DE19625524C2 - New synthetic catechol-antibiotic conjugates and medicinal products containing them - Google Patents

New synthetic catechol-antibiotic conjugates and medicinal products containing them

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Publication number
DE19625524C2
DE19625524C2 DE19625524A DE19625524A DE19625524C2 DE 19625524 C2 DE19625524 C2 DE 19625524C2 DE 19625524 A DE19625524 A DE 19625524A DE 19625524 A DE19625524 A DE 19625524A DE 19625524 C2 DE19625524 C2 DE 19625524C2
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Prior art keywords
arh
acid
ampicillin
mmol
substance
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DE19625524A
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German (de)
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DE19625524A1 (en
Inventor
Lothar Heinisch
Ute Moellmann
Matthias Schnabelrauch
Rolf Reissbrodt
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Gruenenthal GmbH
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Gruenenthal GmbH
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Priority claimed from DE19654920A external-priority patent/DE19654920A1/en
Priority to DE19654920A priority Critical patent/DE19654920A1/en
Priority to DE19625524A priority patent/DE19625524C2/en
Priority to SI9730139T priority patent/SI0907633T1/en
Priority to DE59704380T priority patent/DE59704380D1/en
Priority to CN97195765A priority patent/CN1106380C/en
Priority to HU0001746A priority patent/HUP0001746A3/en
Priority to NZ332519A priority patent/NZ332519A/en
Priority to CZ19984297A priority patent/CZ9804297A3/en
Priority to PCT/EP1997/002453 priority patent/WO1997049670A1/en
Priority to AU29542/97A priority patent/AU728669B2/en
Priority to PL97330899A priority patent/PL330899A1/en
Priority to IL12670397A priority patent/IL126703A0/en
Priority to EP97923887A priority patent/EP0907633B1/en
Priority to BR9709964A priority patent/BR9709964A/en
Priority to PT97923887T priority patent/PT907633E/en
Priority to UA99010372A priority patent/UA54437C2/en
Priority to JP10502161A priority patent/JP2000514042A/en
Priority to SK1788-98A priority patent/SK283560B6/en
Priority to ES97923887T priority patent/ES2163161T3/en
Priority to US09/202,955 priority patent/US6380181B1/en
Priority to CA002252809A priority patent/CA2252809A1/en
Priority to DK97923887T priority patent/DK0907633T3/en
Priority to AT97923887T priority patent/ATE204563T1/en
Priority to RU99101045/04A priority patent/RU2180898C2/en
Priority to KR1019980710534A priority patent/KR20000022120A/en
Priority to ARP970102549A priority patent/AR008391A1/en
Priority to PE1997000491A priority patent/PE70098A1/en
Priority to UY24596A priority patent/UY24596A1/en
Priority to CO97035121A priority patent/CO4900028A1/en
Priority to ZA9705638A priority patent/ZA975638B/en
Publication of DE19625524A1 publication Critical patent/DE19625524A1/en
Priority to NO19985858A priority patent/NO311975B1/en
Priority to HK99103611A priority patent/HK1018613A1/en
Publication of DE19625524C2 publication Critical patent/DE19625524C2/en
Application granted granted Critical
Priority to GR20010401527T priority patent/GR3036667T3/en
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Expired - Fee Related legal-status Critical Current

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    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/547—Chelates, e.g. Gd-DOTA or Zinc-amino acid chelates; Chelate-forming compounds, e.g. DOTA or ethylenediamine being covalently linked or complexed to the pharmacologically- or therapeutically-active agent
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
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    • C07C245/00—Compounds containing chains of at least two nitrogen atoms with at least one nitrogen-to-nitrogen multiple bond
    • C07C245/02—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides
    • C07C245/06—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings
    • C07C245/08—Azo compounds, i.e. compounds having the free valencies of —N=N— groups attached to different atoms, e.g. diazohydroxides with nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings with the two nitrogen atoms of azo groups bound to carbon atoms of six-membered aromatic rings, e.g. azobenzene
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    • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
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    • C07C251/74—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C251/78—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
    • C07C251/80—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description

Es ist bekannt, daß bestimmte Catecholstrukturen in na­ türlichen Siderophoren als eisenkomplexierende Struk­ turelemente eine wesentliche Rolle spielen ("Iron Transport in Microbes, Plants and Animals", Hrsg.: Win­ kelmann, G., van Helm, D., Neilands, J. B., V. Ch.-Ver­ lagsgesellschaft Weinheim, 1987), z. B. ist das Entero­ bactin, ein Siderophor bei E. coli und anderen Bakteri­ enstämmen, ein Trimeres aus N-(2,3-Dihydroxybenzoyl)- L-serin. Auch das Monomer ist als Siderophor wirksam (Hantke, K., FEMS Microbiol. Lett. 67 (1990), 5). Das N-(2,3-Dihydroxybenzoyl)glycin ist als Siderophor bei B. subtilis gefunden worden (Ito, T., Neilands, J. B., J. Amer. Chem. Soc. 80 (1958), 4645). Einige catechol­ substituierte Aminosäurederivate sind bereits synthe­ tisch hergestellt worden, z. B. das N-(2,3-Dihydroxy­ benzoyl)-L-threonin (Kanai, F. Kaneko, T., Morishima, H., Isshiki, K., Taketa. T., Takeuchi, T., Umezawa, H., J. Antibiot. 38 (1985), 39), das N2,N6-Bis-(2,3-dihy­ droxybenzoyl)-L-lysin (Corbin, J. L., Bulen, W. A., Biochemistry 8 (1969), 757; McKee, J. A., Sharma, S. K., Miller, M. J.; Bioconjugate Chem. 2 (1991) 281) und N2,N6-Bis-(2,3-dihydroxybenzoyl)-Iysyl-N6-(2,3-di­ hydroxybenzoyl)lysin (Chimiak, A., Neilands, J. B. Structure and Bonding 58, (1984), 89). Weiterhin ist bekannt, daß bei verschiedenen Bakterienstämmen be­ stimmte Glyoxylsäurebenzhydrazone, Oxanilsäurederivate u. a. als Siderophore dienen können (Reissbrodt, R., Heinisch, L., Möllmann, U., Rabsch, W., Ulbricht, H., Bio. Metals 6 (1993), 155). Einige Dihydroxybenzyliden­ aminobenzoesäuren sind bereits in der Literatur be­ schrieben, jedoch ohne Angaben einer Siderophorwirksam­ keit (Takita, H., Noda, S., Inada, K., Mukaida, Y. S., Toji, M. K., Kobayashi, H., DE 34 14 049 (1984), H. Wolf, Monatsh. Chem. 31 (1910), 903).It is known that certain catechol structures in natural siderophores play an important role as iron-complexing structural elements ("Iron Transport in Microbes, Plants and Animals", ed .: Win kelmann, G., van Helm, D., Neilands, JB, V. Ch.-Verlag Weinheim, 1987), z. B. is enterobactin, a siderophore in E. coli and other bacterial strains, a trimer of N- (2,3-dihydroxybenzoyl) - L-serine. The monomer is also effective as a siderophore (Hantke, K., FEMS Microbiol. Lett. 67 (1990), 5). The N- (2,3-dihydroxybenzoyl) glycine has been found as a siderophore in B. subtilis (Ito, T., Neilands, JB, J. Amer. Chem. Soc. 80 (1958), 4645). Some catechol substituted amino acid derivatives have already been prepared synthetically, e.g. B. N- (2,3-Dihydroxybenzoyl) -L-threonine (Kanai, F. Kaneko, T., Morishima, H., Isshiki, K., Taketa. T., Takeuchi, T., Umezawa, H ., J. Antibiot. 38 (1985), 39), the N 2 , N 6 bis (2,3-dihydroxybenzoyl) -L-lysine (Corbin, JL, Bulen, WA, Biochemistry 8 (1969), 757; McKee, JA, Sharma, SK, Miller, MJ; Bioconjugate Chem. 2 (1991) 281) and N 2 , N 6 -Bis- (2,3-dihydroxybenzoyl) -ysyl-N 6 - (2,3- di hydroxybenzoyl) lysine (Chimiak, A., Neilands, JB Structure and Bonding 58, (1984), 89). Furthermore, it is known that certain glyoxylic acid benzhydrazones, oxanilic acid derivatives and others can serve as siderophores for various bacterial strains (Reissbrodt, R., Heinisch, L., Möllmann, U., Rabsch, W., Ulbricht, H., Bio. Metals 6 (1993 ), 155). Some dihydroxybenzylidene aminobenzoic acids have already been described in the literature, but without information on a siderophore activity (Takita, H., Noda, S., Inada, K., Mukaida, YS, Toji, MK, Kobayashi, H., DE 34 14 049 (1984), H. Wolf, Monthly Chem. 31 (1910), 903).

Obwohl verschiedene Catecholverbindungen mit β-Lactamen verknüpft wurden, mit denen eine Steigerung der antibakteriellen Wirksamkeit dieser Antibiotika, be­ dingt durch eine Einschleusung über bakterielle Eisen­ transportwege in die Bakterienzelle, erzielt wurde, (z. B. Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, R. L., Antimicrob. Agents Chemo­ ther. 35 (1991), 653) besteht ein großer Bedarf nach weiteren neuen synthetischen Siderophor-Antibiotika-Konjugaten mit verbes­ serten pharmakologischen und pharmakokinetischen Eigen­ schaften.Although different catechol compounds with β-lactams were linked with an increase in antibacterial effectiveness of these antibiotics, be is due to the introduction of bacterial iron transport routes into the bacterial cell, was achieved  (e.g. Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, R.L., Antimicrob. Agents chemo ther. 35 (1991), 653) there is a great need further new synthetic siderophore-antibiotic conjugates with verbes serten pharmacological and pharmacokinetic Eigen companies.

Der Erfindung liegt die Aufgabe zugrunde, neue synthe­ tische Catechol-Antibiotika-Konjugate aufzufinden, die eine verbesserte Penetration dieser Verbindungen in Bakterienzellen bewirken und damit deren antibakterielle Wirksamkeit erhöhen sowie eine bessere Bekämpfung penetrationsbezogener Antibiotika­ resistenz bei bakteriellen Infektionen ermöglichen.The invention is based, new synthe task tables catechol-antibiotic conjugates find the an improved penetration of this Cause connections in bacterial cells and thus increase their antibacterial effectiveness and a better control of penetration-related antibiotics enable resistance to bacterial infections.

Die erfindungsgemäßen Verbindungen sind bei gramnegativen Bakterien wirksam, als Konjugate und werden über Ei­ sentransportwege in die Bakterienzelle eingeschleußt. Sie verbessern und erweitern die Wirksamkeit der Antibiotika. The compounds of the invention are effective on gram-negative bacteria, as conjugates and are about egg transport routes into the bacterial cell. They improve and expand the effectiveness of antibiotics.  

Diese Verbindungen können insbesondere zur Bekämpfung penetrationsbezogener Antibiotikaresistenz eingesetzt werden.These compounds can be used in particular for Combating penetration-related antibiotic resistance be used.

Die Aufgabe wird erfindungsgemäß durch die Catechol-Antibiotika-Konjugate der allgemeinen Formel I gemäß Anspruch 1 und 2 sowie durch die Arznei­ mittel gemäß Anspruch 3 gelöst. The object is achieved by the Catechol-antibiotic conjugates of the general formula I according to claim 1 and 2 and by the drug solved according to claim 3.  

Der Rest R15 kann in al­ len möglichen Positionen stehen. The rest R 15 can be in all possible positions.

Im Falle des Vorliegens asymmetrischer C-Atome sind die entsprechenden D- und L-Formen, Enantiomere und Diaste­ reomere sowie die Racemate bzw. Enantiomeren- und Dia­ stereomerengemische ebenfalls Gegenstand der Erfindung.In the case of asymmetric carbon atoms, they are corresponding D and L forms, enantiomers and diasts reomers and the racemates or enantiomers and dia stereomeric mixtures also the subject of the invention.

Die erfindungsgemäßen Verbindungen werden z. B. herge­ stellt, indem
The compounds of the invention are, for. B. Herge provides by

  • a) 2,3-(Di(benzyloxy)benzoylchlorid (Formel I mit R1 = OCH2C6H5 und R2 = COCI) in einem geeigneten Lösungsmittel wie Tetrahydrofuran zusammen mit ei­ nem tertiären Amin, z. B. Triethylamin, bei einer Temperatur zwischen -30°C und +20°C, oder in wäß­ riger Natriumbicarbonatlösung bei 0°C bis +10°C, mit Aminosäuren, Diaminosäuren oder Dipeptiden zu entsprechenden geschützten N-[(2,3-Di(benzyloxy)- benzoyl]-aminosäuren umgesetzt werden und diese dann nach üblichen Verfahren zur Entfernung der Schutzgruppen, beispielsweise durch katalytische Hydrierung in Ethanol, in die freien catecholsub­ stituierten Aminosäure- bzw. Peptidderivate umgewandelt werden,a) 2,3- (di (benzyloxy) benzoyl chloride (formula I with R 1 = OCH 2 C 6 H 5 and R 2 = COCI) in a suitable solvent such as tetrahydrofuran together with a tertiary amine, e.g. triethylamine, at a temperature between -30 ° C and + 20 ° C, or in aqueous sodium bicarbonate solution at 0 ° C to + 10 ° C, with amino acids, diamino acids or dipeptides to corresponding protected N - [(2,3-di (benzyloxy) benzoyl] amino acids are reacted and these are then converted into the free catechol-substituted amino acid or peptide derivatives by customary processes for removing the protective groups, for example by catalytic hydrogenation in ethanol,

oder indem
or by

  • a) Dihydroxy- bzw. Diacyloxybenzoylchlorid (Formel I mit R1 = OH, OAcyl und R2 = COCI) mit Oxazolidin­ carboxylat, erhalten nach bekannten Verfahren aus Serin und Aldehyden, beispielsweise Formaldehyd, in Alkalilauge und anschließendem Ansäuern, in einem geeigneten Lösungsmittel, beispielsweise in Ethanol oder Ethanol/Wasser-Gemisch bei einer Temperatur zwischen -10°C bis +10°C zu substituierten Oxazo­ lidincarbonsäurederivaten umgesetzt werden.a) dihydroxy- or diacyloxybenzoyl chloride (formula I with R 1 = OH, OAcyl and R 2 = COCI) with oxazolidine carboxylate, obtained by known processes from serine and aldehydes, for example formaldehyde, in alkali metal hydroxide solution and subsequent acidification, in a suitable solvent, for example in ethanol or ethanol / water mixture at a temperature between -10 ° C to + 10 ° C to be substituted oxazo lidincarbonsäurederivaten.

Die erfindungsgemäßen Verbindungen der Formel I werden z. B. hergestellt, indem eine Verbindung der Formel I mit Y = OH, z. B. nach der Gemischtanhydridmethode zunächst mit Chlor­ ameisensäureester und einem tertiären Amin, z. B. Tri­ ethylamin, und dann mit dem entsprechenden Rest eines Antibiotikums das eine freie NH-Gruppe enthält, zusammen mit einem geeig­ neten tertiären Amin, z. B. Triethylamin in einem ge­ eigneten Lösungsmittel, z. B. Tetrahydrofuran, umge­ setzt wird.The compounds of formula I according to the invention z. B. made by a compound of formula I with Y = OH, z. B. using the mixed anhydride method, first with chlorine formic acid ester and a tertiary amine, e.g. B. Tri ethylamine, and then the appropriate remainder of an antibiotic which is a free NH group contains, together with a suitable Neten tertiary amine, e.g. B. triethylamine in a ge  suitable solvents, e.g. B. tetrahydrofuran, vice versa is set.

Die Verbindungen der Formel I mit einer Carboxylgruppe können als freie Säuren, in Form ihrer Salze oder als leicht spaltbare, insbesondere unter physiologischen Bedingungen spaltbare, Ester vorliegen. Die Reinigung der Verbindungen erfolgt nach üblichen, aus dem Stand der Technik bekannten Verfahren, beispielsweise durch Umkristallisation oder mittels chromatographischer Me­ thoden. Verbindungen der allgemeinen Formel I besitzen antibakterielle Wirksamkeit, zum Teil auch bei gegenüber anderen β-Lactamen resistenten Bakterien. Dafür wurden in einem Agardiffusionstest einige Verbindungen der allgemeinen Formel I und z. B. die Substanzen 30, 31 und 35 gegen spezielle, gegenüber anderen β-Lactamen zum Teil resistente Bakterienstämme getestet (Tabelle 2). Die folgenden Stämme wurden verwendet: Pseudomonas aeruginosa SG 137 (Carbenicillin-resistent), KW 799/WT (Wildtyp), KW 799/61 (Penetrationsmutante, Zellwand geschädigt, Penetration erleichtert), ATCC 27853 (Wildtyp), ATCC 9027 (Wildtyp), NCTC 10662 (ATCC 25668, Klinikisolat Carbenicillin-sensibel), NCTC 10701 (Carbenicillin-sensibel), NPS1 und Oxa6 (Plasmid­ codierte β-Lactamase); E. coli DCO (Wildtyp), DC2 (Penetrationsmutante, Zellwand geschädigt, Penetration erleichtert), Klebsiella pneumoniae ATCC 10031 (Wildtyp) sowie SG 117; Salmonella gallinarum ATCC 9184; Stenotrophomonas maltophilia GN 12873 (Ampicillin-, Azlocillin- und Carbapenemresistent) und IMET 10402.The compounds of formula I with a carboxyl group can as free acids, in the form of their salts or as easily cleavable, especially under physiological Cleavable conditions, esters are present. The cleaning the connections are made according to the usual, from the stand methods known in the art, for example by Recrystallization or by means of chromatographic measurements methods.  Compounds of the general formula I have antibacterial activity to Some also resistant to other β-lactams Bacteria. For this purpose, in an agar diffusion test some compounds of general formula I and z. B. the substances 30, 31 and 35 against special, compared to other β-lactams in part resistant bacterial strains tested (Table 2). The the following strains were used: Pseudomonas aeruginosa SG 137 (carbenicillin resistant), KW 799 / WT (Wild type), KW 799/61 (penetration mutant, cell wall damaged, penetration facilitated), ATCC 27853 (Wild type), ATCC 9027 (wild type), NCTC 10662 (ATCC 25668, Clinic isolate carbenicillin sensitive), NCTC 10701 (Carbenicillin sensitive), NPS1 and Oxa6 (plasmid encoded β-lactamase); E. coli DCO (wild type), DC2 (Mutant penetration, damaged cell wall, penetration relieved), Klebsiella pneumoniae ATCC 10031 (Wild type) and SG 117; Salmonella gallinarum ATCC 9184; Stenotrophomonas maltophilia GN 12873 (Ampicillin, azlocillin and carbapenem resistant) and IMET 10402.

Überraschenderweise wurde gefunden, daß die getesteten Substanzen nicht nur bei den Ampicillin-resistenten und/oder β-Lactamaseinhibitor-resistenten Wildtyp­ stämmen eine hervorragende Wirksamkeit aufwiesen, sondern daß sie auch bei zwei Pseudomonas-Stämmen mit plasmidcodierter β-Lactamase (NPS1, Oxa6) und multiresistenten Stenotrophomonas-Stämmen wirksam waren, während z. B. Azlocillin und zum Teil auch Meropenem oder Imipenem unwirksam waren. Surprisingly, it was found that the tested Substances not only in ampicillin-resistant  and / or wild type β-lactamase inhibitor resistant strains had excellent efficacy, but that they also with two Pseudomonas strains plasmid-encoded β-lactamase (NPS1, Oxa6) and multi-resistant Stenotrophomonas strains effective were while z. B. azlocillin and partly also Meropenem or Imipenem were ineffective.  

Auch in einem Mikrodilutionstest wurde die überraschend gute Wirksamkeit belegt. Die minimalen Hemmkon­ zentrationen (MHK) wurden bei den folgenden Bakterienstämmen bestimmt: Pseudomonas aeruginosa NCTC 10701, NCTC 10662, SG 137, ATCC 27853, KW 799/WT und KW 799/61; E. coli DCO, DC2 und ATCC 25922, Serratia marcescens SG621; Salmonella gallinarium ATCC 9184; Klebsiella pneumoniae ATCC 10031 und SG 117.This was also surprising in a microdilution test proven effectiveness. The minimal inhibition concentrations (MIC) were found in the following Strains of bacteria determined: Pseudomonas aeruginosa NCTC 10701, NCTC 10662, SG 137, ATCC 27853, KW 799 / WT and KW 799/61; E. coli DCO, DC2 and ATCC 25922, Serratia marcescens SG621; Salmonella gallinarium ATCC 9184; Klebsiella pneumoniae ATCC 10031 and SG 117.

Die Ergebnisse sind in Tabelle 3 wiedergegeben. Danach sind alle Siderophor-Ampicillin-Konjugate im Vergleich zu Ampicillin und Azlocillin als Standard gut wirksam, besonders bei Pseudomonas aeruginosa SG 137, einem gegenüber Carbenicillin resistenten Keim, sowie Wildtypstämmen von Pseudomonas, aber z. T. auch gegen E. coli und Serratia.The results are shown in Table 3. After that all siderophore-ampicillin conjugates are compared well effective with ampicillin and azlocillin as standard, especially with Pseudomonas aeruginosa SG 137, one germ resistant to carbenicillin, and Wild-type strains of Pseudomonas, but e.g. T. also against E. coli and serratia.

Mit den Testkeimen KW 799/WT und /61 von Pseudomonas und DC0 und DC2 von E. coli wurde der Anteil der verbesserten Penetrationsfähigkeit an der Wirksamkeit der Substanzen untersucht. Bei KW 799/61 und DC2 handelt es sich um Mutanten mit durchlässiger äußerer Membran im Vergleich zur den Wildtypen KW 799/WT bzw. DC0. Bei den Vergleichssubstanzen Azlocillin und Ampicillin ist an Hand der starken Unterschiede in der Aktivität gegen Wildtyp und Mutante die mehr oder weniger schlechte Penetrationsfähigkeit festzustellen, im Gegensatz zu den Konjugaten mit guter Penetrationsfähigkeit. With the test germs KW 799 / WT and / 61 from Pseudomonas and DC0 and DC2 of E. coli was the proportion of improved penetration ability to effectiveness of substances examined. KW 799/61 and DC2 are mutants with permeable outer Membrane compared to the wild types KW 799 / WT or DC0. In the comparison substances azlocillin and Ampicillin is due to the strong differences in the Activity against wild type and mutant the more or less poor penetration ability, in contrast to the conjugates with good Penetration capability.  

Bereits die Ergebnisse mit den Penetrationsmutanten von Pseudomonas, KW 799/61, und E. coli DC2 und deren Wildtypen belegen, daß die meisten der neuen Substanzen über eine wesentlich bessere Penetrationsfähigkeit verfügen als Ampicillin und Azlocillin. Es wurde mit Hilfe weiterer Experimente mit speziellen E. coli- Mutanten, denen die Porine ompC und ompF, über die die β-Lactame normalerweise in die Bakterienzelle gelangen, oder das für einen aktiven Eisentransport essentielle Membranprotein tonB fehlen, gezeigt, daß die beschriebenen Siderophor-Antibiotika-Konjugate zwei Penetrationswege nutzen können (über die Porine ompC und ompF und über den Eisentransportweg tonB), während die antibiotische Aktivität von Ampicillin und Azlocillin nur vom Vorhandensein der Porine abhängig ist. Die Wirksamkeit gegen β-Lactamasebildner und multiresistente Keime ist daher auf einen neuartigen Mechanismus zur Überwindung der Penetrationsresistenz zurückzuführen, durch den das Verhältnis von Wirkstoff zu Enzym in der Bakterienzelle so beeinflußt wird, daß nicht alle Antibiotikummoleküle inaktiviert werden, bevor sie ihr Target erreichen. Already the results with the penetration mutants from Pseudomonas, KW 799/61, and E. coli DC2 and their Wild types show that most of the new substances about a much better penetration ability have as ampicillin and azlocillin. It was with Help of further experiments with special E. coli Mutants to which the Porine ompC and ompF are, via which the β-lactams normally get into the bacterial cell, or the essential for an active iron transport Membrane protein tonB is missing, shown that the described siderophore-antibiotic conjugates two Can use penetration routes (via the Porine ompC and ompF and via the iron transport path tonB), while the antibiotic activity of ampicillin and Azlocillin only depends on the presence of the porins is. The effectiveness against β-lactamase and multi-resistant germs is therefore on a novel Mechanism to overcome penetration resistance attributed by which the ratio of active ingredient to enzyme in the bacterial cell is so affected that not all antibiotic molecules are inactivated, before they reach their target.  

Tabelle 4 Table 4

Abhängigkeit der antibakteriellen Aktivität der neuen Substanzen von Porinen und TonB bei Mutanten von E. coli (Hemmhofdurchmesser im Agardiffusionstest in mm) Dependence of the antibacterial activity of the new substances on porins and TonB in mutants of E. coli (inhibitory zone diameter in the agar diffusion test in mm)

In Tabelle 5 sind weiterhin die Ergebnisse des CAS- Testes verzeichnet. Der CAS-Test (Chromazurol-S-Test) nach Schwyn und Neilands (Anal. Biochem. 160, 47 (1987) beruht auf einer Farbreaktion bedingt durch die Ablösung des Fe aus dem Chromazurol-S-Komplex und die Bindung durch die Catecholverbindung, womit die Siderophoreigenschaft der Verbindung nachgewiesen wird. Die CAS-Tests waren bei den neuen Substanzen positiv, währen sie mit Ampicillin und Azlocillin völlig negativ verliefen. Auch dies bestätigt den überraschenden Befund, daß die neuen Antibiotika zusätzlich zum Porinweg verstärkt über den Eisentransportweg in die Bakterienzelle gelangen. Table 5 also shows the results of the CAS Testes listed. The CAS test (Chromazurol-S test) according to Schwyn and Neilands (Anal. Biochem. 160, 47 (1987) is based on a color reaction caused by the Detachment of the Fe from the Chromazurol-S complex and the Binding through the catechol compound, with which the Siderophore property of the compound is detected. The CAS tests were positive for the new substances, with ampicillin and azlocillin they are completely negative ran. This also confirms the surprising Finding that the new antibiotics in addition to Porinweg intensified via the iron transport route to the Bacteria cell.  

Tabelle 5 Table 5

Fe-Komplexierung durch neuartige Antibiotika (CAS-Test) Fe complexation through novel antibiotics (CAS test)

Die Verbindungen der Formel I können entweder allein oder in Form von pharma­ zeutischen Präparaten mit physiologisch verträglichen, aus dem Stand der Technik bekannten Hilfs- oder Träger­ stoffen angewandt werden, wobei prinzipiell alle übli­ chen pharmakologischen Anwendungsformen möglich sind. The connections of the formula I can either alone or in the form of pharma zeutische preparations with physiologically compatible, auxiliaries or carriers known from the prior art substances are applied, whereby in principle all usual Chen pharmacological application forms are possible.  

Beispiele für die Herstellung der Aus­ gangsverbindungenExamples of making the Aus starting compounds a. Aminosäurederivatea. amino acid derivatives Allgemeine Vorschrift für die Beispiele 20 und 25General rule for examples 20 and 25 1. Stufe (Acylierung)1st stage (acylation)

2,5 mmol der jeweiligen Aminosäure oder des Dipep­ tids (in freier Form oder als Hydrochlorid bzw. -acetat vorliegend) wurden in 10 ml wäßriger NaOH- Lösung (2,5 mmol NaOH für Alanin, 7,6 mmol für Di­ aminosäuren, 11,5 mmol für das Dipeptid) gelöst. Bei 0°C tropfte man unter Rühren eine Lösung von 2,3-Di(benzyloxy)-benzoylchlorid (2,5 mmol für Ala­ nin, 5,1 mmol für Diaminosäuren, 9 mmol für das Di­ peptid) in 10 ml THF langsam zu und erwärmte danach auf 20 bis 25°C. Bei dieser Temperatur wurde 4 Stunden gerührt und das Reaktionsgemisch an­ schließend mit 2 M Salzsäure auf pH 2 eingestellt. Man extrahierte das Reaktionsgemisch mit Ethylace­ tat, wusch die organische Phase mit gesättigter wäßriger Natriumchloridlösung, trocknete über Na­ triumsulfat und entfernte das Lösungsmittel im Va­ kuum. Das Rohprodukt ließ sich durch Umkristallisa­ tion (Ethanol/Wasser im Falle des Alaninderivates) oder Säulenchromatographie (Kieselgel 60, Merck, Eluent: Chloroform : Ethylacetat : Eisessig = 30 : 10 : 1 oder Ethylacetat : Toluol : Eisessig = 10 : 10 : 2) reinigen.2.5 mmol of the respective amino acid or dipep tids (in free form or as hydrochloride or -acetate present) were in 10 ml of aqueous NaOH Solution (2.5 mmol NaOH for alanine, 7.6 mmol for Di amino acids, 11.5 mmol for the dipeptide). At 0 ° C., a solution of 2,3-Di (benzyloxy) benzoyl chloride (2.5 mmol for Ala nin, 5.1 mmol for diamino acids, 9 mmol for di peptide) in 10 ml of THF and then warmed up to 20 to 25 ° C. At this temperature Stirred for 4 hours and the reaction mixture finally adjusted to pH 2 with 2 M hydrochloric acid. The reaction mixture was extracted with ethyl acetate did, washed the organic phase with saturated aqueous sodium chloride solution, dried over Na trium sulfate and removed the solvent in Va uum. The crude product could be recrystallized tion (ethanol / water in the case of the alanine derivative) or column chromatography (Kieselgel 60, Merck, Eluent: chloroform: ethyl acetate: glacial acetic acid = 30: 10: 1 or ethyl acetate: toluene: glacial acetic acid = 10: 10: 2) clean.

2. Stufe (Debenzylierung)2nd stage (debenzylation)

500 mg des in der 1. Stufe angefallenen Produktes wurden in einem Gemisch von 9 ml Ethanol und 1 ml Eisessig gelöst, mit 50 mg Palladium auf Aktivkohle (10% Pd) versetzt und bei 20°C unter Normaldruck in einer Wasserstoffatmosphäre bis zur Aufnahme der erforderlichen stöchiometrischen Menge Wasserstoff (normalerweise 4 bis 6 Stunden) gerührt. Dann wurde das Reaktionsgemisch über Celite filtriert, das Lö­ sungsmittel abdestilliert und der Rückstand im Va­ kuum getrocknet.500 mg of the product obtained in the 1st stage were in a mixture of 9 ml of ethanol and 1 ml Glacial acetic acid dissolved with 50 mg palladium on activated carbon (10% Pd) and at 20 ° C under normal pressure in a hydrogen atmosphere until the absorption of the  required stoichiometric amount of hydrogen (usually 4 to 6 hours). Then was the reaction mixture is filtered through Celite, the Lö distilled off the solvent and the residue in Va vacuum dried.

Allgemeine Vorschrift für die Beispiele 21, 24 und 26General rule for Examples 21, 24 and 26 1. Stufe (Acylierung)1st stage (acylation)

2 mmol Aminosäurebenzylester-hydrochlorid oder -to­ sylat wurden in 10 ml Dichlormethan gelöst und die Lösung mit 4 mmol Triethylamin (8 mmol im Falle der Diaminosäurederivate) versetzt. Bei -30°C tropfte man eine Lösung von 2 mmol 2,3-Diacetoxybenzoyl­ chlorid (4 mmol für Diaminosäurederivate) in 10 ml Dichlormethan langsam zu. Anschließend wurde noch jeweils 1 Stunde bei -30°C und bei 20 bis 25°C gerührt. Die Reaktionslösung wurde nacheinander mit 1 M Salzsäure gesättigter wäßriger Natriumhydrogen­ carbonatlösung und gesättigter wäßriger Natrium­ chloridlösung gewaschen. Die organische Phase wurde über Natriumsulfat getrocknet, das Lösungsmittel im Vakuum entfernt und der Rückstand durch Umkristal­ lisation aus Ethanol oder Toluol (im Falle des Se­ rinderivats) bzw. Säulenchromatographie (Lysinderi­ vat; Kieselgel 60, Merck, Laufmittel: Ethylace­ tat : Toluol = 2 : 1) gereinigt.2 mmol benzyl amino acid hydrochloride or to sylat were dissolved in 10 ml dichloromethane and the Solution with 4 mmol triethylamine (8 mmol in the case of Diamino acid derivatives) added. Dripped at -30 ° C a solution of 2 mmol 2,3-diacetoxybenzoyl chloride (4 mmol for diamino acid derivatives) in 10 ml Dichloromethane slowly. Then was still 1 hour each at -30 ° C and at 20 to 25 ° C touched. The reaction solution was added in succession 1 M hydrochloric acid saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution washed. The organic phase was dried over sodium sulfate, the solvent in Vacuum removed and the residue through umkristal lization from ethanol or toluene (in the case of Se beef derivatives) or column chromatography (Lysinderi vat; Kieselgel 60, Merck, eluent: Ethylace tat: toluene = 2: 1) cleaned.

2. Stufe (Benzylesterspaltung)2nd stage (benzyl ester cleavage)

1 g des in der 1. Stufe angefallenen Produktes wur­ de in einem Gemisch aus 20 ml Ethanol und 1 ml Eis­ essig gelöst, mit 100 mg Palladium auf Aktivkohle (10% Pd) versetzt und bei 20°C unter Normaldruck in einer Wasserstoffatmosphäre 2 Stunden gerührt. 1 g of the product obtained in the 1st stage was de in a mixture of 20 ml of ethanol and 1 ml of ice dissolved in vinegar, with 100 mg palladium on activated carbon (10% Pd) and at 20 ° C under normal pressure stirred in a hydrogen atmosphere for 2 hours.  

Das Reaktionsprodukt wurde über Celite filtriert und das Lösungsmittel im Vakuum entfernt. Der Rückstand wurde in Ethylacetat aufgenommen, mit ge­ sättigter wäßriger Natriumchloridlösung gewaschen und die organische Phase über Natriumsulfat ge­ trocknet. Nach Entfernung des Lösungsmittels im Va­ kuum kristallisierte das Produkt aus bzw. wurde durch Umkristallisation gereinigt.The reaction product was filtered through Celite and the solvent removed in vacuo. The Residue was taken up in ethyl acetate, with ge saturated aqueous sodium chloride solution and the organic phase over sodium sulfate dries. After removing the solvent in Va The product crystallized out or became vacuum purified by recrystallization.

Beispiel 18Example 18 L-2,5-Bis-(2,3-dihydroxybenzoylamino)-pentansäure (18)L-2,5-bis- (2,3-dihydroxybenzoylamino) -pentanoic acid (18)

Substanz (18) wurde aus L-Ornithin-Monohydrochlorid mit einer Ausbeute von 66% der Theorie als weißer Feststoff erhalten.Substance (18) was made from L-ornithine monohydrochloride with a yield of 66% of theory as white Get solid.

1H-NMR (DMSO-d6, δ in ppm): 7,41 (dd, 1H, ArH), 7,27 (dd, 1H, ArH), 6,92 (m, 2H, ArH), 6,69 (m, 2H, ArH), 4,46 (m, 1H, CH-N), 3,36 (m, 2H, CH2-N), 1,84 (m, 2H, CH2), 1,65 (m, 2H, CH2). 1 H-NMR (DMSO-d 6 , δ in ppm): 7.41 (dd, 1H, ArH), 7.27 (dd, 1H, ArH), 6.92 (m, 2H, ArH), 6. 69 (m, 2H, ArH), 4.46 (m, 1H, CH-N), 3.36 (m, 2H, CH 2 -N), 1.84 (m, 2H, CH 2 ), 1, 65 (m, 2H, CH 2).

Beispiel 19Example 19 L-2-(2,3-Dihydroxybenzoylamino)-propionsäure (19)L-2- (2,3-Dihydroxybenzoylamino) propionic acid (19)

Substanz (19) wurde aus L-Alanin mit einer Ausbeute von 88% der Theorie als weißer Feststoff erhalten. Substance (19) was obtained from L-alanine in one yield obtained from 88% of theory as a white solid.  

1H-NMR (DMSO-d6, δ in ppm): 7,40 (dd, 1H, ArH), 6,94 (dd, 1H, ArH), 6,72 (dd, 1H, ArH), 4,44 (m, 1H, CH), 1,42 (d, 3H, CH3) 1 H-NMR (DMSO-d 6 , δ in ppm): 7.40 (dd, 1H, ArH), 6.94 (dd, 1H, ArH), 6.72 (dd, 1H, ArH), 4, 44 (m, 1H, CH), 1.42 (d, 3H, CH 3 )

Beispiel 20Example 20 L-2-(2,3-Diacetoxybenzoylamino)-propionsäure (20)L-2- (2,3-diacetoxybenzoylamino) propionic acid (20)

Substanz (20) wurde aus L-Alaninbenzylester-hydro­ chlorid mit einer Ausbeute von 75% der Theorie als farblose Kristalle mit einem Fp. von 109° bis 111°C erhalten.Substance (20) was derived from L-alanine benzyl ester hydro chloride with a yield of 75% of theory as colorless crystals with a melting point of 109 ° to Get 111 ° C.

1H-NMR (DMSO-d6, δ in ppm): 7,50 (dd, 1H, ArH), 7,39 (m, 2H, ArH), 4,33 (m, 1H, CH), 2,29 (s, 3H, CH3CO), 2,23 (s, 3H, CH3CO), 1,34 (d, 3H, CH3). 1 H-NMR (DMSO-d 6 , δ in ppm): 7.50 (dd, 1H, ArH), 7.39 (m, 2H, ArH), 4.33 (m, 1H, CH), 2, 29 (s, 3H, CH 3 CO), 2.23 (s, 3H, CH 3 CO), 1.34 (d, 3H, CH 3 ).

Beispiel 21Example 21 L-2,4-Bis-(2,3-dihydroxybenzoylamino)-buttersäure (21)L-2,4-bis (2,3-dihydroxybenzoylamino) butyric acid (21)

Substanz (21) wurde aus L-2,4-Diaminochlorsäuredi­ hydrochlorid mit einer Ausbeute von 81% der Theo­ rie als grauweißer Feststoff erhalten.Substance (21) was derived from L-2,4-diaminochloric acid di hydrochloride with a yield of 81% of Theo obtained as an off-white solid.

1H-NMR (DMSO-d6, δ in ppm): 7,42 (dd, 1H, ArH), 7,27 (dd, 1H, ArH), 6,94 (m, 2H, ArH), 6,72 (m, 2H, ArH), 4,48 (m, 1H, CH-N), 3,42 (m, 2H, CH2), 2,21 (m, 1H, CH2), 2,05 (m, 1H, CH2). 1 H-NMR (DMSO-d 6 , δ in ppm): 7.42 (dd, 1H, ArH), 7.27 (dd, 1H, ArH), 6.94 (m, 2H, ArH), 6. 72 (m, 2H, ArH), 4.48 (m, 1H, CH-N), 3.42 (m, 2H, CH 2 ), 2.21 (m, 1H, CH 2 ), 2.05 ( m, 1H, CH 2 ).

Beispiel 22Example 22 L-3-[2,6-Bis-(2,3-dihydroxybenzoylamino)-hexanoyl­ amino]-2-(2,3-dihydroxybenzoylamino)-propionsäure (22)L-3- [2,6-bis (2,3-dihydroxybenzoylamino) -hexanoyl amino] -2- (2,3-dihydroxybenzoylamino) propionic acid (22)

Substanz (22) wurde aus L-2-Amino-3-(2,6-diamino­ hexanoylamino)-propionsäure mit einer Ausbeute von 70% der Theorie als weißer Feststoff erhalten.Substance (22) was derived from L-2-amino-3- (2,6-diamino hexanoylamino) propionic acid with a yield of 70% of theory obtained as a white solid.

1H-NMR (DMSO-d6, δ in ppm): 7,42 (dd, 1H, ArH), 7,26 (m, 2H, ArH), 6,91 (m, 3H, ArH), 6,69 (m, 2H, ArH), 6,67 (m, 3H, ArH), 4,55-4,28 (m, 3H, CH-N, CH2-N), 4,10-3,09 (m, 3H, CH-N, CH2-N), 1,72 (m, 2H, CH2), 1,51-1,28 (m, 4H, CH2) 1 H-NMR (DMSO-d 6 , δ in ppm): 7.42 (dd, 1H, ArH), 7.26 (m, 2H, ArH), 6.91 (m, 3H, ArH), 6, 69 (m, 2H, ArH), 6.67 (m, 3H, ArH), 4.55-4.28 (m, 3H, CH-N, CH 2 -N), 4.10-3.09 ( m, 3H, CH-N, CH 2 -N), 1.72 (m, 2H, CH 2 ), 1.51-1.28 (m, 4H, CH 2 )

Beispiel 23Example 23 L-2-[2,3-(Diacetoxybenzoylamino)-3-hydroxypropion­ säure (23)L-2- [2,3- (diacetoxybenzoylamino) -3-hydroxypropion acid (23)

Substanz (23) wurde aus L-Serinbenzylester-hydro­ chlorid mit einer Ausbeute von 53% der Theorie als farblose Nadeln mit einem Fp. von 165 bis 168°C (Aceton/n-Hexan) erhalten.Substance (23) was derived from L-serine benzyl ester hydro chloride with a yield of 53% of theory as colorless needles with a melting point of 165 to 168 ° C (Acetone / n-hexane) obtained.

1H-NMR (DMSO-d6, δ in ppm): 7,59 (dd, 1H, ArH, 7,42 (m, 2H, ArH), 4,42 (m, 1H, CH), 3,76 (m, 2H, CH2O), 2,29 (s, 3H, CH3CO), 2,28 (s, 3H, CH3CO). 1 H NMR (DMSO-d 6 , δ in ppm): 7.59 (dd, 1H, ArH, 7.42 (m, 2H, ArH), 4.42 (m, 1H, CH), 3.76 (m, 2H, CH 2 O), 2.29 (s, 3H, CH 3 CO), 2.28 (s, 3H, CH 3 CO).

Beispiel 23aExample 23a L-3-Benzyloxy-2-(2,3-diacetoxy-benzoylamino)-propi­ onsäureL-3-benzyloxy-2- (2,3-diacetoxy-benzoylamino) -propi oic acid

Die Substanz wurde aus O-Benzyl-L-serinbenzylester Hydrochlorid analog Substanz 23, jedoch in Stufe 2 unter Verwendung von Palladium auf Aktivkohle (10% Pd) und Cyclohexadien, in Form weißer Kristalle erhalten.The substance was derived from O-benzyl-L-serine benzyl ester Hydrochloride analogous to substance 23, but in stage 2 using palladium on activated carbon (10% Pd) and cyclohexadiene, in the form of white crystals receive.

Beispiel 24Example 24 D-2,5-Bis-(2,3-dihydroxybenzoylamino)-pentansäure (24)D-2,5-bis (2,3-dihydroxybenzoylamino) -pentanoic acid (24)

Substanz (24) wurde aus D-Ornithin-Monohydrochlorid mit einer Ausbeute von 66% der Theorie als weißer Feststoff erhalten.Substance (24) was made from D-ornithine monohydrochloride with a yield of 66% of theory as white Get solid.

1H-NMR (DMSO-d6, δ in ppm): 7,41 (dd, 1H, ArH), 7,27 (dd, 1H, ArH), 6,93 (m, 2H, ArH), 6,70 (m, 2H, ArH), 4,46 (m, 1H, CH-N), 3,33 (m, 2H, CH2-N), 1,84 (m, 2H, CH2), 1,64 (m, 2H, CH2). 1 H-NMR (DMSO-d 6 , δ in ppm): 7.41 (dd, 1H, ArH), 7.27 (dd, 1H, ArH), 6.93 (m, 2H, ArH), 6. 70 (m, 2H, ArH), 4.46 (m, 1H, CH-N), 3.33 (m, 2H, CH 2 -N), 1.84 (m, 2H, CH 2 ), 1, 64 (m, 2H, CH 2).

Beispiel 25Example 25 L-2,6-Bis-(2,3-diacetoxybenzoylamino)-hexansäure (25)L-2,6-bis- (2,3-diacetoxybenzoylamino) -hexanoic acid (25)

Substanz (25) wurde aus L-Lysinbenzylester-ditosy­ lat mit einer Ausbeute von 71% der Theorie als weißer Feststoff erhalten.Substance (25) was derived from L-lysine benzyl ester ditosy lat with a yield of 71% of theory as obtained white solid.

1H-NMR (CDCl3, δ in ppm, J in Hz): 7,65 (dd, J = 1,9, 7,4, 1H, ArH), 7,47 (dd, J = 2,3, 7,2, 1H, ArH), 7,32-7,22 (m, J = 1,8, 7,3, 5H, ArH, CONH, 6,59 (t, J = 5,7, 1H, CONH), 4,75 (m, J = 5,2 7,2, 1H, CH-N), 3,38 (m, 2H, CH2-N), 2,34 (s, 3H, CH3CO), 2,30 (s, 3H, CH3CO), 2,30 (s, 3H, CH3CO), 2,29 (s, 3H, CH3CO), 1,99 (m, 1H, CH2), 1,85 (m, 1H, CH2), 1,60 (m, 2H, CH2), 1,28 (m, 2H, CH2). 1 H-NMR (CDCl 3 , δ in ppm, J in Hz): 7.65 (dd, J = 1.9, 7.4, 1H, ArH), 7.47 (dd, J = 2.3, 7.2, 1H, ArH), 7.32-7.22 (m, J = 1.8, 7.3, 5H, ArH, CONH, 6.59 (t, J = 5.7, 1H, CONH ), 4.75 (m, J = 5.2 7.2, 1H, CH-N), 3.38 (m, 2H, CH 2 -N), 2.34 (s, 3H, CH 3 CO) , 2.30 (s, 3H, CH 3 CO), 2.30 (s, 3H, CH 3 CO), 2.29 (s, 3H, CH 3 CO), 1.99 (m, 1H, CH 2 ), 1.85 (m, 1H, CH 2 ), 1.60 (m, 2H, CH 2 ), 1.28 (m, 2H, CH 2 ).

b. Oxazolidincarbonsäureresteb. Oxazolidincarbonsäurereste Beispiel 26Example 26 (S)-3-(2,3-Diacetoxybenzoyl)-oxazolidin-4-carbon­ säure (26)(S) -3- (2,3-diacetoxybenzoyl) oxazolidin-4-carboxylic acid (26)

L-Serin (105 mg, 1 mmol) wurde in 0,5 ml 2 M Na­ tronlauge gelöst und bei 0°C mit 0,1 ml wäßriger Formaldehyd-Lösung (36,5%) versetzt. Man ließ das Reaktionsgemisch 24 Stunden bei 0°C stehen, fügte anschließend 84 mg (1 mmol) Natriumhydrogencarbonat und 1 ml Aceton hinzu und kühlte auf -5°C. Unter Rühren wurden portionsweise 257 mg (1 mmol) 2,3-Di- (acetoxy)benzoylchlorid zugegeben. Nach 1 Stunde Rühren bei -5° bis 0°C wurde mit 10 ml Wasser ver­ dünnt und das Reaktionsgemisch mit Diethylether ex­ trahiert. Die wäßrige Phase wurde mit 1 M Salzsäure auf pH 2-3 angesäuert und erneut mit Diethylether (3 × 20 ml) extrahiert. Die organische Phase wurde über Natriumsulfat getrocknet und das Lösungsmittel im Vakuum entfernt. Das erhaltene Produkt wurde im Vakuum getrocknet. Ausbeute: 263 mg (78% der Theorie). Weißer Schaum.L-serine (105 mg, 1 mmol) was dissolved in 0.5 ml of 2 M Na dissolved tron solution and at 0 ° C with 0.1 ml aqueous Formaldehyde solution (36.5%) added. They left that Stand reaction mixture for 24 hours at 0 ° C, added  then 84 mg (1 mmol) sodium hydrogen carbonate and 1 ml acetone and cooled to -5 ° C. Under 257 mg (1 mmol) of 2,3-di- (acetoxy) benzoyl chloride added. After 1 hour Stirring at -5 ° to 0 ° C was mixed with 10 ml of water thins and the reaction mixture with diethyl ether ex tracted. The aqueous phase was washed with 1 M hydrochloric acid Acidified to pH 2-3 and again with diethyl ether (3 x 20 ml) extracted. The organic phase was dried over sodium sulfate and the solvent removed in vacuum. The product obtained was in Vacuum dried. Yield: 263 mg (78% of the Theory). White foam.

1H-NMR (CDCl3, δ in ppm): 7,35-7,27 (m, 3H, ArH), 4,90 (s, 2H, O-CH2-N), 4,82 (m, 1H, CH), 4,39 (m, 1H, CH2), 4,28 (m, 1H, CH2), 2,33 (s, 3H, CH3), 2,31 (s, 3H, CH3). 1 H-NMR (CDCl 3 , δ in ppm): 7.35-7.27 (m, 3H, ArH), 4.90 (s, 2H, O-CH 2 -N), 4.82 (m, 1H, CH), 4.39 (m, 1H, CH 2 ), 4.28 (m, 1H, CH 2 ), 2.33 (s, 3H, CH 3 ), 2.31 (s, 3H, CH 3 ).

AntibiotikakonjugateAntibiotikakonjugate Beispiel 27Example 27 N-[L-2-(2,3-Diacetoxybenzoylamino)-propionyl]-ampi­ cillinN- [L-2- (2,3-diacetoxybenzoylamino) -propionyl] -ampi cillin (nach IUPAC: 6-{2-[2-(2,3-Diacetoxybenzoylamino)- propionylamino]-2-phenyl-acetylamino}-3,3-dimethyl- 7-oxo-4-thia-1-azabicyclo[3.2.0]heptan-2-carbonsäu­ re) (27)(according to IUPAC: 6- {2- [2- (2,3-diacetoxybenzoylamino) - propionylamino] -2-phenyl-acetylamino} -3,3-dimethyl- 7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic right) (27)

500 mg (1,62 mmol) L-2-(2,3-Diacetoxybenzoylamino)- propionsäure (Substanz 20) wurden in 15 ml Tetrahy­ drofuran gelöst und dazu unter Rühren bei -20°C 0,18 ml (1,62 mmol) N-Methylmorpholin und an­ schließend 0,21 ml (1,62 mmol) Chlorameisensäure­ isobutylester zugetropft. Nach 1 Stunde Rühren wur­ de eine auf 0°C gekühlte Lösung von 565 mg (1,62 mmol) Ampicillintrihydrat in 5 ml 80%-igem Tetrahydrofuran zugetropft. Die Mischung wurde 1 Stunde bei -20°C und 1 Stunde bei Raumtemperatur gerührt und dann im Vakuum eingeengt. Anschließend wurden Wasser und Ethylacetat zugegeben und mit 1 M Salzsäure vorsichtig auf pH 2 angesäuert. Die Mi­ schung wurde bis zur vollständigen Lösung geschüt­ telt, die Ethylacetatphase abgetrennt, mit wäßriger Kochsalzlösung neutral gewaschen und über Natrium­ sulfat getrocknet. Nach Einengen im Vakuum wurde mit Petrolether ausgefällt. Ausbeute an Rohprodukt: 1 g Reinheit nach HPLC (Europher 100-7): ca. 75%. Die Reinigung erfolgte über präparative HPLC (RP18, Acetonitril/Wasser = 40 : 60 + 0,50% Trifluores­ sigsäure, Flußrate 10 ml/min). Die das Produkt ent­ haltenden Fraktionen wurden sofort mit Ethylacetat extrahiert, die organische Phase mit Wasser gewa­ schen, getrocknet, eingeengt und mit Petrolether gefällt. Reinheit nach HPLC: 95%500 mg (1.62 mmol) of L-2- (2,3-diacetoxybenzoylamino) propionic acid (substance 20) were dissolved in 15 ml of tetrahydrofuran and 0.18 ml (1.62 mmol ) N-methylmorpholine and then 0.21 ml (1.62 mmol) isobutyl chloroformate added dropwise. After stirring for 1 hour, a solution of 565 mg (1.62 mmol) of ampicillin trihydrate in 5 ml of 80% tetrahydrofuran, cooled to 0 ° C., was added dropwise. The mixture was stirred at -20 ° C for 1 hour and at room temperature for 1 hour and then concentrated in vacuo. Then water and ethyl acetate were added and carefully acidified to pH 2 with 1 M hydrochloric acid. The mixture was shaken until completely dissolved, the ethyl acetate phase was separated off, washed neutral with aqueous sodium chloride solution and dried over sodium sulfate. After concentration in vacuo, it was precipitated with petroleum ether. Yield of crude product: 1 g purity according to HPLC (Europher 100-7): approx. 75%. The purification was carried out by preparative HPLC (RP 18 , acetonitrile / water = 40: 60 + 0.50% trifluoroacetic acid, flow rate 10 ml / min). The product-containing fractions were immediately extracted with ethyl acetate, the organic phase was washed with water, dried, concentrated and precipitated with petroleum ether. HPLC purity: 95%

1H-NMR (300 MHz, CDCl3, δ in ppm, J in Hz): 7,63 (dd, J = 1,9, 7,4, ArH), 7,33-7,19 (m, 7H, ArH), 5,61 (m, J = 4,1, 2H, CH-N), 5,42 (d, J = 4,1, 1H, CH-S), 5,00 (m, J = 7,3, 1H, CH-Me), 4,29 (s, 1H, CH-COO), 2,30 (s, 3H, CH3CO), 2,27 (s, 3H, CH3CO), 1,43 (s, 3H, CH3), 1,40 (d, J = 7,1, 3H, CH3), 1,37 (s, 3H, CH3). 1 H NMR (300 MHz, CDCl 3 , δ in ppm, J in Hz): 7.63 (dd, J = 1.9, 7.4, ArH), 7.33-7.19 (m, 7H , ArH), 5.61 (m, J = 4.1, 2H, CH-N), 5.42 (d, J = 4.1, 1H, CH-S), 5.00 (m, J = 7.3, 1H, CH-Me), 4.29 (s, 1H, CH-COO), 2.30 (s, 3H, CH 3 CO), 2.27 (s, 3H, CH 3 CO), 1.43 (s, 3H, CH 3 ), 1.40 (d, J = 7.1, 3H, CH 3 ), 1.37 (s, 3H, CH 3 ).

Beispiel 30Example 30 (S)-N-[3-(2,3-Di-methoxycarbonyloxy-benzoyl)-oxazo­ lidin-4-oyl]-ampicillin(S) -N- [3- (2,3-di-methoxycarbonyloxy-benzoyl) -oxazol lidin-4-oyl] -ampicillin (nach IUPAC: (S)-6-(2-{[3-(2,3-Di-methoxycarbonyl­ oxy-benzoyl)-oxazolidin-4-carbonyl]-amino}-2-phe­ nyl-acetylamino)-3,3-dimethyl-7-oxo-4-thia-1-aza­ bicyclo[3.2.0]-heptan-2-carbonsäure) (30)(according to IUPAC: (S) -6- (2 - {[3- (2,3-dimethoxycarbonyl oxy-benzoyl) oxazolidin-4-carbonyl] -amino} -2-phe nyl-acetylamino) -3,3-dimethyl-7-oxo-4-thia-1-aza bicyclo [3.2.0] -heptane-2-carboxylic acid) (30)

Substanz 30 wurde aus (S-3-(2,3-Di-methoxycarbonyloxy-benzoyl)-oxazoli­ din-4-carbonsäure und Ampicillintrihydrat herge­ stellt.Substance 30 was made (S-3- (2,3-di-methoxycarbonyloxy-benzoyl) -oxazoli din-4-carboxylic acid and ampicillin trihydrate provides.

Zu einer Lösung von 1 mmol der Oxazolidin-4-carbonsäure in 5 ml absolutem Tetrahydrofuran wurden bei -20°C zu­ nächst 0,11 ml (1 mmol) N-Methylmorpholin sowie ei­ ne katalytische Menge 4-Dimethylaminopyridin und dann unter Rühren 126 µl Chlorameisensäureisobutyl­ ester zugefügt. Die Mischung wurde 1 Stunde bei -20°C gerührt, dann wurde die Lösung von 371 mg (1 mmol) Ampicillin-Natriumsalz in 3 ml 80%-igen Tetrahydrofuran portionsweise zugefügt. Es wurde 1 Stunde bei -20°C und 2 Stunden bei Raumtempera­ tur gerührt. Dann wurde das Lösungsmittel im Vakuum abdestilliert und zu dem Rückstand 20 ml Wasser und 20 ml Ethylacetat zugegeben. Die Mischung wurde vorsichtig mit 1 M Salzsäure auf pH 3 angesäuert und durchgeschüttelt. Die organische Phase wurde abgetrennt, dreimal mit wäßriger Kochsalzlösung ge­ waschen und über Natriumsulfat getrocknet. Nach Einengen wurde mit Petrolether ausgefällt.To a solution of 1 mmol of the oxazolidine-4-carboxylic acid in 5 ml absolute tetrahydrofuran were added at -20 ° C next 0.11 ml (1 mmol) of N-methylmorpholine and egg ne catalytic amount of 4-dimethylaminopyridine and then with stirring 126 µl chloroformic acid isobutyl added ester. The mixture was at 1 hour Stirred at -20 ° C, then the solution of 371 mg (1 mmol) ampicillin sodium salt in 3 ml 80% Tetrahydrofuran added in portions. It was 1 hour at -20 ° C and 2 hours at room temperature door stirred. Then the solvent was in vacuo distilled off and to the residue 20 ml of water and 20 ml of ethyl acetate were added. The mixture was carefully acidified to pH 3 with 1 M hydrochloric acid and shaken. The organic phase was separated, three times with aqueous saline wash and dry over sodium sulfate. To Concentration was precipitated with petroleum ether.

Das Rohprodukt wurde mittels präparativer HPLC ge­ trennt (Nucleosil 7 C 18, Macherey & Nagel, Lauf­ mittel Acetonitril/Wasser 50/50 + 0,05% Trifluor­ essigsäure)The crude product was ge by preparative HPLC separates (Nucleosil 7 C 18, Macherey & Nagel, Lauf medium acetonitrile / water 50/50 + 0.05% trifluor acetic acid)

Beispiel 31Example 31 N-[L-2,6-Bis-(2,3-diacetoxy-benzoylamino)-hexan­ oyl]-ampicillinN- [L-2,6-bis- (2,3-diacetoxy-benzoylamino) hexane oyl] -ampicillin (nach IUPAC: 6-{L-2-[2,6-Bis-(2,3-diacetoxy-benzo­ ylamino)-hexanoylamino]-2-phenyl-acetylamino}-3,3- dimethyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]-heptan- 2-carbonsäure) (31)(according to IUPAC: 6- {L-2- [2,6-bis- (2,3-diacetoxy-benzo ylamino) -hexanoylamino] -2-phenyl-acetylamino} -3,3- dimethyl-7-oxo-4-thia-1-aza-bicyclo [3.2.0] -heptan- 2-carboxylic acid) (31)

Substanz 31 wurde analog zu Substanz 30 aus L-2,6-Bis-(2,3-diacetoxybenzoylamino)-hexansäure (Substanz 25) und Ampicillin-Trihydrat erhalten. Substance 31 became analogous to substance 30 L-2,6-bis- (2,3-diacetoxybenzoylamino) -hexanoic acid (Substance 25) and ampicillin trihydrate obtained.  

Beispiel 35Example 35 N-[L-2,6-Bis-(2,3-diacetoxy-benzoylamino)- hexanoyl]-amoxicillinN- [L-2,6-bis- (2,3-diacetoxy-benzoylamino) - hexanoyl] -amoxicillin

Die Substanz wurde analog zu Substanz 30 aus L-2,6- Bis-(2,3-diacetoxy benzoylamino)-hexansäure (Sub­ stanz 25) und Amoxicillin-Trihydrat in einer Ausbeute von 84% der Theorie erhalten. The substance was analogous to substance 30 from L-2,6- Bis- (2,3-diacetoxy benzoylamino) hexanoic acid (sub punch 25) and amoxicillin trihydrate in one Obtained yield of 84% of theory.  

Beispiel 38Example 38 a) D-2,5-Bis-(2,3-diacetoxybenzoylamino)-pentansäurea) D-2,5-bis (2,3-diacetoxybenzoylamino) pentanoic acid

C27H28N5O12 (572,5) aus D-Ornithin und 2,3-Diacetoxy­ benzoylchlorid
Ausbeute: 60%C 27 H 28 N 5 O 12 (572.5) from D-ornithine and 2,3-diacetoxy benzoyl chloride
Yield: 60%

1H NMR (500 MHz, DMSO-d6, δ in ppm): 8,52 (d, 1H, NH); 8,34 (m, 1H, NH); 7,49-7,32 (m, 6H, ArH); 4,33 (m, 1H, CHN); 3,19 (m, 2H, CH2N); 2,27 (s, 6H, 2 × COOCH3); 2,22 (s, 6H, 2 × COOCH3); 1,90-1,50 (m, 4H, 2 × CH2); 1 H NMR (500 MHz, DMSO-d6, δ in ppm): 8.52 (d, 1H, NH); 8.34 (m, 1H, NH); 7.49-7.32 (m, 6H, ArH); 4.33 (m, 1H, CHN); 3.19 (m, 2H, CH 2 N); 2.27 (s, 6H, 2x COOCH 3 ); 2.22 (s, 6H, 2x COOCH 3 ); 1.90-1.50 (m, 4H, 2 x CH 2 );

b) N-[D-2,5-Bis-(2,3-diacetoxybenzoylamino)-pentanoyl]- cefalexinb) N- [D-2,5-bis (2,3-diacetoxybenzoylamino) pentanoyl] - cefalexin (nach IUPAC: 7-{2-[2,5-Bis-(2,3-diacetoxybenzoyl­ amino)-pentanoylamino]-2-phenyl-acetylamino}-3-methyl-8- oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carbon­ säure) (38)(according to IUPAC: 7- {2- [2,5-bis- (2,3-diacetoxybenzoyl amino) -pentanoylamino] -2-phenyl-acetylamino} -3-methyl-8- oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-en-2-carbon acid) (38)

C43H43N5O15S (901,9), analog zu Substanz 30 aus dem Produkt aus Beispiel 38a) und Cefalexin,
Ausbeute: 40%C 43 H 43 N 5 O 15 S (901.9), analogously to substance 30 from the product from Example 38a) and cefalexin,
Yield: 40%

MS (Es-) 900,3 (100, M-H) 1H NMR (300 MHz, DMSO-d6, δ in ppm): 9,28 (d, 1H, NH); 8,55 (d, 1H, NH); 8,40 (d, 1H, NH); 8,35 (m, 1H, NH); 7,52-7,25 (m, 17H, ArH); 5,67 (d, 1H, CH); 5,63 (q, 1H, CH); 4,96 (d, 1H, CH); 4,58 (m, 1H, CHN); 3,30 (dd, 2H, CH2), 3,22 (m, 2H, CH2N); 2,27 (s, 6H, 2 × COOCH3); 2,22 (s, 6H, 2 × COOCH3); 1,98 (s, 3H, CH3); 1,90-­ 1,50 (m, 4H, 2 × CH2) MS (Es-) 900.3 (100, MH) 1 H NMR (300 MHz, DMSO-d6, δ in ppm): 9.28 (d, 1H, NH); 8.55 (d, 1H, NH); 8.40 (d, 1H, NH); 8.35 (m, 1H, NH); 7.52-7.25 (m, 17H, ArH); 5.67 (d, 1H, CH); 5.63 (q, 1H, CH); 4.96 (d, 1H, CH); 4.58 (m, 1H, CHN); 3.30 (dd, 2H, CH 2 ), 3.22 (m, 2H, CH 2 N); 2.27 (s, 6H, 2x COOCH 3 ); 2.22 (s, 6H, 2x COOCH 3 ); 1.98 (s, 3H, CH 3); 1.90 - 1.50 (m, 4H, 2 × CH 2 )

Tabelle 6 Table 6

MHK-Werte µg/ml MIC values µg / ml

Tabelle 7 Table 7

Vergleich der antibakteriellen Wirksamkeit der erfindungsgemäßen Substanz 31 und der Substanzen 7a und 7c aus Entgegenhaltung (9) Comparison of the antibacterial activity of substance 31 according to the invention and substances 7a and 7c from document (9)

Tabelle 8 Table 8

Vergleich der antibakteriellen Wirksamkeit der erfindungsgemäßen Substanz 31, der Substanzen 7a und 7c aus Entgegenhaltung (9) und der Substanz 1 aus Entgegenhaltung (2) unter Einsatz weiterer Stämme Comparison of the antibacterial activity of substance 31 according to the invention, substances 7a and 7c from document (9) and substance 1 from document (2) using further strains

Claims (3)

1. Catechol-Antibiotika-Konjugate der allgemeinen Formel I
in der R1 identisch C1-C4-O-Alkanoyl oder C1-C4-O-Alkoxy­ carbonyl bedeutet und R2 folgende Gruppen darstellt:
  • a) Aminosäurereste:
    Y = N-Ampicillino, N-Amoxicillino oder N-Cefalexino ist,
    R15 C1-C4-O-Alkanoyl oder C1-C4-O-Alkoxycarbonyl bedeutet,
    n eine ganze Zahl zwischen 1 und 5 ist,
  • b) Oxazolidincarbonsäurereste:
    Z = O,
    R16 und R17 H bedeuten,
    Y = N-Ampicillino ist.
1. Catechol-antibiotic conjugates of the general formula I
in which R 1 is identical to C 1 -C 4 -O-alkanoyl or C 1 -C 4 -O-alkoxy carbonyl and R 2 represents the following groups:
  • a) Amino acid residues:
    Y = N-ampicillino, N-amoxicillino or N-cefalexino,
    R 15 is C 1 -C 4 -O-alkanoyl or C 1 -C 4 -O-alkoxycarbonyl,
    n is an integer between 1 and 5,
  • b) Oxazolidine carboxylic acid residues:
    Z = O,
    R 16 and R 17 mean H,
    Y = N-ampicillino.
2. Verbindungen der allgemeinen Formel I gemäß Anspruch 1:
N-[L-2-(2,3-Diacetoxybenzoylamino)-propionyl]-ampicillin
N-[L-2,6-Bis-(2,3-diacetoxy-benzoylamino)-hexanoyl]-ampicillin
(S)-N-[3-(2,3-Dimethoxycarbonyloxybenzoyl)-oxazolidin-4-oyl]- ampicillin.2. Compounds of the general formula I according to claim 1:
N- [L-2- (2,3-diacetoxybenzoylamino) -propionyl] -ampicillin
N- [L-2,6-bis- (2,3-diacetoxy-benzoylamino) hexanoyl] -ampicillin
(S) -N- [3- (2,3-dimethoxycarbonyloxybenzoyl) oxazolidin-4-oyl] ampicillin. 3. Arzneimittel zur Bekämpfung von bakteriellen Infektionen enthaltend eine Verbindung der Formel I nach Anspruch 1 oder 2 zusammen mit üblichen Trägermaterialen.3. Medicines to fight bacterial infections containing a compound of formula I according to claim 1 or 2 together with usual carrier materials.
DE19625524A 1996-06-26 1996-06-26 New synthetic catechol-antibiotic conjugates and medicinal products containing them Expired - Fee Related DE19625524C2 (en)

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PE1997000491A PE70098A1 (en) 1996-06-26 1997-06-13 SYNTHETIC DERIVATIVES OF CATECOL
UY24596A UY24596A1 (en) 1996-06-26 1997-06-24 NEW SYNTHETIC DERIVATIVES OF CATECOL
CO97035121A CO4900028A1 (en) 1996-06-26 1997-06-24 DERIVATIVES OF CATECOL, ITS THERAPEUTIC APPLICATION AND MEDICINES THAT CONTAIN IT
ZA9705638A ZA975638B (en) 1996-06-26 1997-06-25 New synthetic catechol derivatives, methods of producing them and their use.
NO19985858A NO311975B1 (en) 1996-06-26 1998-12-14 New synthetic catechol derivatives, as well as drug containing such a compound
HK99103611A HK1018613A1 (en) 1996-06-26 1999-08-20 New synthetic cathecol derivatives, method for production and use thereof
GR20010401527T GR3036667T3 (en) 1996-06-26 2001-09-18 New synthetic catechol derivatives, method for production and use thereof

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DE10111164A1 (en) * 2001-03-01 2002-09-05 Gruenenthal Gmbh New catechol derivatives derived from amino acids have siderophore activity and are useful as growth factors in bacterial cultures and as prodrugs for iron chelators

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