JPS611696A - Novel aminoglycoside derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R<1> is (substituted) higher alkanoylamino; R<2> and R<3> are amino, or acylamino; R<4> is H, or lower alkyl; R<5> and R<6> are (substituted)amino] and its salt. EXAMPLE:1-N-Palmitoyl-3''-N-trifluoroacetylgentamicin C. USE:A preventive and remedy for infectious diseases of pathogenic microorganism. PREPARATION:A compound shown by the formula II (R<1> is amino) or its reactive derivative (salt) at its amino group (e.g., 3,2',6'-tri-N-benzyloxycarbonyl-3''-N- trifluoroacetylgentamicin C, etc.) is acylated with an acylating agent shown by the formula R<1>-OH.

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 antiphilic and immunostimulatory activities, methods 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, R1 is higher alkanoylamino which may have a suitable substituent, R2 and R3 are amino or acylamino, R4 is hydrogen or lower alkyl, and R5 and R6 may have a suitable substituent. 1 each meaning good amino; According to the present invention, novel aminoglycoside derivatives (I+
can be produced, for example, by the method below.

Production method 1 (II) or a reactive derivative thereof at the amino group or a salt thereof (I) or a salt thereof Production method 2 (Ia) or a salt thereof (Ib) or a salt thereof [□In the formula, R1, R2, R3, R4 , R5 and R6 each have the same meaning as before; R4, R% and R8 each mean amino, and RA' and R3 each mean acylamino].

Among the raw material compounds of this invention, compound (n) includes a novel compound, and can be produced by the following method.

Production method A (Ha) or a reactive derivative thereof in an amine group or a salt thereof (Ilb) or a salt thereof (■C) or a salt thereof (Ild) or a salt thereof (■e) or a salt thereof [wherein R' , RA, Kazu, R'$'-yo R
5 each has the same meaning as before, R1 is acylamino, R: amino substituted with hahalo(lower)alkanoyl and lower alkyl, R%Ii-lower alkylamino, R is a(lower)alkoxycarbonyl and lower alkyl means an amine substituted with ].

Suitable pharmaceutically acceptable salts of the aminoglycoside derivative (I) are the customary salts, such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, carbonate, phosphate, acetate, Examples include organic or inorganic acid addition salts such as fumarate, maleate, tartrate, mecnesulfonate, benzenesulfonate, toluenesulfonate, and the like.

Preferred examples and explanations of the various definitions set out above and below in this specification are set out in detail below.

"Lower" shall mean 1 to 6 carbon atoms unless otherwise specified.

Suitable "acyl" moieties for "acylamino" include carbamoyl, aliphatic acyl, aromatic acyl, heterocyclic acyl, and aliphatic acyl substituted with an aromatic or heterocyclic group.

Examples of the aliphatic acyl include lower alkanoyl such as formyl, acetyl, propionyl, butyryl, imbutyryl, valeryl, invaleryl, pivaloyl, and hexamethyl; lower alkanoyl such as mesyl, exonsulfonyl, and propanesulfonyl; / Z /l/honyl; ,example,
tfd' Lower alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, bucarbonylponyl, tertiary butoxycarbonyl, lower alkenoyl such as acryloyl, mekuacryloyl, tarotonoyl, (03-C7)- such as cyclohexanecarbonyl, etc. Saturated or unsaturated acyclic or cyclic acylamino acids such as cycloalkadicarbonyl and the like.

Examples of the aromatic acyl include aroyl such as benzoyl, toluoyl, and xyloyl; for example, benzenesulfony/
L/, allenesulfonyl such as tosyl, and the like.

Examples of the heterocyclic acyl group include heterocyclic carbonyls such as furoyl, thenoyl, nicotinoyl, innicotinoyl, thiazolylcarbonyl, thiadiazolylcarbonyl, and tetrazolylcarbonyl.

Examples of the aliphatic acyl substituted with an aromatic group include phenyl (lower) alkanoyl such as phenylacetyl, phenylpropionyl, and phenylhexanoyl; phenyl (lower) alkoxycarbonyl such as evabenzyloxycarbonyl and phenethyloxycarbonyl; Examples include 7-enoxy (lower) alkanoyl such as phenoxyacetyl and phenoxypropionyl.

Aliphatic acyl substituted with a heterocyclic group includes thenyl acetyl, imigzolylacetyl, furylacetyl, tetrazolylacetyl, thiazolyl acetyl, thiadiazolylacetyl, thenylpropionyl, thiadiazolylpropionyl, etc. can be mentioned.

These acyl groups may further include hydroxy, amine, carboxy such as methyl, ethyl, propyl, impropino, lower alkyl such as -butyl, pentyl, hexyl, halogen such as chlorine, bromine, iodine, fluorine such as methoxy, ethoxy, Lower alkoxy such as propoxy, impropoxy, butoxy, pentyloxy, hexyloxy, such as methylthio, ethylthio, propylthio,
Lower alkylthio such as isopropylthio, butylthio, pentylthio, hexylthio, nitro, acylamino,
Aryloxy such as benzyloxy, tolyloxy, formyloxy, acetyloxy, propionyloxy, butyloxy, imbutyryloxy,
It may be substituted with a suitable substituent such as lower alkanoyloxy such as valeryloxy, invaleryloxy, piparoyloxy, hexanoyloxy, etc. Preferred acyls having such substituents include bachloro, Mono(or di- or tri)halo(lower)alkanoyl such as acetyl, bromoacetyl, dichloroacetyl, trifluoroacetyl, amino(lower)alkamyls such as glycyl, aminopropionyl, diaminobutyryl, such as benzyloxycarbonylglycyl, etc. phenyl (lower) alkoxycarbonylamino (lower)
Alkanoyl, phenyl(lower)alkoxycarbonylcarbamoyl e.g. benzyloxycarbonyl fJ)
L/hamoyl, e.g. i1d'benzyloxyacetyl,
Phenyl(lower)alkoxy(lower)alkanoyl such as benzyloxycarbonyl, carboxy(lower)alkanoyl such as carboxyacetyl, carboxypropionyl, hydroxy(lower)alkanoyl such as glycoloyl, hydroxypropionyl, hydroxybutyryl, etc. Can be mentioned.

Suitable "higher alkanoyl" moieties in "higher alkanoylamino" include ocukunoyl, nonanoyl,
Those having 8 or more carbon atoms, preferably those having 8 to 24 carbon atoms, such as decanoyl, kundecanoyl, lafuroyl, myristoyl, pentadecanoyl, balmitoyl, hepkudecanoyl, stearoyl, icosanoyl, docosanoyl, tetracosa, noyl, etc. Can be mentioned.

The above “higher alkanoylamine/” is, for example, methyl,
It has 1 to 3 suitable substituents such as lower alkyl such as ethyl, propyl, butyl, pentyl, hexyl, hydroxy, lower alkanoyloxy such as formyloxy, acetoxy, propionyloxy, butyryloxy, etc. It's okay.

Suitable "lower alkyl" includes methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like.

"Amino which may have an appropriate substituent" includes:
Examples include amino which may have one or two substituents such as lower alkyl, acyl, etc. as mentioned above, and when there are two substituents, they may be the same or different.

Suitable halogens for [halo(lower)alkanoyl] include chlorine, bromine, fluorine, and iodine.

Suitable "al(lower)alkoxycarbonyl" includes benzyloxycarbonyl, phenethyloxycarbonyl, 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 The target compound (Il or its salt is compound (II) or its reactive derivative at the amino group or its salt,
It can be produced by subjecting it to an acylation reaction.

This acylation reaction is carried out by reacting the compound (I) or its reactive derivative or salt at the amino group with an acylating agent.

Suitable reactive derivatives at the amino group of compound (If) include compound (II) and bis(trimethylsilyl).
Examples include silyl derivatives produced by reaction with silyl compounds such as acetamide, mono(trimethylsilyl)acetamide, and the like.

Suitable salts of compound (■) include organic acid salts such as acetate, maleate, tartrate, benzenesulfonate, toluenesulfonate, or hydrochloride, hydrobromide, sulfate, etc. and acid addition salts such as inorganic acid salts such as phosphates.

Suitable acylating agents are conventional and have the formula: R'-OH
@) (wherein R1 means a higher alkanoyl which may have an appropriate substituent) or a reactive derivative thereof in a carboxyl group, or a salt thereof.

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

Suitable reactive derivatives at the carboxy group of compound (il) include acid halides, acid anhydrides, activated amides, activated esters, and the like. Suitable examples are acid chlorides; acid azides; e.g. dialkyl phosphoric acids, phenyl phosphoric acids,
Substituted phosphoric acids such as diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acids, other sulfuric acids, thiosulfuric acids, sulfuric acids, alkyl carbonates such as piparic acid, pentanoic acid, impentanoic acid, 2-ethylbutyric acid or trichloroacetic acid, etc. mixed acid anhydrides with acids such as aliphatic carboxylic acids or aromatic carboxylic acids such as benzoic acid; symmetric acid anhydrides; activation with imidazole, 4-substituted, imidazole, dimethylpyrazole, triazole or tetrazole amide; or for example cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH3)
2N=cu) ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2.
4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester 1. phenylthioester, p-nitrophenylthioester, p
- activated esters such as cresyl thioester, carboxymethyl thioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolyl thioester, or for example N,N-dimethylhydroxylamine, l-hydroxy-2-(IH)-pyridone , N-hydroxysuccinimide, N-hydroxyphthalimide,
Examples include esters with N-hydroxy compounds such as 1-hydroxy-6-chloro-IH-benzotriazole. These reactive derivatives can be arbitrarily selected from the above compounds depending on the type of compound (2) to be used.

The reaction may be carried out using an alkali metal such as sodium, an alkaline earth metal such as calcium, an alkali metal or alkaline earth metal hydride such as sodium hydride, lucium hydride, e.g. sodium hydroxide, potassium hydroxide, hydroxides of alkali metals or alkaline earth metals, such as lucium hydroxide, e.g. sodium carbonate;
Carbonates or hydrogen carbonates of alkali metals or alkaline earth metals such as potassium carbonate or sodium hydrogen carbonate; alkoxides of alkali metals or alkaline earth metals such as sodium ethoxide, lyticum methoxide, magnesium methoxide; Alkylamines, organic or inorganic such as triethylamine, pyridine, bicyclodiaza compounds such as 1,5-diazabicyclo[3,4,0]nonene-5,1,5-diazabicyclo[5,4,01 kundecene-5, etc. It is preferable to carry out the reaction in the presence of a base.

When the acylating agent is used in the free acid form, for example N,
N'-carbonyldiimidazole, N,hT'-disitalohexyllupodiimide, N-cyclohexyl-N'
-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide, N,N'-diethylcarbodiimide, N,
N'-diisopropylcarbodiimide, N-ethyl-N
Carbodiimide compounds such as '-(3-dimethylamino/propyl)carbodiimide, NlN-carbonyldi(2-
methylimidazole), pentamethyleneketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, l-alkoxy-1-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, e.g. phosphorous oxychloride ,
Phosphorus compounds such as phosphorus trichloride, thionyl chloride, oxalyl chloride, 2-xftv-7-hyoxybenzisoxazolicum salt, 2-ethyl-5-(m-sulfophenyl)inoxazolicum hydroxide , (chloromethylene) dimethylammonium chloride F, 2,2,4,4,
6.6-hexachloro-1,3,5,2,4,6-)diazatriphosphorine, 1-benzenesulfonyloxy-6-10-IH-benzotriazole, p-toluenesulfonyl chloride, impropoxybenzene Sur,
condensing agents such as honyl chloride, or triphenylphosphine and tetrachloride such as carbon tetrachloride, carbon tetrabromide, etc.
The reaction of this process is carried out in combination with halogenated carbon or in the presence of a mixed condensing agent such as the so-called Vilsmeier reagent, for example the complex salt of N,N-dimethylformamide with phosphoryl chloride, phosgene or thionyl chloride. Uno is preferable.

The reaction is usually carried out using water, acetone, dioxane, acetonitrile, ethyl acetate, N,N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, dichloromethane, chloroform, pyridine, -N-1+ lumorpholine, N-methylpyrrolidine, etc. It is carried out in customary solvents or mixtures thereof that do not cause

The reaction temperature is not particularly limited, and if this reaction is carried out in a temperature range from cooling to heating, 7 can be obtained.

In this acylation reaction R2, R3, R5 and R
The amino group of 6 may likewise be acylated during the reaction or during the work-up of this reaction, which is also included within the scope of this reaction.

Production method 2 Compound (Ib) or a salt thereof is produced by subjecting compound (Ia) or a salt thereof to a deacylation reaction.
You can do it.

This deacylation reaction involves hydrolysis, reduction, deacylation using a Lewis acid, reacting compound (Ia) with an iminologenating agent, then an iminoetherifying agent, and optionally hydrolyzing the product. This can be carried out by conventional methods such as deacylation methods and the like.

Suitable examples include phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride, phosgene, and the like. I get kicked.

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 alkanols optionally substituted with alkoxy such as methoxy, ethoxy, propoxy, impropoxy, butoxy, methanol, ethanol, propatool, isopropyl, butanol, tertiary butanol. , 1,3-butanediol 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 baricum 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. Alternatively, 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 amine group and the type of the above-mentioned elimination method.
This reaction is preferably carried out under cooling, at room temperature, or under mild conditions at a 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 phosphoric acid,
Examples include trifluoroacetic acid, benzenesulfonic acid, p-)luenesulfonic 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 or absence of a solvent. Suitable solvents include organic solvents, aqueous solution 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, potassium hydroxide, alkaline earth metal hydroxides such as magnesium hydroxide, lucium hydroxide, etc., such as sodium carbonate, potassium carbonate, etc. Alkali metal carbonates such as magnesium carbonate, alkaline earth metal carbonates such as lucium carbonate, alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate, alkali metal acetates such as sodium acetate and potassium acetate. , for example, 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; and trialkylamines such as trimethylamine and triethylamine. , Picolin, 'N
-Methylpyrrolidine, N-methylmorpholine, 1.5-
diazabicyclo[4,3,0]non-5-ene, 1,4
-diazobicyclo[2,2,2]octane, 1,5-diazabicyclo[5,4,0]]kundecene-5. Hydrolysis with a base is often carried out in water or a hydrophilic organic solvent or a mixture thereof.

Examples of the reduction method 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 defined, and the reaction is usually carried out in a range of cooling to heating. In this deacylation reaction, the acylamino groups of R'5 and R6 may be similarly deacylated during the reaction or during the post-treatment of this reaction, but these cases are also included within the scope of this reaction. Ru.

Production method A-(1) Target compound (nb) or its salt is compound (Ila)
Alternatively, it can be produced by reacting a reactive derivative thereof at an amino group or a salt thereof with an acylated compound.

The reaction can be carried out in the same manner as in Production Method 1.

In this acylation reaction, the amine group of BS may be similarly acylated during the reaction or during the post-treatment of this reaction, and such cases are also included within the scope of this reaction.

Production method A-(11) Target compound (Ilc) or its salt is compound (nb)
Alternatively, it can be produced by subjecting a salt thereof to a deacylation reaction.゛The reaction can be carried out in the same manner as Production Method 2.

In this elimination reaction, the acylamino groups of R:, RA and R5 may be similarly deacylated during the reaction or during post-treatment of this reaction, and such cases are also included within the scope of this reaction.

Production method A-(■) The target compound (lid) or its salt is a compound (Ilc
) or a salt thereof to an acylation reaction.

The reaction can be carried out in the same manner as Production Method 1.

In this acylation reaction, the amino group of R5 may be similarly acylated during the reaction or during post-treatment of this reaction, and such cases are also included within the scope of this reaction.

Production method A-(IV) The target compound (Ile) or a salt thereof is the compound (Ile)
d) or a salt thereof can be produced by subjecting it to a deacylation reaction.

The reaction can be carried out in the same manner as Production Method 2.

In this elimination reaction, the acylamino groups of R:, R:, R5 and R8 may be similarly deacylated during the reaction or during the post-treatment of the reaction, but such cases are also included within the scope of this reaction. be done.

The target compound (Il and its salts) has antiviral activity and immunostimulatory activity, and is therefore useful as an antiviral agent for humans, animals, and plants, and as a preventive agent for pathogenic microbial infections.

For prophylactic or therapeutic purposes, the object compound of this invention (I
) and pharmaceutically acceptable salts thereof contain the above compound as an active ingredient in a pharmaceutically acceptable carrier such as an organic or inorganic, solid or liquid excipient suitable for oral, parenteral and topical administration. It 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, lemonate, etc. If necessary, adjuvants, stabilizers, humectants, 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. It may also contain commonly used additives such as kerosene butter, kao butter, ethylene glycol, etc.

The dosage of Compound (I) or a pharmaceutically acceptable salt thereof depends on the age and condition of the patient, the type of disease, and the Compound (I) to be applied! It varies depending on the type of salts that are acceptable as bamboo medicines. Generally, the preferred dosage for a patient of Compound (I) or a pharmaceutically acceptable salt thereof is selected in the range of 0.1 to 100 to 971 days.

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

In the examples, the position numbers of carbon atoms in the aminoglycoside derivatives shall follow the position numbers shown below.

However, the complex of gentamicin C1, gentamicin CI&, and gentamicin C2 is named gentamicin C.

In order to demonstrate the usefulness of the target compounds, 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 was in 5% tallow baby serum (FBS).
The cells were grown and allowed to fuse in Eagle's minimal medium (MEM) supplemented with .

FIL anti-H5v (monoM herpesvirus) activity (A)
Test method medium was changed to 0.5% FBS-MEN. Cell culture K
Inoculate 50 from about 100 TC of H8V-I Myama strain,
Immediately thereafter, various concentration levels of the test compound are added and the CO
It was incubated for 2 days at 37° C. in a humidified atmosphere of 25% air and 95 cm air. Four wells were used for each concentration. These were fixed with 5% trifluoroacetic acid and stained with 0.1% crystal violet. Virus CPE under the microscope (
Observe at 40x magnification. Antiviral activity was determined by ID5o (50
% inhibition), i.e., the concentration of compound required to reduce fils CPE by 50% (in the wells) when viral CPE reached completion (100% cell destruction) in control virus-infected cell cultures.

(B) Test compound 1') 1-N-palmitoylsagamicin tetrabasic acid salt.

2) 1'-N-valmitoyl-3''-N-trifluoroacetylgen cumicin C dihydrochloride.

(2) Cytotoxicity (A) Test Method In a study conducted in parallel with the antiviral assay on confluent Vero cell cultures (uninfected), compounds were tested for their effects on cells of normal morphology. Cytotoxicity was expressed as the lowest drug concentration that destroyed a monolayer of cells.

CB) Test Ibi compound 1) 1-H-valmitoyl sagamicin tetrabasic acid salt.

, 2) 1-N-valmitoyl-3''-N-)lifluoroacetylgentamicin C dihydrochloride.

(C) Test results Manufacturing example 1 3, 2. '6'-tri-N-benzyloxycarbonyl-3''-N-trifluoroacetylsagamicin (3,
1y) dioxane (45rne) and water (15me
) To the mixture solution, 2-tert-butoxycarbonyloxyimino-2-phenylacetonitrile (1,59y) and triethylamine (0,9me) were added at room temperature, the mixture was stirred at the same temperature for 1 hour, and further at the same temperature. Leave it overnight. The solution was concentrated under reduced pressure, and the resulting residue was diluted with ethyl acetate (15'O
m/), washed sequentially with a saturated aqueous sodium bicarbonate solution and an aqueous sodium chloride solution, dried with sulfuric acid (IJ), and concentrated under reduced pressure to obtain a residual solution. The residual liquid was subjected to column chromatography using silica gel (70y), and a chloroform-methanol mixed solvent [40:l (v/
v) Elute with [□]. Combine both parts containing the target compound,
Concentrate under reduced pressure, 3, 2. '6'-)di-N-benzyloxycarbonyl-1-N-tert-butoxycarbonyl=
3”-N-)'J fluoroacetylsagamicin (3,
4y) is obtained.

Melting point: 127-128°C [α): +96.4° (C1,0, CHCl3) IR (
Nujol): 1680. 1500. 1250
．． 1140°1050, 10210 20zN'CDC/3. δ) : 1.05(3H,s
), 1.40 (9H, s).

2.83 (3H, 8) Production Example 2 3,2. '6'-) ') -N-benzyloxycarbonyl-3''-N-)lifluoroacetyl-1-N-tertiary-butoxylated sagamicin (3,365F), tetrahydrofuran (40d), concentrated ammonia (20r
nl) and methanol (8+++t') mixture solution is stirred at slightly room temperature for one hour. Concentrate the solution under reduced pressure.

The residue □ was dissolved in ethyl acetate (100 Wd, washed with an aqueous sodium chloride solution, dried over sodium sulfate, concentrated under reduced pressure, and diluted with 3,2.'6'-)soN-benzyloxycarboxylic acid. A residue of tertiary butoxycarbonyl sagamicin is obtained. The residue (2,96y-) was added to a solution of a mixture of tetrahydrofuran (40mff) and water (10me), adjusted to pH 8-9 with triethylamine, and added to a solution of 2-5.
Benzyloxycarbonyl chloride (
A solution of 0.52 mt') in tetrahydrofuran was added dropwise, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture is concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate (100me), washed successively with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, and dried over sodium sulfate.
Concentrate under reduced pressure, 3. '2. "6.'3"-tetra-N-
Benzyloxycarbonyl-1-N-tert-butoxycarbonyl sagamicin (3,83y) is obtained.

Melting point = 91-93°C [α]20: +70.3 (C1,0,CHC/3)
IR (Nujol): 3280. 1675. 1
500. 1250°1150, 1050. 102
0cm ”NMR(CDCj?3.δ): 2.82(
3H,s),' 3.06 (3H,s) Example 1 3.2. '6'-)di-N-benzyloxycarbonyl-3''-N-)IJ fluoroacetylgentamicin C (
A solution of 1,8y) in tetrahydrofuran C40me) and water (10+++t') was adjusted to pH 8-8.5 with triethylamine, and balmitoyl chloride (0,54y) was added with stirring at 2-5°C. Tetrahydro7rane (10ml solution) is added dropwise and stirred for further 1 hour at the same temperature.The reaction mixture is concentrated under reduced pressure.The residue is dissolved in ethyl acetate (100ml) and dissolved in sodium bicarbonate and saturated aqueous sodium chloride solution. The residue was washed with sodium sulfate, dried over sodium sulfate, and concentrated under reduced pressure.The residue was subjected to column chromatography using silica gel (60y), and a mixture of taloloform and methanol [40:1
(, v/v)]. Both fractions containing the target compound were combined and concentrated under reduced pressure, and 3.2. '6'-)di-N-benzyloxycarbonyl-1-N-valmitoyl-3/
'N-trifluoroacetylgentamicin C' (1,3
5P).

Melting point: 156-157°C 1] +81.4° (C = 2.0. CHCl!3) I
R (Nujol): 3280-3250. 1700～
1665°1510, 1300. 1240. 11
40. 1050cm-1NMR (CD105Oδ)
: 2.57 (3H, m), 3.2'4 (3H
, m) Example 2 3, 2. '6'-) So N-benzyloxycarbonyl-1-N-valmitoyl-317N-trifluoroacetylgentamicin C (1,3y) in methanol (30+
++e) and concentrated hydrochloric acid (1 ml') mixture solution for 10
6 in a hydrogen atmosphere in the presence of Chibarajikumu carbon (1y)
Hydrogenate for an hour. The catalyst is removed and the p liquid is concentrated under reduced pressure. Suspend the residue in ethanol (20me) and concentrate it under reduced pressure. The residue was dissolved in water (40 ml') and lyophilized to obtain 1-N-valmitoyl-3〃-N-)lifluoroacetylgencumicin C trihydrochloride (814~).

Melting point:) 174℃ (decomposition) 1α] Eagle: +70.3 (C= 1.0 * H2O”
) IR (Nujol): 3350. 1680.
．． 1650-1630°1245, 1190. 11
50. 1090. 1050. 1035c+i-”
NMR (D20.J): 2.78 (3H, 5) FD
Mass: 812 (M, C+)7
84 (M r C+a ) 798 (M, C2) Example 3 3,2. '6. A solution of a mixture of anisole (3 mt) and trifluoroacetic acid (12 mff) of '3''-tetra-N-benzyloxycarbonyl-1-N-tert-butoxyluponylsagamicin (1,44p) was cooled with water for 1 hour. Stir. The reaction mixture is concentrated under reduced pressure. The residue was dissolved in toluene (20+++ l') and dried under reduced pressure until the toluene completely evaporated, 3.2. '6. '3''-tetra N-penzyloxylponylsagamicin was obtained. The residue was diluted with tetrahydrofuran (40 Wd) and water (1
0me) Add triethylamine to the mixture solution to pH 8-9.
A solution of balmitoyl chloride (0.38/7) in tetrahydrofuran was added dropwise while stirring at 0 to 5°C, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture is concentrated under reduced pressure.

The residue is dissolved in ethyl acetate ('60 d), washed successively with saturated aqueous sodium bicarbonate solution, water and aqueous sodium chloride solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue is subjected to column chromatography using silica gel (50y) and eluted with a taloloform-methanol mixture [40:1 (v/v)]. 3. Combine the two fractions containing the target compound and concentrate under reduced pressure. z,
I6. / a#-tetra-N-benzyloxycarbonyl-1-H-palmitoylsagamicin (616fng
).

Melting point = 124-126 °C [α]”: 87.5 ° (CO, 5, CHCl3) IR (
Nujol): 3250. 1680. 1520
．． 1140°1050, 1020cIn 1020cInN! 3.? ): 2.82 (3H
, s), 3.06 (3H, s') Example 4 3, 2; 6. '3'/-Tetra N-benzyloxycarbonyl-1-N-valmitoylsagamicin (600
methanol (121 nl) and concentrated hydrochloric acid (0,5
me ) mixture solution was mixed with 10% palladium carbon (60
Hydrogenation is carried out in the presence of 0.0%) in a hydrogen atmosphere at room temperature and pressure for 5 hours. The catalyst is removed and the p liquid is concentrated under reduced pressure. The residue was suspended in ethanol (20me) and concentrated under reduced pressure. Repeat this operation twice.

The residue is dissolved in water (50 me) and the solution is treated with activated carbon to remove the activated carbon. Lyophilize solution F to obtain 1-N-palmitoylsagamicin tetrabasic acid salt (299-).

Melting point:) 154°C (decomposition) + [ff1D: +98.1° (C1,0,H2O)IR
(potassium bromide): 1640. 1540. 12
80°1120, 1030α-1 NMR (D20.δ): 2.76 (3H, s),
2.90 (3H, s).

5, 30 (I H2d+ J”4Hz), 5.81
(l Hr d+ J””3Hz)=

Claims (1)

[Claims] 1) General formula: ▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 is higher alkanoylamino which may have an appropriate substituent, R^2 and R^ 3 is amino or acylamino, R^
4 represents hydrogen or lower alkyl, and R^5 and R^6 each represent amino which may have an appropriate substituent. Aminoglycoside derivatives and salts thereof. 2) The compound according to claim 1, wherein R^1 is palmitoylamino. 3) The compound according to claim 2, which is 1-N-palmitoyl-3''-N-trifluoroacetylgentamicin C or its trihydrochloride. 4) 1-N-palmitoyl sagamicin or its tetrahydrochloride. The compound according to claim 2, which is a salt. 5) Formula (a): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1_b is amino, R^2 and R^3 are amino or acylamino, R^
4 means hydrogen or lower alkyl, R^5 and R^6 each mean amino which may have an appropriate substituent] or its reactive derivative or salt thereof in the amino group is acylated. For reactions, there are formulas: ▲Mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^2, R^3, R^4, R^5 and R^6
each has the same meaning as before, and R^1 means higher alkanoylamino which may have an appropriate substituent] or a salt thereof], or (b) Formula: ▲ Formula, There are chemical formulas, tables, etc. ▼ [In the formula, R^1, R^4, R^5 and R^6 each have the same meaning as before, and R^2_a and R^3_a each mean acylamino] When the indicated compound or its salt is subjected to a deacylation reaction, the formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1, R^4, R^5 and R^6 are respectively and R^2_b and R^3_b each mean amino] A general formula characterized by obtaining a compound or a salt thereof: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula , R^1, R^2, R^3, R^4, R^5 and R^6 each have the same meanings as above.] A method for producing an aminoglycoside derivative or a salt thereof. 6) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R^1 is higher alkanoylamino which may have an appropriate substituent, R^2 and R^3 are amino or acylamino, R^
4 means hydrogen or lower alkyl, and R^5 and R^6 each mean amino which may have an appropriate substituent.
therapeutic agent.