EP0000199B1 - 4-o-aminoglycosyl-1,3-diaminocyclitols and process for their preparation - Google Patents

4-o-aminoglycosyl-1,3-diaminocyclitols and process for their preparation Download PDF

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Publication number
EP0000199B1
EP0000199B1 EP78100255A EP78100255A EP0000199B1 EP 0000199 B1 EP0000199 B1 EP 0000199B1 EP 78100255 A EP78100255 A EP 78100255A EP 78100255 A EP78100255 A EP 78100255A EP 0000199 B1 EP0000199 B1 EP 0000199B1
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Prior art keywords
formula
radical
compounds
acid addition
addition salts
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German (de)
French (fr)
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EP0000199A1 (en
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Hans Prof. Dr. Paulsen
Rolf Jansen
Peter Dr. Stadler
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Bayer AG
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Bayer AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/22—Cyclohexane rings, substituted by nitrogen atoms
    • C07H15/222—Cyclohexane rings substituted by at least two nitrogen atoms
    • C07H15/224—Cyclohexane rings substituted by at least two nitrogen atoms with only one saccharide radical directly attached to the cyclohexyl radical, e.g. destomycin, fortimicin, neamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the invention relates to new pseudodisaccharides and processes for their preparation.
  • the new compounds can be used as pharmaceuticals and as intermediates in the synthesis of pseudotrisaccharides.
  • acid addition salts are those of the pseudodisaccharides with hydrochloric, sulfuric, phosphoric, nitric, hydrogen bromide, benzenesulfonic, formic, acetic, propionic, maleic, ascorbic or citric acid.
  • the invention further relates to a process for the preparation of compounds of formula (1) .
  • which is characterized in that compounds of the formula in which X and Y have the meaning given above, where the radical Y is linked in the 4-position glycosidically to X and in the 6-position glycosidically to the garosaminyl radical, optionally in the form of N-protected derivatives, cleaved by treatment with an oxidizing agent at temperatures from -20 to 100 ° C and a pH between 3 and 12, any protective groups present are removed and the products in free form or in the presence of acid Form of their acid addition salts isolated.
  • the starting compounds of the formula (III) are pseudotrisaccharides known from the literature, such as the antibiotics verdamicin, sisomicin, G 52, mutamicin 1, mutamicin 2, mutamicin 4, mutamicin 5 and mutamicin 6 (see DT-OS 2 437 160).
  • the double bond is in the vinyl position relative to the ring oxygen.
  • a structurally similar pseudodisaccharide is already known from the literature (Bull. Chem. Soc. Jap. 1973, 46, page 3508), but in which the double bond is in the allyl position relative to the ring oxygen. Because of the completely different behavior of allyl and vinyl compounds, the pseudodisaccharides according to the invention were not suggested by this.
  • the known compound is produced by synthetic introduction of the double bond between the C atoms 3 and 4 in a neamine derivative, ie a saturated pseudodisaccharide.
  • the method according to the invention thus shows for the first time a way in which 4,5-unsaturated pseudodisaccharides can be produced at all.
  • the pseudodisaccharides according to the invention already have good antibiotic properties and are compounds known here (for example the neamine of FR-A 2 232 326). However, as explained in more detail below, they can also serve as starting material for the production of valuable new and known pseudotrisaccharides.
  • the type of blocking should be such that all amino or methylamino groups present in the molecule, with the exception of the methylamino group present in the cleavage of the garosaminyl group, are blocked.
  • the compounds protected in this way are therefore 1,2 ', 3,6'-tetra-N-blocked or, in the case of mutamicin 5, 1,2', 3,5,6'-penta-N-blocked Derivatives of the aminotrisaccharides according to formula (III).
  • Amino protective groups 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, Vol. XV, 1, Georg Thieme Verlag, Stuttgart, 1974).
  • N-protected derivatives of the aminotrisaccharides of the formula (III) which are acyl protective groups of the type are preferably used in the oxidation reaction the meaning of A can be found in the formulas (1) and (2) - or included, in the protective group residues mentioned B and D independently of one another represent hydrogen, phenyl or substituted phenyl and n, n 1 , n 2 , n 3 independently denote a number from 0 to 5.
  • Conventional oxidizing agents can be used to cleave the compounds of the formula (III) or their N-blocked derivatives.
  • oxidizing agents that can be used in the pH range between 3 and 12 to be maintained according to the invention are heavy metal salts, peroxides, halogens, salts of halogen oxygen acids, 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 tetraoxide, vanadate, lead tetraacetate, chlorine, bromine, iodine, hypochlorite, chlorate, hypobromite, bromate, periodate, nitrous oxide, nitrogen dioxide and air.
  • Particularly preferred oxidizing agents are manganese dioxide, sodium periodate, potassium hexacyanoferrate (III) and potassium permanganate.
  • 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.
  • a diluent which is inert under the reaction conditions, preferably one in which the reactants dissolve.
  • Suitable diluents of the type mentioned are methanol, ethanol, i-propanol, tetrahydrofuran, dimethylformamide, dioxane, pyridine and ethylene glycol dimethyl ether, acetone and acetic acid, and water or mixtures of water with the organic solvents mentioned.
  • 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.
  • 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.
  • corresponding 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 reaction according to the invention is carried out at temperatures from about -20 to about 100 ° C., preferably from about 0 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 which may still be present in the molecule after the reaction are split off in a known manner by alkaline or acidic hydrolysis, selective 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 with aqueous alkalis of alkali metal or alkaline earth metal hydroxides.
  • the starting compound V which can be used according to the invention can be obtained in accordance with the process described in published European patent application 0000057 by reacting sisomicin with diethyl pyrocarbonate in aqueous alcohol.
  • the oxidative cleavage of (V) can in principle be carried out using the oxidizing agents mentioned above; In the present case, however, preference is given to using sodium periodate, which is used in the form of an aqueous solution.
  • a suitable solvent for the cleavage reaction in the present case especially methanol or a methanol-water mixture. It is advantageous to work with the addition of 5-10% concentrated ammonium hydroxide.
  • the preferred reaction temperature is -5 ° to + 5 ° C. Further processing takes place by evaporating the reaction mixture in vacuo, extracting the residue with ethanol and deionizing the extracts with basic ion exchange resin (OH Q F O rm).
  • reaction product thus obtained can be used directly or, if desired, purified by chromatography or "Barry degradation” i.e. the reaction with N, N-dimethylhydrazine in acetic acid [cf. P. S. O'Colla in Methods in Carbohydrate Chemistry 5, 382-392 (1965)].
  • 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 good for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine caused by gram-negative bacteria, e.g. E. coli, Proteus, Klebsiella and Pseudomonas are suitable.
  • disaccharides according to the invention are extremely valuable intermediates for the synthesis of pseudotrisaccharides, which can be used as valuable antibiotics.
  • the use of the intermediates according to the invention opens up a new, advantageous way of producing the known antibiotics 66-40 B and 66-40 D, which up to now have only been formed in the fermentative preparation of sisomicin to about 2% each (DT-OS 2437 160).
  • N-protected pseudodisaccharides are obtained (see e.g. formula VI), which can be converted into semisynthetic aminotrisaccharides according to the known glycosidation reactions.
  • the brown-yellow solution is diluted onto acidic ion exchanger (R) Amberlite IRC 50, HForm.
  • R acidic ion exchanger
  • the product is eluted from the thoroughly neutral washed ion exchanger with 2 N ammonia.
  • the eluate is evaporated to dryness in a high vacuum. An amorphous, colorless solid is obtained.
  • the product obtained according to Example 1 is in 7 ml of methanol / water 5: 2 with 0.85 ml of carbo benzoxychloride and 0.3 g Na 2 CP 3 stirred overnight. The mixture is diluted with water until all salts are dissolved and filtered. The residue is washed with water, methanol and petroleum ether, stirred in as little CHCI 3 as possible and filtered again. The white residue is washed with a little CHCI 3 and reprecipitated from pyridine with methanol.
  • the filtrate is treated with a strongly basic ion exchanger (Amberlite IRA 400) and concentrated to the syrup.
  • the brown-yellow solution is diluted with water, neutralized with Na 2 C0 3 and evaporated to dryness in a high vacuum.
  • the residue is stirred with CHCI 3 and shaken out with water.
  • the aqueous phase is separated off.
  • the organic phase is dried over MgS0 4 and concentrated.

Description

Die Erfindung betrifft neue Pseudodisaccharide und Verfahren zu ihrer Herstellung. Die neuen Verbindungen können als Arzneimittel sowie als Zwischenprodukte bei der Synthese von Pseudotrisacchariden Verwendung finden.The invention relates to new pseudodisaccharides and processes for their preparation. The new compounds can be used as pharmaceuticals and as intermediates in the synthesis of pseudotrisaccharides.

Die neuen Pseudodisaccharide lassen sich durch die nachstehende Formel (1) wiedergeben

Figure imgb0001
in der

  • Y für einen Rest
Figure imgb0002
Figure imgb0003
steht und
  • (a) falls Y einen Rest
    Figure imgb0004
    darstellt, X für einen Rest
    Figure imgb0005
    steht,
  • b) falls Y einen anderen Rest darstellt, X für den Rest
    Figure imgb0006
    steht, oder
  • c) für den Fall, daß Y für den Rest
    Figure imgb0007
    steht, X auch die Reste
    Figure imgb0008
    bezeichnen kann, wobei X jeweils (1-4)-glykosidisch mit Y verbunden ist, und wobei
    die Reste R gleich sind und für Wasserstoff oder
    Figure imgb0009
    stehen sowie deren physiologisch unbedenkliche Säureadditionssalze, wobei Säureadditionssalze der Verbindungen
    Figure imgb0010
    Figure imgb0011
    Figure imgb0012
    ausgenommen sind.
  • Ein besonders wertvolles Pseudodisaccharid ist die Verbindung der Formel (11)
    Figure imgb0013
The new pseudodisaccharides can be represented by the following formula (1)
Figure imgb0001
 in the
  • Y for a rest
Figure imgb0002
Figure imgb0003
 stands and
  • (a) if Y is a remainder
    Figure imgb0004
     represents X for a remainder
    Figure imgb0005
     stands,
  • b) if Y represents another radical, X for the rest
    Figure imgb0006
     stands, or
  • c) in the event that Y for the rest
    Figure imgb0007
     stands, X also the remnants
    Figure imgb0008
     can denote where X is in each case (1-4) -glycosidically linked to Y, and wherein
    the radicals R are the same and represent hydrogen or
    Figure imgb0009
     stand as well as their physiologically acceptable acid addition salts, with acid addition salts of the compounds
    Figure imgb0010
    Figure imgb0011
    Figure imgb0012
     with exception of.
  • A particularly valuable pseudodisaccharide is the compound of the formula (11)
    Figure imgb0013

Als Säureadditionssalze seien beispielhaft jene der Pseudodisaccharide mit Chlorwasserstoff-, Schwefel-, Phosphor-, Salpeter-, Bromwasserstoff-, Benzolsulfon-, Ameisen-, Essig-, Propion-, Malein-, Ascorbin- oder Zitronensäure genannt.Examples of acid addition salts are those of the pseudodisaccharides with hydrochloric, sulfuric, phosphoric, nitric, hydrogen bromide, benzenesulfonic, formic, acetic, propionic, maleic, ascorbic or citric acid.

Die Erfindung betrifft weiterhin ein Verfahren zur Darstellung von Verbindungen der Formel (1),. welches dadurch gekennzeichnet ist, daß man Verbindungen der Formel

Figure imgb0014
in der X und Y die oben genannte Bedeutung haben, wobei der Rest Y in 4-Stellung glykosidisch mit X und in 6-Stellung glykosidisch mit dem Garosaminylrest verknüpft ist,
gegebenenfalls in Form N-geschützter Derivate, durch Behandlung mit einem Oxydationsmittel bei Temperaturen von -20 bis 100°C und einem pH-Wert zwischen 3 und 12 spaltet, gegebenenfalls vorhandene Schutzgruppen entfernt und die Produkte in freier Form oder bei der Anwesenheit von Säure in Form ihrer Säureadditionssalze isoliert.The invention further relates to a process for the preparation of compounds of formula (1) . which is characterized in that compounds of the formula
Figure imgb0014
 in which X and Y have the meaning given above, where the radical Y is linked in the 4-position glycosidically to X and in the 6-position glycosidically to the garosaminyl radical,
optionally in the form of N-protected derivatives, cleaved by treatment with an oxidizing agent at temperatures from -20 to 100 ° C and a pH between 3 and 12, any protective groups present are removed and the products in free form or in the presence of acid Form of their acid addition salts isolated.

Die Ausgangsverbindungen der Formel (III) sind literatur-bekannte Pseudotrisaccharide wie die Antibiotika Verdamicin, Sisomicin, G 52, Mutamicin 1, Mutamicin 2, Mutamicin 4, Mutamicin 5 und Mutamicin 6 (siehe DT-OS 2 437 160).The starting compounds of the formula (III) are pseudotrisaccharides known from the literature, such as the antibiotics verdamicin, sisomicin, G 52, mutamicin 1, mutamicin 2, mutamicin 4, mutamicin 5 and mutamicin 6 (see DT-OS 2 437 160).

Kennzeichnend für die erfindungsgemäßen Pseudodisaccharide ist, daß sich die Doppelbindung in Vinylstellung zum Ringsauerstoff befindet. Aus der Literatur (Bull. Chem. Soc. Jap. 1973, 46, Seite 3508) ist bereits ein strukturell ähnliches Pseudodisaccharid bekannt, bei welchem allerdings die Doppelbindung in Allylstellung zum Ringsauerstoff steht. Aufgrund des völlig andersartigen Verhaltens von Allyl- und Vinylverbindungen waren die erfindungsgemäßen Pseudodisaccharide hierdurch nicht nahegelegt. Darüberhinaus wird die bekannte Verbindung erzeugt durch synthetische Einführung der Doppelbindung zwischen den C-Atomen 3 und 4 in einem Neaminderivat, d. h. einem gesättigten Pseudodisaccharid. Bei Kenntnis der Lehre der genannten Literaturstelle bestand für den Fachmann weder die Veranlassung noch die Möglichkeit, ausgehend von einem derartigen Neaminderivat eine Doppelbindung in der 4,5-Stellung einzuführen. Das erfindungsgemäße Verfahren weist somit erstmals einen Weg, auf welchem 4,5-ungesättigte Pseudodisaccharide überhaupt hergestellt werden können. Die erfindungsgemäßen Pseudodisaccharide weisen als solche bereits gute antibiotische Eigenschaften auf und sind hierin bekannten Verbindungen (beispielsweise dem Neamin der FR-A 2 232 326) überlegen. Sie können jedoch, wie unten näher ausgeführt wird, auch als Ausgangsmaterial für die Herstellung wertvoller neuer und bekannter Pseudotrisaccharide dienen.It is characteristic of the pseudodisaccharides according to the invention that the double bond is in the vinyl position relative to the ring oxygen. A structurally similar pseudodisaccharide is already known from the literature (Bull. Chem. Soc. Jap. 1973, 46, page 3508), but in which the double bond is in the allyl position relative to the ring oxygen. Because of the completely different behavior of allyl and vinyl compounds, the pseudodisaccharides according to the invention were not suggested by this. In addition, the known compound is produced by synthetic introduction of the double bond between the C atoms 3 and 4 in a neamine derivative, ie a saturated pseudodisaccharide. With knowledge of the teaching of the cited literature reference, there was neither the cause nor the possibility for the person skilled in the art to introduce a double bond in the 4,5-position starting from such a neamine derivative. The method according to the invention thus shows for the first time a way in which 4,5-unsaturated pseudodisaccharides can be produced at all. As such, the pseudodisaccharides according to the invention already have good antibiotic properties and are compounds known here (for example the neamine of FR-A 2 232 326). However, as explained in more detail below, they can also serve as starting material for the production of valuable new and known pseudotrisaccharides.

In einigen Fällen empfiehlt es sich, bei der Darstellung der erfindungsgemäßen Pseudodisaccharide von selektiv N-blockierten Derivaten von Verbindungen der Formel (III) auszugehen.In some cases it is advisable to start with the pseudodisaccharides according to the invention from selectively N-blocked derivatives of compounds of the formula (III).

Die Art der Blockierung sollte so beschaffen sein, daß alle im Molekül vorhandenen Amino- oder Methylaminogruppen, mit Ausnahme der im abzuspaltenden Garosaminylrest vorhandenen Methylaminogruppe, blockiert sind.The type of blocking should be such that all amino or methylamino groups present in the molecule, with the exception of the methylamino group present in the cleavage of the garosaminyl group, are blocked.

Bei den solcherart geschützten Verbindungen handelt es sich demnach um 1,2', 3,6'-Tetra-N-blockierte bzw. im Falle von Mutamicin 5 um 1,2', 3,5,6'-Penta-N-blockierte Derivate der Aminotrisaccharide gemäß Formel (III).The compounds protected in this way are therefore 1,2 ', 3,6'-tetra-N-blocked or, in the case of mutamicin 5, 1,2', 3,5,6'-penta-N-blocked Derivatives of the aminotrisaccharides according to formula (III).

Als Aminoschutzgruppen können alle unter den Oxidationsbedingungen des oben geschilderten Verfahrens stabilen, im Bereich der Aminozucker- und der Peptidchemie üblichen Schutzgruppen verwendet werden. Solche Schutzgruppen und die Verfahren zu ihrer Herstellung sind bekannt (s. z.B. Houben-Weyl, Methoden der organischen Chemie, Bd. XV, 1, Georg Thieme Verlag, Stuttgart, 1974).Amino protective groups 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, Vol. XV, 1, Georg Thieme Verlag, Stuttgart, 1974).

Bevorzugt werden in die Oxidationsreaktion solche N-geschützten Derivate der Aminotrisaccharide gemäß Formel (III) eingesetzt, die Acylschutzgruppen vom Typ

Figure imgb0015
wobei die Bedeutung von A den Formeln (1) und (2) zu entnehmen ist-
Figure imgb0016
oder
Figure imgb0017
enthalten, wobei in den genannten Schutzgruppenresten
B und D unabhängig voneinander für Wasserstoff, Phenyl oder substituiertes Phenyl stehen und n, n1, n2, n3 unabhängig voneinander eine Zahl von 0 bis 5 bezeichnen.Those N-protected derivatives of the aminotrisaccharides of the formula (III) which are acyl protective groups of the type are preferably used in the oxidation reaction
Figure imgb0015
 the meaning of A can be found in the formulas (1) and (2) -
Figure imgb0016
 or
Figure imgb0017
 included, in the protective group residues mentioned
B and D independently of one another represent hydrogen, phenyl or substituted phenyl and n, n 1 , n 2 , n 3 independently denote a number from 0 to 5.

Zur Herstellung dieser selektiv geschützten Aminotrisaccharide setzt man nach einem neuen Verfahren (veröffentlichte europäische Patentanmeldung Nr. 0000057) ein Aminotrisaccharid gemäß Formel (111) mit einer Verbindung der Formel (IV)

Figure imgb0018
in der

  • A für einen Rest der Formeln (1) oder (2) steht und
  • G' Halogen oder eine bei Acylierungsreaktionen gebräuchliche Abgangsgruppe, vorzugsweise eine aktivierenden Ester, oder eine Gruppe -O-CO-A mit der obigen Bedeutung von A bezeichnet, in einem inerten Lösungsmittel gegebenenfalls unter Zusatz von Wasser bei Temperaturen zwischen etwa -80°C und etwa +50°C in Gegenwart einer Base um und arbeitet das Reaktionsprodukt in üblicher Weise auf.
To produce these selectively protected aminotrisaccharides, an aminotrisaccharide according to formula (111) with a compound of formula (IV) is used according to a new process (published European patent application No. 0000057)
Figure imgb0018
 in the
  • A represents a radical of the formulas (1) or (2) and
  • G 'halogen or a leaving group customary in acylation reactions, preferably an activating ester, or a group -O-CO-A with the above meaning of A, in an inert solvent, if appropriate with the addition of water at temperatures between about -80 ° C. and about + 50 ° C in the presence of a base and works up the reaction product in the usual manner.

Zur Spaltung der Verbindungen gemäß Formel (III) bzw. deren N-blockierten Derivaten können übliche Oxidationsmittel verwendet werden.Conventional oxidizing agents can be used to cleave the compounds of the formula (III) or their N-blocked derivatives.

Beispiele für derartige Oxidationsmittel, die im erfindungsgemäß einzuhaltenden pH-Bereich zwischen 3 und 12 eingesetzt werden können, sind Schwermetallsalze, Peroxide, Halogene, Salze von Halogensauerstoffsäuren, Stickstoffoxide sowie molekularer Sauerstoff. Bevorzugte Oxidationsmittel sind Permanganate, Manganate, Mangandioxid, Chromtrioxid, Bichromate, Chromate, Alkylchromate, Chromylchlorid, Selendioxid, Kobalt (III)-Salze, Cer (lV)-Salze, Kaliumhexacyanoferrat (III), Kupferoxid, Bleioxid, Quecksilberoxid, Gemische von Wasserstoffperoxid mit Eisen (II)-Salzen, Eisen (III)-Salze, Selendioxid, Osmiumtetraoxid, Vanadate, Bleitetraacetat, Chlor, Brom, Jod, Hypochlorite, Chlorate, Hypobromite, 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.Examples of such oxidizing agents that can be used in the pH range between 3 and 12 to be maintained according to the invention are heavy metal salts, peroxides, halogens, salts of halogen oxygen acids, 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 tetraoxide, vanadate, lead tetraacetate, chlorine, bromine, iodine, hypochlorite, chlorate, hypobromite, bromate, periodate, 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.

Besonders bevorzugte Oxidationsmittel sind Mangandioxid, Natriumperjodat, Kaliumhexacyanoferrat (III) und Kaliumpermanganat.Particularly preferred oxidizing agents are manganese dioxide, sodium periodate, potassium hexacyanoferrate (III) and potassium permanganate.

Die Spaltungsreaktion wird vorzugsweise in Gegenwart eines unter den Reaktionsbedingungen inerten Verdünnungsmittels, bevorzugt eines solchen, in dem sich die Reaktionsteilnehmer lösen, durchgeführt. Geeignete Verdünnungsmittel der genannten Art sind Methanol, Ethanol, i-Propanol, Tetrahydrofuran, Dimethylformamid, Dioxan, Pyridin und Ethylenglykoldimethylether, Aceton und Essigsäure sowie Wasser oder Gemische von Wasser mit den genannten organischen Lösungsmitteln.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 methanol, ethanol, i-propanol, tetrahydrofuran, dimethylformamide, dioxane, pyridine and ethylene glycol dimethyl ether, acetone and acetic acid, and water or mixtures of water with the organic solvents mentioned.

Die erfindungsgemäße Umsetzung wird je nach Art des verwendeten Oxidationsmittels bei einem pH-Wert von 3 bis 12 durchgeführt. Die Einstellung des pH-Wertes kann durch Zusatz einer entsprechenden Säure oder Base erreicht werden. Dabei sind solche Säuren oder Basen zu verwenden, die die Ausgangsverbindungen oder die Endprodukte nicht zersetzen und keine Aktivitätsverringerung der Oxidationsmittel hervorrufen. Vielmehr ist es wünschenswert, daß sie die Aktivität der Oxidationsmittel erhöhen. Als anorganische Säuren können beispielsweise Salzsäure oder Schwefelsäure und als organische Säuren beispielsweise Essigsäure oder Ameisensäure verwendet werden. Beispiele für entsprechende Basen sind Ammoniumhydroxid, Alkalimetallhydroxide, Erdalkalimetallhydroxide, Alkalimetallcarbonate, Erdalkalimetallcarbonate, Alkalimetallalkoholate und Alkali- und Erdalkalimetallsalze von Carbonsäuren.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 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.

Die erfindungsgemäße Umsetzung wird bei Temperaturen von etwa -20 bis etwa 100°C, vorzugsweise von etwa 0 bis etwa 70°C. Die Reaktionsdauer beträgt eine halbe Stunde bis 50 Stunden. Im allgemeinen wird die Umsetzung bei Normaldruck ausgeführt.The reaction according to the invention is carried out at temperatures from about -20 to about 100 ° C., preferably from about 0 to about 70 ° C. The reaction time is half an hour to 50 hours. In general, the reaction is carried out at normal pressure.

Die Abspaltung der nach der Reaktion im Molekül gegebenenfalls noch vorhandenen Schutzgruppen gelingt im bekannter Weise durch alkalische oder saure Hydrolyse, selektive Hydrogenolyse oder Verdrängungsreaktionen. Setzt man zur Spaltung Verbindungen ein, die Acylschutzgruppen vom Typ (1) oder (2) enthalten, so können diese vorzugsweise mit wäßrigen Laugen von Alkali- oder Erdalkalihydroxiden gespalten werden.The protective groups which may still be present in the molecule after the reaction are split off in a known manner by alkaline or acidic hydrolysis, selective 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 with aqueous alkalis of alkali metal or alkaline earth metal hydroxides.

Verwendet man z.B. 1,2', 3,6'-Tetra-N-ethyloxycarbonylsicomicin und Natriumperjodat als Ausgangsstoffe, so kann der Reaktionsverlauf durch das folgende Schema wiedergegeben werden:

Figure imgb0019
If, for example, 1,2 ', 3,6'-tetra-N-ethyloxycarbonylsicomicin and sodium periodate are used as starting materials, the course of the reaction can be represented by the following scheme:
Figure imgb0019

Die erfindungsgemäß verwendbare Ausgangsverbindung V ist gemäß dem in der veröffentlichten europäischen Patentanmeldung 0000057 beschriebenen Verfahren durch Umsetzung von Sisomicin mit Pyrokohlensäurediethylester in wäßrigem Alkohol zugänglich. Die oxidative Abspaltung von (V) kann im Prinzip mit den vorstehend genannten Oxidationsmitteln durchgeführt werden; zu bevorzugen ist im vorliegenden Falle jedoch die Verwendung von Natriumperjodat, das in Form einer wäßrigen Lösung eingesetzt wird. Als Lösungsmittel für die Spaltungsreaktion eignet sich im vorliegenden Falle insbesondere Methanol oder ein Methanol-Wasser-Gemisch. Man arbeitet vorteilhafterweise mit einem Zusatz von 5-10% konzentriertem Ammoniumhydroxid. Die bevorzugte Reaktionstemperatur beträgt -5° bis +5°C. Die Weiterverarbeitung erfolgt durch Eindampfen des Reaktionsgemisches in Vakuum, Extrahieren des Rückstandes mit Ethanol und Entionisieren der Extrakte mit basischem lonenaustauscherharz (OHQFOrm).The starting compound V which can be used according to the invention can be obtained in accordance with the process described in published European patent application 0000057 by reacting sisomicin with diethyl pyrocarbonate in aqueous alcohol. The oxidative cleavage of (V) can in principle be carried out using the oxidizing agents mentioned above; In the present case, however, preference is given to using sodium periodate, which is used in the form of an aqueous solution. A suitable solvent for the cleavage reaction in the present case especially methanol or a methanol-water mixture. It is advantageous to work with the addition of 5-10% concentrated ammonium hydroxide. The preferred reaction temperature is -5 ° to + 5 ° C. Further processing takes place by evaporating the reaction mixture in vacuo, extracting the residue with ethanol and deionizing the extracts with basic ion exchange resin (OH Q F O rm).

Das so erhaltene Reaktionsprodukt kann direkt verwendet oder gewünschtenfalls durch Chromatographie gereinigt oder dem "Barry-Abbau", d.h. der Umsetzung mit N,N-Dimethylhydrazin in Essigsäure [vgl. P. S. O'Colla in Methods in Carbohydrate Chemistry 5, 382-392 (1965)] zugeführt werden.The reaction product thus obtained can be used directly or, if desired, purified by chromatography or "Barry degradation" i.e. the reaction with N, N-dimethylhydrazine in acetic acid [cf. P. S. O'Colla in Methods in Carbohydrate Chemistry 5, 382-392 (1965)].

Die Tetra-N-ethyloxycarbonylverbindung der Formel (Vl) wird nach der Aufarbeitung als kristallines Produkt in hoher Ausbeute gewonnen. Die Abspaltung der Schutzgruppen in wäßriger alkalischer Lösung liefert das bisher unbekannte Disaccharid der Formel (VII)

Figure imgb0020
After working up, the tetra-N-ethyloxycarbonyl compound of the formula (VI) is obtained as a crystalline product in high yield. The removal of the protective groups in aqueous alkaline solution provides the hitherto unknown disaccharide of the formula (VII)
Figure imgb0020

Die erfindungsgemäßen Verbindungen sind antimikrobielle Mittel mit einem breiten Wirkungsspektrum und besonderer Wirksamkeit gegen gram-negative Bakterien. Diese Eigenschaften ermöglichen ihre Verwendung als Arzneimittel bei der Bekämpfung von bakteriellen Erkrankungen bei Mensch und Tier. Sie sind gut zur Prophylaxe und Chemotherapie von lokalen und systemischen Infektionen in der Human- und Tiermedizin die durch gram-negative Bakterien, z.B. E. coli, Proteus, Klebsiella und Pseudomonas verursacht werden, geeignet.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 good for the prophylaxis and chemotherapy of local and systemic infections in human and veterinary medicine caused by gram-negative bacteria, e.g. E. coli, Proteus, Klebsiella and Pseudomonas are suitable.

Des weiteren handelt es sich bei den erfindungsgemäßen Disacchariden um äußerst wertvolle Zwischenprodukte für die Synthese von Pseudotrisacchariden, die als wertvolle Antibiotika Verwendung finden können.Furthermore, the disaccharides according to the invention are extremely valuable intermediates for the synthesis of pseudotrisaccharides, which can be used as valuable antibiotics.

So eröffnet sich durch die Verwendung der erfindungsgemäßen Zwischenprodukte ein neuer, vorteilhafter Weg zur Herstellung der bekannten Antibiotika 66-40 B und 66-40 D, die bisher lediglich bei der fermentativen Darstellung von Sisomicin zu jeweils etwa 2% gebildet wurden (DT-OS 2437 160).Thus, the use of the intermediates according to the invention opens up a new, advantageous way of producing the known antibiotics 66-40 B and 66-40 D, which up to now have only been formed in the fermentative preparation of sisomicin to about 2% each (DT-OS 2437 160).

Hierbei kann man das bei der oxidativen Spaltung von z.B. Tetra-N-acylsisomicinen gebildete Tetra-N-acyldisaccharid, das noch zwei freie Hydroxylgruppen besitzt im Zuge einer Glykosidierungsreaktion nach den in der Kohlenhydratchemie bekannten Methoden mit einem reaktiven Monosaccharidderivat wie z.B. einem entsprechend geschütztem Glykosylhalogenid der 3-Desoxy-3-methyl- amino-L-arabinopyranose umsetzen, wobei die glykosidische Verknüpfung erwartungsgemäß an de Hydroxylgruppe an C-6 eintritt. [S. Umezawa, Advan. Carbohydr. Chem. 30, 111 (1974)].This can be done in the oxidative cleavage of e.g. Tetra-N-acylsisomicins formed tetra-N-acyldisaccharide, which still has two free hydroxyl groups in the course of a glycosidation reaction according to the methods known in carbohydrate chemistry with a reactive monosaccharide derivative such as e.g. implement an appropriately protected glycosyl halide of 3-deoxy-3-methylamino-L-arabinopyranose, the glycosidic linkage occurring as expected at the hydroxyl group at C-6. [P. Umezawa, Advan. Carbohydr. Chem. 30, 111 (1974)].

Die anschließende Entblockierung der Glykosidierungsprodukte nach bekannten Methoden liefert das gewünschte Pseudotrisaccharid.The subsequent unblocking of the glycosidation products by known methods provides the desired pseudotrisaccharide.

Im Falle der Verwendung von partiell blockierten Aminotrisacchariden für die Oxidationsreaktion erhält man N-geschützte Pseudodisaccharide (siehe z.B. Formel VI), die sich nach den bekannten Glykosidierungsreaktionen in semisynthetische Aminotrisaccharide überführen lassen.If partially blocked aminotrisaccharides are used for the oxidation reaction, N-protected pseudodisaccharides are obtained (see e.g. formula VI), which can be converted into semisynthetic aminotrisaccharides according to the known glycosidation reactions.

Beispiel 1example 1 4-O-(2,6-Diamino-2,3,4,6-tetradesoxy-a-D-glycero-hex-4-enopyranosyl)-2-desoxystreptamin4-O- (2,6-diamino-2,3,4,6-tetradesoxy-a-D-glycero-hex-4-enopyranosyl) -2-deoxystreptamine

2 g (4,47 mmol) Sisomicin in 20 ml Wasser werden bei 0°C langsam mit einer Lösung von 2,88 g (13,4 mMol) NaJ04 in 40 ml Wasser unter Rühren versetzt. Nach 2 Stunden wird im Hochvakuum zur Trockne eingedampft. Der Rückstand wird mit Ethanol aufgerührt und nach 15 Minuten filtriert.2 g (4.47 mmol) of sisomicin in 20 ml of water are slowly added at 0 ° C with a solution of 2.88 g (13.4 mmol) of NaJ0 4 in 40 ml of water with stirring. After 2 hours, the mixture is evaporated to dryness in a high vacuum. The residue is stirred with ethanol and filtered after 15 minutes.

Das Filtrat wird zum Sirup eingeengt, in 40 ml Wasser aufgenommen, mit 2,4 ml = 1,9 g (32 mMoi) N,N-Dimethylhydrazin versetzt, mit Essigsäure auf pH 6 eingestellt und bei 40°C über Nacht gelagert. Die braungelbe Lösung wird verdünnt auf sauren lonenaustauscher (R) Amberlite IRC 50, HForm gegeben. Aus dem gründlich neutral gewaschenen Ionenaustauscher wird das Produkt mit 2 N Ammoniak eluiert. Das Eluat wird am Hochvakuum zur Trockne eingedampft. Man erhält einen amorphen, farblosen Feststoff.The filtrate is concentrated to the syrup, taken up in 40 ml of water, mixed with 2.4 ml = 1.9 g (32 mMO) of N, N-dimethylhydrazine, adjusted to pH 6 with acetic acid and stored at 40 ° C. overnight. The brown-yellow solution is diluted onto acidic ion exchanger (R) Amberlite IRC 50, HForm. The product is eluted from the thoroughly neutral washed ion exchanger with 2 N ammonia. The eluate is evaporated to dryness in a high vacuum. An amorphous, colorless solid is obtained.

Beispiel 2Example 2 4-O-(2,6-Di-benzyloxycarbonylamino-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl)-1,3-di-N-benzyloxycarbonyl-2-desoxystreptamin4-O- (2,6-di-benzyloxycarbonylamino-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl) -1,3-di-N-benzyloxycarbonyl-2-deoxystreptamine

Das nach Beispiel 1 erhaltene Produkt wird in 7 ml Methanol/Wasser 5:2 mit 0,85 ml Carbobenzoxychlorid und 0,3 g Na2CP3 über Nacht gerührt. Das Gemisch wird mit Wasser verdünnt, bis alle Salze gelöst sind und filtriert. Der Rückstand wird mit Wasser, Methanol und Petroläther gewaschen, in möglichst wenig CHCI3 aufgerührt und erneut filtriert. Der weiße Rückstand wird mit wenig CHCI3 gewaschen und aus Pyridin mit Methanol umgefällt.The product obtained according to Example 1 is in 7 ml of methanol / water 5: 2 with 0.85 ml of carbo benzoxychloride and 0.3 g Na 2 CP 3 stirred overnight. The mixture is diluted with water until all salts are dissolved and filtered. The residue is washed with water, methanol and petroleum ether, stirred in as little CHCI 3 as possible and filtered again. The white residue is washed with a little CHCI 3 and reprecipitated from pyridine with methanol.

Schmp. = 244-246,5°C

Figure imgb0021
(c = 1,0 Pyridin)
Figure imgb0022
 Mp = 244-246.5 ° C
Figure imgb0021
 (c = 1.0 pyridine)
Figure imgb0022

Beispiel 3Example 3 4-0-(2,6-Di-ethyloxycarbonylamino-2,3,4,6-tetradesoxy-a-D-glycero-hex-4-enopyranosyl)-1,3-di-N-ethyloxycarbonyl-2-desoxystreptamin4-0- (2,6-di-ethyloxycarbonylamino-2,3,4,6-tetradesoxy-a-D-glycero-hex-4-enopyranosyl) -1,3-di-N-ethyloxycarbonyl-2-deoxystreptamine

Zu einer Lösung von 950 mg (1,3 mMol) Tetra-N-ethyloxycarbonyl-sisomicin in 15 ml Methanol und 1 ml konz. Ammoniumhydroxid werden unter Rühren bei 0°C langsam 0,83 g (3,9 mMol) NaJ04 in 10 ml Wasser getropft. Nach Entfernung der Kühlung wird eine Stunde bei Raumtemperatur gerührt und anschließend am Hochvakuum zur Trockne eingedampft. Der Rückstand wird in 30 ml Methanol aufgerührt, mit 30 ml Ethanol versetzt, 15 Minuten gerührt und filtriert. Der Rückstand wird mit Ethanol gewaschen. Das Filtrat wird mit stark basischen Ionenaustauscher (Amberlite IRA 400) behandelt und zum Sirup eingeengt. Der Sirup wird mit 40 ml Methanol aufgenommen, mit 0,89 ml = 0,7 g (11,6 mM) N,N-Dimethylhydrazin versetzt, mit Essigsäure auf pH 6,5 eingestellt und bei 40°C über Nacht gelagert. Die braungelbe Lösung wird mit Wasser verdünnt, mit Na2C03 neutralisiert und im Hochvakuum zur Trockne eingedampft. Der Rückstand wird mit CHCI3 aufgerührt und mit Wasser ausgeschüttelt. Die wäßrige Phase wird abgetrennt. Die organische Phase wird über MgS04 getrocknet und eingeengt. Der Rückstand wird in weniger Methanol aufgenommen, mit Ether verdünnt und nach Zugabe von Petrolether in der Tiefkühlung gelagert. Es ergeben sich 370 mg, in einer zweiten Abscheidung 150 mg Tetra-N-carboethoxy-sisomicin als schwach gelbes Pulver. Ausbeute 530 mg (71%). Zur Charakterisierung wird aus Methanol/Ether mit Petrolether umgefällt. (Dünnschichtchromatographie: Toluol, Triethylamin, Methanol 10:3:1)To a solution of 950 mg (1.3 mmol) of tetra-N-ethyloxycarbonyl-sisomicin in 15 ml of methanol and 1 ml of conc. Ammonium hydroxide are slowly added dropwise 0.83 g (3.9 mmol) NaJ0 4 in 10 ml water with stirring at 0 ° C. After removal of the cooling, the mixture is stirred for one hour at room temperature and then evaporated to dryness in a high vacuum. The residue is stirred in 30 ml of methanol, mixed with 30 ml of ethanol, stirred for 15 minutes and filtered. The residue is washed with ethanol. The filtrate is treated with a strongly basic ion exchanger (Amberlite IRA 400) and concentrated to the syrup. The syrup is taken up in 40 ml of methanol, mixed with 0.89 ml = 0.7 g (11.6 mM) of N, N-dimethylhydrazine, adjusted to pH 6.5 with acetic acid and stored at 40 ° C. overnight. The brown-yellow solution is diluted with water, neutralized with Na 2 C0 3 and evaporated to dryness in a high vacuum. The residue is stirred with CHCI 3 and shaken out with water. The aqueous phase is separated off. The organic phase is dried over MgS0 4 and concentrated. The residue is taken up in less methanol, diluted with ether and, after the addition of petroleum ether, stored in the freezer. The result is 370 mg, in a second separation 150 mg of tetra-N-carboethoxy-sisomicin as a pale yellow powder. Yield 530 mg (71%). For characterization, methanol / ether is reprecipitated with petroleum ether. (Thin layer chromatography: toluene, triethylamine, methanol 10: 3: 1)

Figure imgb0023
(c = 1,0 CH30H) Fp 213,5-215,0°C
Figure imgb0024
Figure imgb0023
 (c = 1.0 CH 3 0H) mp 213.5-215.0 ° C
Figure imgb0024

Beispiel 4Example 4 4-O-(2,6-Di-acetamido-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl)-1,3-di-N-acetyl-2- desoxystreptamin4-O- (2,6-di-acetamido-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl) -1,3-di-N-acetyl-2-deoxystreptamine

1,9 g 1,2',3,6'-Tetra-N-acetylsisomicin in 20 ml Wasser werden bei 60°C zu einer Lösung von 3 g Kaliumhexacyanoferrat-(III) und 900 mg Kaliumhydroxid in 20 ml Wasser getropft. Anschließend tropft man eine Lösung von 9 g Kaliumhexacyanoferrat-(III) und 1 g Kaliumhydroxid in 90 ml Wasser innerhalb 1,5 Stunden dazu. Nach beendeter Zugabe wird mit 250 ml Aceton versetzt, vom ausgefallenen anorganischen Material abfiltriert und das Filtrat im Vakuum von Lösungsmittel befreit. Der so erhaltene Rückstand wird mit 10 ml einer aus gleichen Teilen bestehenden Mischung aus Methylenchlorid und Methanol extrahiert, die Extrakte filtriert und in Vakuum eingedampft. Man erhält so 1,1 g der Titelverbindung, die zur Reinigung aus Ethanol/Ether kristallisiert wird.1.9 g of 1,2 ', 3,6'-tetra-N-acetylsisomicin in 20 ml of water are added dropwise at 60 ° C. to a solution of 3 g of potassium hexacyanoferrate (III) and 900 mg of potassium hydroxide in 20 ml of water. A solution of 9 g of potassium hexacyanoferrate (III) and 1 g of potassium hydroxide in 90 ml of water is then added dropwise over the course of 1.5 hours. After the addition has ended, 250 ml of acetone are added, the precipitated inorganic material is filtered off and the filtrate is freed from solvent in vacuo. The residue thus obtained is extracted with 10 ml of a mixture of methylene chloride and methanol consisting of equal parts, the extracts filtered and evaporated in vacuo. This gives 1.1 g of the title compound, which is crystallized from ethanol / ether for purification.

Figure imgb0025
(c = 1,0 CH3OH) Fp 238,5-242,0°C
Figure imgb0026
Figure imgb0025
 (c = 1.0 CH 3 OH) mp 238.5-242.0 ° C
Figure imgb0026

Beispiel 5Example 5 4-O-(2,6-Diamino-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl)-2-desoxystrcptamin aus 4-O-(2,6-Di-acetamido-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranoxyl)-1,3-di-N-acetyl-2- desoxystreptamin n4-O- (2,6-diamino-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl) -2-deoxystrcptamine from 4-O- (2,6-di-acetamido -2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranoxyl) -1,3-di-N-acetyl-2-deoxystreptamine n

410 mg 4-O-(2,6-Di-acetamido-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl)-1,3-di-N-acetyl-2-desoxystreptamin und 5 g Ba(OH)2 x 8H20 werden in 5 ml Wasser 6 Stunden bei einer Ölbadtemperatur von 110-120°C unter Rühren erhitzt. Dann wird mit Wasser verdünnt, durch Zugabe von festem Kohlendioxid neutralisiert und durch eine Glasfritte filtriert. Der Rückstand wird mit Wasser gewaschen. Das Filtrat wird auf ca. 40 ml eingeengt, mit 2 N H2S04 auf pH 6 eingestellt, filtriert und zur Trockne eingedampft. Der Rückstand wird in wenig Methanoi/Wasser aufgenommen, filtriert und getrocknet. Ausbeute 421 mg (97%) amorpher Feststoff als Sulfat.410 mg of 4-O- (2,6-di-acetamido-2,3,4,6-tetradesoxy-α-D-glycero-hex-4-enopyranosyl) -1,3-di-N-acetyl-2- deoxystreptamine and 5 g Ba (OH) 2 x 8H 2 0 are heated in 5 ml water for 6 hours at an oil bath temperature of 110-120 ° C with stirring. Then it is diluted with water, neutralized by adding solid carbon dioxide and filtered through a glass frit. The residue is washed with water. The filtrate is concentrated to about 40 ml, adjusted to pH 6 with 2 NH 2 S0 4 , filtered and evaporated to dryness. The residue is taken up in a little methanoi / water, filtered and dried. Yield 421 mg (97%) amorphous solid as sulfate.

Claims (9)

1. Compounds of the formula (I)
Figure imgb0061
in which
Y represents a radical
Figure imgb0062
Figure imgb0063
and
a) if Y represents a radical
Figure imgb0064
X represents a radical
Figure imgb0065
b) if Y represents another radical, X represents the radical
Figure imgb0066
c) in the case where Y represents the radical
Figure imgb0067
X can also denote the radicals
Figure imgb0068
wherein the bond between X and Y is a (1→4)-glycosidic bond in each case, and wherein the radicals R are identical and represent hydrogen or
Figure imgb0069
and physiologically acceptable acid addition salts thereof, with the exception of acid addition salts of the compounds
Figure imgb0070
Figure imgb0071
Figure imgb0072
2. Compounds of the formula
Figure imgb0073
and physiologically acceptable acid addition salts thereof.
3. Compound of the formula
Figure imgb0074
4. Compounds of the formula
Figure imgb0075
5. Compound of the formula
Figure imgb0076
6. Process for the preparation of compounds of the formula (I) according to Claim 1, characterised in that compounds of the formula
Figure imgb0077
in which
X and Y have the meaning given in Claim 1, wherein the radical Y is linked glycosidically with X in the 4-position and glycosidically with the garosaminyl radical in the 6-position,

optionally in the form of N-protected derivatives, are cleaved by treatment with an oxidising agent at temperatures from -20 to 100°C and at a pH value between 3 and 12, any protective groups which may be present are removed and the products are isolated in their free form or, if an acid is present, in the form of their acid addition salts.
7. Process according to Claim 6, characterised in that the oxidation reaction is carried out in the presence of a diluent which is inert under the reaction conditions.
8. Process according to Claim 6 or 7, characterised in that heavy metal salts, peroxides, halogens, salts of hydrogen halide acids, nitrogen oxides or molecular oxygen are used as oxidising agent.
9. Process according to Claim 6 to 8, characterised in that manganese dioxide, sodium periodate, potassium hexacyanoferrate-III or potassium permanganate are used as oxidising agent.
EP78100255A 1977-07-05 1978-06-28 4-o-aminoglycosyl-1,3-diaminocyclitols and process for their preparation Expired EP0000199B1 (en)

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