EP0000889A1 - 3"-N-Demethyl-3"-N-substituted-4,6-di-0-(aminoglycosyl)-1,3-diaminocyclitols, methods for their preparation and their application as antibiotics - Google Patents

Abstract

Pseudotrisaccharides of the formula <IMAGE> in which X stands for a residue <IMAGE>, and Y denotes a residue <IMAGE>, U, V, W are hydrogen or hydroxy, Z can be hydrogen, hydroxy or amino and R can be alkyl (except Methyl), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl, cycloalkenylalkyl, aryl or aralkyl are antimicrobial agents with a broad spectrum of activity and particular activity against gram-negative bacteria.

Description

The invention relates to new pseudotrisaccharides, processes for their preparation and their use as medicaments.

In particular, the invention relates to new, antibacterial aminoglycoside antibiotics of the 4,6-di-O- (aminoglycosyl) -1,3-diaminocyclitole type.

Aminoglycoside antibiotics are important substances for the effective fight against bacterial infections. In many cases, however, the emergence of resistant germs reduces their broad applicability; further side effects such as ototoxicity and nephrotoxicity can occur. In some cases, derivatization can overcome these disadvantages.

in der X für einen Rest

Y einen Rest

bezeichnet,

• U,V,W Wasserstoff oder Hydroxy bedeuten,
• Z Wasserstoff, Hydroxy oder Amino sein kann und
• R für Alkyl (außer Methyl), Alkenyl, Alkinyl, Cycloalkyl, Cycloalkenyl, Cycloalkyl-alkyl, Cycloalkenylalkyl, Aryl oder Aralkyl steht,

wobei die genannten Kohlenwasserstoffreste einen oder mehrere Substituenten tragen können sowie deren Säureadditionssalze. Alkyl bezeichnet bevorzugt einen geradkettigen oder verzweigten Alkylrest mit vorzugsweise 2 bis 8 Kohlenstoffatomen, der vorzugsweise 1 bis 3, insbesondere 1 oder 2, gleiche oder verschiedene Substituenten tragen kann. Als Substituenten seien beispielhaft aufgeführt: Hydroxy, Alkoxy mit vorzugsweise 1 bis 4 Kohlenstoffatomen, Alkylthio mit vorzugsweise 1 bis 4 Kohlenstoffatomen, Halogen, vorzugsweise Fluor, Chlor oder Brom, Nitro, Amino, Monoalkyl- und Dialkylamino mit vorzugsweise 1 bis 4 Kohlenstoffatomen je Alkylgruppe. Beispiele für Alkylreste der genannten Art sind: Ethyl, n-Propyl, n-Butyl, n-Pentyl, n-Heptyl, B-Methylpropyl, t-Butyl, ß-Propylpentyl, δ-Ethylhexyl, ß-Dimethylpropyl, ß-Hydroxypropyl, ß,γ -Dihydroxypropyl, E-Hydroxypentyl, δ-Hydroxybutyl-,γ -Hydroxypropyl, ß-Methoxyethyl, ß-Butoxyethyl, ß-Methoxypropyl, γ -Methoxybutyl, γ,ε -Dimethoxyhexyl, ß-n-Propoxyethyl, ß-Ethoxyethyl-.ß-i-Propoxyethyl, ß-Aminoethyl, ß-Aminopropyl, γ-Aminopropyl, ß-Amino-γ-methylbutyl, N-Methyl-ß-aminoethyl, N-Methyl-ß-aminopropyl, N-Methyl-T -aminopropyl, N-Methyl-ß-amino-γ-methylbutyl, N,N-Dimethyl-ß-aminoethyl, N,N-Dimethyl-ß-aminopropyl, N,N-Dimethyl-T -aminopropyl, N,N-Dimethyl-ß-amino-γ-methylbutyl, N-Ethyl-ß-aminoethyl, N-Ethyl-ß-aminopropyl, N-Ethyl-γ-aminopropyl, N-Ethyl-ß-amino-γ-methylbutyl, N,N-Diethyl- ß-aminoethyl, N,N-Diethyl-ß-aminopropyl, N,N-Diethyl-γ-aminopropyl, N,N-Diethyl-ß-amino-γ-methylbutyl, N-Propyl-ß-aminoethyl, N-Propyl-B-aminopropyl, N-Propyl-γ-aminopropyl, N-Propyl-ß-amino-γ -methylbutyl, N,N-Dipropyl-ß-aminoethyl, N,N-Dipropyl-ß-aminopropyl, N,N-Dipropyl-γ-aminopropyl, N,N-Dipropyl-ß-ajnino-γ -methylbutyl, ß-Hydroxy-ε -aminopentyl, ß-Hydroxy-δ-aminobutyl, ß-Methoxy-ε-aminopentyl, ß-Ethoxy-δ-aminobutyl, ß-Methoxy-δ-N-methylaminobutyl, ß-Bromisopropyl, ß-Chlorethyl.The pseudotrisaccharides according to the invention can be represented by formula (I)

in the X for a rest

Y a rest

designated,

• U, V, W represent hydrogen or hydroxy,
• Z can be hydrogen, hydroxy or amino and
• R represents alkyl (other than methyl), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkyl-alkyl, cycloalkenylalkyl, aryl or aralkyl,

wherein said hydrocarbon radicals can carry one or more substituents and their acid addition salts. Alkyl preferably denotes a straight-chain or branched alkyl radical having preferably 2 to 8 carbon atoms, which can preferably carry 1 to 3, in particular 1 or 2, identical or different substituents. Examples of substituents are: hydroxy, alkoxy with preferably 1 to 4 carbon atoms, alkylthio with preferably 1 to 4 carbon atoms, halogen, preferably fluorine, chlorine or bromine, nitro, amino, monoalkyl and dialkylamino with preferably 1 to 4 carbon atoms per alkyl group. Examples of alkyl radicals of the type mentioned are: ethyl, n-propyl, n-butyl, n-pentyl, n-heptyl, B-methyl propyl, t-butyl, ß-propylpentyl, δ-ethylhexyl, ß-dimethylpropyl, ß-hydroxypropyl, ß, γ-dihydroxypropyl, E-hydroxypentyl, δ-hydroxybutyl-, γ-hydroxypropyl, ß-methoxyethyl, ß-butoxyethyl, ß -Methoxypropyl, γ -Methoxybutyl, γ, ε -dimethoxyhexyl, ß-n-propoxyethyl, ß-ethoxyethyl-.ß-i-propoxyethyl, ß-aminoethyl, ß-aminopropyl, γ-aminopropyl, ß-amino-γ-methylbutyl, N-methyl-ß-aminoethyl, N-methyl-ß-aminopropyl, N-methyl-T-aminopropyl, N-methyl-ß-amino-γ-methylbutyl, N, N-dimethyl-ß-aminoethyl, N, N- Dimethyl-ß-aminopropyl, N, N-dimethyl-T-aminopropyl, N, N-dimethyl-ß-amino-γ-methylbutyl, N-ethyl-ß-aminoethyl, N-ethyl-ß-aminopropyl, N-ethyl γ-aminopropyl, N-ethyl-ß-amino-γ-methylbutyl, N, N-diethyl-ß-aminoethyl, N, N-diethyl-ß-aminopropyl, N, N-diethyl-γ-aminopropyl, N, N- Diethyl-ß-amino-γ-methylbutyl, N-propyl-ß-aminoethyl, N-propyl-B-aminopropyl, N-propyl-γ-aminopropyl, N-propyl-ß-amino-γ-methylbutyl, N, N- Dipropyl-ß-aminoethyl, N, N-Dipropyl-ß-aminopropyl, N, N-Dipropyl-γ-aminopropyl, N, N-Dipropyl-ß- ajnino-γ-methylbutyl, ß-hydroxy-ε-aminopentyl, ß-hydroxy-δ-aminobutyl, ß-methoxy-ε-aminopentyl, ß-ethoxy-δ-aminobutyl, ß-methoxy-δ-N-methylaminobutyl, ß- Bromoisopropyl, ß-chloroethyl.

The alkenyl and alkynyl radicals preferably have 2 to 6 carbon atoms. Examples include: allyl, crotyl, methallyl, β-methyl-β-butenyl, propyn (2) yl, butyn (2) yl. If they are substituted, they preferably carry one of the substituents listed above for alkyl.

Cycloalkyl and cycloalkenyl preferably denote a cyclic radical having preferably 3 to 10, in particular 3 to 6, carbon atoms, which has 1 to 3, in particular 1 or 2, may have the same or different of the substituents mentioned above for alkyl. Cycloalkylalkyl and cycloalkenylalkyl preferably represent cycloalk (en) ylmethyl or cycloalk (en) ylethyl, the cycloalk (en) yl radical being defined as previously indicated. Examples of suitable cycloalk (en) yl and cycloalk (en) ylalkyl radicals are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexenylmethyl. Aryl preferably denotes a phenyl or naphthyl radical. The aryl group may have 1 to 3 identical or different substituents such as alkyl preferably having 1 to 4 carbon atoms s, preferably fluorine, chlorine or bromine, nitro, amino, monoalkyl and dialkylamino each having 1 to 4-K hlenstoffatomen per alkyl group, _H ydroxy, Wear alkyloxy and alkylthio with 1 to 4 carbon atoms per alkyl group. Examples of aryl radicals are: o-ethylphenyl, m-ethylphenyl, p-ethylphenyl, p-hydroxyphenyl, nitrophenyl, aminophenyl, nitrobenzyl.

The aralkyl radicals are preferably phenylmethyl or phenylethyl radicals which can carry the substituents mentioned above for aryl. Examples include: β-phenylethyl, B-tolylethyl.

Of particular interest are the aminoglycoside antibiotics according to formula (I) which are derived from the antibiotics gentamicin A, gentamicin B, gentamicin B ₁ gentamicin C ₁ , gentamicin C _1a , gentamicin C ₂ , gentamicin C _{2a '} gentamicin C _2b' gentamicin X ₂ , sisomicin, JI-20A, JI-20B, verdamicin G52, G418, 66-40B, 66-40D, mutamicin 1, mutamicin 2, mutamicin 4, mutamicin 5 and mutamicin 6, thereby derived propyl, t-butyl, ß-propylpentyl, δ-ethylhexyl, ß-dimethylpropyl, ß-hydroxypropyl, ß, γ-dihydroxypropyl, ε-hydroxypentyl. δ-hydroxybutyl-, γ-hydroxypropyl, ß-methoxyethyl, ß-butoxyethyl, ß-methoxypropyl, γ-methoxybutyl, γ, ε-dimethoxyhexyl, ß-n-propoxyethyl, ß-ethoxyethyl-.ß-i-propoxyethyl, ß- Aminoethyl, β-aminopropyl, γ-aminopropyl, ß-amino-γ-methylbutyl, N-methyl-ß-aminoethyl, N-methyl-ß-aminopropyl, N-methyl-γ-aminopropyl, N-methyl-ß-amino- γ-methylbutyl, N, N-dimethyl-ß-aminoethyl, N, N-dimethyl-ß-aminopropyl, N, N-dimethyl-γ-aminopropyl, N, N-dimethyl-ß-amirlo- γ-methylbutyl, N- Ethyl-ß-aminoethyl, N, N-dimethyl-ß-amino-γ-methyl-, N-ethyl-γ-aminopropyl, N-ethyl-ß-amino-γ-methylbutyl, N, N-diethyl-ß-aminoethyl , N, N-diethyl-ß-aminopropyl, N, N-diethyl-γ-aminopropyl, N, N-diethy-ß-amino-γ-methylbutyl, N-propyl-ß-aminoethyl, N-propy-ß-aminopropyl , N-propyl-γ-aminopropyl, N-propyl-B-amino-γ-methylbutyl, N, N-dipropyl-ß-aminoethyl, N, N-diprogyl-ß-aminopropyl, N, N-dipropyl-γ-aminopropyl , N, N-dipropyl-ß-amino-γ-methylbutyl, ß-hydroxy-ε-aminopentyl, ß-hydroxy-δ-aminobutyl, ß-methoxy-ε-aminopentyl, ß-ethoxy-δ-aminobu tyl, ß-methoxy-δ-N-methylaminobutyl, ß-bromoisopropyl, ß-chloroethyl.

The alkenyl and alkynyl radicals preferably have 2 to 6 carbon atoms. Examples include: allyl, crotyl, methallyl, β-methyl-β-butenyl, propyn (2) yl, butyn (2) yl. If they are substituted, they preferably carry one of the substituents listed above for alkyl.

Cycloalkyl and cycloalkenyl designate preferably a c ^y clischen radical having preferably 3 to 10, especially 3 to 6 carbon atoms, 1 to 3, in particular 1 or 2, 3 "-N-Demethyl-3" -N-heptylsisomicin 3 "-N-Demethyl-3" -N- (ß-dimethylpropyl) -sisomicin 3 "-N-Demethyl-3" -N-allylsisomicin 3 "-N- Demethyl-3 "-N- (ß-butenyl) -sisomicin 3" -N-demethyl-3 "-N-tolylethylsisomicin 3" -N-demethyl-3 "-N- (ß-aminoethyl) -sisomicin 3" -H -Demethyl-3 "-N- (ß-methoxyethyl) -sisomicin 3" -N-Demethyl-3 "-N- (1-methoxybutyl) -sisomicin 3" -N-Detnethyl-3 "-N- (γ,, ε-dimethoxyhexyl) -sisomicin 3 "-N-demethyl-3" -N- (ß-butoxyethyl) -sisomicin 3 "-N-demethyl-3" -N- (ß-propoxyethyl) -sisomicin 3 "-N-demethyl -3 "-N- (ß-eth oxyethyl) -sisomicin 3" -N-demethyl-3 "-N- (ß-i-propoxyethyl) -sisomicin 3" -N-desnethyl-3 "-N- (ß- bromo-i-propyl) -sisomicin 3 "-N-demethyl-3" -N- (N-methyl-B-aminoethyl) -sisomicin 3 "-N-demethyl-3" -N- (N ', N'- dimethyl-ß-aminoethyl) -sisomicin 3 "-N-demeth'yl-3" -N- (N ', N'-diethyl-ß-aminoethyl) -sisomicin

The invention further encompasses the acid addition salts, in particular the pharmaceutically usable salts of the new aminoglycoside antibiotics, of which the addition salts with hydrogen chloride, sulfur, phosphorus, saltpetre, hydrogen bromide, benzenesulfone, ants, vinegar, propion, Maleic, ascorbic or citric acid may be mentioned as examples.

The invention further relates to processes for the preparation of the pseudotrisaccharides represented by formula (I).

Compounds of the formula (III) are treated - can think that the 3 "methylamino group present in the latter antibiotics is replaced by a substituted amino group of the type -NH-R, where R has the meaning given above.

R die oben angegebene Beduetung besitzt, besonders wertvoll.Of these, the sisomicin derivatives represented by formula (II) are those

R has the meaning given above, particularly valuable.

• 3"-N-Demethyl-3"-N-propylsisomicin
• 3"-N-Demethyl-3"-N-butylsisomicin
• 3"-N-Demethyl-3"-N-pentylsisomicin
• 3"-N-Demethyl-3"-N-isopropylsisomicin
  
  
  bezeichnet,wobei R' die vorstehende Bedeutung hat-mit einem Oxidationsmittel bei Temperaturen von etwa -20°C bis etwa 100°C vorzugsweise in Gegenwart eines unter den Reaktionsbedingungen inerten Verdünnungsmittels, wobei die 3"-N-Methylgruppe abgespalten wird, der von Methyl verschiedene Rest R jedoch unangegriffen bleibt. Nach Entfernen gegebenenfalls vorhandener Aminoschutzgruppen isoliert man die neuen Pseudotrisaccharide der Formel (I) in freier Form oder bei Anwesenheit von Säuren in Form ihrer Säureadditionssalze.
  
  in welcher
  • A Hydroxy oder Wasserstoff,
  • B Hydroxy, Wasserstoff oder Methyl bedeuten,
  • R.U,V,W die oben angegebenen Bedeutung haben,
  • Z' für Wasserstoff, Hydroxy oder Amino bzw. durch R' geschütztes Amino,
  • R' für Aminoschutzgruppen,wie sie unten definiert sind, stehen und in der
  • X' die Reste
    
    
    wobei
  • _X die zu Formel (I) angegebene Bedeutung hat und
  • Y'
    
    bezeichnet.

Examples of antibiotics of the formula (II) according to the invention are:

• 3 "-N-Demethyl-3" -N-propylsisomicin
• 3 "-N-Demethyl-3" -N-butylsisomicin
• 3 "-N-Demethyl-3" -N-pentylsisomicin
• 3 "-N-Demethyl-3" -N-isopropylsisomicin
  
  
  denotes, wherein R 'has the above meaning - with an oxidizing agent at temperatures from about -20 ° C to about 100 ° C, preferably in the presence of a diluent which is inert under the reaction conditions, the 3 "-N-methyl group being split off, that of methyl various residue R remains unaffected, however, after removal of any amino protective groups that may be present, the new pseudotrisaccharides of the formula (I) are isolated in free form or, in the presence of acids, in the form of their acid addition salts.
  
  in which
  • A hydroxy or hydrogen,
  • B is hydroxy, hydrogen or methyl,
  • RU, V, W have the meaning given above,
  • Z 'for hydrogen, hydroxy or amino or amino protected by R',
  • R 'stands for amino protecting groups, as defined below, and in the
  • X 'the leftovers
    
    
    in which
  • _{X has} the meaning given for formula (I) and
  • Y '
    
    designated.

in derExamples of such trisaccharides are sisomicin, gentamicins, utamicine _M as well as the antibiotic 66-40 66-40 B and D. For the preparation of used according to the invention as starting materials, selectively N-blocked Aminotrisaccharide of formula (III) (wherein each R 'denotes an amino ), _about a Aminotrisaccharid of formula (IV) with a compound of formula (V)

in the

Amino protective groups R 'which can be used are all protective groups which are stable under the oxidation conditions of the process described above and which are customary in the field of aminosugar and peptide chemistry. Such protecting groups and the processes for their preparation are known (see, for example, Houben-Weyl, Methods of Organic Chemistry, Volume XV, 1, Georg Thieme Verlag, Stuttgart, 1974).

wobei

• D und E unabhängig voneinander für Wasserstoff, Phenyl oder substituiertes Phenyl stehen und
• n,n₁,n₂,n₃ unabhängig voneinander Zahlen von 0-5 bezeichnen.

Preferred examples of such protective groups are acyl groups of type (1) or (2)

in which

• D and E independently represent hydrogen, phenyl or substituted phenyl and
• n, n ₁ , n ₂ , n ₃ independently denote numbers from 0-5.

The starting materials used according to the invention are aminotrisaccharides of the general formula (IV) which are known per se from the literature

wobei
X',R',U,V,W,Z',A und B die in Formel (III) angegebene Bedeutung haben.The selectively N-blocked pseudotrisaccharides which are generally accessible in this way can be represented by the general formula (VII)

in which
X ', R', U, V, W, Z ', A and B have the meaning given in formula (III).

The invention also encompasses processes by which the selectively protected pseudotrisaccharides of the formula (VII) are N-alkylated on the 3 "-methylamino group, whereby 3" -N- _A alkyl derivatives of the formula (III) with the meaning of the newly occurred Rest of R receives.

• F für einen Rest der Formel (1) und (2) steht und
• G' Halogen oder eine bei Acylierungsreaktionen gebräuchliche Abgangsgruppe, vorzugsweise eine aktivierte Ester-, oder eine Gruppe
  
  mit der oben angegebenen Bedeutung von F bezeichnet, in einem inerten organischen Lösungsmittel gegebenenfalls unter Zusatz von Wasser bei Temperaturen zwischen etwa -80°C und etwa +5₀°_C gegebenenfalls in Gegenwart einer Base um und arbeitet das Reaktionsprodukt in üblicher Weise auf.

One of the preferred processes according to the invention for the preparation of the 3 "-N-substituted derivatives of the 4,6-di-O- (aminoglycosyl) -1,3-diaminocyclitols of the formula (III) which contain amino protecting groups in all positions except in position 3" , is that you have connections

• F represents a radical of the formula (1) and (2) and
• G 'halogen or a leaving group customary in acylation reactions, preferably an activated ester group, or a group
  
  designated with the meaning of F given above, in an inert organic solvent, optionally with the addition of water at temperatures between about -80 ° C and about +5 ₀ ° _C, optionally in the presence of a base, and works up the reaction product in a conventional manner.

In this way, pseudotrisaccharides are obtained in which all amino groups except the 3 "-N-methylamino group are blocked by protective groups.

Das Verfahren wird üblicherweise in einem inerten Lösungsmittel durchgeführt. Das Lösungsmittel kann ein organisches oder anorganisches sein, in dem das selektiv geschützte 4,6-Di-O-(aminoglycosyl)-1,3-diaminocyclitol und die anderen Reagentien löslich sind und das unter den Reaktionsbedingungen nach Möglichkeit Nebenreaktionen herabsetzt oder verhindert. Obwohl wasserfreie aprotische Lösungsmittel mit Vorteil eingesetzt werden können (z.B. Tetrahydrofuran,wenn das Reduktionsmittel Morpholinoboran ist), wird gewöhnlich doch ein protisches Lösungsmittel verwendet. Als solches eignet sich z.B. ein niederes Alkanol oder vorzugsweise Wasser oder ein wäßriges niedriges Alkanol, vorzugsweise wäßriges Methanol oder Ethanol oder andere Lösungsmittelsysteme, die Wasser enthalten wie z.B. wäßriges Dimethylformamid, wäßriges Hexamethylphosphoramid, wäßriges Tetrahydrofuran oder wäßriger Ethylenglycoldimethylether.If, for example, sisomicin is used as the starting substance and diethyl pyrocarbon is used as the acylating agent, then 1.2 ', 3,6'-tetra-N-ethoxycarbonylsisomicin of the formula (VI) is obtained quantitatively by reaction in aqueous ethanol.

The process is usually carried out in an inert solvent. The solvent can be an organic or inorganic one in which the selectively protected 4,6-di-O- (aminoglycosyl) -1,3-diaminocyclitol and the other reagents are soluble and which, if possible, reduces or prevents side reactions under the reaction conditions. Although anhydrous aprotic solvents can be used to advantage (e.g. tetrahydrofuran if the reducing agent is morpholinoborane), a protic solvent is usually used. Suitable as such is, for example, a lower alkanol or preferably water or an aqueous lower alkanol, preferably aqueous methanol or ethanol or other solvent systems which contain water, such as aqueous dimethylformamide, aqueous hexamethylphosphoramide, aqueous tetrahydrofuran or aqueous ethylene glycol dimethyl ether.

The process is usually carried out in a pH range from 1 to 11 and preferably at pH 4 to 8.

Typical aldehydes of the formula R "CHO, wherein R" is as defined above, which can be used in the process, include straight or branched chain alkyl aldehydes such as acetaldehyde, n-propanal, n-butanal, 2-methylpropanal, n-pentanal, 2 -Methylbutanal, 3-methylbutanal, 2,2-dimethylpropanal, n-hexanal, 2-ethylbutanal, n-heptanal and n-octanal; Alkenyl aldehydes such as propenal, 2-methylpropenal, 2-butenal, 2-methyl-2-butenal, 2-ethyl-2-hexenal; Cyclic aldehydes such as cyclopropane carbaldehyde, cyclopentane carbaldehyde, cyclopentane acetaldehyde, cyclohexane carbaldehyde; Benzaldehyde, o-, m-, and _E- toluenecarbaldehyde and phenylacetaldehyde; by according to formula (VII) or their acid addition salts with an aldehyde of the formula R "-CHO, where R" CH _{2 has} the meaning given above for R and, if this radical contains amino and / or hydroxyl groups, also contains amino and / or may have hydroxyl protective groups, reacted in the presence of a hydrogen donor reducing agent and the mixture worked up in a manner known per se to the compounds of type (III) and any protective groups present were split off.

This process, in which the 3 "amino group in a 4,6-di-0- (aminoglycosyl) -1,3-diaminocyclitol reacts with an aldehyde and is simultaneously reduced in situ, is usually carried out at room temperature in the presence of air, although it may be more convenient to carry out the reaction under inert gas (argon, nitrogen) The reaction is usually very rapid, often in less than 60 minutes, which can be determined by thin layer chromatography.

Hydrogen donor reducing agents used in this process include dialkylaminoborane (e.g. dimethylaminoborane, and preferably morpholinoborane), tetraalkylammonium cyanoborohydride (e.g. tetrabutylammonium cyanoborohydride), alkali metal borohydride (e.g. sodium borohydride), and preferably sodium borohydride (e.g.

There is also the possibility of an acetal or hemiacetal of the aldehyde to be used when the reaction in an acid medium, which gives rise to the in situ formation of the free _A ldehydes, is performed.

The process is preferably carried out in such a way that a solution of 4,6-di-0- (aminoglycosyl) -1,3-diaminocyclitol, which contains amino protective groups in all positions except in position 3 "(for example 1,2 ', 3,6'-Tetra-N-ethoxycarbonyl-sisomicin) in aqueous methanol gives 1-10 equivalents of the respective aldehyde (eg acetaldehyde) and then (after about 0.5 hours) approximately 1.3 equivalents of alkali metal cyanoboranate (eg sodium cyanoboranate). Working up according to customary methods provides the desired ₃ "NR derivative of the corresponding protected pseudotrisaccharide (eg 3" N ethyl 1,2 ', 3,6' tetra N ethoxy carbonylsisomicin).

wobei
R die oben angegebene Bedeutung besitzt undAnother process according to the invention for the preparation of the 3 "-N-alkylated derivatives of 4,6-di-0- (aminoglycosyl) -1,3-diaminocyclitole of the formula (III) consists in the reaction of compounds of type (VII) with halogen compounds of the formula (3)

in which
R has the meaning given above and

Hydroxy substituted straight and branched chain alkyl aldehydes such as 5-hydroxypentanal, 2-hydroxy-3-methylbutanal, 2-hydroxy-2-methylpropanal, 4-hydroxybutanal, 2-hydroxypropanal and 8-hydroxyoctanal as well as glyceraldehyde; straight-chain and branched-chain alkyl aldehydes substituted by amino, such as 5-aminopentanal, 2-aminopropanal, 3-aminopropanal, 4-aminobutanal, 2-amino-3-methylbutanal, 8-aminooctanal and mono-N-alkyl derivatives thereof; and straight and branched chain alkyl aldehydes disubstituted by amino and hydroxy, such as 2-hydroxy-5-aminopentanal, 3-hydroxy-3-methyl-4-amino-bu-tanal, 2-hydroxy-4-aminobutanal, 2-hydroxy-3- aminopropanal, 2-hydroxy-2-methyl-3-aminopropanal, 2-amino-3-hydroxyoctanal and mono-N-alkyl derivatives thereof.

If an aldehyde with an optically active center is used in this process, each enantiomer can be separated or the racemate can be used and the corresponding diastereoisomers or a mixture thereof are obtained.

The aldehydes used in the process are either known compounds or can be easily prepared from known compounds by standard procedures.

When carrying out the process, it may be advantageous to protect the aldehyde which has an amino group on this amino group, for example as acetamido, phthalimido or ethoxycarbonyl derivative, and to release the amino group after completion of the reaction. It may also be advantageous to protect any hydroxy groups in aldehydes, but this is generally not necessary.

Working up, the desired 3 "-N-substituted derivatives are obtained in pure form and in mostly quantitative yield.

Other processes for the alkylation of compounds of the formula (VII) for the preparation of compounds of the formula (III) consist in the reaction of these with sulfur and sulfonic acid esters, epoxides and compounds with activated double bonds and are familiar to the person skilled in the art.

The invention further encompasses processes for the selective removal of the methyl group from the 3 "-N (CH ₃ ) R-trisaccharides of the formula (III) obtained with the aid of the alkylation methods described above.

One of the preferred methods of cleavage according to the invention is the oxidative demethylation of the tertiary 3 "amino group.

Conventional oxidizing agents can be used to cleave the compounds of the formula (III).

Examples of oxidizing agents are heavy metal salts, peroxides, halogens, halogen oxyacids and their salts, nitrogen oxides and molecular oxygen. Preferred oxidizing agents are permanganates, manganates, manganese dioxide, chromium trioxide, bichromates, chromates, alkyl chromates, chromyl chloride, selenium dioxide, cobalt (III) salts, cerium (IV) salts, potassium hexacyanoferrate (III), copper oxide, lead oxide, mercury oxide, and mixtures of hydrogen peroxide Iron (II) salts, iron (III) salts, selenium dioxide, osmium tetroxide, vanadates, tungstic acid and / or chromium Hal means halogen, such as chlorine, bromine or iodine.

Such alkylations of amines are already known from the literature. e.g. Houben-Weyl, Methods of Organic Chemistry, Vol. XI, 1, Georg Thieme Verlag, Stuttgart 1957). The reaction is preferably carried out in the presence of a diluent which is inert under the reaction conditions, preferably one in which the reactants dissolve well. Preferred diluents of this type are ethers such as tetrahydrofuran, ethylene glycol dimethyl ether or dioxane, ketones such as acetone or methyl ethyl ketone, alcohols, dimethylacetamide and dimethylformamide. The use of dimethylformamide as a solvent is particularly preferred. Depending on the reactivity of the alkyl halide used, 1-10 molar equivalents of alkylating agent are used and the pH is from about 5 to about 12. It is preferable to use an auxiliary base to capture the hydrogen halide liberated in the reaction. Examples of corresponding bases are alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal and alkaline earth metal carbonates, alkaline earth metal oxides, carbonates and oxides of heavy metals such as e.g. Lead carbonate and silver carbonate as well as mercury oxide or silver oxide. In principle, all compounds which are stable under the reaction conditions and are able to trap the hydrogen halide formed can be used as auxiliary bases.

The reaction according to the invention is carried out at temperatures from about -20 to + 80 °, preferably from 0 ° to 30 °. The reaction time is normally 1-48 hours and the process is generally carried out under normal pressure. After over Bases are ammonium hydroxide, alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal alcoholates and alkali and alkaline earth metal salts of carboxylic acids.

The pH can be adjusted either from the start of the reaction or during the reaction.

The reaction according to the invention is carried out at temperatures from about -20 ° to about 100 ° C, preferably from about -5 ° to about 70 ° C. The reaction time is half an hour to 50 hours. In general, the reaction is carried out at normal pressure.

The protective groups present in the molecule after the reaction can be split off in a known manner by alkaline or acidic hydrolysis, hydrogenolysis or displacement reactions. If compounds which contain acyl protective groups of type (1) or (2) are used for the cleavage, these can preferably be cleaved off with aqueous alkalis of alkali metal or alkaline earth metal hydroxides.

säure, Bleitetraacetat,Chlor, Brom, Jod, Hypochlorate, Chlorite, Hypobromate, Bromate, Perjodate, Distickstoffmonoxid, Stickstoffdioxid und Luft. Bei Verwendung von molekularem Sauerstoff werden vorzugsweise Edelmetalle wie Platin, Palladium, Rhodium, Ruthenium oder Rhenium sowie Nickel als Katalysatoren verwendet.The processes according to the invention described above are described by the following formula scheme using the example of the representation of 3 "-N-ethyl-3" -N-demethylsisomicin of the formula (II) with R = C ₂ H ₅ starting from sisomicin.

Acid, lead tetraacetate, chlorine, bromine, iodine, hypochlorates, chlorites, hypobromates, bromates, periodates, nitrous oxide, nitrogen dioxide and air. When using molecular oxygen, noble metals such as platinum, palladium, rhodium, ruthenium or rhenium and nickel are preferably used as catalysts.

Particularly preferred oxidizing agents are manganese dioxide, potassium hexacyanoferrate (III) and potassium permanganate. In the event that potassium hexacyanoferrate III is the oxidizing agent and ammonium hydroxide is the auxiliary base, copper (II) sulfate can be added to the solution to be oxidized. The hexacyanoferrate-II formed during the oxidation then precipitates out as a poorly soluble copper salt.

The cleavage reaction is preferably carried out in the presence of a diluent which is inert under the reaction conditions, preferably one in which the reactants dissolve. Suitable diluents of the type mentioned are water or mixtures of water with methanol, ethanol, i-propanol, tetrahydrofuran, dimethylformamide, dioxane, pyridine, ethylene glycol dimethyl ether and acetone.

Depending on the type of oxidizing agent used, the reaction according to the invention is carried out at a pH of 3 to 12. The pH can be adjusted by adding an appropriate acid or base. Those acids or bases are to be used which do not decompose the starting compounds or the end products and which do not cause a reduction in the activity of the oxidizing agents. Rather, it is desirable that they increase the activity of the oxidizing agents. Hydrochloric acid or sulfuric acid, for example, can be used as inorganic acids and acetic acid or formic acid, for example, can be used as organic acids. Examples of corresponding The 1,2 ', 3,6'-tetra-N-acetyl-sisomicin (VIII) used according to the invention can be obtained in quantitative yield by reacting sisomicin with acetic anhydride in methanol / water.

The subsequent introduction of the ethyl group on the 3 "nitrogen is carried out by reacting (VIII) with ethyl iodide in dimethylformamide as the solvent and with, for example, silver oxide as the base. It is worked up in a manner known per se and gives 3" -N-ethyl-1,2 ', 3,6'-tetra-N-acetylsisomicin * (IX) in quantitative yield. To split off the 3 "-N-methyl group, (IX) is treated with potassium permanganate in aqueous acetone with the addition of sodium hydroxide as the base. After the end of the reaction, as determined by thin-layer chromatography, the inorganic salts are precipitated by adding acetone, and the solution which remains is isolated the 3 "-N-demethyl compound (X) in high yield. The acetyl protective groups are split off by heating in an aqueous barium hydroxide solution and the previously unknown 3 "-N-ethyl-3" -N-demethylslsomicin is thus obtained.

The 3 "-N-methyl group can also be cleaved from the 3" -N-derivatives of the formula (III) by reaction with cyanogen bromide. Convert heating with dilute acids to the corresponding secondary amines of formula (XI) (with R "'= H).

wobei die im Molekül vorhandenen Aminogruppen in freier Form vorliegen. A,B,U,V,W,X,Z und R haben in (XII) die oben angegebene Bedeutung.The 3 "-N-methyl group can also be split off by adding 3" -N-derivatives of the formula - III according to the known methods - e.g. B. oxidized with hydrogen peroxide on the tertiary 3 "amino group to the corresponding N-oxide and this product by treatment with acetic anhydride in the corresponding 3" -N-acetyl-3 "-N-alkyl-3" -N-desmethyl-l, 2 ', 3.6'-

wherein the amino groups present in the molecule are in free form. A, B, U, V, W, X, Z and R have the meaning given above in (XII).

Im allgemeinen hängt die zu verabreichende Dosis der Verbindungen der Erfindung vom Alter und Gewicht des Lebewesens, von der Verabreichungsart, vom Typ und von der Schwere der bakteriellen Infektion ab. Die Dosierung der tetra-N-acyl-verbindung überführt. Nach Abspaltung der Acylgruppen erhält man so die erfindungsgemäßen 3"-N-Alkyl-3"-desmethylderivate mit freien Aminogruppen.The compounds according to the invention are antimicrobial agents with a broad spectrum of activity and particular activity against gram-negative bacteria. These properties enable them to be used as pharmaceuticals in combating bacterial diseases in humans and animals. They are well suited for the prophylaxis and chemotherapy of local and systemic infections, in particular infections of the genitourinary system in human and veterinary medicine, which are caused by gram-negative bacteria, for example E. coli, Proteus, Klebsiella and Pseudomonas. Depth of inhibition in the agar hole test was found, for example, against the following bacterial strains at a concentration of 100 micrograms / 1 ml;

In general, the dose of the compounds of the invention to be administered will depend on the age and weight of the subject, the mode of administration, the type and the severity of the bacterial infection. The dosage of the Tetra-N-acyl compound transferred. After the acyl groups have been split off, the 3 "-N-alkyl-3" desmethyl derivatives according to the invention having free amino groups are obtained.

Similar to the action of cyanogen bromide, the reaction with chloroformic acid esters, phosgene and carboxylic acid halides such as benzoyl chloride with 3 "-N- (CH ₃ ) R derivatives of pseudotrisaccharides of the formula (III) takes place, with the corresponding 3 "-N-acyl derivatives of the formula (XI) (with R"'= acyl) are formed, which can be saponified to the corresponding free amines of the formula (I).

The symbols X ', R', U, V, Z ', W, A, B and R have the meaning given above. R "'can be hydrogen or acyl.

The corresponding unprotected compounds of the formula (XII) can also be used for oxidative demethylation

Formulation 1

Manufacturing

A slurry of 3 "-N-demethyl-ethylsisomicin, lactose and polyvinylpyrrolidone is prepared and these are spray dried. The corn starch and magnesium stearate are added, mixed and compressed into tablets.

Formulation 2

erfindungsgemäßen Verbindungen ist gewöhnlich der Dosierung der 3"-N-Methyl-Verbindung ähnlich. Der Dosierungsspielraum beträgt von 20 mg/Tag/Mensch bis 2000 mg/Tag/Mensch, vorzugsweise 100 mg - 500 mg/Tag.

Compounds according to the invention are usually similar to the dosage of the 3 "-N-methyl compound. The dosage range is from 20 mg / day / person to 2000 mg / day / person, preferably 100 mg - 500 mg / day.

The compounds of the invention can be administered orally. The administration can take place in single doses or in several doses. They can also be administered topically in the form of ointments, creams or lotions. Pharmaceutical excipients for these formulations include water, oils, fats, polyesters and polyols.

Tablets, capsules or elixirs can be used for oral administration of the compound of this invention, but the compounds can also be admixed to animal feed.

In general, topical preparations contain about 0.1 to about 3.0 g of the compounds of the invention per 100 g of ointment, cream or lotion. Topical administration takes place about 2 to 5 times a day.

The antibacterial agents of the invention may be in liquid form as solutions or suspensions for use in the ears and eyes or for parenteral administration in the form of intramuscular injections. Injection solutions or suspensions are usually administered in such a way that approximately 1 to 15 mg of active ingredient per kilogram of body weight reaches the infected organism in 2 to 4 doses per day. The exact dose depends on the type of infection, the sensitivity of the infecting germ and the individual characteristics of the person being treated.

example 1 1,2 ', 3,6'-tetra-N- (ethoxycarbonyl) sisomicin

1.1 g sisomicin are dissolved in 50 ml ethanol and 70 ml water. After cooling to -10 ° C., 1.35 ml of diethyl pyrocarbonate is added dropwise with thorough stirring. After a further 2 1/2 hours at -10 ° C, 100 ml of water are added. The mixture is then extracted with 150 ml of petroleum ether and the aqueous phase is evaporated to dryness in vacuo. The residue is dissolved in methanol. The desired product is precipitated by adding excess ether and petroleum ether. Yield = 1.5 g (91%)

¹³ C NMR (CD ₃ OD / CDCl ₃ ): δ = 50.86 (C-1); 49.90 (C-2-); 46.33 (C-2 '); 42.87 (C-6 '); 157.94, 157.73, 157.29 and 157.22 c = o) ppm.

Example 2 1,2 ', 3,6'-tetra-N-acetyl sisomicin

1.1 g sisomicin are dissolved in 120 ml water. After adding 60 ml of methanol, 2.5 ml of acetic anhydride are added dropwise with stirring. After 15 minutes, the mixture is evaporated to dryness in vacuo. The residue is dissolved in 10 ml of methanol and this solution is added dropwise to a mixture of 30 ml of ether and 30 ml of petroleum ether, the desired product precipitating. Yield = 1.43 g, MS: m / e = 615.

Manufacturing

• (1) The petrolatum is melted;
• (2) _M an mixes 3 "- _N -Demethyl-3" -N-ethylsisomicin, methylparaben and propylparaben with about 10% of the melted petrolatum;
• (3) Place the mixture in a colloid mill;
• (4) Add the remaining petrolatum while stirring and cool until it becomes semi-solid. The product is filled into suitable containers.

Formulation 3

dampft und der Rückstand aus Chloroform mit Petrolether umgefüllt. Ausbeute = 1,1 g
¹³C-NMR (CD₃OD) : δ = 62.₀2 (C_H2-Ar); 124,39, 131,00 148.57 (aromatische H); 102.05 (C-1"); 67.03 (C-3") ppm

evaporates and the residue from chloroform is poured with petroleum ether. Yield = 1.1 g
¹³ C-NMR (CD ₃ OD): δ = 62. ₀ 2 (C _H2 -Ar); 124.39, 131.00 148.57 (aromatic H); 102.05 (C-1 "); 67.03 (C-3") ppm

Example 5 3 "-N-Cyclohex-3-enylmethyl-1,2'-3,6'-tetra-N-acetyl-sisomicin

650 mg of the product from Example 2 in 3 ml of water are stirred with 150 mg of 1,2,5,6-tetrahydrobenzaldehyde in 10 ml of methanol for 30 minutes at room temperature. After adding 95 mg of sodium cyanoboranate, the mixture is stirred for a further 10 hours at room temperature. For working up, the reaction mixture is filtered through a short column with basic ion exchanger ( _OH ^e - _form , Lewatit ( ^R ) MP 500 Bayer Leverkusen), the filtrate is evaporated to dryness in vacuo, the residue is extracted with methylene chloride / methanol in a ratio of 1/1 filters the undissolved and evaporates the filtrate to dryness in vacuo. Yield 600 mg of colorless solid (mixture of diastereomers).

• δ = 33,60, 33,35, 27,95, 21,48, 25.74, 25,45 (Ringmethylene); 127,55; 126.95 ( >c=c < ) 67.46 (C-3") ppm.
• ¹³C-NMR (CD₃OD) : δ= 50,14 (C-1 ) ; 49,20 (D-3); 46,88 (C-2'); 42,26 (C-6'); 173,24, 173,13, 173,63 ( C=O) ppm.

¹³ C-NMR (CD ₃ OD / CDCl ₃ ):

• δ = 33.60, 33.35, 27.95, 21.48, 25.74, 25.45 (ringmethylene); 127.55; 126.95 (> c = c <) 67.46 (C-3 ") ppm.
• ¹³ C NMR (CD ₃ OD): δ = 50.14 (C-1); 49.20 (D-3); 46.88 (C-2 '); 42.26 (C-6 '); 173.24, 173.13, 173.63 (C = O) ppm.

Example 3 3 "-N-ethyl-1,2 ', 3,6'-tetra-N-acetyl-sisomicin

= + 168°(C = 1.0 CH₃0H)1.9 g of the tetra-N-acetylsisonicine shown in Example 2 are dissolved in 30 ml of dimethylformamide and 2 g of silver oxide and then 0.6 ml of ethyl iodide in 3 ml of dimethylformamide are added with stirring at 0 ° C. After stirring overnight, 10 ml of methanol and 25 ml of methylene chloride are added, the mixture is decolorized with charcoal, filtered and the filtrate is evaporated in vacuo. The desired product is thus obtained as a colorless solid. Yield 1.9 g.

= + 168 ° (C = 1.0 CH ₃ 0H)

Example 4 3 "-N-p-nitrobenzyl-1,2 ', 3,6'-tetra-N-acetyl-sisomicin

1.3 g of the product from Example 2 in 20 ml of dimethylformamide are stirred with 2.5 g of silver oxide and 2.2 g of p-nitrobenzyl bromide for 1 hour at room temperature. Then diluted with 50 ml of chloroform, stirred briefly with a little charcoal and filtered. The filtrate is vacuum-dried. 2 g of 3 "-N-ethyl-1,2 ', 3,6'-tetra-N-acetyl-sisomicin (see Example 3) are dissolved in 22 ml of water and 5 ml of acetone, and the solution is after adding 400 mg of potassium hydroxide in 5 ml of water are cooled to 0 ° C. 500 mg of potassium permanganate in 50 ml of water are then added dropwise, with thorough stirring and cooling, and after 1.5 hours the inorganic salts are precipitated by adding 70 ml of acetone Undissolved, the filtrate is evaporated in vacuo and the residue obtained is extracted with methanol / chloroform, filtered again, the filtrate is evaporated in vacuo and the crude product thus obtained is purified by column filtration on silica gel.
In this way, the title compound is obtained as an amorphous solid.

¹³ C-NMR (CD ₃ OD): δ = 1 ₀ 0.87 (C-1 "); 70.39 (C-2"); 63.83 (C-3 "); 51.17 (C-1); 34.65 (C-2); 50.09 (C-3); 97.63 (C-1 '); 46.58 (C-2'); 15.12 (CH ₂ - CH ₃ ) ^ppm

Example 9 3 "-N-Demethyl-3" -N-ethyl-sisomicin

To split off the acetyl groups, the product obtained according to Example 8 is dissolved in 30 ml of water and, after addition of 20 g of barium hydroxide hydrate, heated to reflux for 5 hours. For working up, the dissolved barium salts are precipitated as barium carbonate. It is filtered, the filtrate is evaporated to dryness in vacuo, the residue thus obtained is extracted with methanol / methylene chloride and the undissolved is filtered off. Evaporation of the filtrate gives the title compound as a colorless solid

Example 6 3 "- N- (β-methylallyl) -1,2 ', 3,6'-tetra-N-acetylsisomicin

130 mg of the product from Example 2 are dissolved in 2 ml of DMF and 90 mg of 3-chloro-2-methylpropene-1 and 200 mg of silver oxide are added at 0.degree. The mixture is stirred for a further 24 hours at room temperature, mixed with 2 ml of methanol and 2 ml of methylene chloride and worked up as described in Example 3. Colorless solid mp = 158 ° C Rf value 0.68

(Solvent system B = _C hloroform: methanol: 15% NH ₃ / H ₂ 0 in ratio 1: 1: 1; TLC plates, silica gel 60 F254 of the company E. Merck, Darmstadt).

Example 7 _{3 "} -N- (β, -dihydroxypropyl) -1,2 ', 3,6'-tetra-N-acetyl-sisomicin

2.6 g of 1,2 ', 3,6'-tetra-N-acetyl-sisomicin in 30 ml of water are mixed with 400 mg of glyceraldehyde in 30 ml of methanol and stirred at room temperature for 45 minutes. Then 360 mg of sodium cyanoboranate are added and the mixture is heated under reflux for 7.5 hours. The procedure is as described in Example 5. 2.5 g of a colorless solid (mixture of diastereomers) are obtained. Mp = 130-140 ⁰ (decomp.)

Example 8 3 "-N-Demethyl-3" -N-ethyl-1,2 ', 3,6'-tetra-N-acetyl-sisomicin

Chromatographed on a short column on silica gel (eluent: mobile phase A)

To split off the N-acetyl groups is dissolved the resulting 3 "-N-demethyl-3" - _N -propyl-1,2 ', 3,6'-tetra-N-acetyl-sisomicin in 6 ml of water, mixed with 4 g of barium hydroxide hydrate and heated to reflux for 5 hours. For working up, the dissolved barium salts are precipitated as barium carbonate. It is filtered, the filtrate is evaporated to dryness in vacuo and the residue thus obtained is extracted with methanol / methylene chloride and the undissolved is filtered off. Evaporation of the filtrate gives the title compound as a colorless solid.

Rf value = 0.32 (solvent system A)

• 1. 3"-H-Desmethyl-3"-N-n-butyl-sisomicin Rf= 0,35
• 2. 3"-N-Desmethyl-3"-N-n-pentyl-sisomicin Rf= 0,37
• 3. 3"-N-Desmethyl-3"-N-n-heptyl-sisomicin Rf= 0,40
• 4. 3"-N-Desmethyl-3"-N-(ß-dimethylpropyl)-sisomicin Rf= 0,38 (δ)²⁰ _D = +179°C (c = 1,0 H₂ ⁰)

The following 3 "-N-demethyl-3" -N-alkyl-sisomicins are prepared as described in Example 10:

• 1. 3 "-H-Desmethyl-3" -Nn-butyl-sisomicin Rf = 0.35
• 2. 3 "-N-desmethyl-3" -Nn-pentyl-sisomicin Rf = 0.37
• 3. 3 "-N-desmethyl-3" -Nn-heptyl-sisomicin Rf = 0.40
• 4. 3 "-N-desmethyl-3" -N- (β-dimethylpropyl) sisomicin Rf = 0.38 (δ) ²⁰ _D = + 179 ° C (c = 1.0 H ₂ ⁰ )

_R f = 0.27 (solvent system A = chloroform: methanol: 20% NH _{3 /} H ₂ 0 in a ratio of 2: 4: 1).

Example 10 3 "-N-Demethyl-3" -N-propyl-sisomicin

400 mg of 1,2 ', 3,6'-tetra-N-acetyl-sisomicin are dissolved in 5 ml of methanol and 1 ml of water. The solution is mixed with 200 mg of propionaldehyde and left at room temperature for 0.5 hours. Now add 100 mg of sodium cyanoboranate and let react for a further 3 hours at room temperature. It is worked up as described in Example 5 and 400 mg of 3 "-N-propyl-1,2 ', 3,6'-tetra-N-acetyl-sisomicin are obtained, which is fed to the oxidative demethylation as a crude product Dissolve the product in 4.5 ml of water and 1 ml of acetone, and add 85 mg of potassium hydroxide in 1 ml of water to this solution After cooling to 0 °, 100 mg of potassium permanganate in 10.5 ml of water are slowly added dropwise with good stirring , 5 hours at room temperature is diluted with 25 ml acetone, filtered from the undissolved and the filtrates evaporated to dryness in vacuo. The crude product thus obtained is used for final purification acid to pH 1, heated to reflux for 10 minutes and then neutralized with dilute sodium hydroxide solution. Now add 400 mg of 1,2 ', 3,6'-tetra-N-acetyl-sisomicin, leave for 0.5 hours at room temperature and then add 100 mg of sodium cyanoboranate. After a further 5 hours the mixture is worked up as described in Example 10. Demethylation and removal of the protective groups are carried out as described in Example 10 and the title compound is obtained as a colorless solid.

Rf = .0.33 (solvent system A)

3 "-N-Demethyl-3" -N- (β-n-butoxyethyl-sisomicin Rf = 0.58 (mobile phase system A) is obtained in an analogous manner.

Example 13 3 "-N-Demethyl-3" -N-ß-butenyl-sisomicin

• 5. 3"-N-Desmethyl-3"-N-(ß-methaxybutyl)-sisomicin Rf= 0,48
• 6. 3"-Desmethyl-3"-N-γ, -dimethoxyhexyl)-sisomicin Rf= 0,53

400 mg of 1,2 ', 3,6'-tetra-N-acetyl-sisomicin in 5 ml of methanol and 3 ml of water are stirred with 100 mg of crotonaldehyde for 0.5 hours at room temperature. After adding 100 mg of sodium cyanoboranate, the mixture is left to react for 2 hours at room temperature and then worked up as described in Example 10. (Rf = 0.64, eluent system B). For oxidative demethylation, the product thus obtained is dissolved in 8 ml of H ₂ O and this solution is added with stirring to a solution of 320 mg of potassium hexacyanoferrate (III) and 150 mg of sodium hydroxide in 8 ml of water. The mixture is left at room temperature for 48 hours, diluted with 40 ml of acetone, filtered off from the precipitated salts and the filtrate is evaporated in

• 5. 3 "-N-Desmethyl-3" -N- (β-methaxybutyl) sisomicin Rf = 0.48
• 6. 3 "-Desmethyl-3" -N-γ, -dimethoxyhexyl) -sisomicin Rf = 0.53

The solvent system for determining the Rf values is chloroform: methanol: 20% NH _{3 /} H ₂ 0 in a ratio of 1: 1: 1. Rf of sisomicin = 0.18

Example 11 3 "-N-Demethyl-3" -N-ß-aminoethyl-sisomicin

The reductive alkylation of 400 mg of 1,2 ', 3,6'-tetra-N-acetyl-sisomicin in 8 ml of methanol and 1 ml of water with N-ethoxycarbonylaminoacetaldehyde gives 380 mg of 3 "-N- (β-ethoxycarbonylaminoethyl) -1 , 2 ', 3,6'-tetra-N-acetyl-sisomicin, which is demethylated and then deacylated as described in Example 10. The title compound is thus obtained as an amorphous solid. Rf = 0.10 (solvent system A).

Example 12 3 "-N-Demethyl-3" - _N -methoxyethyl-sisomicin

220 mg methoxyace. idehyddiethylacetal are dissolved in 2 ml H ₂ 0 and 4 ml methanol. _M an with diluted sulfur

Example 14 3 "-N-desmethyl-3" -N-ethyl-sisomicin

= +179° (c = 1,0 H₂0)12.5 g of 3 "-N-ethyl-sisomicin are added to a solution of 16 g of cadmium carbonate hydrate and 120 ml of 25% aqueous ammonia in 400 ml of water. The mixture is cooled to 0 to 1 ° C. and mixed within 1 hour a solution of 18 g of potassium hexacyanoferrate (III) in 440 ml of water with vigorous stirring After neutralization with 20% aqueous sulfuric acid, the precipitate is filtered off with suction and the filtrate is passed through a short column with basic ion exchanger (OH ^⊝ form, Lewatit MP 500 ^® , Bayer AG, Leverkusen), the eluate is evaporated to dryness in vacuo, the residue is taken up in methanol / methylene chloride and the resulting mixture is filtered, after evaporation of the filtrate, 10.0 g of the title compound remain as an amorphous solid.

= + 179 ° (c = 1.0 H ₂ 0)

= + 148° (c= 1,0 CH₃OH) Rf = 0,7 (Laufmittelsystem B) Zur Abspaltung der Acetygruppen verfährt man wie bei Beispiel 10 beschrieben und erhält die Titelverbindung als amorphen Feststoff. Rf = 0,36 (Laufmittelsystem A)Vacuum on. For purification, the crude product obtained in this way is filtered through a short silica gel column (eluent system B). This gives 3 "-N-demethyl-3" -N-β-butenyl-1,2 ', 3,6'-tetra-N-acetylsisomicin as an amorphous solid.

= + 148 ° (c = 1.0 CH ₃ OH) Rf = 0.7 (solvent system B) To split off the acety groups, the procedure is as described in Example 10 and the title compound is obtained as an amorphous solid. Rf = 0.36 (solvent system A)

=+ 134 ⁰ (c= 0,84 CH₃OH) und daraus durch Abspaltung der Schutzgruppen

• 1. 3"-N-Demethyl-3"-N-tolylethyl-sisomicin _Rf= 0,45 (Laufmittelsystem A)
  und
• 2. 3"-N-Demethyl-3"-N-allyl-sisomicin _Rf= 0,33 (Laufmittelsystem A)
  
  
  

In the same way, 3 "-N-demethyl-3" -N-tolylethyl-1 is obtained by oxidative demethylation of 3 "-N-tolylethyl-1,2 ', 3,6'-tetra-N-acetyl-sisomicin , 2 ', 3,6'-tetra-N-acetyl-sisomicin with

= + 134 ⁰ (c = 0.84 CH ₃ OH) and from this by splitting off the protective groups

• 1. 3 "-N-demethyl-3" -N-tolylethyl-sisomicin _R f = 0.45 (solvent system A)
  and
• 2. 3 "-N-demethyl-3" -N-allyl-sisomicin _R f = 0.33 (eluent system A)
  
  
  

Claims (10)

1. Compounds of formula (I)

in the X for a rest

stands, and Y a rest

designated, U, V, W represent hydrogen or hydroxy, Z can be hydrogen, hydroxy or amino and R in the saccharide part symbolized by Y represents alkyl (except methyl), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, where the hydrocarbon radicals mentioned for R can be substituted. 2. Compounds according to claim 1, which 3 "-N _R derivatives of the antibiotics gentamicin A, gentamicin B, gentamicin B1, gentamicin C ₁ , gentamicin C _1a , gentamicin C ₂ , gentamicin C2a, gentamicin C _2b . Gentamicin X ₂ , sisomicin , JI-20 A, JI-20 B, Verdamicin, G 52, G 418, 66-40 B, 66-40 D, Mutamicin 1, Mutamicin 2, Mutamicin 4, Mutamicin 5 and Mutamicin 6. 3. Compounds according to claims 1 and 2, in which
R is an alkyl radical with 2 to 8 carbon atoms, an alkenyl radical with 2 to 6 carbon atoms, an alkynyl radical with 2 to 6 carbon atoms, a cycloalk (en) yl radical with 3 to 10 carbon atoms, a cycloalk (en) ylmethyl or -ethyl radical, a phenyl or naphthyl radical or a phenylmethyl or phenylethyl radical, the hydrocarbon radicals mentioned having 1 to 3 substituents from the series hydroxyl, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, halogen, nitro, amino, monoalkyl and dialkylamino having 1 to 4 carbon atoms per alkyl group can be substituted. 4. 3 "-N-Demethyl-3" -N-ethylsisomicin. 5. The acid addition salts of the compounds according to claims 1 to 4. 6. Process for the preparation of compounds of formula (I)

in the U, V, W, X, Y and Z have the meaning given above,
characterized in that compounds of the formula (III)

in the A hydroxy or hydrogen and B is hydroxy, hydrogen or methyl, R, U, V, W have the meaning given above, Zt is hydrogen, hydroxy, amino or by R '
protected amino mean R 'stands for an amino protecting group and in the X 'for a remainder of the formulas

stands in which R '
has the meaning given above, at temperatures from about -20 ° C. to about 100 ° C., preferably in the presence of a diluent which is inert under the reaction conditions, and after removal of the amino protecting groups, the pseudotrisaccharides of the formula (I) in free form or in the presence of acid isolated as acid addition salts. 7. Pharmaceutical preparation, characterized by a content of a compound according to claims 1 to 5. 8. procedural ren 'for the preparation of a pharmaceutical preparation according to claim 7, characterized in that a compound according to claims 1 to 5 is mixed with inert, pharmaceutically suitable carriers and / or additives. 9. Use of a compound according to claims 1 to 5 in the control of diseases caused by bacteria in humans and animals. 10. A method for the treatment of diseases caused by bacteria, characterized in that a compound according to claims 1 to humans or animals suffering from these diseases is applied.