JPS615089A - Novel aminoglycoside derivative - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R<1> is higher alkanoylamino which may be substituted; R<2>-R<4> are amino, acylamino) and its salts. EXAMPLE:1-N-Palmitoylribostamycin. USE:Preventive and remedy for infectious diseases. PREPARATION:A compound of formula II such as 3',4';2'',3''-di-O-cyclohexylidene-3,2',6'-tri-N-benzyloxycarbonyl-5'' -O-trityl-1-N-palmitoylribostamycin is hydrolyzed, e.g., in acetic acid-water solvent mix at 80 deg.C for 10hr to remove OH- protecting groups and, when needed, R<2>-R<4> are deacylated. The starting compound is novel and obtained from a compound of formula I where R<1> is acylamino.

Description

DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel aminoglycoside derivatives and salts thereof. More specifically, the present invention relates to novel aminoglycoside derivatives and salts thereof having antiviral activity and immunostimulatory activity, methods for producing them, and 2) 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 [formula,
R1 means higher alkanoylamine/, R", R" and Rfl amino or acylamino, respectively, which may have a suitable substituent.] According to the present invention, the novel aminoglycoside derivative (1) is, for example, , it can be manufactured by the following method.

Manufacturing method 1: Salt OHQl (or Salt manufacturing method 2: Salt is salt OHQl) In the formula, R1, R2, R3 and R4 have the same meanings as before. R and R each represent acylamino, and R represents protected hydroxy.] Among the starting compounds of this invention, compound a) is a new compound and can be produced by the following method.

or a salt thereof, or a salt thereof, or a salt thereof, or a salt thereof [in the formula, R1, R2, R3, R4, and R5 each have the same meanings as before, and the term "corona" means acylamino] of the aminoglycoside derivative (1). Preferred pharmaceutically acceptable salts are the conventional salts, such as hydrochlorides, hydrobromides, hydroiodides, sulfates, nitrates, phosphates, phosphates, acetates, fumarates, maleates. Examples include organic acid addition salts or inorganic acid addition salts such as acid salts, tartrate salts, methanesulfonate salts, benzene nulphonic acid L)/Renth lephonate salts, 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 ash atoms, unless otherwise specified.

Suitable "acyl" moieties of "acylamino" include lebamoyl, 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 W, Isobutyryl, Valeryl,
Lower alkanoyl sulfonyl such as isovaleryl, pivaloyl, hexanoyl, lower alkanoyl sulfonyl such as propanesulfonyl, lower alkanoyl such as methoxycarbonyl, ethoxycarbonyl, propoquine carbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc. Examples of alkoxycarbonyl include lower alkenoyl (C3-(wa)-cycloalkanecarbonyl) such as saturated or unsaturated acyclic acyclic or cyclic acyl such as acryloyl, methacryloyl, and crotonoyl.

Examples of the aromatic acyl include aloino V1 examples such as benzoyl, toluoyl, and xyloyl, ethbenzene Nulfonyl, and allene Nulfonyl N such as tosyl.

Examples of the heterocyclic acyl include furoyl, thenoyl, nicotinoyl, innicotinoyl, thiasiri! Shiriki Lebonil, Chiashiasori! Examples include sulfonyl, tetrazolylcarbonyl, and tetrazolylcarbonyl.

Aliphatic acyl substituted with an aromatic group includes, for example, phenylacetyl, phenylpropionyl, phenyl (lower) alkanoyl such as phenylrehexanoyl, e.g. Examples include phenyl(lower)alkoxyl such as carbonyl, levonyl, phenoxy(lower)alkanoyl such as evaphenoxyacetyl and phenoxypropionyl, and the like.

Examples of the aliphatic acetate substituted with a complex group include thienyl acetyl acetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolyl acetyl, thienylpropioni 7, thiadiazolyl propioni 7V, etc. can be mentioned.

These acyl groups are further divided into hydroxy, amino, and force!
Levoxy, lower alkyl such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl, halogen such as chlorine, bromine, iodine, fluorine, such as methoxy, ethoxy, propoxy, impropoxy, butoxy, pentyloxy, hexyloxy, etc. Lower alkoxy, such as hamethio, ethylthio, propylthio,
Lower alkylthio such as isopropylthio, butylthio, pentylthio, hexylthio, nitro, acylamino,
For example, aryloxy such as benzyloxy, tolyloxy, etc., e.g. homyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy, isovaleryloxy, pivaloyloxy, hexanoyloxy, etc. Preferred acyl having such a substituent may be substituted with a suitable substituent such as lower alkanoyloxy such as oxy, etc.
For example, mono(di or tri)halo(lower)alkanoia such as chloroacetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, etc., such as glycyl,
Amino(lower)alkanoyl such as aminopropionyl, diaminobutyryl, phenyl((l)alkoxycarbonylamino(lower)alkanoyl, phenyl(lower)alkoxycarbonylcarbamoyl, e.g. ehapenzyloxycarbonylglycyl) carbamoyl, e.g. evabenzyloxyacetyl,
The power of phenolic (lower) alkanoyl such as benzyloxypropionyl, IV boxyacetyl, carboxypropionyl, etc.! Levoxy(lower)alkanoyl, such as hydroxy(lower)alkanoyl, such as glycolyl, hydroxypropionyl, hydroxypropylene, and hydroxy(lower)alkanoyl.

Suitable "higher alkanoyl" moieties in "higher alkanoylamino" include octanoyl, nonanoyl,
Decanoyl, undecanoyl, lauroyl, myristoyl, pentadecanoyl, valmitoyl, heptadecanoyl 1V1 stearoyl, icosanoyl, docosanoyl,
Examples include those having 8 or more carbon atoms, preferably 8 to 24 carbon atoms, such as tetracosanoyl.

The above-mentioned "higher alkanoylamino" refers to lower alkyl (methyl, ethyl, propylene), 7" methyl, pentyl, hexyl, etc., hydroxy, such as phoremyloxy, acetoxy, propionylleoquine, butyrifleoxy, etc. It may have 1 to 3 suitable substituent groups such as lower alkanoyloxy and the like.

Suitable hydroxy-protecting groups for "protected hydroxy" include the above-mentioned acyl, for example, al(lower) alkyl such as benzyl, trityl, etc. Examples include lower alkoxy-substituted cyclo(lower) alkyl such as metquine-substituted cyclohexyl.

Suitable "cyclo(lower)alkyl" has 3 to 6 carbon atoms, and includes cyclopropyl, cyclobutyl, cyclobentyl, cyclohexyl, etc., but preferably has 5 to 6 carbon atoms. be.

The method for producing the target compound and raw material compound of this invention will be explained in detail below.

Production method 1 The target compound (1) or a salt thereof can be produced by subjecting compound (Il) 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 2 described below.

In this reaction, the acylamino groups of R, R and R4 may likewise be deacylated during the reaction or after-treatment of this reaction, which is also included within the scope of this reaction.

Production method 2 Compound (lc) f or a salt thereof can be produced by deacylation method in which a salt of compound (lb) is subjected to a deacylation reaction. chemical agent,
This is then carried out by conventional methods such as deacylation by reaction with an iminoetherification agent and optionally by hydrolysis of the product by 7X.

Suitable iminohalogenating agents include, for example,
Examples include halogen north-sides such as five-salt north-sides, three-smells north-sides, and five-smells north-sides, phosphorus oxychloride, thionino chloride V1 honugen, and the like.

The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or at room temperature.

A suitable iminoetherification agent to be reacted with the reaction product obtained in this way is A! Examples include lecor, metal alkoxides, and the like. Suitable alcohols include alkanols which may be substituted with alkoxides such as methoxy, ethoxy, propoxy, isopropoquine, and ethoxy, such as methanol, ethanol, propatool, isopropanol, butanol, and tertiary alcohols. Examples thereof include butanol, 1,3-butanedio-1, and the like. 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 7JD
Subject to water splitting. Hydrolysis can be easily carried out by pouring the reaction mixture obtained above into water. A base or an acid such as dilute hydrochloric acid or acetic acid may be added.

The reaction temperature is not particularly limited, and may be appropriately selected depending on the type of protecting group for the amino group and the type of the above-mentioned elimination method.
This reaction is preferably carried out under mild conditions such as cooling, room temperature or slightly elevated temperature.

Hydrolysis includes methods using acids or bases. These methods may be selected according to the type of acyl group to be eliminated.

Suitable acids include organic or inorganic acids, such as
acetic acid,) lifluoroacetic acid, benzenesulfonic acid, p-)
Examples include luenulphonic acid and hydrochloric acid.

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 of a solvent without the presence of any 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, for example, sodium hydroxide,
Alkali metal hydroxides such as potassium oxide, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide, etc., alkaline metal salts such as potassium carbonate, e.g. magnesium carbonate, Alkaline earth metal salts such as calcium carbonate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal acetates such as sodium acetate and potassium acetate, alkalis such as magnesium phosphate and calcium phosphate. Inorganic bases such as earth metal phosphates, such as alkali metal hydrogen phosphates such as disodium hydrogen phosphate, dipotassium hydrogen phosphate, etc.;
triethylamine, etc.) V-kirnamine, picoline, N-methylpyrrolidine, N-methylmorpholine, 1
．． 5-diazabicyclo(4,3,0)non-5-ene,
1,4-diazabicyclo[2,2,2)octane, 1,
Examples include 5-diazabicyclo[5,4,[1) undecene-5. 711+ Ice decomposition using a base is often carried out in a water strainer, a hydrophilic organic solvent, or a mixture thereof.

Examples of the reduction method include reduction with an alkali gold-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.

Production method A-(1) The target compound (llb) or a salt thereof can be produced by subjecting the compound (I) or a salt thereof to a reaction for introducing a hydroxy protecting group.

Suitable hydroxy protecting group introduction agents are conventional introduction agents of the formula: Ra-OH (IIDc, where Ra is (lower) alkyl, e.g. benzene, trityl) V, e.g. methoxy-substituted cyclohexyl, etc. cyclo(lower) alkyl substituted with lower anonokoxy, etc.), or its reactive derivative in the hydroxy group, or its salt.

The reaction can be carried out under the same conditions as in production method p, -(5).

Production method A-(2) Target compound (110)'! or its salt is the compound (h
) or a salt thereof, can be produced by reacting with 1,1-dimethoxine chlorhexane.

The reaction can be carried out under the same conditions as in Production Method A-(5).

Production method p, -(3) The target compound (Ild) obtained tobacco salt is converted to the compound (Ilc
) It can be produced by reacting the salt of Ushitakeso with sodium hydride.

The reaction is usually carried out using water, acetone, dioxane, dichloromethane, iH ethyl, N,N-dimethylpho! Remamide,
It can be used in solvents or mixtures thereof that do not adversely affect the reaction, such as dimethylnulphoxide, tetrahydrofuran, dichloromethane, chloroform, pyridine, N-methylmorpholine, N-methylpyrrolidine, etc.
be called.

The reaction temperature is not particularly limited, and the reaction can be carried out in a temperature range from cooling to heating.

Production method A-(4) Target compound (Ie)-r or a salt thereof is a compound (Ild
) or its salts can be prepared by reacting with a suitable base.

As examples of suitable bases and reactions, those mentioned in Production Method 2 can also be mentioned here.

Production method A-(5) The target compound (B) can be produced by reacting the compound (lle)t or a salt thereof with an acylating agent.

Suitable salts of the compound (Ice) include, for example, acetate,
Acids such as organic acid salts such as maleate, tartrate, benzenesulfonate, toluene lephonate, and inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, etc. Examples include addition salts.

Suitable acylating agents are conventional and have the formula =IR-OH
The compound represented by (V') (wherein R means a higher alkanoyl which may have an appropriate substituent) or a reactive derivative thereof at a carboxy group, or a salt thereof.

Suitable salts of the compound (VI) include metal salts such as sodium, potassium, calcium and magnesium salts; ammonium salts; organic amine salts such as triethylamine salt and dicyclohexylamine salt.

Suitable reactive derivatives at the carboxy group of the compound include acid halides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples are acid chlorides; acids and, substituted phosphoric acids such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, siafurekyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid, alkyl phosphoric acid, e.g. Mixed acid anhydrides with acids such as aliphatic carboxylic acids such as pivalic acid, pentanoic acid, impentanoic acid, 2-ethylbutyric acid or trichloroacetic acid or aromatic carboxylic acids such as benzoic acid; symmetrical acids Anhydrous;
Imidazole, 4-substituted imidazo-μ, dimethylbilacy 1), triacy/L7! ! activated amides of tetrazo-1; or e.g. cyanomethyl ester, methoxymethyl ether, dimethyliminomethyl [(CH
3) 2N ant CH-] ester, hini l re en tel, fluoro lo l reki! p-nitrophenyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, medi)
V-phenylene ester, phenyl asophenyl ester, phenyl thioester, p-nitrophenyl thioemether, p-cresyl thioester, carboxymethylthioesteno V1 hyranyl ester, hyridyl esteno V1 piveridyl ether, 8 -activated esters such as quinolylthioester, or for example N,N-dimethylhydroxylamine, 1-hydroxy-2-(IH)-
Pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-6-chloro-1H
-Nether with an N-hydroxy compound such as benzotriazole, and the like. These reactive derivatives can be arbitrarily selected from the above compounds depending on the type of compound (tlV) to be used.

The reaction is carried out using an alkali metal such as sodium, an alkaline earth metal such as sium, an alkali metal such as sodium hydride, calcium hydride, and an alkaline earth metal hydride such as sulfur hydroxide. - Hydroxides of alkali metals or alkaline earth metals such as potassium hydroxide, hydroxide n/Vum, etc., carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc. or bicarbonate,
alkoxides of alkali metals or alkaline earth metals such as sodium ethoxide, lithium methoxide, magnesium methoxide, trialkylamines such as triethylamine, pyridine, e.g. 1,5-diazabicyclo(3,4.0 Enonene-5, Preferably, the reaction is carried out in the presence of an organic or inorganic base such as a bicyclodiaza compound such as 1,5-diazabicycloC 5,4.0 ) undecene-5.

When the acylating agent is used in the free acid form, for example N. N
-Carbonyldiimide:,'-/Shi,N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N-
Morpholinoethylcarbodiimide, N-cyclohexyl-N-' (4-diethylaminocyclohexyl)-added levodiimide, N,N'-diethylcarbodiimide, N. N
-diisopropylcarbosiimide, N-ethyl-N'-
Carbodiimide compounds such as (3-dimethino V aminopropy) L/) carbodiimide Th, N. N-Carponyl di(
2-methylimidazole), pentamethyleneketene-N
-cyclohexy IV imine, diphenylketene-N-cyclohexyflamine, alkoxyacenalene, 1-alkoxy-1-chloroethylene, trialkyl phosphite,
Phosphorus compounds such as ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, 3-group north neighbor, etc., yF chloride "-"
, oxalyl chloride, 2-ethyl-7=hydroxybenzisoxazolium salt, 2-ethyl-5-(m-s)V
fophenyl) isoxazolium hydroxide, (chloromethylene) dimethylammonium chloride l', 2,2
,4,4,6.6-hexachloro-t3,5,2,4.
6-) Riazatrihonuphorin, 1-benzenesulfonyloxy-6-chloro-honylrechloride, isopropoxybenzenesulfonylchloridolphosphine and tetrahalides such as nitrogen tetrachloride, nitrogen tetrabromide, etc. A combination of so-called Birnemeier reagents such as N,N-methylphon/L/mamide and honufolil chloride, honugenmoshik reacts in this preparation in the presence of a mixed condensing agent such as a complex salt with thionyl chloride. is preferable.

The reaction is usually carried out using water, acetone, dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroethylene, pyridine, N-methylmolleforin, N-methylpyrrolidine, etc. The use of solvents without adverse effects is often carried out in mixtures thereof.

The reaction temperature is not particularly limited, and the reaction can be carried out in a temperature range from cooling to heating.

The target compound (1) 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.

The objective compound of this invention (1) is used for prevention or treatment.
) and pharmaceutically acceptable salts thereof, as the entire active ingredient of said compound, as a pharmaceutically acceptable organic or inorganic, solid or liquid excipient suitable for oral, parenteral and topical administration. The compound is used in the form of a conventional pharmaceutical preparation containing the compound. Pharmaceutical preparations are tablets,
It may be in a solid form such as a dragee, ointment, granule, powder, capsule, or in a liquid form such as a solution, suspension, syrup, emulsion, lemonade, etc. If necessary, adjuvants, stabilizers, wetting agents, and others such as lactose, magnesium stearate, clay, sucrose,
Corn starch, tartar, nutearic acid, gelatin, agar, pectin, peanut oil, olive oil, cacao butter,
Commonly used ITA additives such as ethylene glycol and the like may be included.

The dosage of compound (1) 1 or its pharmaceutically acceptable salts varies depending on the age and condition of the patient, the type of disease, and the type of compound (1) t: or its pharmaceutically acceptable salts to be applied. do. Generally, the preferred dose for administering compound (1) or a pharmaceutically acceptable salt thereof to a patient is selected within the range of 1 to 100 kg/day.

The present invention will be explained below according to production examples and examples.

In the Examples, the position numbers of carbon atoms in lipostamycin derivatives shall follow the position numbers shown below.

(Lipostamycin) 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 culture is in 5% tallow baby serum (FBS)
-q-supplemented Eagle's minimal medium (MEM) to fusion.

(1) a-HS V ('RH novel virus) activity (A) Test method The medium was changed to 0.5% FBS-MEM. Cell cultures were inoculated with 5° of H6V-Emyama strain approximately IDDTC and immediately followed by inoculation of test compounds at various concentration levels.
0025%, in a humid atmosphere of 95% air, 37
Incubated for 2 days at °C. Four wells were used for each concentration. These were fixed with 5% trifluoroacetic acid,
It was stained with 0.1% crystal violet. Virus C
PE was observed under a microscope (40x magnification). Antiviral activity is determined by ■D5o (50% inhibition amount), i.e., Lyle-less CPE.
control virus 7, complete in infected cell cultures (100
% cell destruction) when reaching viral CPE15[]%
Expressed as the compound concentration required to reduce (in the well).

(B) Test Compound 1-N-Puff V Mitoi 7 Reribonutamycin Trihydrochloride (C) Test Results (2) Cell Inertia (A) Test Method Antiviral assay on fused Pero cell cultures (uninfected) In parallel studies, the compounds were tested for their effects on cells of normal morphology. Cell inertia was expressed as the lowest drug concentration that disrupted the cell monolayer.

CB) Test compound 1-N-paremitoy! Relipostamine Filtration Hydrochloride (C) Test Results Production Example 1 1.6. z', 6'-tetra-N-benzyloxycarboxylic acid
Reponylribonutamycin (1g) in pyridine (20I)
I! /) Trityl chloride (1.4 g) is added to the solution and the mixture is stirred at 60° C. for 5 hours. The reaction mixture is concentrated under reduced pressure. The residue was washed three times with hexane (20 rAt), and the resulting precipitate was collected and air-dried to obtain a solid of 1,6,2.6=tetra-N-benzyloxycarbonyl-〇-trityllipostamycin. and (D solid% (2.5
7 1 ) and p-1-luenurphone Ei2 (3
6+++y) dimethylpho)Vamide (40*+J)
Add 1,1-dimethoxycyclohexane (48ml) to the solution.
) was added dropwise under reduced pressure at 50°C for 4 hours.

The reaction mixture is concentrated under reduced pressure. The residue was dissolved in ethyl acetate (8D+
The solution is washed with saturated sodium hydrogen chloride solution and water sequentially, dried over sodium sulfate, and concentrated under reduced pressure to obtain a residue. This residue was dissolved in silica gel (5
Column chromatography using chloroform-ethyl acetate/'C5:1 (V/V)
). Fractions containing the target compound were collected and concentrated under reduced pressure to obtain 3,4 i 2,3-di-0-cyclohexylidene-1,3,2,6-chitler N-benzijVoxycarponylidene 5-0-)IJ. Tirripostamycin (581+IW)'& obtain.

IR (Nushor): 6320.1710-1700,
1530.125 [J.

NMR(CDC(13'.δ): 1.42(IQH,
m), 1.61J (1DH.

m), 5.10 (8H.s), 5.28 (In,a.

J=3Hz), 7.1 0~7.50 (35
H, m) Production Example 2 3,4 i 2,3-di-0-cyclohexylidene-1
, 3,2.6-Citler N-benzyloxycarbonyl-5-0-)linaribonutamycin (19.7 g) in dimethylformamide (200 ml) solution K and sodium hydride (2.4 g) were added. , the mixture is stirred on a water bath for 3 hours while bubbling with nitrogen. Add an aqueous solution (1B) of ammonium chloride (5.5 g) to the reaction mixture, extract the mixture twice with ethyl acetate (601 hzl), wash the solution with saturated aqueous sodium chloride solution, dry over sodium sulfate and concentrate under reduced pressure. . The residue was soaked in silica gel (5
00g) and subjected to column chromatography using
Chloroform-methanol mixture [4[]:1(
v/v): ].

The fractions containing the target compound were combined and concentrated under reduced pressure to obtain -)I
J-N-benzyloxycarbonyl-5-.

- Tritylribostamycin - 1.6-73) to obtain a notebook (13.37 g).

IR (Nushor): 326 [], 1765, 1715
．． 1650, 1520.

1250, 1220CM NMR (CD (43, δ): 1.1 ~ 1.85 (2
0H. m), 5. []5 (6H, 8), 7
．． 1 0 ~ 7.50 (Ro QH, m) Production example Ro 3, 4; 2,3-di-O-cyclohexylidene = 3
, 2.6-)IJ-N-benzyloxycarbonyl-5-0-to)-f-lurifonutamycin-1.6-carbamate (13-7V) in dioxane (210y+J)
and water (70y+l) was added to the solution in a mixture of barium 871 (4.1g) and the mixture was stirred at 8[1"C for 4 hours without bubbling with nitrogen. To the reaction mixture, Add barium oxide 871 (2. Concentrate. The residue was subjected to column chromatography using silica gel (5Dg) and chromatographed with chloroform, tanol, and ammonia [10:1:0.1 (V
/V) )). The fractions containing the target compound were combined and subjected to reduced pressure 'lU+f4 to give 3,4 i 2,ro-cyo-cyclohexylidene=6,2.6-)so-N-benzyloxycarbonyl-5-〇-trinal. Obtain ribostamycin (12.55 g).

Production Example 4 (1) 3,4 i 2, rosy 0-cyclohexylidene-3, 2.6-) IJ-N-benzyloxycarbonyl-5-0-) lytyl lipostamycin (
12.55 L) in tetrahydrofuran ( 2 DO
ml) and 7K (401〃υ), adjusted the pH to 8-9 with triethylamine, cooled with water, added balmitoyl chloride (3.01 g) dropwise with stirring, and further added i at the same temperature. Stir for +qp.The reaction mixture is concentrated under total vacuum.The residue is diluted with ethyl acetate (4
The solution was washed with water and saturated sodium chloride, dried over sodium sulfate, and evaporated to vacuum.

The residue was subjected to column chromatography using silica powder (500 g) and eluted with chloroform-methanol solution (CIDO: 1 (V/V)).

Both parts containing the target compound were combined and condensed under reduced pressure to obtain -tri-N-benzyloxycarbonyl--trinanano V-1-
N-palmitoylribonutamycin (7.31) is obtained.

■B (Nushor): 170D. 1650.1535.
125 Y "1 NMR (CD0g3, δ): D.93 (3
u, m), 1.37 (28H.

s), 1.42 (10H, m), 1.60 (1[IH,
m).

7,2 D ~7.5 0 (Ro[]am) (2) The following compound is obtained according to the method of Production Example 4 (1).

3,4; 2,3-di-0-cyclohexylidene-3
, 2.6-tri-N-pendyloxyl-5
-0-(1-methoxycyclohexy!v) -1-
N-halmitoylribostamycin.

IR (C!Hc#3): 17DD, 1590Cn+ 1
NMR (CDC43, δ): 3.1 7(s) Example 1 (1) 3,4; 2,3-diO-cyclohexylidene-3,2.6-)-N-benzyloxycarbonyl- Acetic acid (120yn
t) and ZK (30 ml)? The combined solution was stirred at 80°C. The reaction mixture is cooled and concentrated under reduced pressure.

The residue was dissolved in ethanol (100πl) and water (20mJ) and concentrated under reduced pressure. This operation was repeated twice, and the residue was washed with hexane (100s+/.') five times and dried. 3.2. 6-) RiN-pencyloxycarponycin 1-N-palmitoylribonutamycin (3.75&) is obtained.

IR (Nushor): 3300.1700, 1690
．． 1640.1540.

129[], 1230.1125.1[165C〃+
1NMR(DMSO-d6,δ) +0.89 (3
H, m), 1.22 (28H.s), 5. O
D (6 nm), 7.25-7, 40 (15 H, m) (2) 3.4:2 according to the method of Example 1 (1).
From 3-C-O-cyclohexylidene-3.2.6-)-N-pencyloxycarpony/R-5-0-(1-methoxycyclohexyl)-1-N-pI remitoylribostamycin as follows Obtain the compound.

6, 2'. 6'-tri-N-pencyloxycarbonyl-1-N-palmitoylribostamycin.

Example 2 3,2.6-II -N-benzyloxycarbonyl-
7) Tetrahydrofuran (50y+l), methanol-7
10011t') and 1N-hydrochloric acid (112 is l)
The volume of the mixture A was added to 7J'C in the presence of 10% palladium-carbon (6 g) under a pressure of 70 kg 7cm'' for 6 hours in a Shiun atmosphere.
Concentrate the liquid under reduced pressure. The residue was dissolved in water (1 [ID*t'), and the solution was added with a cation exchange resin,
(trade name, manufactured by Rohm & Half Co.) and adjust the pH to 6.

Wash with water and extract with 2N ammonia aqueous solution.

Concentrate the solution under reduced pressure. The remaining layer was mixed with water (50 ml.
) and lyophilized to obtain 1-N-paIV mitoi7reribonutamycin filtrate hydrochloride (3.15 g).

Luo point: 166°C (decomposition) IR (Nushor): 330 [1.1640-1620
．． 1240.1120.

ID3[IC)+1 1 NMR (D20, δ): 0.88 (3H.m), 1.0
5-1.50 (28H.S)

Claims (1)

[Claims] 1) General formula: ▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R1^ is higher alkanoylamino, R^2, R^3 which may have an appropriate substituent. and R^4 means amino or acylamino, respectively.] Aminoglycoside derivatives and salts thereof. 2) R^1 is higher alkanoylamino, R^2, R^3
and R^4 is amino or phenyl (lower) alkoxycarbonylamino, the compound according to claim 1). 3) The compound according to claim 2), which is 1-N-palmitoylribostamycin or its hydrochloride. 4) Formula (a): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is higher alkanoylamino which may have an appropriate substituent, R^2, R^3 and R^ 4 means amino or acylamino, R^5 means protected hydroxy] or its salt is subjected to a hydroxy-protecting group elimination reaction to form the formula: ▲There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3 and R^4 each have the same meaning as before] Or obtain a compound or a salt thereof represented by (b) Formula: ▲ Numerical formula, chemical formula, There are tables, etc. ▼ [In the formula, R^1 has the same meaning as before, R^2_a, R
^3_a and R^4_a mean acylamino]
A compound represented by the formula or a salt thereof is subjected to a deacylation reaction to form a compound represented by the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 has the same meaning as above] General formulas characterized by obtaining salts: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^2, R^3 and R^4 have the same meanings as before] A method for producing an aminoglycoside derivative or a salt thereof. 5) General formulas: ▲ Numerical formulas, chemical formulas, tables, etc. meaning amino or acylamino, respectively] A preventive/therapeutic agent for infectious diseases containing an aminoglycoside derivative or a salt thereof as an active ingredient.