide for 2 hours to remove 3,6′,3″-Tris.
-N-benzyloxycarbonylkanamycin
Obtain A. monotrifluoroacetate (901 mg). IR (Nujiyor): 3300−3250, 1690, 1540−
1510, 1080, 1050cm^-1 NMR (DMSO−d₆, δ): 5.00, 7.30 (15H, s) Manufacturing example 8 6'-N-Benzyloxycarbonyl Kanamaishi
A (4.19g) and zinc acetate dihydrate (6.54g)
Add a solution of g) in dimethyl sulfoxide (140 ml).
Stir at night. Add 2-(tert-butoxycarbonate) to this solution.
(rubonyloxyimino)-2-phenylacetoni
Tolyl (1.83g) and triethylamine (1.04
g) at room temperature. Stir this mixture overnight at the same temperature.
Stir. Mixture in diethyl ether (3)
Pour and decant the supernatant to remove the syrup.
obtain. Powder the syrup twice with diethyl ether.
crushed, 1,4-dioxane (100ml) and water (100ml)
ml). This solution is cationized
Replacement resin, Amberlite IRC-50 (trademark, H
Fill the mold (manufactured by Rohm and Haas) (200ml).
50% 1,4-dioxa
aqueous solution (600ml) and 50% 1,4-dioxa
Elute with 1N ammonia in aqueous solution. desired transformation
The fractions containing the compound are combined and concentrated under reduced pressure. residue
Dissolve in a mixed solvent of ethanol and toluene.
The solvent was completely distilled off under reduced pressure to give 6'-N-benzene.
hydroxycarbonyl-3-N-tert-butoxyca
Rubonylkanamycin A (3.98 g) is obtained. NMR (DMSO-d₆, δ): 1.33 (9H, s), 7.27
(5H, s) Manufacturing example 9 6'-N-benzyloxycarbonyl-3-N-
Tertiary-butoxycarbonylkanamycin A (3.9
g) of tetrahydrofuran (40 ml) and water (7
ml) in a mixture solution of benzyloxycarbonyl
Add chloride (1.7ml) to triethylamine under ice cooling.
Add while maintaining the pH between 8 and 9. mixture
Stir for 1 hour under the same conditions. Concentrate this mixture under reduced pressure
The solid obtained is washed with water and dried under reduced pressure over phosphorus pentoxide.
and 1,6′,3″-tris-N-benzyloxy
Carbonyl-3-N-tertiary butoxycarbonyl
Kanamycin A (5.15 g) is obtained. IR (nujiyor): 1680, 1520cm^-1 NMR (DMSO−d₆, δ): 1.37 (9H, s), 7.33
(15H, s) Manufacturing example 10 1,6′,3″-tris-N-benzyloxycarl
Bonyl-3-N-tert-butoxycarbonylkana
Suspension of Mycin A (987 mg) in Anisole (3 ml)
Add trifluoroacetic acid (10ml) to the solution under ice cooling.
Ru. Stir the mixture under ice cooling for 3 hours and at room temperature for 2 hours.
do. Toluene is added to the residue obtained by concentrating the mixture under reduced pressure.
was added and the mixture was concentrated under reduced pressure. The residue and dirt
Mixture with Kagel (2g) in tetrahydrofuran
Concentrate under reduced pressure. Powder the residue with silica gel (30
g) for column chromatography using
and chloroform-methanol mixed solvent [10:1
(V/V), then 8:z(V/V)].
Combine the fractions containing the desired compound and concentrate under reduced pressure.
1,6′,3″-tris-N-benzyloxycarboxylate
Rubonylkanamycin A (309 mg) is obtained. IR (nujiyor): 1670, 1510cm^-1 NMR (DMSO-d₆, δ): 7.33 (s) Manufacturing example 11 6'-N-benzyloxycarbonyl-3-N-
Tertiary-butoxycarbonylkanamycin A (2.69
g) in dimethyl sulfoxide (25 ml).
Add ethyl fluoroacetate (693mg) at room temperature,
Stir the mixture for 30 minutes. Mixture with diethyl ether
Pour into solution (500 ml) to form a precipitate. Shen
Remove the precipitate and wash with diethyl ether and water sequentially.
The 6′-N-base was washed, dried under reduced pressure with phosphorous pentoxide, and
ndyloxycarbonyl-3-N-tertiary butoxycarbonyl
cyclocarbonyl-3″-N-trifluoroacetylka
Namycin A (2.84 g) is obtained. IR (nujiyor): 1700-1670, 1520cm^-1 NMR (DMSO-d₆, δ): 1.37 (9H, s), 7.33
(5H, s) Manufacturing example 12 Crude 6'-N-benzyloxycarbonyl-1,
3,3″-tris-N-tertiary butoxycarbonyl
Kanamycin A (2.15g) dissolved in pyridine (22ml)
Add acetic anhydride (2.64 ml) to the solution at room temperature, and mix
Stir overnight at the same temperature. Add more acetic anhydride to the mixture
(2.6ml) and stirred the mixture for a further 4 hours.
Ru. Add methanol (10 ml) to the reaction mixture at room temperature.
to decompose excess acetic anhydride and concentrate the mixture under reduced pressure.
do. Dissolve the residue in ethyl acetate, water, 2N sulfuric acid
and water and dried over magnesium sulfate.
and concentrate. Use silica gel (70g) for the residue
Column chromatography
Elute with lum-methanol [100:1 (V/V)],
refine. Collect fractions containing the desired compound and apply vacuum
Concentrate to 2′,3′,4′,2″,4″,6″-hex-O
-acetyl-6'-N-benzyloxycarbonyl
-1,3,3″-tris-N-tert-butoxylic
Bonilkanamycin A (1.46 g) is obtained. IR (nujiyor): 1750-1700, 1510cm^-1 NMR (CDCl)₃, δ): 1.43, 2.03−2.30, 7.33 Manufacturing example 13 The following compound is obtained according to the method of Production Example 12. 2′,3′,4′,2″,4″,6″-hex-O-acetylene
Ru-3″-N-acetyl-3,6′-bis-N-ben
Zyloxycarbonyl-N-tert-butoxycal
Bonilkanamycin A. IR (Nujiyor): 3330, 1740, 1520, 1240,
1170, 1040cm^-1 NMR (CDCl)₃, δ): 1.32 (9H, s), 1.90−2.20
(21H) Manufacturing example 14 (a) 2′, 3′, 4′, 2″, 4″, 6″-hex-O-a
Se
Tyl-3″-N-acetyl-3,6′-bis-N-
benzyloxycarbonyl-1-N-tertiary butyl
Toxiccarbonylkanamycin A (2.5g)
Lifluoroacetic acid (30ml) and anisole (7ml)
ml) mixture solution was stirred for 1 hour under ice-cooling.
The reaction mixture was concentrated under reduced pressure to give 2′, 3′, 4′, 2″,
4″,6″-hex-O-acetyl-3″-N-acetyl
Chil-3,6'-bis-N-benzyloxycarl
A residue containing bonilkanamycin A is obtained. (b) Add phosphorus oxychloride (0.29 ml) to dimethylforma.
Mido (0.25ml) and tetrahydrofuran
(0.5 ml) of the mixture and add tetrafluor to this suspension.
Hydrofuran (5 ml) and 3-acetoxyte
tradecanoic acid (706 mg) sequentially at -5 to 0°C.
Add under stirring. Stir the mixture for 30 minutes at the same temperature.
An activation solution is prepared. obtained by the above operation
intermediate, tetrahydrofuran (40ml) and
solution in a mixture of water (10 ml) and activated acid solution.
Maintain pH between 8 and 9 with triethylamine.
dripping. Stir the mixture for 30 minutes at the same temperature.
Ru. The reaction mixture is concentrated under reduced pressure. Dilute the residue with acetic acid
Dissolve in chill (120ml) and dilute the solution with sodium bicarbonate.
Sodium sulfate solution and water.
Dry with a vacuum cleaner and concentrate under reduced pressure. Silica gel residue
Column chromatography using (50g)
and chloroform-methanol mixture [30:
1 (V/V)]. Images containing the target compound
2′, 3′, 4′, 2″,
4″,6″-hex-O-acetyl-3″-N-acetyl
Chil-1-N-(3-acetoxytetradecano
yl)-3,6'-bis-N-benzyloxyca
Rubonylkanamycin A (1.95 g) is obtained. IR (Nujiyor): 3270, 1720−1700, 1650,
1530−1510, 1060−1020cm^-1 NMR (CDCl)₃, δ): 2.88 (3H, m) Manufacturing example 15 2′,3′,4′,2″,4″,6″-hex-O-acetylene
Ru-6'-N-benzyloxycarbonyl-1,
3,3″-tris-N-tertiary butoxycarbonyl
Kanamycin A (1.41g) in methanol (28ml)
Add potassium hydroxide (811 mg) to the solution at room temperature.
The mixture is stirred at the same temperature for 2 hours. Add water to the mixture (75
ml). Remove the formed precipitate, wash it with water, and
Dry under reduced pressure with phosphorous oxide to obtain 6′-N-benzyl chloride.
xycarbonyl-1,3,3″-tris-N-tertiary
Butoxycarbonylkanamycin A (1.04g)
get. IR (nujiyor): 1670, 1520cm^-1 NMR (DMSO−d₆, δ): 1.33 (27H, s), 7.33
(5H, s) Manufacturing example 16 6'-N-Benzyloxycarbonyl Kanamaishi
of A (1.5 g), 1,4-dioxane (20 ml) and
2-(tertiary butyl alcohol) was added to a mixture solution of
Toxicarbonyloxyimino)-2-phenyl
Acetonitrile (3.58g) and triethylamine
(2 ml) at room temperature. Stir the mixture overnight
The solid obtained by concentrating the reaction mixture was diluted with diethyl ethyl ethyl ether.
The crude 6'-N-benzyloxycarboxylic acid was washed with
rubonyl-1,3,3″-tris-N-tert-buto
Oxycarbonylkanamycin A (2.16 g) is obtained. Manufacturing example 17 3,2',6'-tris-N-benzyloxycarl
Bonyl-3′,4′-dideoxy-3″-N-triful
Oloacetylkanamycin B (2.0g), tetra
Mixture of hydrofuran (30ml) and water (7ml)
Add 2-(tert-butoxycarbonyloxy) to the solution.
imino)-2-phenylacetonitrile (1.03g)
and triethylamine (0.59ml).
Add warm. The mixture is stirred at room temperature overnight. reaction
Concentrate the mixture under reduced pressure. Residual N,N-dimethyl
Formamide (30ml) solution with concentrated ammonia water (30ml)
ml) at room temperature and stir the mixture overnight. mixture
Concentrate the substance under reduced pressure. The residue was dissolved in N,N-dimethylform.
Dissolve it in Muamide (30ml) and add concentrated ammonia to this.
Add water (10ml) at room temperature. Bring the mixture back to room temperature
Stir overnight. Evaporate the mixture to dryness under reduced pressure
Ru. The residue was washed with diethyl ether and
A mixture of hydrofuran (40ml) and water (10ml)
dissolve in Add benzyloxycarbonyl to this solution.
triethylamine under ice-cooling.
Add while maintaining the pH between 7 and 8. this
The mixture is stirred under the same conditions for 1 hour. reaction mixture?
Tetrahydrofuran is distilled off. Precipitate formed
Remove, wash with water, and dry with phosphorus pentoxide. This precipitation
A suspension of trifluorochloride in anisole (5.5 ml)
Add to acetic acid (18.3ml) under ice cooling. Chill the mixture on ice
Stir for 1 hour. The mixture was concentrated under reduced pressure and the residue
is completely evaporated to dryness by azeotroping with toluene.
The residue was purified by column chromatography using silica gel (45 g).
Subjected to chromatography, chloroform-methanol
mixture of chlorine (10:1), then chloroform-meth
Elute with a mixture of alcohol (4:1). the first fraction
Concentrate under reduced pressure to obtain 3,2′,6′,3″-tetrakis-N
-benzyloxycarbonyl-3',4'-dideoxy
Cikanamycin B (303 mg) is obtained. IR (CHCl₃): 1680, 1510cm^-1 Manufacturing example 18 According to the method of Production Example 7, the following compound is obtained. (1) 3,6'-bis-N-benzyloxycarbonylate
Le-3″-N-[N-(benzyloxycarbonylate)
[glycyl] kanamycin A. (2) 3″-N-acetyl-3,6′-bis-N-ben
Zyloxycarbonylkanamycin A. (3) 3″-benzyloxyacetyl-3,6′-bis
-N-benzyloxycarbonylkanamycin
A. (4) 3,6'-bis-N-benzyloxycarbonylate
Le-3″-N-[N-(benzyloxycarbonylate)
) Glycyl Kanamycin A Monotriflu
Oroacetate. Manufacturing example 19 The following compound is obtained according to the method of Production Example 10. 1,6'-bis-N-benzyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. Manufacturing example 20 Hexadecanethiol (3g) in anhydrous dichloro
Dissolved in methane (50ml) and anhydrous pyridine (1.9ml)
Add p-nitrophenyl chloroformate (2.57g) to the liquid.
Add to ice-cold. Stir the reaction mixture at the same temperature for 1 hour.
Stir and then stir overnight at room temperature. Add 1N salt to the solution
Wash sequentially with acid, water and saturated aqueous sodium chloride solution.
After cleaning and drying with sodium sulfate, concentrate under reduced pressure.
, S-hexadecylthiocarboxylic acid p-nitro
Phenyl (5.04 g) is obtained as a solid. IR (Nujiyor): 1705, 1620, 1590, 1530,
1490, 1350, 1195, 1160, 1120cm^-1 Manufacturing example 21 (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-palmitoyl-3″-N-triful
Oloacetylkanamycin A (1g) pyridine
Trityl chloride (0.77
g) was added at room temperature and the mixture was stirred at 70℃ for 4 hours.
do. The residue obtained by concentrating the reaction mixture under reduced pressure was
-Wash 3 times with hexane (20ml) and dry under reduced pressure.
Ru. Dissolve this residue in pyridine (20ml) and
Add acetic anhydride (3 ml) to the solution while stirring at room temperature.
Ru. Leave the mixture at room temperature overnight. reaction mixture
Concentrate under reduced pressure to obtain a residue. This residue was evaporated with acetic acid.
Dissolve in chill (50 ml) and dilute the solution with 1N hydrochloric acid and carbonic acid.
Sodium hydrogen aqueous solution and sodium chloride aqueous solution
Wash with solution, dry with sodium sulfate, and concentrate under reduced pressure.
Reduce to obtain a residue. This residue was dissolved in silica gel (60
g) for column chromatography using
and chloroform-methanol [100:1 (V/
V)]. Collect fractions containing the target compound
2′, 3′, 4′, 2″, 4″, −pen
ter-O-acetyl-3,6'-bis-N-bendi
-1-N-palmitoyl-
3″-N-trifluoroacetyl-6″-O-tri
Tilkanamycin A (693 mg) is obtained. IR (Nujiyor): 1740, 1720, 1520, 1220,
1150, 1030cm^-1 NMR (CDCl)₃, δ): 0.91 (3H, m), 1.70 (3H,
s), 1.74 (3H, s), 1.99 (3H, s), 2.00
(3H, s), 2.10 (3H, s) (2) 2′,3′,4′,2″,4″-penta-O-acetyl
-3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-palmitoyl-3″-N-triful
Oloacetyl-6″-O-tritylkanamycin
A (653 mg) with acetic acid (16 ml) and water (4 ml)
The mixture solution is stirred at 80°C for 2 hours. reaction mixture
Concentrate the product under reduced pressure to obtain a residue. The residue is n-hex
Grind in Sun (20 ml). The precipitate that forms
Remove, air dry, 2′, 3′, 4′, 2″, 4″-penta-
O-acetyl-3,6'-bis-N-benzyl
Xycarbonyl-1-N-palmitoyl-3″-
N-trifluoroacetylkanamycin A (500
mg). NMR (DMSO−d₆, δ): 1.90 (15H, m) (3) 2′,3′,4′,2″,4″-penta-O-acetyl
-3,6'-bis-N-benzyloxycarbony
Ru-1-N-palmitoyl-3″-N-triful
Oloacetylkanamycin A (1g), 1-methy
limidazole (278mg) and dichlorophosphate
Phenyl (455 mg) in dioxane (20 ml) solution
Stir on ice for 10 minutes, then at room temperature for 2 hours.
Ru. Acetic acid of the residue obtained by concentrating the reaction mixture under reduced pressure
Add ethyl (60 ml) solution to saturated sodium hydrogen carbonate solution.
Wash with a saturated aqueous solution of sodium chloride and a saturated aqueous solution of sodium chloride.
After drying with sodium sulfate, concentrate under reduced pressure.
Ru. Drain the residue using silica gel (50g).
Subjected to mucochromatography, chloroform-
Elute with methanol mixture [40:1 (V/V)]
Ru. Collect fractions containing the target compound and concentrate under reduced pressure.
2′,3′,4′,2″,4″-penta-O-acetyl
Ru-3,6'-bis-N-benzyloxycarbo
Nyl-6″-O-(diphenylphosphoryl)-1-
N-palmitoyl-3″-N-trifluoroacetate
Obtain tilkanamycin A (453 mg). IR (nujiol + ethanol): 1740, 1710,
1645, 1520, 1210cm^-1 NMR (CDCl)₃, δ): 0.90 (3H, m), 1.75 (3H,
s), 1.95 (3H, s), 2.00 (3H, s), 2.02
(3H, s), 2.10 (3H, s), 7.10−7.50 (20H,
m) Manufacturing example 22 The following compound is obtained according to the method of Production Example 12. 2′,3′,4′,2″,4″,6″-hex-O-acetylene
Ru-3,6'-bis-N-benzyloxycarbonylate
Root-1-N-n-pentadecanoyl-3″-N-t
Lifluoroacetylkanamycin A. IR (Nujiyor): 3200, 1745, 1720, 1690,
1640, 1530, 1230, 1165, 1040cm^-1 NMR (CDCl)₃, δ): 0.92 (3H, m), 1.90−2.15
(18H) Manufacturing example 23 3,6'-bis-N-benzyloxycarbonyl
-3″-N-(N-benzyloxycarbonyl glycerol)
Kanamycin A trifluoroacetate
(Add 8.6 g of methanol (50 ml) solution to 1N carbonate solution.
Adjust the pH to 8-9 with a lium aqueous solution. water mixture
(200ml) to remove the formed precipitate, wash it with water, and air it.
Dry, 3,6'-bis-N-benzyloxycarboxylic acid
Bonyl-3″-N-(N-benzyloxycarbonyl
Kanamycin A (4.45 g) is obtained. IR (Nujiyor): 3320, 1690, 1540, 1270,
1155, 1050cm^-1 Example 1 (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-palmitoyl-1-N-triflu
Oloacetylkanamycin A (650mg) methano
(10 ml) and 1N hydrochloric acid (2 ml) mixture.
The suspension in the presence of palladium black (650 mg)
Hydrogenation in hydrogen atmosphere at room temperature and 1 atm for 2.5 hours
do. Filter and wash the catalyst with water. liquid and washing liquid
Combine and lyophilize to 3″-N-palmitoyl
-1-N-trifluoroacetylkanamycin
Obtain A. dihydrochloride (503 mg). Melting point 193℃ (decomposition) IR (nujiyor): 1700, 1620, 1550cm^-1 NMR (CD₃OD, δ): 0.87−1.07 (3H, m),
5.03 (1H, d, J = 3Hz), 5.50 (1H, d, J
=3Hz) FD Mass: 819 (M⁺), 723(M⁺-96) (2) 3″-N-acryloyl-3,6′-bis-N-
Benzyloxycarbonyl-1-N-palmito
Ilkanamycin A (491 mg) in methanol (20
ml), tetrahydrofuran (10ml) and concentrated salt
(0.5ml) mixture solution with 10% palladium-
In the presence of carbon (500 mg), at room temperature in a hydrogen atmosphere,
Hydrogenate under normal pressure for 5 hours. remove the catalyst,
Concentrate the liquid under reduced pressure to obtain a residue. Water the residue (30
ml) and the solution was treated with activated carbon (200 mg).
Remove the activated carbon. Lyophilize the liquid to obtain 1
-N-palmitoyl-3″-N-propionylka
Namycin A dihydrochloride (292 mg) is obtained. Melting point >134℃ (decomposition) [α]²⁰ _D:49.2゜(C1.0H₂O) IR (nujiyor): 1630, 1540, 1140, 1020cm
^-1 NMR (CD₃OD, δ): 5.06 (1H, d, J=3
Hz) FD Mass: 779 (M⁺) Example 2 The following compounds were prepared according to the methods of Examples 1(1) and 1(2).
get something (1) 1-N-n-docosanoyl-3″-N-trif
Luroacetylkanamycin A dihydrochloride. Melting point >223℃ (decomposition) [α]²⁰ _D:39.3゜(C1.0, H₂O) IR (Nujiyor): 3300, 1700, 1630, 1550,
1160, 1030cm^-1 NMR (CD₃OD, δ): 0.92 (3H, m), 5.13
(1H, d, J=4Hz) (2) 1-N-n-pentadecanoyl-3″-N-t
Lifluoroacetylkanamycin A. Melting point >176℃ [α]²⁰ _D:+59.8゜(C1.0H₂O) IR (Nujiyor): 1700, 1630, 1560, 1160,
1030cm^-1 NMR (CD₃OD, δ): 5.13 (1H, d, J=4
Hz), 5.52 (1H, d, J = 3Hz) FD Mass: 805 (M⁺) (3) 1-N-(2-hexyldecanoyl)-3″-N
-Trifluoroacetylkanamycin A di-salt
acid salt. Melting point >183℃ (decomposition) [α]²⁰ _D: +82.2゜(C1.0, H₂O) IR (nujiyor): 1700, 1630, 1160, 1030cm
^-1 NMR (CD₃OD, δ): 5.17 (1H, d, J = 3.5
Hz) FD Mass: 819 (M⁺) (4) 1-N-(3-acetoxy-n-tetradeca
Noyl)-3″-N-trifluoroacetylkana
Mycin A dihydrochloride. Melting point >163℃ (decomposition) [α]²⁰ _D:59.4゜(C1.0, H₂O) IR (Nujiyor): 3250, 1700, 1640, 1560,
1155, 1025cm^-1 NMR (CD₃OD, δ): 2.03 (3H, s) (5) 1-N-(3-hydroxytetradecanoyl)
-3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point >116℃ (decomposition) [α]²⁰ _D: +63.8゜(C1.0, H₂O) IR (Nujiyor): 1700, 1630, 1560, 1150,
1030cm^-1 NMR (CD₃OD, δ): 5.13 (1H, d, J=3
Hz), 5.25 (1H, d, J = 3Hz) FD Mass: 807 (M⁺) (6) 1-N-(3-acetoxy-n-tetradeca
Kanamycin A trihydrochloride. Melting point >153℃ (decomposition) [α]²⁰ _D:66.0゜(C1.0, H₂O) IR (Nujiyor): 1710, 1640, 1500, 1260−
1240, 1140cm^-1 NMR (CD₃OD, δ): 2.00 (3H, s), 5.43
(1H, d, J=3Hz) (7) 3″-N-acetyl-1-N-(3-hydroxy
C-n-tetradecanoyl) kanamycin A.
Dihydrochloride. Melting point >113℃ (decomposition) [α]²⁰ _D:71.8゜(C1.0, H₂O) IR (nujiyor): 1630, 1560, 1140, 1030cm
^-1 NMR (CD₃OD, δ): 2.10 (3H, s), 5.45
(1H, d, J=4Hz) (8) 3″-N-acetyl-1-N-palmitoyl
Namycin A dihydrochloride. Melting point >193℃ (decomposition) [α]²⁰ _D:74.5゜(C1.0, H₂O) IR (nujiyor): 1630, 1540, 1025cm^-1 NMR(D₂O, δ): 0.83 (3H, m), 1.23 (28H,
s), 2.02 (3H, s) FD Mass: 765 (M⁺) (9) 3″-N-benzoyl-1-N-palmitoyl
Kanamycin A dihydrochloride. Melting point >166℃ (decomposition) [α]²⁰ _D: +65.5゜(C1.0, H₂O) IR (Nujiyor): 1630, 1550, 1140, 1080,
1030cm^-1 NMR (CD₃OD, δ): 5.25 (1H, d, J=4
Hz), 7.35-8.00 (5H, m) FD Mass: 828 (M⁺+1) (10) 3″-N-(3-carboxypropionyl)-1
-N-Palmitoykanamycin A dihydrochloride
salt. Melting point >145℃ (decomposition) [α]²⁰ _D: +54.0゜(C1.0, H₂O) IR (Nujiyor): 3250, 1720, 1640, 1550,
1140, 1030cm^-1 NMR (CD₃OD, δ): 2.60 (4H, s), 5.50
(1H, d, J=3Hz) (11) 1-N-(3-acetoxytetradecanoyl)
-3″-N-glycylkanamycin A trihydrochloric acid
salt. Melting point >161℃ (decomposition) [α]²⁰ _D:49.2゜(C1.0, H₂O) IR (Nujiyor): 1630, 1560, 1300, 1250,
1025cm^-1 NMR (CD₃OD, δ): 2.00 (3H, s) FD Mass: 810 (M⁺) (12) 3″-N-glycyl-1-N-palmitoyl
Namycin A trihydrochloride. Melting point >163℃ (decomposition) IR (Nujiyor): 1620, 1560, 1300, 1140,
1080, 1030cm^-1 NMR (CD₃OD, δ): 0.97 (3H, m), 1.30
(28H, s) FD Mass: 780 (M⁺) [α]²⁰ _D:47.6゜(C1.0, H₂O) (13) 1-N-acetyl-3″-N-palmitoyl
Kanamycin A dihydrochloride. Melting point 168℃ (decomposed) [α]²⁶ _D: +72.7゜(C=0.74, H₂O) IR (nujiyor): 1630, 1550cm^-1 NMR (CD₃OD, δ): 0.87 (3H, m), 1.97
(3H, s), 5.07 (1H, d, J=3Hz), 5.47
(1H, d, J=3Hz) FD Mass: 765 (M⁺) (14) 3″-N-glycoloyl-1-N-palmito
Ilkanamycin A dihydrochloride. Melting point 159℃ (decomposed) [α]²⁶ _D:+73.2 (C=0.55, H₂O) IR (nujiyor): 1640, 1550cm^-1 NMR (CD₃OD, δ): 5.10 (1H, d, J=3
Hz), 5.47 (1H, m) FDMass: 803 (M⁺+22) (15) 1,3″-bis-N-n-octanoylcana
Mycin A dihydrochloride. Melting point 197℃ (decomposition) IR (nujiyor): 1640, 1550cm^-1 NMR (CD₃OD, δ): 0.90 (6H, t, J=5
Hz), 5.07 (1H, d, J = 3Hz), 5.47 (1H,
d, J=3Hz) FD Mass: 737 (M⁺) (16) 1-N-tertiary butoxycarbonyl-3″-
N-Palmitoykanamycin A dihydrochloride. Melting point 192℃ (decomposition) IR (nujiyor): 1680, 1640, 1540cm^-1 NMR (CD₃OD, δ): 0.87−1.03 (3H, m),
1.47 (9H, s), 5.10 (1H, d, J=3Hz),
5.43−5.57 (1H, m) FD Mass: 823 (M⁺), 723(M⁺-100) (17) 1-N-n-tridecyloxyacetyl-
3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point 173℃ (decomposition) [α]²⁶ _D: +65.1 (C=0.34, H₂O) IR (KBr): 1700, 1650, 1560cm^-1 NMR (CD₃OD, δ): 0.90−1.03 (3H, m),
5.07 (1H, d, J = 3Hz), 5.47−5.53 (1H,
m) FD Mass: 843 (M⁺+22), 821(M⁺), 747(M⁺
−74), 725(M⁺-96) (18) 1-N-n-hexadecyloxycarbonylate
Ru-3″-N-trifluoroacetyl kanamaysi
N A dihydrochloride. Melting point >156℃ (decomposition) IR (Nujiyor): 3300, 1700, 1560−1540,
1510, 1270, 1155, 1080, 1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.12
(1H, d, J=3Hz), 5.48 (1H, d, J=
3Hz) (19) 1-N-n-hexadecylthiocarbonyl
-3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point >213℃ (decomposition) IR (Nujiyor): 3300-3250, 1705, 1635,
1520, 1210, 1160cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.13
(1H, d, J=3Hz), 5.48 (1H, d, J=
3Hz) FD Mass: 864 (M⁺-1) (20) 1-N-n-pentadecylaminocarboni
Ru-3″-N-trifluoroacetyl kanamaysi
N A dihydrochloride. Melting point 135℃ (decomposition) IR (Nujiyor): 1705, 1570, 1210, 1185,
1160, 1030cm^-1 NMR (CD₃OD, δ): 0.93 (3H, m), 5.12
(1H, d, J = 3Hz), 5.47 (1H, d, J =
3Hz) Example 3 1,6'-bis-N-benzyloxycarbonyl
-3-N-palmitoyl-3″-N-trifluoro
Acetylkanamycin A (800mg) in methanol
(8 ml) in a mixture of 1N hydrochloric acid (2 ml)
in a hydrogen atmosphere in the presence of palladium black (400 mg)
Hydrogenate in air at room temperature and 1 atm for 6 hours. catalyst
Filter and rinse with water. Combine the liquid and washing liquid and freeze-dry.
After drying, 3-N-palmitoyl-3″-N-trif
Luroacetylkanamycin A dihydrochloride (627
mg). Melting point 181℃ (decomposition) IR (nujiyor): 1710, 1620, 1550cm^-1 NMR (CD₃OD, δ): 0.87−1.03 (3H, m), 5.10
(1H, d, J=3Hz), 5.40 (1H, d, J=3
Hz) FD Mass: 819 (M⁺), 723(M⁺-96) Example 4 3,2',6'-tris-N-benzyloxycarl
Bonyl-1-N-palmitoyl-3″-N-trif
fluoroacetylkanamycin B (510mg))
Mixture of tanol (10ml) and 1N hydrochloric acid (1.5ml)
medium suspension in the presence of palladium black (500 mg),
Hydrogenate in hydrogen atmosphere at room temperature and 1 atm for 5 hours.
Ru. Filter and wash the catalyst with water. Combine the liquid and washing liquid.
and lyophilized to give 1-N-palmitoyl-3″-
N-trifluoroacetylkanamycin B trisalt
Obtain the acid salt (312 mg). Melting point 220℃ (decomposition) [α]²⁶ _D: +69.8゜(C=0.65, H₂O) IR (nujiyor): 1700, 1630, 1550cm^-1 NMR (CD₃OD, δ): 0.90−1.08 (3H, m), 5.08
(1H, d, J = 3Hz), 5.43-5.53 (1H, m) FD Mass: 819 (M⁺+1), 722 (M⁺−96), 6.58
(M⁺−160), 562(M⁺−256) Example 5 According to the method of Example 4, the following compound is obtained. 3',4'-dideoxy-1-N-palmitoyl-
3″-N-trifluoroacetylkanamycin B・
Trihydrochloride. Melting point 206℃ (decomposition) [α]²⁶ _D:+55.67゜(C=0.374, H₂O) IR (nujiyor): 1700, 1630cm^-1 FD Mass: 809 (M⁺+23), 808(M⁺+22), 787
(M⁺+1), 713(M⁺−73), 691(M⁺-95) Example 6 3,2′,6′,3″-tetrakis-N-benzyl
oxycarbonyl-3',4'-dideoxy-1-N-
palmitoyl kanamycin B (300 mg), methano
Mixture solution of alcohol (12ml) and 1N hydrochloric acid (0.9ml)
in a hydrogen atmosphere in the presence of palladium black (300 mg)
Hydrogenate in air at room temperature and 1 atm for 7 hours. catalyst
Remove and wash with aqueous methanol solution. liquid and washing
3′,4′-dideoxy
Sea-1-N-palmitoykanamycin B tetrasalt
Obtain the acid salt (183 mg). Melting point 167℃ (decomposed) [α]²⁶ _D: +63.49゜(C=0.158, H₂O) IR (KBr): 2900, 1640, 1500cm^-1 FD Mass: 690 (M⁺) Example 7 (1) 1,3,6'-tris-N-benzyloxyca
rubonyl-3″-N-palmitoykanamycin
Acetic anhydride (0.96
ml) at room temperature. Stir the solution for 10 minutes, then
Leave it overnight. Add water (0.2ml) to this solution,
The reaction mixture is concentrated under reduced pressure. Dilute the residue with ethyl acetate
(40ml) dissolved in water, 1N hydrochloric acid, sodium bicarbonate
Lium saturated aqueous solution and sodium chloride saturated aqueous solution
Wash sequentially with solutions and dry with anhydrous sodium sulfate.
After that, the residue obtained by concentration under reduced pressure was immersed in silica gel (50%
g) for column chromatography using
and chloroform-methanol mixture [50:1
(V/V)]. Fraction containing target compound
Concentrate under reduced pressure to 2′, 3′, 4′, 2″, 4″, 6″-he
Xa-O-acetyl-1,3,6'-tris-N
-benzyloxycarbonyl-3″-N-palmi
Tolykanamycin A (454 mg) is obtained. Melting point 233-234℃ IR (Nujiyor): 1730, 1680, 1650, 1520,
1230, 1030cm^-1 NMR (CDCl)₃, δ): 0.90 (3H, m), 1.27
(28H, s), 1.99−2.15 (18H) (2)(a) Potassium hydroxide (215 mg) in methanol
(10 ml) 2′, 3′, 4′, 2″, 4″, 6″-hexyl
Cir-O-acetyl-1,3,6'-tris-N
-benzyloxycarbonyl-3″-N-pal
Add mitoyl kanamycin A (440 mg) and mix.
Stir the mixture for 40 minutes at room temperature. reaction mixture
Pour into ice water (100ml) and remove the formed precipitate.
Take and wash three times with water (20 ml). Air dry the precipitate
1,3,6'-tris-N-benzyloxy
Cycarbonyl-3″-N-palmitoyl canama
Isin A (335 mg) is obtained. (b) 1,3,6'-tris-N-benzyloxy
Carbonyl-3″-N-palmitoyl kanamay
Syn A (335 mg) in methanol (10 ml) and
Add concentrated hydrochloric acid (0.5 ml) mixture solution to 10% paradia.
Hydrogen atmosphere in the presence of um-carbon (300mg)
Hydrogenate at medium temperature and normal pressure for 4 hours. catalyst
and concentrate the liquid under reduced pressure. Ethanol the residue
Suspend in 20 ml of water and concentrate under reduced pressure to remove the residue.
obtain. Repeat this operation twice. Dissolve the residue in water (20
ml), lyophilized and 3″-N-Pal
Mitoylkanamycin A trihydrochloride (145mg)
get. Melting point >183℃ (decomposition) [α]²⁰ _D: +58.0゜(C1.0, H₂O) IR (Nujiyor): 3300-3200, 1620, 1510,
1080, 1030cm^-1 FD Mass: 723 (M⁺) Example 8 1,3,3″-tris-N-tertiary butoxylic
Bonyl-6'-N-palmitoykanamycin A
(500 mg) in anisole (1.5 ml).
Add lifluoroacetic acid (5 ml) under ice cooling. mixture
The mixture was stirred at the same temperature for 2 hours and then concentrated under reduced pressure.
Dissolve the residue in water and concentrate the solution under reduced pressure. of residue
Domex 1×2 (COH) in aqueous solution^-types, trademarks,
(manufactured by Dom Chemical Co.) and adjust the pH to 10.5.
Filter out insoluble matter and wash with methanol. insoluble matter
Suspended in water and adjusted to PH4.5 with trifluoroacetic acid.
do. Remove insoluble matter and wash with water. liquid and washing liquid
were combined and lyophilized to give 6′-N-palmitoyl.
Kanamycin A trifluoroacetate (230mg)
get. Melting point 193℃ (decomposition) [α]²⁶ _D: +57.7゜(C=1.22, H₂O) IR (nujiyor): 1670cm^-1 NMR(D₂O, δ): 1.27 FD Mass: 723 (M⁺) Example 9 1,6′,3″-tris-N-benzyloxycarl
Bonyl-3-N-palmitoykanamycin A
(800mg) of methanol (30ml) and 1N hydrochloric acid
(3 ml) of the suspension in a mixture of palladium black (800
mg) in a hydrogen atmosphere at room temperature and 1 atm for 6 hours.
Hydrogenate for a while. Remove the catalyst and wash with water. liquid and
Combine the washing liquid and lyophilize to obtain 3-N-palmium.
Tolykanamycin A trihydrochloride (580mg) was obtained.
Ru. Melting point: 181℃ (decomposition) [α]²⁶ _D: +62.9゜(C=0.12, H₂O) IR (nujiyor): 1620cm^-1 NMR (CD₃OD, δ): 0.80−1.10 (3H, m), 5.13
(d, J=3Hz, 1H), 5.37 (d, J=3Hz,
1H) FD Mass: 723 (M⁺) Example 10 (1) 3,6′,3″-tris-N-benzyloxyca
Rubonyl-1-N-palmitoykanamycin
A (650mg), dioxane (10ml), methanol
(10ml) and 1N hydrochloric acid (2ml).
The solution was dissolved in the presence of 10% palladium-carbon (650 mg).
Add hydrogen for 4 hours at room temperature and pressure in a hydrogen atmosphere.
Ru. Remove the catalyst and concentrate the liquid under reduced pressure to remove the residue.
obtain. The residue was dissolved in water (40ml) and filtered.
Lyophilize the liquid to obtain 1-N-palmitoyl
Namycin A trihydrochloride (417 mg) is obtained. Melting point >221℃ (decomposition) IR (KBr): 3400−3300, 1640, 1630, 1540,
1510, 1140, 1050cm^-1 NMR(D₂O, δ): 0.91 (3H, m), 1.26 (28H,
s) FD Mass: 723 (M⁺) (2)(a) Phosphorous oxychloride (0.29ml) in dimethylform
Amide (0.24ml) and tetrahydrofuran
(0.5 ml) and this suspension was added to the mixture of -5
Stir for 10 minutes at ~0°C. Tet in this suspension
Lahydrofuran (5 ml) then 3-aceto
Xytetradecanoic acid (687mg) at 0-2℃
Add under stirring. Stir the mixture for 30 minutes at the same temperature.
to prepare an activated acid solution. On the other hand,
3,6′,3″-tris-N-benzyloxyca
rubonylkanamycin A monotrifluoro
Acetate (1.2g) in tetrahydrofuran
(40ml) and water (10ml).
Ru. Add 0 of the activated acid solution obtained above to this solution.
pH8~ with triethylamine under stirring at ~5℃
Drip while keeping the temperature at 9. Isothermal reaction mixture
Stir for 30 minutes. Concentrate the solution under reduced pressure to form a solid.
get. This solid was dissolved in diethyl ether (20
ml) twice, removed and air-dried to obtain a solid.
Ru. Using silica gel (50g) to remove the solid
Subjected to pressure column chromatography, chloro
Form-methanol-concentrated ammonia water mixture
Elute at [4:1:0.1 (V/V)]. objectification
The fractions containing the compound were combined and concentrated under reduced pressure.
3,6′,3″-tris-N-benzyloxyca
rubonyl-1-N-(3-acetoxy-n-
Tetradecanoyl) Kanamycin A (1.03g)
get. (b) 3,6′,3″-tris-N-benzyloxy
Carbonyl-1-N-(3-acetoxy-n
-tetradecanoyl) kanamycin A (976
mg) in pyridine (20 ml), acetic anhydride.
(0.96ml), stir at room temperature for 30 minutes, and then
Leave at warm temperature for 2 days. Concentrate the reaction mixture under reduced pressure
to obtain a residue. The residue was dissolved in ethyl acetate (60ml).
Dissolve this solution in 1N hydrochloric acid, water, carbonated water
Sodium saturated aqueous solution and sodium chloride
Wash sequentially with saturated aqueous solutions and anhydrous sodium sulfate.
After drying with a vacuum cleaner, the mixture was concentrated under reduced pressure to obtain a residue. residue
Column chromatography using silica gel (60g)
The chloroform-meth
Elute with a mixture of alcohol [50:1 (V/V)].
Collect fractions containing the target compound and concentrate under reduced pressure.
2′, 3′, 4′, 2″, 4″, 6″-hex-O-
Acetyl-3,6',3''-tris-N-benzi
carbonyl-1-N-(3-aceto
xy-n-tetradecanoyl) kanamycin
A (864 mg) is obtained. Melting point 184-186℃ (melting) IR (Nujiyor): 3300, 1730, 1710, 1695,
1645, 1510, 1220, 1030cm^-1 NMR (CDCl)₃, δ): 0.90 (3H, m), 1.27,
1.92−2.10 (18H, m) (c) 2′, 3′, 4′, 2″, 4″, 6″-hex-O-
a
Cetyl-3,6′,3″-tris-N-benzyl
Oxycarbonyl-1-N-(3-acetoki
C-n-tetradecanoyl) kanamycin A
(830mg) of potassium hydroxide (463mg) meth
Mixture in Nord (17 ml) solution at room temperature for 1 hour.
Stir. Add this mixture to ice water (100ml)
pour. Next, collect the formed precipitate and add water three times.
(20 ml) Wash, air dry, 3,6′,3″-tri
Su-N-benzyloxycarbonyl-1-N
-(3--hydroxy-n-tetradecanoy
) Kanamycin A (597 mg) is obtained. IR (Nujiyor): 1680, 1640, 1530, 1290,
1260, 1140, 1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m),
1.22 (20H, s), 7.32 (15H, s) (d) 3,6′,3″-tris-N-benzyloxy
carbonyl-1-N-(3-hydroxy-n
-tetradecanoyl) kanamycin A (580
mg) of methanol (20 ml) and concentrated hydrochloric acid
(0.5 ml) mixture solution, 10% palladium on charcoal
In the presence of element (0.5g), at room temperature in a hydrogen atmosphere,
Hydrogenate at normal pressure for 4 hours. remove the catalyst,
Concentrate the liquid under reduced pressure to obtain a residue. Water the residue
(40 ml), lyophilized, 1-N-
(3-hydroxy-n-tetradecanoyl)
Kanamycin A trihydrochloride (349 mg) is obtained. Melting point >178℃ (decomposition) IR (KBr): 3400−3250, 1630, 1140, 1050
cm^-1 FD Mass: 711 (M⁺) Example 11 1-N-(3-acetoxy-n-tetradecano
yl)-3,6'-bis-N-benzyloxycarl
Bonyl-3″-N-trifluoroacetylkanamai
Syn A (0.8g) and tetrahydrofuran (20ml)
and 5N-ammonia water (5 ml) mixture solution.
Stir overnight at warm temperature. Pour the solution into ice water (150ml).
Remove the formed precipitate, wash it with water, and reduce it with phosphorus pentoxide.
Pressure-dried to give 1-N-(3-acetoxy-n-thene)
tradecanoyl)-3,6'-bis-N-benzyl
Oxycarbonylkanamycin A (669 mg) was obtained.
Ru. Melting point >263℃ (decomposition) IR (Nujiyor):: 3270, 1685, 1630, 1520,
1260, 1230, 1140, 1050cm^-1 NMR (DMSO−d₆, δ): 1.95 (3H, s) Example 12 Potassium hydroxide (1.05g) methanol (40g)
ml) and dimethyl sulfoxide (15 ml) mixture
Add 1-N-(3-acetoxy-n-tetra) to the solution.
decanoyl)3,6'-bis-N-benzyloxy
Carbonyl-3″-N-trifluoroacetylkana
Add Mycin A (3.5g) and keep the mixture at room temperature for 1 hour.
Stir for a while. Pour the reaction mixture into ice water (150ml).
Collect the precipitate that forms, and the pH of the washing liquid shows 7.
3,6′-bis-N-ben
Zyloxycarbonyl-1-N-(3-hydroxy
C-n-tetradecanoyl) kanamycin A
(2.86g) is obtained. IR (Nujiyor): 1690, 1640, 1540, 1150,
1050, 1030cm^-1 NMR (DMSO-d₆, δ): 0.95 (3H, m) Example 13 (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-palmitoyl-3″-N-triful
Oloacetylkanamycin A (5g) pyridine
Add acetic anhydride (5.2 ml) to the solution (100 ml).
Then, stir at room temperature for 6 hours. Acetic anhydride (1ml)
was further stirred, and the mixture was left at the same temperature overnight.
place The reaction mixture was concentrated under reduced pressure and the residue obtained was
Sodium bicarbonate dissolved in ethyl acetate (200ml)
Wash with an aqueous solution of aluminum and water, and concentrate under reduced pressure.
Ru. Drain the residue using silica gel (60g).
Subjected to mucochromatography, chloroform-
Elute with methanol [50:1 (V/V)]. eye
The fractions containing the target compound were combined and concentrated under reduced pressure.
2′,3′,4′,2″,4″,6″-hex-O-acetylene
Ru-3,6'-bis-N-benzyloxycarbo
Nyl-1-N-palmitoyl-3″-N-trif
Obtained fluoroacetylkanamycin A (6.76g)
Ru. NMR (CDCl)₃, δ): 0.93 (3H, m), 1.28
(28H, s) (2) Potassium hydroxide (4g) in methanol (140g)
ml) solution, add 2′, 3′, 4′, 2″, 4″, 6″-hex
-O-acetyl-3,6'-bis-N-benzyl
Oxycarbonyl-1-N-palmitoyl-
3″-N-trifluoroacetylkanamycin A
(6.76g) and stirred the mixture at room temperature for 2 hours.
do. Pour the reaction mixture into ice water (400ml) and
Collect the formed precipitate and wash until the pH of the washing liquid shows 7.
3,6′-
Bis-N-benzyloxycarbonyl-1-N
- Palmitoylkanamycin A (4.23g) was obtained.
Ru. IR (Nujiyor): 3290, 1685, 1640, 1540,
1275, 1230, 1050cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.63
(28H, s) Example 14 Potassium hydroxide (1.16g) methanol (40g)
ml) solution, add 2′, 3′, 4′, 2″, 4″, 6″-hex-
O-acetyl-3″-N-acetyl-1-N-(3
-acetoxy-n-tetradecanoyl)-3,
6'-bis-N-benzyloxycarbonylkanama
Add Isin A (1.9g) and keep the mixture at room temperature for 3 hours.
Stir. The resulting suspension was placed in ice water (200 ml).
pour. Remove the precipitate, wash with water, air dry, and place in a 3″-N-A.
Cetyl-3,6'-bis-N-benzyloxycarl
Bonyl-1-N-(3-hydroxy-n-tetra
Decanoyl) kanamycin A (1.20g) as a solid
and get it. Melting point >266℃ (decomposition) IR (Nujiyor): 3280, 1685, 1640, 1520,
1270, 1230, 1150cm^-1 NMR (DMSO−d₆, δ): 1.84 (3H, s) Example 15 Phosphorous oxychloride (0.23ml) in dimethylformamide
(0.20ml) and tetrahydrofuran (0.4ml)
and stir the suspension at -5 to 0°C for 10 minutes.
Stir. This suspension was added to tetrahydrofuran (4
ml) and n-pentadecanoic acid (471 mg) sequentially.
under stirring at -5 to 0°C. Bring the mixture to the same temperature
Stir for 30 minutes to prepare an activated acid solution. 3,
6′-bis-N-benzyloxycarbonyl-3″-
N-trifluoroacetylkanamycin A (1.5
g) of tetrahydrofuran (40 ml) and water (12
ml) Add the activated acid solution to the mixture solution.
Add dropwise while maintaining pH 8-9 with thylamine. Mixed
The mixture was stirred at the same temperature for 30 minutes and concentrated under reduced pressure. Generate
Take the solid and add 1N hydrochloric acid (20ml), isopropyl
Alcohol (30ml) and diethyl ether
(30ml) mixture, sequentially with water and diethyl ether
Wash, air dry, and remove 3,6′-bis-N-benzyl.
Oxycarbonyl-1-N-n-pentadecanoy
Ru-3″-N-trifluoroacetylkanamycin
A (1.59 g) is obtained. Melting point >284℃ (decomposition) IR (Nujiyor): 3290, 1690, 1640, 1530,
1260, 1210, 1180, 1050cm^-1 NMR (DMSO-d₆, δ): 0.93 (3H, m), 1.07
(26H, s) Example 16 The following compound is obtained according to the method of Example 15. (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-1,3″-bis-N-n-octanoylcana
Mycin A. IR (nujiyor): 1690, 1640, 1540cm^-1 (2) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-(2-hexyl-n-decanoyl)
-3″-N-trifluoroacetylkanamycin
A. Melting point >276℃ (decomposition) IR (Nujiyor): 3280, 1690, 1640, 1530,
1270, 1175, 1050cm^-1 NMR (DMSO-d₆, δ): 1.20 (24H, s) (3) 1-N-(3-acetoxy-n-tetradeca
(noyl)-3,6'-bis-N-benzyloxy
Carbonyl-3″-N-trifluoroacetylka
Namycin A. Melting point >188℃ (decomposition) IR (Nujiyor): 3270, 1685, 1630, 1530,
1160, 1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.92
(3H, s) (4) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-tridecyloxyacetyl-
3″-N-trifluoroacetylkanamycin
A. Melting point 240℃ (decomposition) IR (nujiyor): 1690, 1540cm^-1 NMR (DMSO-d₆, δ): 0.83−1.00 (3H,
m), 7.30 (10H, s) (5) 1-N-(3-acetoxy-n-tetradeca
(noyl)-3,6'-bis-N-benzyloxy
carbonyl-3″-N-[N-(benzyloxycarbonyl)
(rubonyl) glycyl] kanamycin A. Melting point >256℃ (decomposition) IR (Nujiyor): 1690, 1530, 1260, 1230,
1140, 1040cm^-1 NMR (DMSO-d₆, δ): 0.88 (3H, m), 1.92
(3H, s) (6) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-(Z)-13-docosenoyl-3″-N
-Trifluoroacetylkanamycin A. Melting point >251℃ (decomposition) IR (Nujiyor): 3290, 1690, 1640, 1540,
1170, 1050cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) (7) 3,6′3″-tris-N-benzyloxycarl
Bonyl-1-N-palmitoykanamycin
A. Melting point >276℃ (decomposition) IR (Nujiyor): 3280−3260, 1680, 1630,
1530, 1290, 1145, 1040cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m), 1.26
(28H, s) (8) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-hexadecyloxycarbonylate
Ru-3″-N-trifluorosetylkanamycin
A. Melting point>268℃ IR (Nujiyor): 3300, 1700, 1680, 1215,
1180, 1040cm^-1 NMR (DMSO-d₆, δ): 0.92 (3H, m) (9) 3,6'-bis-N-tertiary butoxycarbonylate
Ru-1-N-n-hexadecylthiocarbonyl
-3″-N-trifluoroacetylkanamycin
A. Melting point >226℃ (decomposition) IR (Nujiyor): 3280, 1700, 1680, 1635,
1530, 1165, 1080cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) (10) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-pentadecylaminocarboni
Ru-3″-N-trifluoroacetyl kanamaysi
N A. Melting point>236℃ (decomposition) IR (Nujiyor): 3300, 1690, 1620, 1540,
1280, 1160, 1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) Example 17 (1) 3″-N-acetyl-3,6′-bis-N-ben
Zyloxycarbonyl-1-N-palmitoyl
Kanamycin A (1.96 g) in anhydrous pyridine (40
ml) Add acetic anhydride (2.26ml) to the solution and mix
Stir at room temperature for 1 hour and leave at the same temperature overnight.
Add water (1 ml) to the reaction mixture at room temperature, and concentrate under reduced pressure.
Shrink. Dissolve the residue in ethyl acetate (80ml) and
1N hydrochloric acid, aqueous sodium chloride solution, sodium bicarbonate
With thorium aqueous solution and sodium chloride aqueous solution
Wash sequentially and dry with anhydrous sodium sulfate.
The residue obtained by distilling off the solvent under reduced pressure is fused to silica gel.
Column chromatography using (60g)
and chloroform-methanol [50:1
(V/V)]. Fraction containing target compound
were combined and concentrated under reduced pressure to give 3″-N-acetyl-
2′,3′,4′,2″,4″,6″-hex-O-acetylene
Ru-3,6'-bis-N-benzyloxycarbo
Nyl-1-N-palmitoykanamycin A
(2.14g) is obtained. Melting point 222-223℃ (decomposition) [α]²⁰ _D:75.3゜(C1.0, CHCl₃) IR (Nujiyor): 3300, 1740, 1650, 1530,
1230, 1040cm^-1 NMR (CDCl)₃, δ): 0.95 (3H, m), 1.20
(28H, s), 1.90 (3H, s), 2.00−2.20
(18H, m) (2) Potassium hydroxide (920 mg) in methanol (40
ml) solution, 3″-N-acetyl-2′,3′,4′,
2″,4″,6″-hexa-O-acetyl-3,6′-
Bis-N-benzyloxycarbonyl-1-N
-Add palmitoylkanamycin A (2.1g)
Ru. The mixture is stirred at room temperature for 1 hour. reaction mixture
Pour the material into ice water (150ml). The precipitate that forms
Wash the solution with water until the pH of the washing solution shows 7.
Clean, air dry, 3″-N-acetyl-3,6′-
Bis-N-benzyloxycarbonyl-1-N
- Palmitoylkanamycin A (1.53g) was obtained.
Ru. IR (Nujiyor): 1680, 1640, 1520, 1270,
1230, 1150cm^-1 Example 18 (a) 3,6'-bis-N-benzyloxycarbonylate
Le-3″-N-[N-(benzyloxycarbonylate)
[glycyl]-1-N-tertiary butoxylic
Trifluorobonilkanamycin A (0.92g)
Mixed with acetic acid (10ml) and anisole (3ml)
The solution was stirred for 1 hour under ice cooling. Reduce solution
Concentrate under pressure to obtain 3,6'-bis-N-benzyl oxychloride.
cyclocarbonyl-3″-N-[N-(benzyloxy
Carbonyl)glycyl]Kanamycin A was obtained.
Ru. (b) 3,6'-bis-N-benzyloxycarbonyl
Le-3″-N-[N-(benzyloxycarbonylate)
) Glycyl] The above residue containing Kanamycin A
of tetrahydrofuran (40 ml) and water (10
ml) into the mixture solution, palmitoyl chloride
(254mg) in tetrahydrofuran (10ml)
PH8~ with triethylamine under stirring at 0~5℃
Drip while keeping the temperature at 9. Keep the mixture at the same temperature for 1 hour.
Stir for a while and concentrate the reaction mixture under reduced pressure to obtain a solid.
and add 1N hydrochloric acid (20ml, twice) and isopropylene.
Alcohol (20ml) and diethyl ether
(20ml), then continue until the washings show a pH of 7.
Isopropyl alcohol (10ml) and diethyl ethyl ether
Wash sequentially with a mixture of ether (10 ml) and air dry.
, 3,6'-bis-N-benzyloxycarbo
Nyl-3″-N-[N-(benzyloxycarbonyl)
Glycyl]-1-N-Palmitol Kanama
Isin A (910 mg) is obtained as a solid. Melting point >269℃ (decomposition) IR (Nujiyor): 3280, 1690, 1650, 1540,
1270, 1150, 1050cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.22
(28H, s) Example 19 The following compound is obtained according to the method of Example 18. (1) 3″-N-acetyl-3,6′-bis-N-ben
Zyloxycarbonyl-1-N-palmitoyl
Kanamycin A. NMR (DMSO-d₆, δ): 0.85 (3H, m), 1.83
(3H, s) (2) 3″-N-benzyloxyacetyl-3,6′-
Bis-N-benzyloxycarbonyl-1-N
-Palmitoykanamycin A. IR (nujiyor): 1690, 1640, 1540cm^-1 NMR (DMSO-d₆, δ): 1.20 (s), 4.57 (s),
7.27(s), 7.30(s), 7.33(s) (3) 1-N-(3-acetoxytetradecanoyl)
-3,6'-bis-N-benzyloxycarbony
Le-3″-N-[N-(benzyloxycarbonylate)
[glycyl] kanamycin A. Melting point >256℃ (decomposition) IR (Nujiyor): 1690, 1530, 1260, 1230,
1140, 1040cm^-1 NMR (DMSO−d₆, δ): 0.88 (3H, m), 1.92
(3H, s) Example 20 (1) 1,3,6'-tris-N-benzyloxyca
Tetrahydride of rubonylkanamycin A (700 mg)
Rofuran (40ml) and water (10ml) mixture solution
Then, cool palmitoyl chloride (0.26g) on ice.
Below, keep the pH between 8 and 8.5 with triethylamine.
While dripping. Stir the mixture at the same temperature for 1 hour.
Ru. The solid obtained by concentrating this solution under reduced pressure is
with ether (50 ml, twice) and water (50 ml).
Wash, remove, air dry, and add 1,3,6′-Tris.
-N-benzyloxycarbonyl-3″-N-p
Lumitoyl kanamycin A (950 mg) is obtained. Melting point >288℃ (decomposition) IR (Nujiyor): 3300, 1685, 1650, 1535,
1520, 1230, 1150, 1040cm^-1 NMR (DMSO−d₆, δ): 0.87 (3H, m), 1.22
(24H, s), 7.25 (15H, s) (2) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-tert-butoxycarbonylkanama
Isin A (3g) in dimethyl sulfoxide (25
ml) solution, N-palmitoyloxysuccine
Add imide (1.37g) at room temperature. Same mixture
Stir overnight at warm temperature. Add this mixture to ice water (150ml)
Pour into the solution to obtain a precipitate. Remove the precipitate and add water and
and diethyl ether, and phosphorous pentoxide.
Dry under reduced pressure to give 3,6'-bis-N-bendi
hydroxycarbonyl-1-N-tert-butoxy
Carbonyl-3″-N-Palmitoykanameshi
Obtain A (3.50 g). IR ((nujiyor): 1690, 1520cm^-1 Example 21 1,6′,3″-tris-N-benzyloxycarl
Bonilkanamycin A (283mg) Tetrahydrof
Add the powder to the run (20 ml) and water (5 ml) mixture solution.
Lumitoyl chloride (88 mg) was added to triethyl chloride under ice-cooling.
Add while keeping the pH between 8 and 9 with luamine. Mixed
The mixture was stirred under the same conditions for 2 hours. Tetrahydrof
The oran is distilled off from the reaction mixture and precipitates suspended in water.
get. The precipitate was collected, washed with water, and evaporated with phosphorus pentoxide under reduced pressure.
dried to give 1,6′,3″-tris-N-benzyl
Oxycarbonyl-3-N-palmitoyl canama
Isin A (310 mg) is obtained. Melting point 292℃ (decomposition) IR (nujiyor): 1680, 1530cm^-1 NMR ((DMSO−d₆, δ): 1.33 (s, 28H), 7.33
(s, 15H) Example 22 (a) 1,6'-bis-N-benzyloxycarbonylate
Ru-3-N-tertiary butoxycarbonyl-3″-
N-trifluoroacetylkanamycin A (800
mg) in anisole (2.4 ml).
Add fluoroacetic acid (8 ml) while cooling with water. mixture
The mixture was stirred at the same temperature for 2 hours, concentrated under reduced pressure, and 1.
6'-bis-N-benzyloxycarbonyl-
3″-N-trifluoroacetylkanamycin A
get. (b) 1,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-trifluoroacetyl kanamaysi
Tetrahydrofuran (40 ml) of the residue containing A
and water (5 ml) mixture solution, palmitoyl
Chloride (254 mg) was added to triethyl chloride under ice cooling.
Add the mixture while maintaining the pH between 8 and 9. Mixed
The mixture was stirred under the same conditions for 1 hour. Tetrahydro
The precipitate obtained by distilling furan off from the reaction mixture is
Take and dilute with 1N hydrochloric acid, water and diethyl ether.
sequentially washed and dried under reduced pressure with phosphorous pentoxide;
1,6'-bis-N-benzyloxycarbonyl
-3-N-palmitoyl-3″-N-trifluoro
Loacetylkanamycin A (850 mg) is obtained. IR (nujiyor): 1700, 1530cm^-1 NMR (DMSO−d₆, δ): 0.87−1.03 (3H,
m), 7.33 (10H, s) Example 23 (a) 6'-N-benzyloxycarbonyl-1,
3,3″-tris-N-tert-butoxycarbonylate
Lucanamycin A (500mg) was added to N,N-dimethylene
formamide (10ml), tetrahydrofuran
(5 ml) and methanol (5 ml).
Add this mixture to palladium black (500mg)
In the presence of water at room temperature and 1 atm in a hydrogen atmosphere for 4 hours
Add element. Add 1N hydrochloric acid (0.6ml) to the mixture
Ru. The mixture is further hydrogenated overnight. catalyst
and washed with N,N-dimethylformamide.
do. Combine the liquid and washing liquid, concentrate under reduced pressure,
1,3,3″-tris-N-tertiary butoxylic
Bonilkanamycin A is obtained. (b) 1,3,3″-tris-N-tert-butoxyca
Tetrahydrof the residue containing rubonylkanamycin A
Dorofuran (50ml) and water (10ml) mixture dissolved
Add palmitoyl chloride (150mg) to the liquid and cool on ice.
Below, while keeping the pH at 8-9 with triethylamine.
Add. The mixture is stirred under the same conditions for 1 hour. Te
Trahydrofuran was distilled from the reaction mixture under reduced pressure.
to obtain a solid. This solid was washed with water and
Dry under reduced pressure with phosphorus to give 1,3,3″-Tris-
N-tertiary butoxycarbonyl-6'-N-pal
Mitoylkanamycin A (518 mg) is obtained. Melting point 238℃ (decomposition) IR (nujiyor): 1690, 1520cm^-1 NMR (DMSO−d₆, δ): 1.23, 1.39 Example 24 (a) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-tertiary butoxycarbonyl-3″-
N-Palmitoykanamycin A (1g)
Suspension in Nisole (3 ml), trifluoro vinegar
Add acid (10 ml) under ice cooling. The reaction mixture was
Stir at warm temperature for 2 hours. The reaction mixture was concentrated under reduced pressure.
3,6'-bis-N-benzyloxycarbonylate
Leu-3″-N-palmitoykanamycin A was obtained.
Ru. (b) 3,6'-bis-N-benzyloxycarbonyl
Contains Ru-3″-N-palmitoykanamycin A
methanol (10 ml), N,N-dimethylene
dimethyl sulfonamide (5 ml) and dimethyl sulfonate.
Trifluoro
Ethyl acetate (2.84g) and triethylamine
(2.8ml) at room temperature. Stir the mixture for 11 days
do. Methanol was distilled off and the residue was dissolved in water (80ml).
Pour the precipitate into water and diethyl
washed sequentially with ether and phosphorus pentoxide under reduced pressure.
Dry to give 3,6'-bis-N-benzyloxy
Carbonyl-3″-N-palmitoyl-1-N-
Trifluoroacetylkanamycin A (683mg)
get. IR (nujiyor): 1690, 1540cm^-1 NMR (DMSO-d₆, δ): 0.77−1.03 (3H,
m), 7.33 (10H, s) Example 25 The following compound is obtained according to the method of Example 24. 1-N-acetyl-3,6'-bis-N-bendi
oxycarbonyl-3″-N-palmitoylcana
Mycin A. IR (nujiyor): 1680, 1630, 1530cm^-1 NMR (DMSO−d₆, δ): 0.87 (m), 1.27, 1.77
(s), 7.30 (s) Example 26 3,6'-bis-N-benzyloxycarbonyl
-1-N-palmitoykanamycin A (500mg)
of tetrahydrofuran (30ml) and water (8ml)
Acryloyl chloride (468mg) to the mixture solution
Stir a solution of in tetrahydrofuran (5 ml) on ice
Below, keep the pH between 8 and 9 with triethylamine.
Drip. The mixture is stirred at room temperature for 1 hour. anti
The reaction mixture was concentrated under reduced pressure to obtain a solid. This solid
1N hydrochloric acid (30ml), diethyl ether (60ml)
ml), washed sequentially with water and diethyl ether,
Air dry and 3″-N-acryloyl-3,6′-bis
-N-benzyloxycarbonyl-1-N-pal
Mitoylkanamycin A (624 mg) is obtained. Melting point >257℃ (decomposition) IR (Nujiyor): 3300, 1690, 1640, 1540,
1270, 1150, 1040cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m), 1.23
(28H, s) Example 27 The following compound is obtained according to the method of Example 26. (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-(3-carboxypropionyl)-
1-N-Palmitoykanamycin A. Melting point >252℃ (decomposition) IR (Nujiyor): 3300, 1690, 1640, 1530,
1270, 1150, 1040cm^-1 (2) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-(3-hydroxytetradecanoy)
)-3″-N-trifluoroacetylkanamai
Shin A. Melting point >265℃ (decomposition) IR (Nujiyor): 1690, 1640, 1540, 1270,
1210, 1160cm^-1 NMR (DMSO−d₆, δ): 0.88 (3H, m), 1.22
(28H, s) (3) 3″-N-benzoyl-3,6′-bis-N-be
ndyloxycarbonyl-1-N-palmitoy
Lucanamycin A. Melting point >284℃ (decomposition) IR (Nujiyor): 3280, 1710, 1680, 1620,
1540, 1300, 1260, 1240, 1080, 1040cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m), 1.20
(28H, s) Example 28 3,2',6'-tris-N-benzyloxycarl
Bonyl-3′,4′-dideoxy-3″-N-triful
Oloacetylkanamycin B (300mg)
Dorofuran (20ml) and water (7ml) mixture solution
Then, add palmitoyl chloride (92 mg) under ice-cooling to
Add while keeping the temperature at 8-9. The mixture under the same conditions 30
Stir for a minute. Tetrahydrofuran from the mixture
To leave. Add water to the residue mixture to form a precipitate
let The precipitate was collected, washed with water, and N,N-dimethyl
Dissolve in formamide (2 ml) and transfer the solution to a sulfuric acid mug.
Dry with nesium. Remove insoluble matter and sift into the liquid.
Add Lycagel (600mg). Concentrate the mixture to dryness
do. Column chromatography of the mixture using silica gel
The methanol-chloroform
Elute sequentially at 1:25, 1:10, 1:4
Ru. Combine fractions containing the desired compound and concentrate under reduced pressure.
and 3,2',6'-tris-N-benzyloxy
Carbonyl-3',4'-dideoxy-1-N-pal
Mitoyl-3″-N-trifluoroacetylkanama
Isin B (176 mg) is obtained. IR (nujiyor): 1680, 1520cm^-1 Example 29 3,2',6'-tris-N-benzyloxycarl
Bonyl-3″-N-trifluoroacetylkanamai
Syn B (500 mg) and N-palmitoyloxys
N,N-dimethylform of succinimide (189mg)
Stir the mixture in Muamide (10 ml) at room temperature for 18 days.
Ru. Pour the reaction mixture into water (50ml). generate
Take the precipitate and add water and diethyl ether sequentially.
Washed and dried under reduced pressure with phosphorous pentoxide to give 3,2′,
6'-tris-N-benzyloxycarbonyl-1
-N-palmitoyl-3″-N-trifluoroacetate
Obtain tilkanamycin B (536 mg). NMR (DMSO−d₆, δ): 0.84 (3H, t, J=6
Hz) Example 30 The following compound is obtained according to the method of Example 29. 3,2′,6′,3″-tetrakis-N-benzyl
oxycarbonyl-3',4'-dideoxy-1-N-
Palmitoyl kanamycin B. IR (nujiyor): 1680, 1540cm^-1 Example 31 The following compound is obtained according to the method of Example 15. (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-octanoyl-3″-N-tri
Fluoroacetylkanamycin A. Melting point >297℃ (decomposition) IR (Nujiyor): 3270, 1690, 1640, 1530,
1160, 1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.23
(12H, s) (2) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-decanoyl-3″-N-trif
Luroacetylkanamycin A, solid. Melting point>285℃ IR (Nujiyor): 1690, 1640, 1540, 1265,
1160, 1040cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m), 1.23
(16H, s) (3) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-Lauroyl-3″-N-Trifluoro
Roacetylkanamycin A. Melting point>278℃ (decomposition) IR (Nujiyor): 3260, 1680, 1630, 1530,
1260, 1160, 1040cm^-1 (4) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-myristoyl-3″-N-triful
Oloacetylkanamycin A. Melting point >273℃ (decomposition) IR (Nujiyor): 1690, 1640, 1540, 1260,
1180, 1050cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m) (5) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-palmitoyl-3″-N-triful
Oloacetylkanamycin A. IR (Nujiyor): 1690−1680, 1530, 1040−
1010cm^-1 (6) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-heptadecanoyl-3″-N-
Trifluoroacetylkanamycin A. Melting point >285℃ (decomposition) IR (Nujiyor): 3260, 1680, 1630, 1520,
1170, 1070, 1050cm^-1 NMR (DMSO−d₆, δ): 0.93 (3H, m) (7) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-stearoyl-3″-N-triful
Oloacetylkanamycin A. Melting point >264℃ (decomposition) IR (Nujiyor): 1680, 1630, 1530, 1160,
1070, 1035cm^-1 NMR (DMSO−d₆, δ): 0.92 (3H, m), 1.24
(32H, s) (8) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-icosanoyl-3″-N-tri
Fluoroacetylkanamycin A. Melting point >288℃ (decomposition) IR (Nujiyor): 3270, 1680, 1630, 1530,
1170, 1070, 1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.25
(36H, s) (9) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-hexanoyl-3″-N-tri
Fluoroacetylkanamycin A. Melting point >298℃ (decomposition) IR (Nujiyor): 1690, 1640, 1530, 1160,
1045cm^-1 NMR (DMSO−d₆, δ): 0.83 (3H, m) Example 32 According to the method of Example 1, the following compound is obtained. (1) 1-N-n-octanoyl-3″-N-triff
Luroacetylkanamycin A dihydrochloride. Melting point >193℃ (decomposition) IR (nujiyor): 1705, 1625, 1160, 1030cm
^-1 NMR (CD₃OD, δ): 5.12 (1H, d, J=4
Hz) FD Mass: 707 (M⁺) (2) 1-N-n-decanoyl-3″-N-triful
Oloacetylkanamycin A dihydrochloride. Melting point >210℃ (decomposition) IR (nujiyor): 1700, 1620, 1160, 1020cm
^-1 NMR(D₂O, δ): 0.90 (3H, m) FD Mass: 735 (M⁺) (3) 1-N-lauroyl-3″-N-trifluoro
Acetylkanamycin A dihydrochloride. Melting point >183℃ (decomposition) IR (Nujiyor): 1700, 1640−1620, 1560−
1540, 1160, 1010cm^-1 FD Mass: 763 (M⁺) (4) 1-N-myristoyl-3″-N-trifluoro
Loacetylkanamycin A dihydrochloride. Melting point >194℃ IR (nujiyor): 1700, 1630, 1160, 1030cm
^-1 NMR(D₂O, δ): 0.90 (3H, m) FD Mass: 791 (M⁺) (5) 1-N-palmitoyl-3″-N-trifluoro
Loacetylkanamycin A dihydrochloride. Melting point 230℃ (decomposition) [α]²⁶ _D: +67.8゜(C1.09, H₂O) IR (Nujiyor): 3250, 1705, 1640−30,
1550, 1210, 1180, 1160, 1080, 1050−1030
cm^-1 NMR (CD₃OD, δ): 0.88 (3H, t, J=6
Hz), 5.11 (1H, d, J = 3Hz), 5.48 (1H,
d, J=3Hz) FD Mass: 819 (M⁺), 723(M⁺−96), 658(M⁺
−161), 562(M⁺−257) (6) 1-N-n-heptadecanoyl-3″-N-t
Lifluoroacetylkanamycin A dihydrochloric acid
salt. Melting point >225℃ (decomposition) IR (Nujiyor): 1700, 1630, 1550, 1160,
1030cm^-1 NMR (CD₃OD, δ): 5.07 (1H, d, J=4
Hz)), 5.43 (1H, d, J = 3Hz) FD Mass: 833 (M⁺+1) (7) 1-N-stearoyl-3″-N-trifluoro
Loacetylkanamycin A dihydrochloride. Melting point >233℃ (decomposition) [α]²⁰ _D: +52.9゜(C2.0, H₂O) IR (Nujiyor): 3300, 1700, 1630, 1550,
1160, 1035cm^-1 NMR(D₂O, δ): 1.26 (s) FD Mass: 847 (M⁺) (8) 1-N-n-icosanoyl-3″-N-trif
Luroacetylkanamycin A dihydrochloride. Melting point >223℃ (decomposition) IR (Nujiyor): 3300, 1700, 1630, 1540,
1160, 1080, 1030cm^-1 NMR (CD₃O.D.₁δ): 0.95 (3H, m), 5.10 (1H,
d, J = 4Hz), 5.46 (1H, d, J = 3.5Hz) FD Mass: 875 (M⁺) (9) 1-N-n-hexanoyl-3″-N-trif
Luroacetylkanamycin A dihydrochloride. Melting point >133℃ (decomposition) IR (Nujiyor): 1710, 1640-1620, 1560,
1150, 1020cm^-1 NMR (CD₃OD, δ): 5.13 (1H, d, J=4
Hz), 5.52 (1H, d, J = 3Hz) FD Mass: 679 (M⁺) Example 33 2′,3′,4′,2″,4″-penta-O-acetyl-
3,6'-bis-N-benzyloxycarbonyl-
6″-O-(diphenylphosphoryl)-1-N-pal
Mitoyl-3″-N-trifluoroacetylkanama
Isin A (855mg), methanol (40ml) and 28%
Mixture solution with concentrated ammonia water (15 ml) at 60℃
Stir for 7.5 hours. Concentrate the reaction mixture under reduced pressure to remove the residue.
Get the residue. Dimethyl sulfoxide (20ml) of the residue
Add triethylamine (0.2ml) and trifle to the solution.
Add ethyl fluoroacetate (0.5ml) at room temperature and mix.
Stir the mixture at the same temperature for 1 hour. Diethyl reaction mixture
Pour into ether (200ml). The precipitate that forms
Remove and wash twice with diethyl ether (30ml).
3,6'-bis-N-benzyl oxychloride.
cyclocarbonyl-6″-O-phosphono-1-N-pal
Mitoyl-3″-N-trifluoroacetylkanama
Isin A (318 mg) is obtained. IR (Nujiyor): 1700, 1685, 1640, 1540,
1275, 1085cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 7.32
(10H, s) Example 34 The following compound is obtained according to the method of Example 26. (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-(N-benzyloxycarbonyl
glycyl)-1-N-n-pentadecanoyl
Namycin A. Melting point >217℃ (decomposition) IR (Nujiyor): 3300, 1690, 1535, 1270,
1150, 1050cm^-1 NMR (DMSO-d₆, δ): 0.92 (3H, m) (2) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-[(R,S)-3-hydroxybutylene
[Ril]-1-N-palmitoykanamycin A. Melting point >205℃ (decomposition) IR (Nuzhiyor): 3380, 1720 (sh), 1690,
1640, 1540, 1270, 1150, 1045cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) (3) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-[(R,S)-2-hydroxypro
Pionyl]-1-N-Palmitoykanamaishi
N A. IR (Nujiyor): 1720, 1680, 1640, 1530,
1280, 1040cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m) (4) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-[(D,L)-2,4-bis-(ben
Zyloxycarbonylamino)butyryl]-1
-N-palmitoykanamycin A. Melting point >230℃ (decomposition) IR (Nujiyor): 3280, 1690, 1640, 1300,
1225, 1150, 1010cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m) Example 35 The following compound is obtained according to the method of Example 15. (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-(N-benzyloxycarbonyl
glycyl)-1-N-n-pentadecylamino
Carbonylkanamycin A. IR (Nujiyor): 3300, 1690, 1540, 1270,
1155, 1045cm^-1 NMR (DMSO-d₆, δ): 0.91 (3H, m) (2) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-[N-benzyloxycarbonyl
glycyl)-1-N-n-hexadecyloxy
Carbonylkanamycin A. Melting point >246℃ (decomposition) IR (Nujiyor): 3200, 1690, 1540, 1270,
1150, 1045cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m) (3) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-tridecyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. Melting point >268℃ (decomposition) IR (Nujiyor): 3280, 1680, 1530, 1220,
1160, 1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) (4) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-tetradecyloxycarbony
Ru-3″-N-trifluoroacetyl kanamaysi
N A. Melting point >263℃ (decomposition) IR (Nujiyor): 3300, 1700, 1685, 1535,
1280, 1165, 1040cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m) (5) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-pentadecyloxycarboni
Ru-3″-N-trifluoroacetyl kanamaysi
N A. Melting point >263℃ (decomposition) IR (Nujiyor): 3300, 1700, 1540, 1290,
1170, 1045cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m) (6) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-heptadecyloxycarbony
Ru-3″-Nn-trifluoroacetylkanama
Ishin A. Melting point >277℃ (decomposition) IR (Nujiyor): 3280, 1700, 1690, 1530,
1220, 1160, 1040cm^-1 NMR (DMSO-d₆, δ): 0.91 (3H, m) (7) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-octadecyloxycarbony
Ru-3″-N-trifluoroacetyl kanamaysi
N A. IR (Nujiyor): 3300, 1690, 1545, 1170,
1045cm^-1 NMR (DMSO−d₆, δ): 0.92 (3H, m) (8) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-n-nonadecyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. IR (Nujiyor): 3300, 1750, 1690, 1530,
1285, 1220, 1165, 1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) (9) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-trifluoroacetyl-1-N-
(3,7,11-trimethyldodecyloxycarboxylic
Bonyl) Kanamycin A. IR (Nuzhiyor): 3320, 1700 (sh), 1695,
1545, 1160, 1075, 1045cm^-1 NMR (DMSO-d₆, δ): 0.90 (12H, blow
C, d, J = 6Hz) (10) 3,6'-bis-N-benzyloxycarbonylate
Ru-1-N-(1-methyltridecyloxycarboxylate)
)-3″-N-trifluoroacetylka
Namycin A. Melting point >272℃ (decomposition) IR (Nujiyor): 3300, 1700, 1530, 1260,
1220, 1160, 1040cm^-1 NMR (DMSO-d₆, δ): 0.93 (3H, m) (11) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-(N-benzyloxycarbonyl
glycyl)-1-N-[(R,S)-3-dodecano
yloxytetradecanoyl]kanamycin
A. Melting point >234℃ (decomposition) IR (Nujiyor): 3300, 1690, 1540, 1270,
1150, 1040cm^-1 NMR (DMSO−d₆, δ): 0.92 (3H, m) (12) 1-N-[(R,S)-3-acetoxyocta
[decanoyl]-3,6'-bis-N-benzyl
xycarbonyl-3″-N-trifluoroacetyl
Lucanamycin A. Melting point >272℃ (decomposition) IR (Nujiyor): 3300, 1690, 1540, 1170,
1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.90
(3H, s) (13) 1-N-[(R,S)-3-acetoxydeca
Noyl]-3,6'-bis-N-benzyloxy
Carbonyl-3″-N-trifluoroacetylka
Namycin A. IR (nujiyor): 3300, 1705, 1540, 1055cm
^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m), 1.93
(3H, s) (14) 1-N-[(R,S)-3-acetoxyhex
[sadecanoyl]-3,6'-bis-N-benzyl
Oxycarbonyl-3″-N-trifluoroacetate
Cirkanamycin A. NMR (DMSO-d₆, δ): 0.91 (3H, m), 1.95
(3H, s) Example 36 According to the method of Example 1, the following compound is obtained. (1) 1-N-palmitoyl-6″-O-phosphono-
3″-N-trifluoroacetylkanamycin
A. Melting point >164℃ (decomposition) [α]²⁰ _D: +27.3゜(C1.0, H₂O) IR (Nujiyor): 1710, 1635, 1550, 1210,
1180, 1155, 1030cm^-1 NMR (CD₃OD, δ): 0.93 (3H, m) (2) 3″-N-glycyl-1-N-n-pentadecy
Ruaminocarbonylkanamycin A/trihydrochloric acid
salt. Melting point >169℃ (decomposition) IR (Nujiyor): 3250, 1680, 1560, 1260,
1140, 1030cm^-1 NMR (CD₃OD, δ): 0.96 (3H, m) (3) 3″-N-glycyl-1-N-n-pentadeca
Nourikanamycin A trihydrochloride. Melting point >97℃ (decomposition) IR (Nujiyor): 1670, 1300, 1140, 1080,
1030cm^-1 NMR (CD₃OD, δ): 0.93 (3H, m), 5.23
(1H, d, J = 4Hz), 5.55 (1H, d, J =
3Hz) FD Mass: 766 (M⁺), 788(M⁺+Na) (4) 1-N-n-hexadecyloxycarbonyl
-3″-N-glycylkanamycin A trihydrochloric acid
salt. Melting point >197℃ (decomposition) IR (Nujiyor): 3300, 1690, 1540, 1260,
1140, 1035cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m) (5) 3″-N-[(R,S)-3-hydroxybutyryl
]-1-N-palmitoykanamycin A.
Dihydrochloride. Melting point 121℃ (decomposition) IR (Nujiyor): 3230, 1720, 1630, 1240,
1030cm^-1 NMR (CD₃OD, δ): 0.90 (3H, m) FD Mass: 810 (M⁺+1) (6) 3″-N-[(R,S)-2-hydroxypropylene
onyl]-1-N-palmitoykanamycin
A. Dihydrochloride. Melting point >122℃ (decomposition) IR (Nujiyor): 1700, 1630, 1220, 1120,
1070cm^-1 NMR (CD₃OD, δ): 0.90 (3H, m) (7) 3″-N-[(D,L)-2,4-diaminobuty
Ril]-1-N-palmitoykanamycin
A. Tetrahydrochloride. Melting point >125℃ (decomposition) IR (Film-MeOH): 1710, 1640, 1540,
1215, 1070cm^-1 NMR (CD₃OD, δ): 0.92 (3H, m) (8) 1-N-n-tridecyloxycarbonyl-
3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point >132℃ (decomposition) IR (Nujiyor): 3300, 1700, 1540, 1270,
1155, 1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m) FD Mass: 808 (M⁺+1) (9) 1-N-n-tetradecyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point >153℃ (decomposition) IR (Nujiyor): 3280, 1700, 1560, 1270,
1150, 1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.18
(1H, d, J=3Hz) (10) 1-N-n-pentadecyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point >179℃ (decomposition) IR (Nujiyor): 3280, 1700, 1540, 1260,
1150, 1040cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.10
(1H, d, J=3Hz) (11) 1-N-n-heptadecyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point >159℃ (decomposition) IR (Nujiyor): 3300, 1700, 1550, 1270,
1155, 1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.12
(1H, d, J=4Hz), 5.48 (1H, d, J=
3Hz) (12) 1-N-n-octadecyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point>219℃ IR (Nujiyor): 3300, 1700, 1540, 1270,
1210, 1160, 1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.15
(1H, d, J=3Hz) FD Mass: 876 (M⁺-1), 898(M⁺+Na) (13) 1-N-n-nonadecyloxycarbonyl
-3″-N-trifluoroacetylkanamycin
A. Dihydrochloride. Melting point >96℃ (decomposition) IR (Nujiyor): 3320, 1700, 1270, 1155,
1030cm^-1 NMR (CD₃OD, δ): 0.96 (3H, m) (14) 3″-N-trifluoroacetyl-1-N-
(3,7,11-trimethyldodecyloxycarboxylic
Bonilkanamycin A dihydrochloride. Melting point>211℃ (decomposition) IR (Nujiyor): 3280, 1700, 1540, 1270,
1155, 1030cm^-1 NMR (CD₃OD, δ): 5.12 (1H, d, J=3
Hz), 5.50 (1H, d, J = 2Hz) FD Mass: 856 (M⁺+Na) (15) 1-N-(1-methyltridecyloxyca
)-3″-trifluoroacetylkanama
Isin A dihydrochloride. Melting point >133℃ (decomposition) IR (Nujiyor): 3250, 1700, 1270, 1155,
1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.15
(1H, d, J=3Hz) (16) 3″-N-carbamoyl-1-N-palmite
Ilkanamycin A dihydrochloride. Melting point >194℃ (decomposition) IR (Nujiyor): 3250, 1700, 1630, 1540,
1240, 1140, 1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m), 5.10
(1H, d, J=3Hz), 5.51((1H, d, J=
3Hz) (17) 1-N-[(R,S)-3-dodecanoyl
xytetradecanoyl]-3″-N-glysylca
Namycin A trihydrochloride. Melting point >147℃ (decomposition) IR (Nujiyor): 3200, 1680, 1540, 1040,
1030cm^-1 NMR (CD₃OD, δ): 0.93 (3H, m) (18) 3″-N-glycyl-1-N-[(R,S)-
3-Hydroxyoctadecanoyl] Kanamaishi
N A trihydrochloride. Melting point >193℃ (decomposition) IR (Nujiyor): 3300, 1640, 1560, 1140,
1030cm^-1 NMR (CD₃OD, δ): 0.93 (3H, m) (19) 3″-N-glycyl-1-N-[(R,S)-
3-Hydroxydecanoyl]Kanamycin A・
Trihydrochloride. Melting point >209℃ (decomposition) IR (Nujiyor): 3200, 1630, 1560, 1140,
1010cm^-1 NMR (CD₃OD, δ): 0.96 (3H, m), 5.52
(1H, d, J=3Hz) (20) 3″-N-glycyl-1-N-[(R,S)-
3-Hydroxy-n-hexadecanoyl]kana
Mycin A trihydrochloride. Melting point >223℃ (decomposition) IR (Nujiyor): 3200, 1630, 1550, 1140,
1080, 1025cm^-1 NMR (CD₃OD, δ): 0.93 (3H, m), 5.50
(1H, d, J=3Hz) Example 37 The following compound is obtained according to the method of Example 13(2). 3,6'-bis-N-benzyloxycarbonyl
-1-N-n-pentadecanoyl kanamycin
A. IR (Nujiyor): 1710, 1685, 1640, 1530,
1265, 1140, 1045cm^-1 NMR (DMSO-d₆, δ): 0.86 (3H, m) Example 38 1-N-n-pentadecanoyl-3″-N-tri
Fluoroacetylkanamycin A dihydrochloride
(500 mg) in water (20 ml), α-cyclodextrin
Add Torin (554 mg) at room temperature. Bring the mixture to the same temperature
Stir for 1 hour. Strain the solution and freeze-dry it.
1-N-n-pentadecanoyl-3″-N-t
Lifluoroacetylkanamycin A dihydrochloride
α-Cyclodextrin complex (1:1, mol/
mol) (1.02 g) is obtained. Melting point >221℃ (decomposition) IR (Nujiyor): 3300, 1700, 1630, 1150,
1080, 1020cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m) Example 39 1-N-palmitoyl-3″-N-trifluoro
Acetylkanamycin A dihydrochloride (500mg)
Add urea (438 mg) to methanol (10 ml) solution.
Add warm. Stir the mixture for 10 minutes at the same temperature. melt
Concentrate the liquid under reduced pressure to obtain a residue. Add the residue to water (30ml)
The solution was filtered and lyophilized to give 1-N
-Palmitoyl-3″-N-trifluoroacetyl
Kanamycin A dihydrochloride-urea complex (1:
13, mol/mol) (907 mg) is obtained. Melting point >212℃ (decomposition) IR (Nujiyor): 3420, 3320, 3200, 1680,
1625, 1590, 1150, 1025cm^-1 NMR(D₂O, δ): 0.90 (3H, m) Example 40 The following compound is obtained according to the method of Example 38. (1) 1-N-n-pentadecanoyl-3″-N-t
Lifluoroacetylkanamycin A dihydrochloride
-α-cyclodextrin complex (1:2, mole)
1/mol). Melting point >227℃ (decomposition) IR (Nujiyor): 3300, 1710, 1635, 1150,
1080, 1030cm^-1 NMR (CD₃OD, δ): 0.92 (3H, m) (2) 1-N-palmitoyl-3″-N-trifluoro
loacetylkanamycin A-dihydrochloride/γ-cy
Clodextrin complex (1:2, mol/mol
). Melting point >224℃ (decomposition) [α]²⁰ _D:+132.9゜(C1.0H₂O) IR (Nujiyor): 1710, 1630, 1150, 1070,
1010cm^-1 NMR (CD₃OD, δ): 0.93 (3H, m) (3) 1-N-palmitoyl-3″-N-trifluoro
loacetylkanamycin A dihydrochloride-β-cy
Clodextrin complex (1:2, mol/mol
). Melting point >210℃ (decomposition) [α]²⁰ _D:+81.7゜(C1.0H₂O) IR (Nujiyor): 3300, 1700, 1630, 1150,
1080, 1020cm^-1 NMR (CD₃OD−D₂O, δ): 0.91 (3H, m) (4) 1-N-palmitoyl-3″-N-trifluoro
loacetylkanamycin A dihydrochloride-β-cy
Clodextrin complex (1:1, mol/mol)
). Melting point >214℃ (decomposition) [α]²⁰ _D:+89.7゜(C1.0H₂O) IR (Nujiyor): 3300, 1705, 1635, 1150,
1080, 1030cm^-1 NMR (CD₃OD−D₂O, δ): 0.90 (3H, m) (5) 1-N-palmitoyl-3″-N-trifluoro
loacetylkanamycin A dihydrochloride-α-cy
Clodextrin complex (1:2, mol/mol
). Melting point >222℃ (decomposition) [α]²⁰ _D+82.5゜(C1.0H₂O) IR (Nujiyor): 3300, 1710, 1630, 1150,
1080, 1030cm^-1 NMR (CD₃OD, δ): 0.95 (3H, m) (6) 1-N-palmitoyl-3″-N-trifluoro
loacetylkanamycin A dihydrochloride-α-cy
Clodextrin complex (1:1, mol/mol)
). Melting point >219℃ (decomposition) [α]²⁰ _D:+82.6゜(C1.0H₂O) IR (Nujiyor): 3300, 1710, 1630, 1150,
1080, 1030cm^-1 NMR (CD₃OD, δ): 0.92 (3H, m) (7) 1-N-n-icosanoyl-3″-N-trif
Luroacetylkanamycin A dihydrochloride-α
-cyclodextrin complex (1:2, mol/
mole). Melting point >225℃ (decomposition) [α]²⁰ _D:+84.24゜(C1.0H₂O) IR (Nujiyor): 3300, 1700, 1630, 1150,
1080, 1025cm^-1 Example 41 The following compound is obtained according to the method of Example 26. (1) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-benzyloxycarbonylcarba
Moyl-1-N-palmitoykanamycin
A. IR (Nujiyor): 3300, 1785, 1740, 1685,
1530, 1300, 1250, 1040cm^-1 NMR (DMSO−d₆, δ): 0.90 (3H, m) (2) 3,6'-bis-N-benzyloxycarbonylate
Le-3″-N-[N-(benzyloxycarbonylate)
phenyl]-1-N-[(R,S)-3-hydro
Roxioctadecanoyl] Kanamycin A. IR (Nujiyor): 3300, 1690, 1640, 1540,
1040cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) (3) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-(N-benzyloxycarbonyl)
Glycyl-1-N-[(R,S)-3-hydroxy
[sidecanoyl] kanamycin A. IR (Nujiyor): 3300, 1695, 1640, 1540,
1270, 1150, 1040cm^-1 NMR (DMSO−d₆, δ): 0.91 (3H, m) (4) 3,6'-bis-N-benzyloxycarbonylate
Ru-3″-N-(N-benzyloxycarbonyl)
Glycyl-1-N-[(R,S)-3-hydroxy
cyhexadecanoyl] kanamycin A. IR (Nujiyor): 3300, 1690, 1640, 1540,
1270, 1155, 1050cm^-1 NMR (DMSO−d₆, δ): 0.91 (3H, m) Example 42 The following compounds were prepared according to the method of Examples 17(1) and 17(2).
get something (1)(1) 3,6'-bis-N-benzyloxycarbo
Nyl-2′,3′,4′,2″,4″,6″-hex-O
-acetyl-1-N-[(R,S)-3-acetyl
Toxioctadecanoyl〕-3″-N-Triff
Luroacetylkanamycin A. IR (Nujiol-EtOH): 1740, 1650,
1540, 1230, 1155, 1030cm^-1 NMR (CDCl)₃, δ): 0.93 (3H, m) (2) 3,6'-bis-N-benzyloxycarbo
Nyl-1-N-[(R,S)-3-hydroxy
octadecanoyl] kanamycin A. IR (Nujiyor): 3300, 1680, 1640, 1540,
1150cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m) (2)(1) 2′, 3′, 4′, 2″, 4″, 6″-hex-O-
a
Cetyl-1-N-[(R,S)-3-acetoxy
sidecanoyl]-3,6'-bis-N-benzi
carbonyl-3″-N-trifluoro
Acetylkanamycin A. IR (Nujiyor): 1750, 1645, 1230, 1155,
1040cm^-1 NMR (CDCl)₃, δ): 0.95 (3H, m) (2) 3,6'-bis-N-benzyloxycarbo
Nyl-1-N-[(R,S)-3-hydroxy
[decanoyl] kanamycin A. IR (Nujiyor): 3300, 1690, 1640, 1540,
1150, 1050cm^-1 NMR (DMSO-d₆, δ): 0.92 (3H, m) (3)(1) 2′, 3′, 4′, 2″, 4″, 6″-hex-O-
a
Cetyl-1-N-[(R,S)-3-acetoxy
cyhexadecanoyl]-3,6'-bis-N-
Benzyloxycarbonyl-3″-N-trif
Luroacetylkanamycin A. IR (Nuzhiyor): 3320, 1740 (sh), 1700,
1640, 1540, 1260, 1170, 1060cm^-1 NMR (CDCl)₃, δ): 0.95 (3H, m) (2) 3,6'-bis-N-benzyloxycarbo
Nyl-1-N-[(R,S)-3-hydroxy
Hexadecanoyl]Kanamycin A. IR (Nujiyor): 1690, 1640, 1540, 1270,
1230, 1150cm^-1 NMR (DMSO-d₆, δ): 0.90 (3H, m)

Claims (1)

[Claims] 1. General formula: [In the formula, at least one of R ¹ , R ² , R ³ and R ⁴ is higher alkanoylamino, higher alkenoylamino, which may each have a suitable substituent;
Higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others are amino or acylamino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ means hydroxy or phosphonooxy, respectively] and salts thereof. 2 Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, in which at least one of R ¹ , R ² , R ³ and R ⁴ may each have lower alkyl, hydroxy, lower alkanoyloxy or higher alkanoyloxy; Higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, other amino, carbamoylamino, aroylamino, lower alkoxycarbonylamino, or lower alkanoyl optionally containing hydroxy, amino, carboxy or halogen 2. A compound according to claim 1, wherein amino, R ⁵ is hydroxy, amino or phenyl(lower)alkoxycarbonylamino. 3 Higher alkanoylamino in which at least one of R ¹ , R ² , R ³ and R ⁴ may have lower alkyl, hydroxy, lower alkanoyloxy or higher alkanoyloxy; higher alkenoylamino; The compound according to claim 2, which is a higher alkoxycarbonylamino which may be a higher alkoxycarbonylamino; a higher alkylaminocarbonylamino; a higher alkoxy (lower) alkanoylamino or a higher alkylthiocarbonylamino. 4 One of R ¹ , R ² , R ³ and R ⁴ is octanoylamino, nonanoylamino, decanoylamino,
Decanoylamino with hexyl or hydroxy, undecanoylamino, lauroylamino, myristoylamino, myristoylamino with hydroxy, myristoylamino with acetyloxy, myristoylamino with lauroyloxy, pentadecanoylamino, palmitoylamino, hydroxy palmitoylamino, heptadecanoylamino, stearoylamino, stearoylamino with hydroxy, icosanoylamino, dodecyloxycarbonylamino, dodecyloxycarbonylamino with methyl, tridecyloxycarbonylamino, tridecyloxycarbonylamino with methyl , tetradecyloxycarbonylamino,
Pentadecyloxycarbonylamino, hexadecyloxycarbonylamino, heptadecyloxycarbonylamino, octadecyloxycarbonylamino, nonadecyloxycarbonylamino, pentadecyloxycarbonylamino, tridecyloxyacetylamino or hexadecylthiocarbonylamino, others are amino , carbamoylamino, acetylamino, trifluoroacetylamino, octanoylamino, tertiary butoxycarbonylamino, aminoacetylamino,
carboxypropionylamino, hydroxyacetylamino, propionylamino, benzoylamino, propionylamino with hydroxy,
4. The compound according to claim 3, wherein butyrylamino having hydroxy, butyrylamino having amino, R ⁵ is hydroxy, amino or benzyloxycarbonylamino. 5 1-N-n-icosanoyl-3''-N-trifluoroacetylkanamycin A or its dihydrochloride, the compound according to claim 4. 6 1-N-n-hexadecyloxycarbonyl-3 ″-N-trifluoroacetylkanamycin A
or its dihydrochloride, the compound according to claim 4. 7 Formula: [In the formula, at least one of R ¹ , R ² and R ³ may have a suitable substituent, such as higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher Alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others are amino or acylamino, R ⁴ _a is acylamino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy ] or a salt thereof is subjected to a deacylation reaction to form the formula: [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, R ⁴ _b is amino, and at least one of R ¹ , R ² and R ³ has a suitable substituent, respectively. higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others mean amino or acylamino, respectively. A method for producing an aminoglycoside derivative, characterized by obtaining a compound or a salt thereof. 8 Formula: [In the formula, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy, R ¹ _a is acylamino, and at least one of R ² , R ³ and R ⁴ is Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a suitable substituent; others are amino or acylamino ] or a salt thereof is subjected to a deacylation reaction to form the formula: [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, R ¹ _b is amino, and at least one of R ² , R ³ and R ⁴ has a suitable substituent, respectively. higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others mean amino or acylamino, respectively. A method for producing an aminoglycoside derivative, characterized by obtaining a compound or a salt thereof. 9 Formula: [In the formula, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy, R ² _a is acylamino, and at least one of R ¹ , R ³ and R ⁴ is Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a suitable substituent; others are amino or acylamino ] or a salt thereof is subjected to a deacylation reaction to form the formula: [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, R ² _b is amino, and at least one of R ¹ , R ³ and R ⁴ has a suitable substituent, respectively. higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others mean amino or acylamino, respectively. A method for producing an aminoglycoside derivative, characterized by obtaining a compound or a salt thereof. 10 Formula: (wherein R ¹ _b is amino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy, R ² , R ³ and R ⁴ are each amino or acylamino ) or a reactive derivative thereof at the amino group or a salt thereof is subjected to an acylation reaction to form the formula: [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ¹ is higher alkanoylamino, higher alkenoylamino, higher alkoxy, each of which may have an appropriate substituent. carbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ² , R ³ and R ⁴ each mean amino or acylamino] or a salt thereof. A method for producing characteristic aminoglycoside derivatives. 11 Formula: (wherein R ² _b is amino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy, R ¹ , R ³ and R ⁴ are each amino or acylamino ) or a reactive derivative thereof at the amino group or a salt thereof is subjected to an acylation reaction to form the formula: [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ² is higher alkanoylamino, higher alkenoylamino, higher alkoxy, each of which may have an appropriate substituent. carbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ¹ , R ³ and R ⁴ each mean amino or acylamino] or a salt thereof. A method for producing characteristic aminoglycoside derivatives. 12 Formula: (wherein R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy, R ³ _b is amino, R ¹ , R ² and R ⁴ are each amino or acylamino ) or a reactive derivative thereof at the amino group or a salt thereof is subjected to an acylation reaction to form the formula: [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ³ is a higher alkanoylamino, higher alkenoylamino, higher alkoxy which each may have an appropriate substituent. carbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ¹ , R ² and R ⁴ each mean amino or acylamino] or a salt thereof. A method for producing characteristic aminoglycoside derivatives. 13 Formula: (wherein R ⁴ _b is amino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy, R ¹ , R ² and R ³ are each amino or acylamino ) or a reactive derivative thereof at the amino group or a salt thereof is subjected to an acylation reaction to form the formula: [In the formula, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as above, and R ⁴ is a higher alkanoylamino, higher alkenoylamino, higher alkoxy which each may have an appropriate substituent. carbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, R ¹ , R ² and R ³ each mean amino or acylamino] or a salt thereof. A method for producing characteristic aminoglycoside derivatives. 14 Formula: [In the formula, R ¹ _b is amino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonooxy, and at least one of R ² , R ³ and R ⁴ is Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a suitable substituent; others are amino or acylamino ] or a reactive derivative thereof at the amino group or a salt thereof is subjected to an acylation reaction to form the formula: [In the formula, R ¹ _a ' is higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, which may each have a suitable substituent,
acylamino, excluding higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino and higher alkylthiocarbonylamino, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as before, R ² , R ³ and R ⁴ Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, at least one of which may have a suitable substituent, respectively; A method for producing an aminoglycoside derivative, which comprises obtaining a compound or a salt thereof, each of which represents amino or acylamino. 15 Formula: [In the formula, R ² _b is amino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, R ¹⁰ is hydroxy or phosphonoxy, and at least one of R ¹ , R ³ and R ⁴ is Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, each of which may have a suitable substituent; others are amino or acylamino ] or a reactive derivative thereof at the amino group or a salt thereof is subjected to an acylation reaction to form the formula: [In the formula, R ² _a ' is higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, which may each have a suitable substituent,
acylamino, excluding higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino and higher alkylthiocarbonylamino, R ⁵ , R ⁶ , R ⁷ and R ¹⁰ each have the same meaning as before, R ¹ , R ³ and R ⁴ Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, at least one of which may have a suitable substituent, respectively; 1. A method for producing an aminoglycoside derivative, which comprises obtaining a compound represented by the formula ``Other means amino or acylamino'' or a salt thereof. 16 Formula: [In the formula, R ⁵ _a , R ⁶ _a , R ⁷ _a , R ⁸ _a , R ⁹ _a and R ¹⁰ _a are each acyloxy, and at least one of R ¹ , R ² , R ³ and R ⁴ is an appropriate substitution Higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or lower alkylthiocarbonylamino, each of which may have a group, and others mean amino or acylamino, respectively. ] or a salt thereof is subjected to a deacylation reaction to form the formula: [In the formula, at least one of R ¹ , R ² , R ³ and R ⁴ is higher alkanoylamino, higher alkenoylamino, which may each have a suitable substituent;
higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others mean amino or acylamino] or a salt thereof. Manufacturing method. 17 Formula: [In the formula, R ⁵ _a , R ⁶ _a , R ⁷ _a , R ⁸ _a and R ⁹ _a are each acyloxy, R ¹⁰ _c is protected phosphonooxy, and at least one of R ¹ , R ² , R ³ and R ⁴ One is higher alkanoylamino, higher alkenoylamino, higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, which each may have a suitable substituent, and the other is amino. or acylamino, respectively] or a salt thereof is subjected to a phosphono-protecting group elimination reaction, and the formula: [In the formula, at least one of R ¹ , R ² , R ³ and R ⁴ is higher alkanoylamino, higher alkenoylamino, which may each have a suitable substituent;
An aminoglycoside derivative characterized by obtaining a compound represented by the following formula: higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino, or higher alkylthiocarbonylamino, and others mean amino or acylamino, respectively, or a salt thereof. manufacturing method. 18 General formula: [In the formula, at least one of R ¹ , R ² , R ³ and R ⁴ is higher alkanoylamino, higher alkenoylamino, which may each have a suitable substituent;
Higher alkoxycarbonylamino, higher alkylaminocarbonylamino, higher alkoxy (lower) alkanoylamino or higher alkylthiocarbonylamino, others are amino or acylamino, R ⁵ is hydroxy, amino or acylamino, R ⁶ and R ⁷ are each hydroxy or hydrogen, ^R10 means hydroxy or phosphonooxy, respectively] for the prevention of infectious diseases using aminoglycoside derivatives or their salts as active ingredients.
therapeutic agent.