DE10111163A1 - New siderophore-antibiotic conjugates with 4- or 6-toothed iron chelators based on amino acids or peptides, process for their preparation and their application - Google Patents

New siderophore-antibiotic conjugates with 4- or 6-toothed iron chelators based on amino acids or peptides, process for their preparation and their application

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DE10111163A1
DE10111163A1 DE10111163A DE10111163A DE10111163A1 DE 10111163 A1 DE10111163 A1 DE 10111163A1 DE 10111163 A DE10111163 A DE 10111163A DE 10111163 A DE10111163 A DE 10111163A DE 10111163 A1 DE10111163 A1 DE 10111163A1
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formula
alkyl
compounds
ampicillin
nhco
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Steffen Wittmann
Lothar Heinisch
Ute Moellmann
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HANS-KNOELL-INSTITUT FUER NATURSTOFF-FORSCHUNG E.V.,
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Gruenenthal GmbH
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Priority to PCT/EP2002/002074 priority patent/WO2002070017A1/en
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    • 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
    • A61K47/55—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds
    • A61K47/552—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 the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug, i.e. a dimer, oligomer or polymer of pharmacologically or therapeutically active compounds one of the codrug's components being an antibiotic

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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to novel conjugates of beta-lactam antibiotics of the general formula (I) with tetra- or hexadentate iron chelators or the acylated derivatives thereof as siderophore components, derived from amino acids or peptides, comprising at least 2 catechol substituents. In formula (I), R<1> represents a beta-lactam antibiotic, optionally with an intercalated further amino acid moiety, or R<1> represents various groups that contain a catechol or hydroxamate group as a complement to a hexadentate chelator structure, optionally in the acylated form or together with spacer groups, and that further contain the group of a beta-lactam antibiotic, especially of a penicillin or cephalosporin derivative, especially ampicillin, amoxicillin or cefaclor (as a free acid, in the form of their salts or their easily cleavable esters). The inventive compounds can be introduced into bacterial cells via the iron transport pathways on account of their siderophore components, thereby efficiently improving or enlarging their activity to a greater extent than known compounds of the kind. The inventive compounds are capable of overcoming resistances of problematic germs that cannot be treated.

Description

Die vorliegende Erfindung betrifft neue Siderophor-Antibiotikakonjugate, wobei als Siderophorkomponenten 6-zähnige Eisenchelatoren bzw ihre mit Acylgruppen maskierten Derivate fungieren, die von Aminosäuren bzw. Peptiden abgeleitet sind. Bei den Siderophorkomponenten (R1 bzw. A = OH) werden mindestens 4 chelatbildende Gruppen von Catecholeinheiten gebildet. Die neuen Siderophor- Antibiotikakonjugate sind antibakteriell wirksam, insbesondere gegen Gram-negative Bakterien, wobei die Antibiotika über Eisentransportwege in die Bakterienzelle eingeschleust werden und somit bei verminderten Nebenwirkungen deren Wirk­ samkeit wesentlich stärker verbessern bzw. erweitern können als bisherige Verbindungen dieser Art. Damit soll ein Beitrag geleistet werden zur Bekämpfung penetrationsbezogener Antibiotikaresistenz, die eine zentrale Rolle bei der Therapie bakterieller Infektionen spielt.The present invention relates to new siderophore-antibiotic conjugates, wherein 6-toothed iron chelators or their derivatives masked with acyl groups, which are derived from amino acids or peptides, function as siderophore components. With the siderophore components (R 1 or A = OH) at least 4 chelating groups of catechol units are formed. The new Siderophor antibiotic conjugates are antibacterially effective, especially against Gram-negative bacteria, whereby the antibiotics are introduced into the bacterial cell via iron transport routes and thus, with reduced side effects, can improve or expand their effectiveness significantly more than previous compounds of this type Contribution is made to combating penetration-related antibiotic resistance, which plays a central role in the treatment of bacterial infections.

Siderophor-Antibiotikakonjugate der Formel I mit den angegebenen Substituenten sind bisher in der Literatur nicht beschrieben.Siderophore-antibiotic conjugates of formula I with the specified substituents have not yet been described in the literature.

Es ist bekannt, daß bestimmte Catecholstrukturen in natürlichen Siderophoren als eisenkomplexierende Strukturelemente eine wesentliche Rolle spielen ("Iron Transport in Microbes, Plants and Animals", Hrsg.: Winkelmann, G., von Helm, D., Neilands, J. B., V. Ch.-Verlagsgesellschaft Weinheim, 1987), z. B. ist das Enterobactin, ein Siderophor bei E.coli und anderen Bakterienstämmen, 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 catecholsubstituierte Aminosäurederivate sind bereits syn­ thetisch hergestellt worden, z. B. das N-(2,3-Dihydroxybenzoyl)-L-threonin (Kanal, F.; Kaneko, T., Morishima, H., Isshiki, K., Takita, T., Takeuchi, T., Umezawa,H., J. Antibiot. 38 (1985), 39), das N2,N6-Bis-(2,3-Dihydroxybenzoyl)-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)-lysyl-N6- (2,3-dihydroxybenzoyl)lysin (Chimiak, A., Neilands, J. B., Structure and Bonding, 58 (1984), 89). Verschiedene O-Acylierte Catecholverbindungen, abgeleitet von Mono- und Diaminosäuren (L. Heinisch, M. Schnabelrauch, U. Möllmann, R. Reissbrodt, DE 196 54 920 A1) sowie auch von diesen Catecholverbindungen abgeleitete Benzoxazin- 2,4-dion-Derivate (L. Heinisch, S. Wittmann, U. Möllmann, R. Reissbrodt, EP 0 863 139 A1) sind bekannt geworden. Von letzteren Verbindungen sind auch bereits einige Derivate von mehrbasischen sekundären Aminosäuren beschrieben. Die genannten Catecholderivate sind mit Antibiotika zu in vitro antibakteriell hochwirksamen Konjugaten umgesetzt worden.It is known that certain catechol structures in natural siderophores play an essential role as iron-complexing structural elements ("Iron Transport in Microbes, Plants and Animals", ed .: Winkelmann, G., von Helm, D., Neilands, JB, V. Ch . Publishing house 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 syn. B. the N- (2,3-dihydroxybenzoyl) -L-threonine (Kanal, F .; Kaneko, T., Morishima, H., Isshiki, K., Takita, 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) -lysyl-N 6 - (2,3 dihydroxybenzoyl) lysine (Chimiak, A., Neilands, JB, Structure and Bonding, 58 (1984), 89). Various O-acylated catechol compounds derived from mono- and diamino acids (L. Heinisch, M. Schnabelrauch, U. Möllmann, R. Reissbrodt, DE 196 54 920 A1) as well as benzoxazine-2,4-dione derivatives derived from these catechol compounds (L. Heinisch, S. Wittmann, U. Möllmann, R. Reissbrodt, EP 0 863 139 A1) have become known. Some derivatives of polybasic secondary amino acids have already been described for the latter compounds. The catechol derivatives mentioned have been converted with antibiotics to conjugates which are highly antibacterial in vitro.

Verschiedene andere Catecholverbindungen wurden mit β-Laktamen verknüpft, wodurch eine beträchtliche Steigerung der antibakteriellen Wirksamkeit dieser Antibiotika erzielt wurde, bedingt durch eine Einschleusung über bakterielle Eisentransportwege in die Bakterienzelle (z. B. Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, R. L., Antimicrob. Agents Chemother. 35 (1991), 653). Bisher sind jedoch keine derartigen Verbindungen zu einer klinischen Anwen­ dungsreife gelangt. Zur Erreichung dieses Zieles muß nach weiteren Siderophor- Antibiotikakonjugaten mit neuen synthetischen Siderophoren gesucht werden, die noch bessere antibakterielle Wirksamkeit, z. B. gegen resistente pathogene Problemkeime wie Stenotrophomonas maltophilia, und geringere Nebenwirkungen besitzen, als die bisher bekannten Verbindungen dieser Art.Various other catechol compounds have been linked to β-lactams, thereby significantly increasing the antibacterial effectiveness of this Antibiotics was achieved due to an introduction via bacterial Iron transport routes into the bacterial cell (e.g. Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, R.L., Antimicrob. Agents chemother. 35: 653 (1991). So far, however, there are no such connections to a clinical application reached maturity. To achieve this goal, further siderophore Antibiotic conjugates with new synthetic siderophores are being sought even better antibacterial activity, e.g. B. against resistant pathogens Problem germs like Stenotrophomonas maltophilia, and fewer side effects own than the previously known compounds of this type.

Die Erfindung dient zur Gewinnung neuer Siderophor-Antibiotika-Konjugate mit 4- oder 6-zähnigen Eisenchelatoren, die mindestens 2 Catecholeinheiten bzw. deren acylierte Derivate enthalten, abgeleitet von Aminosäuren oder Peptiden, sowie zu ihrer Verwendung. Mit der Erfindung wird angestrebt, geeignete Verbindungen zur Einschleusung von Wirkstoffen, z. B. von Antibiotika in die Bakterienzelle, zu entwickeln, die die bisher beschriebenen Verbindungen dieser Art übertreffen. Durch Anwendung acylierter Catecholderivate soll erreicht werden, daß die Verbindungen verbesserte pharmakologische Eigenschaften erhalten bzw. als pharmakologische Transportformen für die eigentlich penetrationsfördernden Catecholverbindungen dienen können und weniger toxisch sind.The invention serves to obtain new siderophore-antibiotic conjugates with 4- or 6-toothed iron chelators containing at least 2 catechol units or their Acylated derivatives contain, derived from amino acids or peptides, as well their use. The invention aims to provide suitable connections for Introduction of active ingredients, e.g. B. of antibiotics in the bacterial cell develop that surpass the previously described compounds of this type. By Application of acylated catechol derivatives should be achieved that the compounds receive improved pharmacological properties or as pharmacological Transport forms for the actually penetration-promoting catechol compounds can serve and are less toxic.

Der Erfindung liegt die Aufgabe zugrunde, neue Siderophor-Antibiotikakonjugate der allgemeinen Formel I aufzufinden, die über stärkere antibakterielle Wirksamkeit verfügen, als vergleichbare bekannte Verbindungen diese Art. Als Siderophorkomponenten sollen dabei 4- oder 6-zähnige Eisenchelatoren bzw ihre acylierten Derivate fungieren, wobei mindestens 2 Catecholsubstituenten bzw. deren acylierte Derivate, abgeleitet von Aminosäuren oder Peptiden, beteiligt sind.The invention is based, new siderophore antibiotic conjugates the task general formula I find the more potent antibacterial effectiveness  have, as comparable known compounds of this kind Siderophore components are said to be 4- or 6-toothed iron chelators or their acylated derivatives act, with at least 2 catechol substituents or their acylated derivatives derived from amino acids or peptides are involved.

Die Aufgabe wird erfindungsgemäß gelöst, indem neue Siderophor- Antibiotikakonjugate mit 4- oder 6-zähnigen Eisenchelatoren bzw. deren acylierten Derivaten auf der Basis von Aminosäuren oder Peptiden der allgemeinen Formel I bereitgestellt werden,
The object is achieved according to the invention by providing new siderophore-antibiotic conjugates with 4- or 6-toothed iron chelators or their acylated derivatives based on amino acids or peptides of the general formula I,

worin
R1 = A ist,
oder R1 =
wherein
R 1 = A,
or R 1 =

mit R6 = H, Alkyl, Hydroxyalkyl, Acyloxyalkyl, Alkyloxyalkyl, Carboxy, Alkyloxycarbonyl, Aryl, Arylalkyl, Arylalkyloxyalkyl, Hetaryl, Hetarylalkyl m = 0-5 = R11
oder R1 =
with R 6 = H, alkyl, hydroxyalkyl, acyloxyalkyl, alkyloxyalkyl, carboxy, alkyloxycarbonyl, aryl, arylalkyl, arylalkyloxyalkyl, hetaryl, hetarylalkyl m = 0-5 = R 11
or R 1 =

= R12
mit o = 1-5
oder R1 =
= R 12
with o = 1-5
or R 1 =

= R13
mit R7 = H, Alkyl, Alkyl, Alkyloxycarbonylalkyl, R8 = H, Aroyl, o = 1-5
oder R1 =
= R 13
with R 7 = H, alkyl, alkyl, alkyloxycarbonylalkyl, R 8 = H, aroyl, o = 1-5
or R 1 =

o = 1-5 = R14
mit R8 = H, Aroyl, R9 = H, Alkyl, Cycloalkyl, Alkyloxycarbonylalkyl, o = 1-5
oder R1 =
o = 1-5 = R 14
with R 8 = H, aroyl, R 9 = H, alkyl, cycloalkyl, alkyloxycarbonylalkyl, o = 1-5
or R 1 =

mit p = 1-5, q = 1-5 = R15
oder R1 =
with p = 1-5, q = 1-5 = R 15
or R 1 =

mit o = 1-5, p = 1-5, R10 = H, COAlkyl, COOAlkyl = R16
R2 = H, COAlkyl, COOAlkyl,
R5 = H
oder R5 stellt zusammen mit einem der Reste R2 oder R10 eine Gruppe -CO- dar,
R3 = H, COAlkyl, COOAlkyl,
R4 = H, Alkyl, subst. Alkyl, Aryl, subst. Aryl, Halogen, Alkoxy, subst. Alkoxy, in allen möglichen Positionen, auch mehrfach auftretend,
A = der Rest eines β-Laktamantibiotikums, vorzugsweise der Rest eines Penicillinderivates insbesondere ein Ampicillin- oder Amoxicillinrest (Formel B) oder ein Bacampicillinrest (α-Ethoxycarbonyloxyethylester des Ampicillins), oder der Rest eines Cephalosporins, insbesondere ein Cefachlorrest (Formel C) oder ein Chinolonrest
with o = 1-5, p = 1-5, R 10 = H, COalkyl, COOalkyl = R 16
R 2 = H, CO alkyl, COO alkyl,
R 5 = H
or R 5 together with one of the radicals R 2 or R 10 represents a group -CO-,
R 3 = H, CO alkyl, COO alkyl,
R 4 = H, alkyl, subst. Alkyl, aryl, subst. Aryl, halogen, alkoxy, subst. Alkoxy, in all possible positions, also occurring several times,
A = the residue of a β-lactam antibiotic, preferably the residue of a penicillin derivative, in particular an ampicillin or amoxicillin residue (formula B) or a bacampicillin residue (α-ethoxycarbonyloxyethyl ester of ampicillin), or the residue of a cephalosporin, in particular a cefachlor residue (formula C) or one quinolone

bedeuten, wobei in den vorstehenden Formeln Acyl insbesondere C1-C4-Alkanoyl oder C1-C4-Alkoxycarbonyl, Alkyl und Alkoxy, auch in Wortkombinationen wie Alkoxycarbonyl, sind insbesondere C1-C8-Alkyl bzw. -Alkoxy, substituiertes Alkyl für durch Halogen, Alkoxy, Hydroxy, Carboxy und Alkoxycarbonyl substituiertes Alkyl, substituiertes Alkoxy für durch Halogen, Alkoxy, Carboxy und Alkoxycarbonyl sub­ stituiertes Alkoxy, ein substituiertes Phenyl ein durch Alkyl, Halogen, Alkoxy, Hydroxy, Carboxy und Alkoxycarbonyl substituiertes Phenyl bedeuten. Im Falle des Vorliegens asymmetrischer C-Atome sind die entsprechenden D- und L-Formen, Enantiomere und Diastereomere sowie die Racemate bzw. Enantiomeren- und Diastereomerengemische ebenfalls Gegenstand der Erfindung. Die genannten Verbindungen können als freie Säuren, in Form ihrer Salze oder als leicht spaltbare, wie unter physiologischen Bedingungen spaltbare Ester vorliegen, mit der Maßgabe, daß R4 und/oder R5 nicht gleich H ist, wenn R1 = A ist.mean, in the above formulas acyl in particular C 1 -C 4 alkanoyl or C 1 -C 4 alkoxycarbonyl, alkyl and alkoxy, also in word combinations such as alkoxycarbonyl, in particular C 1 -C 8 alkyl or alkoxy, are substituted Alkyl for alkyl substituted by halogen, alkoxy, hydroxy, carboxy and alkoxycarbonyl, substituted alkoxy for alkoxy substituted by halogen, alkoxy, carboxy and alkoxycarbonyl, a substituted phenyl being a phenyl substituted by alkyl, halogen, alkoxy, hydroxy, carboxy and alkoxycarbonyl. If asymmetric carbon atoms are present, the corresponding D and L forms, enantiomers and diastereomers and the racemates or mixtures of enantiomers and diastereomers are likewise the subject of the invention. The compounds mentioned can be present as free acids, in the form of their salts or as easily cleavable esters which can be cleaved under physiological conditions, with the proviso that R 4 and / or R 5 is not H when R 1 = A.

Die erfindungsgemäß bereitgestellten Verbindungen der Formel I werden folgendermaßen hergestellt:The compounds of formula I provided according to the invention are manufactured as follows:

Zunächst werden nach an sich bekannten Verfahren Biscatecholderivate der Formel 1 mit R1 bzw. A = OH aus entsprechenden Diaminosäuren und Derivaten von 2,3-Dihydroxybenzoesäure (z. B. 2,3-Diacyloxybenzoylchlorid) hergestellt und diese dann mit den entsprechenden Aminosäurederivaten R1H, wobei R1 = R11-R16 ist, nach üblichen Methoden, z. B. nach der Gemischtanhydridmethode oder nach der Aktivestermethode, umgesetzt, wodurch die Siderophorkomponenten (Formel I mit R1 = R11-R16 und A = OH) erhalten werden. Diese Verbindungen werden dann mit einem entsprechenden Antibiotikum, insbesondere mit einem β- Laktamantibiotikum, z. B. Ampicillin oder Amoxicillin, oder einem geeigneten Cephalosporinderivat nach üblichen Verfahren, vorzugsweise nach dem Anhydridverfahren (beispielsweise mittels Chlorameisensäureisobutylester), nach dem Aktivesterverfahren (z. B. mit N-Hydroxysuccinimid und Dicyclohexylcarbodiimid) oder nach der Chloridmethode zu den Siderophor- Antibiotikakonjugaten der Formel I mit A = Antibiotikum umgesetzt.First of all, biscatechol derivatives of the formula 1 with R 1 or A = OH are prepared from corresponding diamino acids and derivatives of 2,3-dihydroxybenzoic acid (for example 2,3-diacyloxybenzoyl chloride) and these are then prepared with the corresponding amino acid derivatives R. 1 H, where R 1 = R 11 -R 16 , by conventional methods, e.g. B. implemented according to the mixed anhydride method or according to the active ester method, whereby the siderophore components (formula I with R 1 = R 11 -R 16 and A = OH) are obtained. These compounds are then treated with an appropriate antibiotic, in particular with a β-lactam antibiotic, e.g. B. ampicillin or amoxicillin, or a suitable cephalosporin derivative by conventional methods, preferably by the anhydride method (for example by means of isobutyl chloroformate), by the active ester method (z. B. with N-hydroxysuccinimide and dicyclohexylcarbodiimide) or by the chloride method to the Sideropjug antibiotics antibiotics I implemented with A = antibiotic.

Die Ausgangsverbindungen der Formel I mit R1 bzw. A = OH werden wie folgt hergestellt: Zunächst werden nach an sich bekannten Verfahren Bis- catecholderivate der Formel I mit R1 = OH aus entsprechenden Diaminosäuren und Derivaten von 2,3-Dihydroxybenzoesäure (z. B. 2,3-Diacyloxybenzoylchlorid) hergestellt und diese dann mit den entsprechenden Aminosäurederivaten R1H, wobei R1 = R11-R16 ist, nach üblichen Methoden, z. B. nach der Gemischtan­ hydridmethode oder nach der Aktivestermethode, umgesetzt, wodurch die Sidero­ phorkomponenten der Formel I mit R1 = R11-R16 erhalten werden.The starting compounds of the formula I with R 1 or A = OH are prepared as follows: First, biscatechol derivatives of the formula I with R 1 = OH are obtained from corresponding diamino acids and derivatives of 2,3-dihydroxybenzoic acid (e.g. B. 2,3-diacyloxybenzoyl chloride) and this then with the corresponding amino acid derivatives R 1 H, where R 1 = R 11 -R 16 , by conventional methods, for. B. implemented by the mixed hydride method or by the active ester method, whereby the siderophore components of the formula I with R 1 = R 11 -R 16 are obtained.

Die Verbindungen der Formel I mit einer Carboxylgruppe können als freie Säuren, in Form ihrer Salze oder als leicht spaltbare, insbesondere unter physiologischen Bedin­ gungen spaltbare, Ester vorliegen. Eine weitere Reinigung der Verbindungen kann nach üblichen, aus dem Stand der Technik bekannten Verfahren, beispielsweise mittels chromatographischer Methoden erfolgen.The compounds of formula I with a carboxyl group can be used as free acids, in Form of their salts or as easily cleavable, especially under physiological conditions conditions cleavable, esters are present. Further cleaning of the connections can by conventional methods known from the prior art, for example using chromatographic methods.

Die erfindungsgemäßen Verbindungen der Formel I zeigen antibakterielle Wirksamkeit, die z. T. die Wirksamkeit bisher bekannter vergleichbarer Verbindungen weit übertrifft.The compounds of formula I according to the invention show antibacterial Effectiveness, the z. T. the effectiveness of previously known comparable compounds far exceeds.

Die Prüfung auf antibakterielle Wirksamkeit erfolgte in einem Mikrodilutionstest nach National Committee for Clinical Laboratory Standards, 1998, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, Approved standard M7-A4, NCCLS, Villanova, Pa. Danach wurden die Verbindungen auf ihre minimalen Hemmkonzentrationen (MHK-Werte) gegen folgende Bakterienstämme geprüft: The test for antibacterial effectiveness was carried out in a microdilution test National Committee for Clinical Laboratory Standards, 1998, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, approved standard M7-A4, NCCLS, Villanova, Pa. After that, the connections were made to their minimum Inhibitory concentrations (MIC values) tested against the following bacterial strains:  

Gegen die Gram-negativen Stämme Pseudomonas aeruginosa SG 137, ATCC 27853, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 10031, Stenotrophomonas maltophilia GN 12873, Serratia marcescens SG 621 sowie gegen den Gram-positiven Stamm Staphylococcus aureus SG 511.Against the Gram-negative strains Pseudomonas aeruginosa SG 137, ATCC 27853, Escherichia coli ATCC 25922, Klebsiella pneumoniae ATCC 10031, Stenotrophomonas maltophilia GN 12873, Serratia marcescens SG 621 and against the Gram-positive strain Staphylococcus aureus SG 511.

Die Ergebnisse der antibakteriellen Testung sind in der Tabelle zusammengefaßt. Zum Vergleich sind die entsprechenden Werte von Azlocillin, Ampicillin und Meropenem angeführt. Aus den Resultaten geht hervor, daß die erfindungsgemäß dargestellten Substanzen z. T. gegen einige Bakterienstämme die Hemmwerte der Vergleichssubstanzen weit übertreffen und erfolgreich bakterielle Resistenzen über­ winden können. Die Verbindungen zeigen auch eine stärkere Wirksamkeit gegen Gram-negative Bakterien als bisher bekannte entsprechende Catecholat-β- Laktamkonjugate nach Angaben der oben genannten Literatur, darunter auch gegen den Problemkeim Stenofrophomonas maltophilla.The results of the antibacterial testing are summarized in the table. For comparison, the corresponding values of azlocillin, ampicillin and Meropenem listed. The results show that the invention substances shown z. T. against some bacterial strains the inhibitory values of Comparative substances far outperform and successfully overcome bacterial resistance can wind. The compounds also show a stronger activity against Gram-negative bacteria as known catecholate-β- Lactam conjugates according to the literature mentioned above, including against the problem germ Stenofrophomonas maltophilla.

Die Verbindungen der allgemeinen Formel I eignen sich aufgrund ihrer antibakteriellen Eigenschaften zur Anwendung als Arzneimittel bei bakteriellen Infektionen. Bei solchen Erkrankungen können die Verbindungen der Formel I entweder allein oder mit physiologisch verträglichen Hilfs- oder Trägerstoffen angewandt werden, wobei prinzipiell alle üblichen pharmakologischen Anwen­ dungsformen und physiologisch verträglichen Dosierungen möglich sind.The compounds of general formula I are suitable because of their antibacterial properties for use as pharmaceuticals in bacterial Infections. In such diseases, the compounds of formula I either alone or with physiologically compatible auxiliaries or carriers are used, in principle all the usual pharmacological applications dosage forms and physiologically compatible doses are possible.

Ausführungsbeispieleembodiments Beispiel 1example 1 N-[N2,N5-Bis-(5-brom-2,3-diacetoxybenzoyl)-L-ornithyl]-ampicillinN- [N 2 , N 5 -Bis- (5-bromo-2,3-diacetoxybenzoyl) -L-ornithyl] ampicillin

Formel I mit R1 = Ampicillino, R2, R3 = COCH3, R4 = 5-Br, R5 = H, n = 3.Formula I with R 1 = Ampicillino, R 2 , R 3 = COCH 3 , R 4 = 5-Br, R 5 = H, n = 3.

Zu einer Lösung von 0,730 g (1 mmol) N2,N5-Bis-(5-brom-2,3-diacetoxy­ benzoyl)-L-ornithin und 0,112 ml N-Methylmorpholin in 10 ml wasserfreiem Tetrahydrofuran wurden bei -20°C unter Rühren 0,131 ml (1 mmol) Chlorameisen­ säureisobutylester zugegeben. Die Mischung wurde eine Stunde bei ca -10°C gerührt und anschließend eine Lösung von 0,412 g (1 mmol) Ampicillin Trihydrat und 0,140 ml (1 mmol) Triethylamin in 5 ml 80%igem Tetrahydrofuran zugefügt. Es wurde eine Stunde bei ca -10 C und eine Stunde bei 20°C gerührt, dann im Vak. eingedampft, der Rückstand mit Essigsäureethylester und Wasser versetzt und vorsichtig mit 1 M Salzsäure angesäuert. Nach Umschütteln wurde die organische Phase abgetrennt, mit wässriger Natriumchloridlösung gewaschen, über Natriumsulfat getrocknet und eingedampft. Der Rückstand wurde durch präparative HPLC an Kieselgel (Eurospher 100 C18, 7 µm, Fa. Knauer, Berlin) mit einem Gemisch Acetonitril/Wasser (37,5/62,5) als Elutionsmittel gereinigt. Von der entsprechenden Fraktion wurde das Acetonitril i. Vak. abdestilliert und der Rückstand lyophilisiert. Dabei fielen 0,40 g (40% d. Th.) der Titelverbindung in Form eines farblosen Feststoffes an.
1H NMR (DMSO-d6): 1,39 (s, 3H, CH3); 1,53 (s, 3H, CH3); 1,45-1,90 (m, 4H, 2 × CH2); 2,16 (s, 3H, COCH3); 2,21 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 3,17 (m, 2H, CH2); 4,19 (s, 1H, 3-CH); 4,62 (1H, m, CH); 5,38 (d, 1H, 7-CH); 5,52 (q, 1H, 6-CH); 5,75 (d, 1H, a-CH); 7,20-7,75 (m, 9H, aromat.); 8,45 (t, 1H, NHCO); 8,52 (d, 1H, NHCO); 8,67 (d, 1H, NHCO); 9,16 (d, 1H, NHCO).A solution of 0.730 g (1 mmol) of N 2 , N 5- bis (5-bromo-2,3-diacetoxybenzoyl) -L-ornithine and 0.112 ml of N-methylmorpholine in 10 ml of anhydrous tetrahydrofuran were added at -20 ° C 0.131 ml (1 mmol) of chloroformate isobutyl ester was added with stirring. The mixture was stirred at about -10 ° C. for one hour and then a solution of 0.412 g (1 mmol) of ampicillin trihydrate and 0.140 ml (1 mmol) of triethylamine in 5 ml of 80% tetrahydrofuran was added. It was stirred for one hour at about -10 C and one hour at 20 ° C, then in vacuo. evaporated, the residue mixed with ethyl acetate and water and carefully acidified with 1 M hydrochloric acid. After shaking, the organic phase was separated, washed with aqueous sodium chloride solution, dried over sodium sulfate and evaporated. The residue was purified by preparative HPLC on silica gel (Eurospher 100 C18, 7 μm, from Knauer, Berlin) with a mixture of acetonitrile / water (37.5 / 62.5) as the eluent. The acetonitrile was i. Vak. distilled off and the residue lyophilized. 0.40 g (40% of theory) of the title compound were obtained in the form of a colorless solid.
1 H NMR (DMSO-d6): 1.39 (s, 3H, CH 3 ); 1.53 (s, 3H, CH 3); 1.45-1.90 (m, 4H, 2 x CH 2 ); 2.16 (s, 3H, COCH 3 ); 2.21 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 3.17 (m, 2H, CH 2); 4.19 (s, 1H, 3-CH); 4.62 (1H, m, CH); 5.38 (d, 1H, 7-CH); 5.52 (q, 1H, 6-CH); 5.75 (d, 1H, a-CH); 7.20-7.75 (m, 9H, aromat.); 8.45 (t, 1H, NHCO); 8.52 (d, 1H, NHCO); 8.67 (d, 1H, NHCO); 9.16 (d, 1H, NHCO).

Das Natriumsalz der Titelverbindung wurde hergestellt, indem eine Lösung von 0,02 g Natriumethylhexanoat in 3 ml Essigsäureethylester zu einer Lösung von 0,10 g der Titelverbindung in 12 ml Essigsäureethylester gegeben wurde. Der ausgefallene Niederschlag wurde nach 10 Minuten Stehen abfiltriert und mit Petrolether gewaschen. Dabei wurde das Natriumsalz der Titelverbindung in Form eines farblosen amorphen Feststoffes in 90%iger Ausbeute erhalten. The sodium salt of the title compound was prepared by a solution of 0.02 g of sodium ethyl hexanoate in 3 ml of ethyl acetate to a solution of 0.10 g of the title compound was added to 12 ml of ethyl acetate. The precipitate was filtered off after 10 minutes standing and with Washed petroleum ether. The sodium salt of the title compound was in the form obtained a colorless amorphous solid in 90% yield.  

Beispiel 2Example 2 N-{N'-[N2,N5-Bis-(2,3-diacetoxybenzoyl)-L-ornithyl]-L-O-benzyl-seryl}-ampicillinN- {N '- [N 2 , N 5 -Bis- (2,3-diacetoxybenzoyl) -L-ornithyl] -LO-benzyl-seryl} -ampicillin

Formel I mit R1 = R11, R4, R5 = H; R2, R3 = COCH3, R6 = CH2OBenzyl, n = 3,m = 0, A = Ampicillino.Formula I with R 1 = R 11 , R 4 , R 5 = H; R 2 , R 3 = COCH 3 , R 6 = CH 2 OBenzyl, n = 3, m = 0, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-[N2,N5-Bis-(2,3-diacetoxybenzoyl)-L-ornithyl]-L-O-benzyl-serin und Ampicillin Trihydrat in 50%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,40 (s, 3H, CH3); 1,55 (s, 3H, CH3); 1,45-1,90 (m, 4H, 2 × CH2); 2,19 (s, 3H, COCH3); 2,20 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 3,18 (m, 2H, CH2); 3,63 (m, 2H, CH2); 4,19 (s, 1H, 3-CH); 4,47 (2H, s, CH2Ph); 4,55 (m, 1H, CH); 4,78 (1H, m, CH); 5,38 (d, 1H, 7-CH); 5,51 (q, 1H, 6-CH); 5,78 (d, 1H, a-CH); 7,20-7,60-(m, 16H, aromat.); 8,18 (d, 1H, NHCO); 8,33 (m, 2H, 2 × NHCO); 8,68 (d, 1H, NHCO); 9,20 (d, 1H, NH).The title compound or its sodium salt was prepared analogously to Example 1 from N- [N 2 , N 5- bis (2,3-diacetoxybenzoyl) -L-ornithyl] -LO-benzyl-serine and ampicillin trihydrate in 50% strength Yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.40 (s, 3H, CH 3 ); 1.55 (s, 3H, CH 3); 1.45-1.90 (m, 4H, 2 x CH 2 ); 2.19 (s, 3H, COCH 3 ); 2.20 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 3.18 (m, 2H, CH 2); 3.63 (m, 2H, CH 2); 4.19 (s, 1H, 3-CH); 4.47 (2H, s, CH 2 Ph); 4.55 (m, 1H, CH); 4.78 (1H, m, CH); 5.38 (d, 1H, 7-CH); 5.51 (q, 1H, 6-CH); 5.78 (d, 1H, a-CH); 7.20-7.60- (m, 16H, aromat.); 8.18 (d, 1H, NHCO); 8.33 (m, 2H, 2x NHCO); 8.68 (d, 1H, NHCO); 9.20 (d, 1H, NH).

Beispiel 3Example 3 N-{N'-[N2,N5-Bis(2,3-diacetoxybenzoyl)-L-ornithyl]-L-tryptophanyl}-ampicillinN- {N '- [N 2 , N 5 bis (2,3-diacetoxybenzoyl) -L-ornithyl] -L-tryptophanyl} -ampicillin

Formel I mit R1 = R11, R2, R3 = COCH3, R4, R5 = H., R6 = L-Indolyl-2-methyl, n = 3, m = 0, L,L-Form A = Ampicillino.Formula I with R 1 = R 11 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., R 6 = L-indolyl-2-methyl, n = 3, m = 0, L, L- Form A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-[N2,N5-Bis(2,3-diacetoxybenzoyl)-L-ornithyl]-L-tryptophan und Ampicillin Trihydrat in 30%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,39 (s, 3H, CH3); 1,54 (s, 3H, CH3); 1,50-1,90 (m, 4H, 2 × CH2); 2,16 (s, 3H, COCH3); 2,17 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 3,18 (m, 2H, NCH2); 3,35 (m, 2H, Tr-CH2); 4,18 (s, 1H, 3-CH); 4,44 (m, 1H, CH); 4,81 (m, 1H, CH); 5,36 (d, 1H, 7-CH); 5,49 (q, 1H, 6-CH); 5,72 (d, 1H, a-CH); 6,85-7,60 (m, 16H, aromat.); 8,07 (d, 1H, NHCO); 8,32 (m, 2H, 2 × NHCO); 8,71 (d, 1H, NHCO); 9,20 (d, 1H, NHCO); 10,78 (s, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N- [N 2 , N 5 -bis (2,3-diacetoxybenzoyl) -L-ornithyl] -L-tryptophan and ampicillin trihydrate in 30% yield in the form a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.39 (s, 3H, CH 3 ); 1.54 (s, 3H, CH 3); 1.50-1.90 (m, 4H, 2 x CH 2 ); 2.16 (s, 3H, COCH 3 ); 2.17 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 3.18 (m, 2H, NCH 2); 3.35 (m, 2H, Tr-CH2); 4.18 (s, 1H, 3-CH); 4.44 (m, 1H, CH); 4.81 (m, 1H, CH); 5.36 (d, 1H, 7-CH); 5.49 (q, 1H, 6-CH); 5.72 (d, 1H, a-CH); 6.85-7.60 (m, 16H, aromat.); 8.07 (d, 1H, NHCO); 8.32 (m, 2H, 2x NHCO); 8.71 (d, 1H, NHCO); 9.20 (d, 1H, NHCO); 10.78 (s, 1H, NHCO).

Beispiel 4Example 4 N-{N'-[Bis-N2,N5-(2,3-diacetoxybenzoyl)-L-ornithyl]-L-phenylalanyl}-ampicillinN- {N '- [Bis-N 2 , N 5 - (2,3-diacetoxybenzoyl) -L-ornithyl] -L-phenylalanyl} -ampicillin

Formel I mit R1 = R11, mit R6 = Benzyl, R2, R3 = COCH3, R4, R5 = H, n = 3, m = 0, A = Ampicillino. Formula I with R 1 = R 11 , with R 6 = benzyl, R 2 , R 3 = COCH 3 , R 4 , R 5 = H, n = 3, m = 0, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-[Bis-N2,N5-(2,3-diacetoxybenzoyl)-ornithyl]-L-phenylalanin und Ampicillin Trihydrat in 30%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,40 (s, 3H, CH3); 1,55 (s, 3H, CH3); 1,50-1,90 (m, 4H, 2 × CH2); 2,18 (s, 3H, COCH3); 2,19 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 2,99 (m, 2H, CH2-Ph); 3,17 (m, 2H, CH2); 4,18 (s, 1H, 3-CH); 4,45 (m, 1H, CH); 4,82 (m, 1H, CH); 5,37 (d, 1H, 7-CH); 5,52 (q, 1H, 6-CH); 5,78 (d, 1H, a-CH); 7,10-7,50 (m, 16H, aromat.H); 8,10 (d, 1H, NHCO); 8,21 (t, 1H, NHCO); 8,30 (d, 1H, NHCO); 8,85 (d, 1H, NHCO); 9,22 (d, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N- [bis-N 2 , N 5 - (2,3-diacetoxybenzoyl) -ornithyl] -L-phenylalanine and ampicillin trihydrate in the form of a 30% yield colorless amorphous solid.
1 H NMR (DMSO-d6): 1.40 (s, 3H, CH 3 ); 1.55 (s, 3H, CH 3); 1.50-1.90 (m, 4H, 2 x CH 2 ); 2.18 (s, 3H, COCH 3 ); 2.19 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 2.99 (m, 2H, CH 2 -Ph); 3.17 (m, 2H, CH 2); 4.18 (s, 1H, 3-CH); 4.45 (m, 1H, CH); 4.82 (m, 1H, CH); 5.37 (d, 1H, 7-CH); 5.52 (q, 1H, 6-CH); 5.78 (d, 1H, a-CH); 7.10-7.50 (m, 16H, aromatic H); 8.10 (d, 1H, NHCO); 8.21 (t, 1H, NHCO); 8.30 (d, 1H, NHCO); 8.85 (d, 1H, NHCO); 9.22 (d, 1H, NHCO).

Beispiel 5Example 5 N-{2-[N2,N5-Bis-(2,3-diacetoxybenzoyl)-L-ornithyl-amino]-4-(benzyloxycarbonyl)-n- butanoyl}-ampicillinN- {2- [N 2 , N 5 -Bis- (2,3-diacetoxybenzoyl) -L-ornithylamino] -4- (benzyloxycarbonyl) -n-butanoyl} amicillin

Formel I mit R1 = R11, R2, R3 = COCH3, R4, R5 = H., R6 = 2- Benzyloxycarbonylethyl, n = 3, m = 0, L,L-Form, A = Ampicillino.Formula I with R 1 = R 11 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., R 6 = 2-benzyloxycarbonylethyl, n = 3, m = 0, L, L-form, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-[N2,N5-Bis-(2,3-diacetoxybenzoyl)-L-ornithyl]-L-glutaminsäure-5- benzylester und Ampicillin Trihydrat in 45%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,39 (s, 3H, CH3); 1,54 (s, 3H, CH3); 1,50-1,90 (m, 6H, 3 × CH2); 2,18 (s, 3H, COCH3); 2,19 (s, 3H, COCH3); 2,26 (s, 6H, COCH3); 2,32 (m, 2H, CH2); 3,17 (m, 2H, CH2); 4,19 (s, 1H, 3-CH); 4,48 (m, 2H, 2 × CH); 5,04 (s, 2H, benzyl. CH2); 5,37 (d, 1H, 7-CH); 5,51 (q, 1H, 6-CH); 5,73 (d, 1H, a-CH); 7,25-7,50 (m, 16H, aromat.); 8,10 (d, 1H, NHCO); 8,29 (m, 1H, NHCO); 8,35 (d, 1H, NHCO); 8,82 (d, 1H, NHCO); 9,17 (d, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N- [N 2 , N 5- bis (2,3-diacetoxybenzoyl) -L-ornithyl] -L-glutamic acid 5-benzyl ester and ampicillin trihydrate in 45 % yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.39 (s, 3H, CH 3 ); 1.54 (s, 3H, CH 3); 1.50-1.90 (m, 6H, 3 x CH 2); 2.18 (s, 3H, COCH 3 ); 2.19 (s, 3H, COCH 3 ); 2.26 (s, 6H, COCH 3 ); 2.32 (m, 2H, CH 2); 3.17 (m, 2H, CH 2); 4.19 (s, 1H, 3-CH); 4.48 (m, 2H, 2x CH); 5.04 (s, 2H, benzyl. CH 2 ); 5.37 (d, 1H, 7-CH); 5.51 (q, 1H, 6-CH); 5.73 (d, 1H, a-CH); 7.25-7.50 (m, 16H, aromat.); 8.10 (d, 1H, NHCO); 8.29 (m, 1H, NHCO); 8.35 (d, 1H, NHCO); 8.82 (d, 1H, NHCO); 9.17 (d, 1H, NHCO).

Beispiel 6Example 6 N-{N',N",N'''-Tris-(2,3-diacetoxybenzoyl)-N2-L-lysyllysyl}-ampicillin NatriumsalzN- {N ', N ", N''' - tris- (2,3-diacetoxybenzoyl) -N 2 -L-lysyllysyl} -ampicillin sodium salt

Formel I mit R1 = R12, R2, R3 = COCH3, R4, R5 = H., n = 4, L-Form, o = 4, L,L- Form, A = Ampicillino.Formula I with R 1 = R 12 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 4, L-form, o = 4, L, L-form, A = Ampicillino.

Die Herstellung der Titelverbindung erfolgte analog zu Beispiel 1 aus N',N",N'''- Tris-(2,3-diacetoxybenzoyl)-N2-L-lysyl-L-lysin und Ampicillin Trihydrat in 70%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,38 (s, 3H, CH3); 1,51 (s, 3H, CH3); 1,20-1,80 (m, 12H, 6 × CH2); 2,21 (s, 9H, COCH3); 2,29 (s, 9H, COCH3); 3,13 (m, 4H, 2 × NCH2); 3,80 (s, 1H, 3-CH); 4,43 (m, 2H, 2 × CH); 5,23 (m, 1H, 7-CH); 5,34 (m, 1H, 6-CH); 5,75 (m, 1H, a-CH); 7,20-7,55 (m, 14H, aromat.); 8,00-9,00 (m, 6H, 6 × NHCO).The title compound was prepared analogously to Example 1 from N ', N ", N""- tris (2,3-diacetoxybenzoyl) -N 2 -L-lysyl-L-lysine and ampicillin trihydrate in 70% yield in Form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.38 (s, 3H, CH 3 ); 1.51 (s, 3H, CH 3); 1.20-1.80 (m, 12H, 6 x CH 2 ); 2.21 (s, 9H, COCH 3 ); 2.29 (s, 9H, COCH 3 ); 3.13 (m, 4H, 2 × NCH 2); 3.80 (s, 1H, 3-CH); 4.43 (m, 2H, 2x CH); 5.23 (m, 1H, 7-CH); 5.34 (m, 1H, 6-CH); 5.75 (m, 1H, a-CH); 7.20-7.55 (m, 14H, aromat.); 8.00-9.00 (m, 6H, 6 x NHCO).

Beispiel 7Example 7 N-{N',N",N'''-Tris-(2,3-diacetoxybenzoyl)-N2-L-lysyl-L-lysyl}-amoxicillinN- {N ', N ", N""- tris (2,3-diacetoxybenzoyl) -N 2 -L-lysyl-L-lysyl} amoxicillin

Formel I mit R1 = R12, R2, R3 = COCH3, R4, R5 = H., n = 4, L-Form, o = 4, L,L- Form, A = Amoxicillino.Formula I with R 1 = R 12 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 4, L-form, o = 4, L, L-form, A = Amoxicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus Tris- N',N",N'''-(2,3-diacetoxybenzoyl)-N2-L-lysyl-L-lysin und Amoxicillin Trihydrat in 50%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,38 (s, 3H, CH3); 1,50 (s, 3H, CH3); 1,20-1,80 (m, 12H, 6 × CH2); 2,21 (s, 9H, COCH3); 2,29 (s, 9H, COCH3); 3,13 (m, 4H, 2 × NCH2); 3,83 (s, 1H, 3-CH); 4,44 (m, 2H, 2 × CH); 5,25 (m, 1H, 7-CH); 5,34 (m, 1H, 6-CH); 5,75 (m, 1H, a-CH); 6,65-7,55- (m, 13H, aromat.); 8,00-9,00 (m, 7H, 6 × NHCO, OH).The title compound or its sodium salt was prepared analogously to Example 1 from tris-N ', N ", N""- (2,3-diacetoxybenzoyl) -N 2 -L-lysyl-L-lysine and amoxicillin trihydrate in 50 % yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.38 (s, 3H, CH 3 ); 1.50 (s, 3H, CH 3); 1.20-1.80 (m, 12H, 6 x CH 2 ); 2.21 (s, 9H, COCH 3 ); 2.29 (s, 9H, COCH 3 ); 3.13 (m, 4H, 2 × NCH 2); 3.83 (s, 1H, 3-CH); 4.44 (m, 2H, 2x CH); 5.25 (m, 1H, 7-CH); 5.34 (m, 1H, 6-CH); 5.75 (m, 1H, a-CH); 6.65-7.55- (m, 13H, aromat.); 8.00-9.00 (m, 7H, 6 x NHCO, OH).

Beispiel 8Example 8 N-{2-{[N',N"-Bis-(2,3-diacetoxybenzoyl)-D-ornithyl]-amino-4-[(N-benzoyloxy-N- methyl)-aminoyl]-L-butanoyl}-ampicillinN- {2 - {[N ', N "-bis- (2,3-diacetoxybenzoyl) -D-ornithyl] amino-4 - [(N-benzoyloxy-N- methyl) -aminoyl] -L-butanoyl} -ampicillin

Formel I mit R1 = R14; R2, R3 = COCH3, R4, R5 = H., n = 3, D-Form, R8 = Benzoyl, R9 = CH3, o = 2, L-Form, A = Ampicillino.Formula I with R 1 = R 14 ; R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 3, D-form, R 8 = benzoyl, R 9 = CH 3 , o = 2, L-form, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-[N',N"-Bis(2,3-diacetoxybenzoyl)-D-ornithyl]-L-glutaminsäure-5-(N'- benzoyloxy-N'-methyl)-amid und Ampicillin Trihydrat in 40%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6) 1,39 (s, 3H, CH3); 1,53 (s, 3H, CH3); 1,45-2,06 (m, 6H, CH2); 2,18 (s, 6H, COCH3); 2,27 (s, 6H, COCH3); 2,39 (m, 2H, CH2); 3,15 (m, 2H, CH2); 3,26 (m, 3H, NCH3); 4,18 (s, 1H, 3-CH); 4,49 (m, 2H, 2 × CH); 5,35 (d, 1H, 7-CH); 5,49 (q, 1H, 6-CH); 5,73 (d, 1H, a-CH); 7,20-7,45- (m, 11H, aromat.); 7,54 (t, 2H, aromat.); 7,75 (t, 1H, aromat.); 8,00 (d, 2H, aromat.); 8,21 (d, 2H, 2 × NHCO); 8,32 (m, 1H, NHCO); 8,65 (d, 1H, NHCO); 9,18 (d, 1H, NHCO). The title compound or its sodium salt was prepared analogously to Example 1 from N- [N ', N "-bis (2,3-diacetoxybenzoyl) -D-ornithyl] -L-glutamic acid-5- (N'-benzoyloxy-N '-methyl) -amide and ampicillin trihydrate in 40% yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6) 1.39 (s, 3H, CH 3); 1.53 (s, 3H, CH 3); 1.45-2.06 (m, 6H, CH 2 ); 2.18 (s, 6H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 2.39 (m, 2H, CH 2); 3.15 (m, 2H, CH 2); 3.26 (m, 3H, NCH 3); 4.18 (s, 1H, 3-CH); 4.49 (m, 2H, 2x CH); 5.35 (d, 1H, 7-CH); 5.49 (q, 1H, 6-CH); 5.73 (d, 1H, a-CH); 7.20-7.45- (m, 11H, aromat.); 7.54 (t, 2H, aromat.); 7.75 (t, 1H, aromat.); 8.00 (d, 2H, aromat.); 8.21 (d, 2H, 2x NHCO); 8.32 (m, 1H, NHCO); 8.65 (d, 1H, NHCO); 9.18 (d, 1H, NHCO).

Beispiel 9Example 9 N-{2-{[N2,N6-Bis(2,3-diacetoxybenzoyl)-L-lysyl]-amino}-4-[(N-benzoyloxy-N-methyl)- aminoyl]-L-butanoyl}-ampicillinN- {2 - {[N 2 , N 6 -Bis (2,3-diacetoxybenzoyl) -L-lysyl] -amino} -4 - [(N-benzoyloxy-N-methyl) - aminoyl] -L-butanoyl} -ampicillin

Formel I mit R1 = R14, R2, R3 = COCH3, R4, R5 = H., n = 4, L-Form, R8 = Benzoyl, R9 = CH3, o = 2, L-Form, A = Ampicillino.Formula I with R 1 = R 14 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 4, L-form, R 8 = benzoyl, R 9 = CH 3 , o = 2, L-shape, A = ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-[N2,N6-Bis(2,3-diacetoxybenzoyl)-L-lysyl]-L-glutaminsäure-5-(N'- benzoyloxy-N'-methyl)-amid und Ampicillin Trihydrat in 20%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,39 (s, 3H, CH3); 1,53 (s, 3H, CH3); 1,45-2,06- (m, 8H, CH2); 2,19 (s, 3H, COCH3); 2,21 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 2,39 (m, 2H, CH2); 3,15 (m, 2H, CH2); 3,30 (m, 3H, NCH3); 4,19 (s, 1H, 3-CH); 4,38 (m, 1H, CH); 4,46 (m, 1H, CH); 5,35 (d, 1H, 7-CH); 5,50 (q, 1H, 6-CH); 5,73 (d, 1H, a-CH); 7,25-7.60 (m, 13H, aromat.); 7,74 (t, 1H, aromat.H); 7,97 (d, 2H, aromat.); 8,10 (m, H, NHCO); 8,30 (m, 2H, 2 × NHCO); 8,55 (d, 1H, NHCO; 9,17 (d, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N- [N 2 , N 6 -bis (2,3-diacetoxybenzoyl) -L-lysyl] -L-glutamic acid-5- (N'-benzoyloxy-N '-methyl) -amide and ampicillin trihydrate in 20% yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.39 (s, 3H, CH 3 ); 1.53 (s, 3H, CH 3); 1,45-2,06- (m, 8H, CH 2); 2.19 (s, 3H, COCH 3 ); 2.21 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 2.39 (m, 2H, CH 2); 3.15 (m, 2H, CH 2); 3.30 (m, 3H, NCH 3); 4.19 (s, 1H, 3-CH); 4.38 (m, 1H, CH); 4.46 (m, 1H, CH); 5.35 (d, 1H, 7-CH); 5.50 (q, 1H, 6-CH); 5.73 (d, 1H, a-CH); 7.25-7.60 (m, 13H, aromat.); 7.74 (t, 1H, aromatic H); 7.97 (d, 2H, aromat.); 8.10 (m, H, NHCO); 8.30 (m, 2H, 2x NHCO); 8.55 (d, 1H, NHCO; 9.17 (d, 1H, NHCO).

Beispiel 10Example 10 N-{2-[N2,N5'-Bis(2,3-diacetoxybenzoyl)-D-ornithyl]-amino]-4-[(N-benzoyloxy-N- cyclohexyl)-amidoyl]-L-butanoyl}-ampicillinN- {2- [N 2 , N 5 ' bis (2,3-diacetoxybenzoyl) -D-ornithyl] amino] -4 - [(N-benzoyloxy-N-cyclohexyl) amidoyl] -L-butanoyl} -ampicillin

Formel I mit R1 = R14, R2, R3 = COCH3, R4, R5 = H., n = 3, D-Form, R8 = Benzoyl, R9 = Cyclohexyl, o = 2, L-Form, A = Ampicillino.Formula I with R 1 = R 14 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 3, D-form, R 8 = benzoyl, R 9 = cyclohexyl, o = 2, L -Form, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-(N2,N5-bis-(2,3-diacetoxybenzoyl)-D-ornithyl)-L-glutaminsäure-5- (N'-benzoyloxy-N'-cyclohexyl)-amid und Ampicillin Trihydrat in 50%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,38 (s, 3H, CH3); 1,53 (s, 3H, CH3); 1,00-2,30 (m, 18H, 10 × CH2); 2,18 (s, 6H, COCH3); 2,27 (s, 6H, COCH3); 3,15 (m, 2H, NCH2); 4,18 (s, 1H, 3-CH); 4,20 (m, 1H, CH); 4,48 (m, 2H, 2 × CH); 5,35 (d, 1H, 7-CH); 5,48 (q, 1H, 6- CH); 5,74 (d, 1H, a-CH); 7,22-8,05- (m, 16H, aromat.); 8,22 (d, 2H, 2 × NHCO); 8,32 (m, 1H, NHCO); 8,65 (d, 1H, NHCO; 9,19 (d, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N- (N 2 , N 5 -bis- (2,3-diacetoxybenzoyl) -D-ornithyl) -L-glutamic acid-5- (N'-benzoyloxy- N'-cyclohexyl) -amide and ampicillin trihydrate in 50% yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.38 (s, 3H, CH 3 ); 1.53 (s, 3H, CH 3); 1.00-2.30 (m, 18H, 10 x CH 2 ); 2.18 (s, 6H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 3.15 (m, 2H, NCH 2); 4.18 (s, 1H, 3-CH); 4.20 (m, 1H, CH); 4.48 (m, 2H, 2x CH); 5.35 (d, 1H, 7-CH); 5.48 (q, 1H, 6-CH); 5.74 (d, 1H, a-CH); 7.22-8.05- (m, 16H, aromat.); 8.22 (d, 2H, 2x NHCO); 8.32 (m, 1H, NHCO); 8.65 (d, 1H, NHCO; 9.19 (d, 1H, NHCO).

Beispiel 11Example 11 N-{N2-[4-(N'-Benzoyl-N'-methyl)-amido-glutaroyl]-N6-(N2,N6-bis-2,3- diacetoxybenzoyl)-L-lysyl]-L-lysyl}-ampicillinN- {N 2 - [4- (N'-Benzoyl-N'-methyl) amido-glutaroyl] -N 6 - (N 2 , N 6 -bis-2,3-diacetoxybenzoyl) -L-lysyl] - L-lysyl} -ampicillin

Formel I mit R1 = R15, R2, R3 = COCH3, R4, R5 = H., n = 4, L-Form, R8 = Benzoyl, R9 = CH3, p = 4, q = 3, A = Ampicillino.Formula I with R 1 = R 15 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 4, L-form, R 8 = benzoyl, R 9 = CH 3 , p = 4, q = 3, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N2-[(N'-Benzoyloxy-N'-methyl-amido-glutaroyl)-N6-(N2,N5-bis-2,3- diacetoxybenzoyl)-L-lysyl]-L-lysin und Ampicillin Trihydrat in 30%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,39 (s, 3H, CH3); 1,53 (s, 3H, CH3); 1,20-2,40 (m, 18H, 4 × CH2); 2,19 (s, 3H, COCH3); 2,22 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 3,10 (m, 4H, 2 × NCH2); 4,19 (s, 1H, 3-CH); 4,33 (m, 2H, 2 × CH); 5,37 (d, 1H, 7-CH); 5,50 (q, 1H, 6-CH); 5,68 (d, 1H, a-CH); 7,30-8,05 (m, 18H, aromat. + 2 × NHCO); 8,20 (d, 1H, NHCO); 8,29 (m, 1H, NHCO); 8,40 (m, 1H, NHCO); 9, 10 (m, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N 2 - [(N'-benzoyloxy-N'-methyl-amido-glutaroyl) -N 6 - (N 2 , N 5 -bis-2,3- diacetoxybenzoyl) -L-lysyl] -L-lysine and ampicillin trihydrate in 30% yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.39 (s, 3H, CH 3 ); 1.53 (s, 3H, CH 3); 1.20 to 2.40 (m, 18H, 4 × CH 2); 2.19 (s, 3H, COCH 3 ); 2.22 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 3.10 (m, 4H, 2 x NCH 2 ); 4.19 (s, 1H, 3-CH); 4.33 (m, 2H, 2x CH); 5.37 (d, 1H, 7-CH); 5.50 (q, 1H, 6-CH); 5.68 (d, 1H, a-CH); 7.30-8.05 (m, 18H, aromat. + 2 x NHCO); 8.20 (d, 1H, NHCO); 8.29 (m, 1H, NHCO); 8.40 (m, 1H, NHCO); 9.10 (m, 1H, NHCO).

Beispiel 12Example 12 N-[N2-{(N'-Benzoyloxy-N'-cyclohexyl-amido-glutaroyl]-N6-[N2',N6'-bis-(2,3- diacetoxybenzoyl)-L-lysyl]-L-lysyl}-ampicillinN- [N 2 - {(N'-benzoyloxy-N'-cyclohexyl-amido-glutaroyl] -N 6 - [N 2 ' , N 6' -bis- (2,3-diacetoxybenzoyl) -L-lysyl] - L-lysyl} -ampicillin

Formel I mit R1 = R15, R2, R3 = COCH3, R4, R5 = H., n = 4, L-Form, R8 = Benzoyl, R9 = Cyclohexyl p = 4, q = 3, A = Ampicillino.Formula I with R 1 = R 15 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 4, L-form, R 8 = benzoyl, R 9 = cyclohexyl p = 4, q = 3, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N2-[(N'-Benzoyloxy-N'-cyclohexyl-amido-glutaroyl]-N6-[N2',N6'-bis-(2,3- diacetoxybenzoyl)-L-lysyl]-L-lysin und Ampicillin Trihydrat in 50%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,32 (s, 3H, CH3); 1,54 (s, 3H, CH3); 1,00-2,30 (m, 28H, 8 × CH2); 2,19 (s, 3H, COCH3); 2,22 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 3,03 (m, 2H, NCH2); 3,15 (m, 2H, NCH2); 4,33 (m, 3H, 3 × CH); 5,37 (d, 1H, 7-CH); 5,51 (q, 1H, 6- CH); 5,68 (m, 1H, a-CH); 7,20-7,95 (m, 16H, aromat.); 8,04 (d, 2H, 2 × NHCO); 8,29 (m, 1H, NHCO); 8,45 (m, 1H, NHCO); 9, 10 (m, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N 2 - [(N'-benzoyloxy-N'-cyclohexyl-amido-glutaroyl] -N 6 - [N 2 ' , N 6' -bis- (2nd , 3-diacetoxybenzoyl) -L-lysyl] -L-lysine and ampicillin trihydrate in 50% yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.32 (s, 3H, CH 3 ); 1.54 (s, 3H, CH 3); 1.00-2.30 (m, 28H, 8 x CH 2 ); 2.19 (s, 3H, COCH 3 ); 2.22 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 3.03 (m, 2H, NCH 2); 3.15 (m, 2H, NCH 2); 4.33 (m, 3H, 3 x CH); 5.37 (d, 1H, 7-CH); 5.51 (q, 1H, 6-CH); 5.68 (m, 1H, a-CH); 7.20-7.95 (m, 16H, aromat.); 8.04 (d, 2H, 2x NHCO); 8.29 (m, 1H, NHCO); 8.45 (m, 1H, NHCO); 9.10 (m, 1H, NHCO).

Beispiel 13Example 13 N-{N2-[ε-(8-Methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl)-n- hexanoyl]-N6-[2,6-bis-(8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo- 2H-1,3-benzoxazin-3-yl)-n-hexanoyl]-L-lysyl}-ampicillinN- {N 2 - [ε- (8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl) -n-hexanoyl] -N 6 - [2, 6-bis- (8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl) -n-hexanoyl] -L-lysyl} -ampicillin

Formel I mit R1 = R16, R2 und R10 = -CO- in Verbindung mit R5, R3 = COOCH3, R4 = H, R5 = -CO- in Verbindung mit R2 bzw R10, n = 4, L-Form, o = 4, p = 5, A = Ampicillino.Formula I with R 1 = R 16 , R 2 and R 10 = -CO- in combination with R 5 , R 3 = COOCH 3 , R 4 = H, R 5 = -CO- in combination with R 2 or R 10 , n = 4, L-shape, o = 4, p = 5, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N2-[ε-(8-Methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benz­ oxazin-3-yl)-n-hexanoyl]-N6-[2,6-bis-(8-methoxycarbonyloxy-3,4-dihydro-2,4- dioxo-2H-1,3-benzoxazin-3-yl)-n-hexanoyl]-L-lysin und Ampicillin Trihydrat in 30%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,39 (s, 3H, CH3); 1,53 (s, 3H, CH3); 1,00-2,30 (m, 20H, CH2); 2,97 (m, 2H, NCH2); 3,79 (m, 4H, NCH2); 3,90 (s, 9H, COCH3); 4,19 (s, Alkyl, 3- CH); 4,25 (m, 1H, CH); 5,07 (m, 1H, CH); 5,37 (d, 1H, 7-CH); 5,50 (q, 1H, 6-CH); 5,65 (m, 1H, a-CH); 7,20-8,02- (m, 16H, aromat. + NHCO); 8,45 (m, 1H, NHCO); 9, 10 (m, 1H, NHCO).The title compound or its sodium salt was prepared analogously to Example 1 from N 2 - [ε- (8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl) -n-hexanoyl] -N 6 - [2,6-bis- (8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1,3-benzoxazin-3-yl) -n-hexanoyl] -L-lysine and ampicillin trihydrate in 30% yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.39 (s, 3H, CH 3 ); 1.53 (s, 3H, CH 3); 1.00 to 2.30 (m, 20H, CH 2); 2.97 (m, 2H, NCH 2); 3.79 (m, 4H, NCH 2); 3.90 (s, 9H, COCH 3 ); 4.19 (s, alkyl, 3-CH); 4.25 (m, 1H, CH); 5.07 (m, 1H, CH); 5.37 (d, 1H, 7-CH); 5.50 (q, 1H, 6-CH); 5.65 (m, 1H, a-CH); 7.20-8.02- (m, 16H, aromat. + NHCO); 8.45 (m, 1H, NHCO); 9.10 (m, 1H, NHCO).

Beispiel 14Example 14 N-{2-[N2,N6-Bis-(2,3-diacetoxybenzoyl)-L-lysyl]-amino]-4-[(N-benzoyloxy-N- cyclohexyl)-amidoyl]L-butanoyl}-ampicillinN- {2- [N 2 , N 6 -Bis- (2,3-diacetoxybenzoyl) -L-lysyl] amino] -4 - [(N-benzoyloxy-N-cyclohexyl) amidoyl] L-butanoyl} - ampicillin

Formel I mit R1 = R14, R2, R3 = COCH3, R4, R5 = H., n = 4, L-Form, R8 Benzoyl, R9 = Cyclohexyl, o = 2, L-Form, A = Ampicillino.Formula I with R 1 = R 14 , R 2 , R 3 = COCH 3 , R 4 , R 5 = H., n = 4, L-form, R 8 benzoyl, R 9 = cyclohexyl, o = 2, L- Form, A = Ampicillino.

Die Herstellung der Titelverbindung bzw. deren Natriumsalzes erfolgte analog zu Beispiel 1 aus N-(N2,N6-bis-(2,3-diacetoxybenzoyl)-L-lysyl)-L-glutaminsäure-5-(N'- benzoyloxy-N'-cyclohexyl)-amid und Ampicillin Trihydrat in 50%iger Ausbeute in Form eines farblosen amorphen Feststoffes.
1H NMR (DMSO-d6): 1,39 (s, 3H, CH3); 1,53 (s, 3H, CH3); 1,00-2,30- (m, 16H, 8 × CH2); 2,19 (s, 3H, COCH3); 2,22 (s, 3H, COCH3); 2,27 (s, 6H, COCH3); 3,14 (m, 2H, NCH2); 4,18 (s, 1H, 3-CH); 4,20 (m, 1H, CH); 4,26 (m, 1H, CH); 4,40 (m, 1H, CH); 5,36 (d, 1H, 7-CH); 5,48 (q, 1H, 6-CH); 5,72 (d, 1H, α-CH); 7,20-8,03- (m, 16H, aromat.); 8,08 (d, 1H, NHCO); 8,30 (m, 2H, 2 × NHCO); 8,53 (d, 1H, NHCO); 9,18 (d, 1H, NHCO).
The title compound or its sodium salt was prepared analogously to Example 1 from N- (N 2 , N 6 -bis- (2,3-diacetoxybenzoyl) -L-lysyl) -L-glutamic acid-5- (N'-benzoyloxy- N'-cyclohexyl) -amide and ampicillin trihydrate in 50% yield in the form of a colorless amorphous solid.
1 H NMR (DMSO-d6): 1.39 (s, 3H, CH 3 ); 1.53 (s, 3H, CH 3); 1,00-2,30- (m, 16H, 8 x CH 2); 2.19 (s, 3H, COCH 3 ); 2.22 (s, 3H, COCH 3 ); 2.27 (s, 6H, COCH 3 ); 3.14 (m, 2H, NCH 2); 4.18 (s, 1H, 3-CH); 4.20 (m, 1H, CH); 4.26 (m, 1H, CH); 4.40 (m, 1H, CH); 5.36 (d, 1H, 7-CH); 5.48 (q, 1H, 6-CH); 5.72 (d, 1H, α-CH); 7.20-8.03- (m, 16H, aromat.); 8.08 (d, 1H, NHCO); 8.30 (m, 2H, 2x NHCO); 8.53 (d, 1H, NHCO); 9.18 (d, 1H, NHCO).

Claims (8)

1. Verbindungen der Formel I
worin
R1 = A ist,
oder R1 =
mit R6 = H, Alkyl, Hydroxyalkyl, Acyloxyalkyl, Alkyloxyalkyl, Carboxy, Alkyloxycarbonyl, Aryl, Arylalkyl, Arylalkyloxyalkyl, Hetaryl, Hetarylalkyl m = 0-5 = R11 =
oder R1
= R12
mit o = 1-5
oder R1 =
= R13
mit R7 = H, Alkyl, Alkyl, Alkyloxycarbonylalkyl, R8 = H, Aroyl, o = 1-5
oder R1 =
o = 1-5 = R14
mit R8 = H, Aroyl, R9 = H, Alkyl, Cycloalkyl, Alkyloxycarbonylalkyl,
o = 1-5
oder R1 =
mit p = 1-5, q = 1-5 = R15
oder R1 =
mit o = 1-5, p = 1-5, R10 = H, COAlkyl, COOAlkyl = R16
R2 = H, COAlkyl, COOAlkyl,
R5 = H
oder R5 stellt zusammen mit einem der Reste R2 oder R10 eine Gruppe -CO- dar,
R3 = H, COAlkyl, COOAlkyl,
R4 = H, Alkyl, subst. Alkyl, Aryl, subst. Aryl, Halogen, Alkoxy, subst. Alkoxy, in allen möglichen Positionen, auch mehrfach auftretend,
A = der Rest eines β-Laktamantibiotikums, vorzugsweise der Rest eines Penicillinderivates insbesondere ein Ampicillin- oder Amoxicillinrest (Formel B) oder ein Bacampicillinrest (α-Ethoxycarbonyloxyethylester des Ampicillins), oder der Rest eines Cephalosporins, insbesondere ein Cefachlorrest (Formel C) oder ein Chinolonrest,
bedeuten, im Falle des Vorliegens asymmetrischer C-Atome die entsprechenden D- und L-Formen, Enantiomere und Diastereomere sowie die Racemate bzw. Enantiomeren- und Diastereomerengemische von Verbindungen der Formel I, wobei die Verbindungen der Formel I als freie Säuren, in Form ihrer Salze oder als leicht spaltbare, wie unter physiologischen Bedingungen spaltbare Ester vorliegen können, mit der Maßgabe, daß R4 und/oder R5 nicht gleich H ist, wenn R1 = A ist.1. Compounds of formula I.
wherein
R 1 = A,
or R 1 =
with R 6 = H, alkyl, hydroxyalkyl, acyloxyalkyl, alkyloxyalkyl, carboxy, alkyloxycarbonyl, aryl, arylalkyl, arylalkyloxyalkyl, hetaryl, hetarylalkyl m = 0-5 = R 11 =
or R 1
= R 12
with o = 1-5
or R 1 =
= R 13
with R 7 = H, alkyl, alkyl, alkyloxycarbonylalkyl, R 8 = H, aroyl, o = 1-5
or R 1 =
o = 1-5 = R 14
with R 8 = H, aroyl, R 9 = H, alkyl, cycloalkyl, alkyloxycarbonylalkyl,
o = 1-5
or R 1 =
with p = 1-5, q = 1-5 = R 15
or R 1 =
with o = 1-5, p = 1-5, R 10 = H, COalkyl, COOalkyl = R 16
R 2 = H, CO alkyl, COO alkyl,
R 5 = H
or R 5 together with one of the radicals R 2 or R 10 represents a group -CO-,
R 3 = H, CO alkyl, COO alkyl,
R 4 = H, alkyl, subst. Alkyl, aryl, subst. Aryl, halogen, alkoxy, subst. Alkoxy, in all possible positions, also occurring several times,
A = the residue of a β-lactam antibiotic, preferably the residue of a penicillin derivative, in particular an ampicillin or amoxicillin residue (formula B) or a bacampicillin residue (α-ethoxycarbonyloxyethyl ester of ampicillin), or the residue of a cephalosporin, in particular a cefachlor residue (formula C) or one quinolone,
mean, in the presence of asymmetric carbon atoms, the corresponding D and L forms, enantiomers and diastereomers and the racemates or enantiomer and diastereomer mixtures of compounds of the formula I, the compounds of the formula I as free acids, in the form of their Salts or as easily cleavable esters, such as cleavable under physiological conditions, with the proviso that R 4 and / or R 5 is not H when R 1 = A. 2. Verbindungen der Formel I nach Anspruch 1, worin R1 = A, R11, R13 oder R14 ist und R2 und/oder R3 = H, COAlkyl oder COOAlkyl, R4 = H oder Halogen, auch mehrfach auftretend, R5 = H bedeuten.2. Compounds of formula I according to claim 1, wherein R 1 = A, R 11 , R 13 or R 14 and R 2 and / or R 3 = H, COalkyl or COOalkyl, R 4 = H or halogen, also occurring repeatedly , R 5 = H. 3. Verbindungen der Formel I nach Anspruch 1, worin R1 = A ist und R2 und/oder R3 = H, COAlkyl oder COOAlkyl, R4 = Halogen, auch mehrfach auftretend, R5 = H und A = ein Ampicillin- oder Amoxicillinrest bedeuten.3. Compounds of formula I according to claim 1, wherein R 1 = A and R 2 and / or R 3 = H, COalkyl or COOalkyl, R 4 = halogen, also occurring repeatedly, R 5 = H and A = an ampicillin or Amoxicillinrest mean. 4. Verbindungen der Formel I nach Anspruch 1, worin R1 = R11, R2 und/oder R3 = H, COAlkyl oder COOAlkyl, R4 H oder Halogen, auch mehrfach auftretend, R5 = H und R6 = H, Alkyl, Hydroxyalkyl, Alkyloxyalkyl, Acyloxyalkyl, Carboxy, Alkyloxy­ carbonyl, Aryl, Arylalkyl, Arylalkyloxyalkyl, Hetarylalkyl, m = 0-5 und A = ein Ampicillin- oder Amoxicillinrest bedeuten.4. Compounds of formula I according to claim 1, wherein R 1 = R 11 , R 2 and / or R 3 = H, COalkyl or COOalkyl, R 4 H or halogen, also occurring repeatedly, R 5 = H and R 6 = H , Alkyl, hydroxyalkyl, alkyloxyalkyl, acyloxyalkyl, carboxy, alkyloxy carbonyl, aryl, arylalkyl, arylalkyloxyalkyl, hetarylalkyl, m = 0-5 and A = an ampicillin or amoxicillin radical. 5. Verbindungen der Formel I nach Anspruch 1, worin R1 = R14, R2 und/oder R3 = COAlkyl oder COOAlkyl, R4 = H oder Halogen, R5 = H, R8 = H oder Aroyl und/oder R9 = H, Alkyl, Cycloalkyl Alkylcarbonyloxyalkyl und A = ein Ampicillin- oder Amoxicil­ linrest bedeuten.5. Compounds of formula I according to claim 1, wherein R 1 = R 14 , R 2 and / or R 3 = COalkyl or COOalkyl, R 4 = H or halogen, R 5 = H, R 8 = H or aroyl and / or R 9 = H, alkyl, cycloalkyl, alkylcarbonyloxyalkyl and A = an ampicillin or amoxicil linrest. 6. Verbindungen der Formel I nach Anspruch 1, worin R1 = R15, R2 und/oder R3 = H, COAlkyl oder COOAlkyl, R4 = H oder Halogen, R5 = H, R8 = H oder Aroyl und/oder R9 = H, Alkyl, Cycloalkyl, Alkylcarbonyloxyalkyl bedeuten.6. Compounds of formula I according to claim 1, wherein R 1 = R 15 , R 2 and / or R 3 = H, COalkyl or COOalkyl, R 4 = H or halogen, R 5 = H, R 8 = H or aroyl and / or R 9 = H, alkyl, cycloalkyl, alkylcarbonyloxyalkyl. 7. Verwendung der Verbindungen der Formel I nach Ansprüchen 1-6 als Mittel gegen bakterielle Infektionen, insbesondere gegen Infektionen mit Gram-negativen Bakterien. 7. Use of the compounds of formula I according to claims 1-6 as agents against bacterial infections, especially against infections with Gram-negative bacteria.   8. Arzneimittel enthaltend eine Verbindung der Formel I nach Ansprüchen 1-6 zu­ sammen mit üblichen Trägermaterialien.8. Medicament containing a compound of formula I according to claims 1-6 together with usual carrier materials.
DE10111163A 2001-03-01 2001-03-01 New siderophore-antibiotic conjugates with 4- or 6-toothed iron chelators based on amino acids or peptides, process for their preparation and their application Withdrawn DE10111163A1 (en)

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