EP1370296A2 - Catecholate beta-lactam conjugates, method for producing the same and the use thereof - Google Patents

Abstract

The invention relates to novel substituted catechol derivatives that are derived from multibase secondary amino acids and analog structures of general formula (I), wherein R<1> = H, alkyl, aryl, R<2> and R<3> = H or acyl, R<4> and R<5> = H, alkyl, aryl, and R<6> or R<7> = H, alkyl or catecholate groups, optionally in the acylated form or together with spacer groups, X and Z are direct bonds or bonds interrupted by certain spacer groups, and Y = OH (as a free acid, in the form of their salts or their easily cleavable esters). The inventive compounds are effective as siderophores in mycobacteria and gram-negative bacteria strains, especially pseudomonades, E. coli and Salmonella strains. They can be used as transport vehicles for introducing active substances, for example antibiotics (as siderophore antibiotic conjugates ) in bacterial cells, thereby improving or enlarging their antibacterial activity to a larger extent than known compounds. The inventive compounds are suitable for use as potential prodrug forms for iron chelators in diseases that are associated with a disturbed iron metabolism.

Description

Catecholate-ß-lactam conjugates, process for their preparation and their use

The present invention relates to new antibiotic conjugates with catechol derivatives derived from polybasic secondary amino acids or analogous structures. The compounds are antibacterially active, in particular against Gram-negative bacteria, the antibiotics being 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. This is intended to contribute to Combating penetration-related antibiotic resistance, which is of central importance in the treatment of bacterial infections.

Compounds of the formula I with the stated substituents have not been described in the literature to date.

It is known that certain catechol structures play an important role in natural siderophores as iron-complexing structural elements ("Iron Transport in icrobes, Plants and Animals", ed .: Winkelmann, G., van Helm, D., Neilands, JB, V.Ch . Publishing house Weinheim, 1987), for example, the enterobactin, a siderophore in E. coli and other bacterial strains, is 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 (lto, T., Neilands, JB, J. Amer. Chem Soc. 80 (1958), 4645). Some catechol-substituted amino acid derivatives have already been prepared synthetically, for example N- (2,3-dihydroxybenzoyl) -L-threonine (Kanai, 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 (Heinisch L, Schnabelrauch M., Möllmann U., Reissbrodt R., DE 19654920 A1) as well as from these catechol compounds Derived benzoxazine-2,4-dione derivatives (Heinisch L, Wittmann S., Möllmann U., Reissbrodt R., 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.

Catechols of diamino and triamino compounds, straight-chain or branched, without carboxyl function are described, e.g. Triscatechol derivatives of bis-aminopropyl-amine (Martell, A., E .; Motekaitis, R.; J., Murase, I .; Sala, LF, Stoldt, R.Ng, Chiu, Y., Rosenkrantz, H .; Inorg Chim. Acta (1987), 138, 215-30.), Bis-catechol derivatives of spermidine (Bergeron RJ, Burton PS, McGovern KA, Onge EJSt; J.Med.Chem. 1980, .23, 1130-1133) and myxochelin derivatives (Ambrosi HD, Hartmann V., Pistorius D., Reissbrodt R., Trowitzsch-Kienast W .; Eur. J.Org.Chem. 1998, 541-551). The only dibasic secondary amino acids or analogous structures that serve as the backbone for the compounds according to the invention have been aminoethyl or aminopropylglycine (Byk, G., Gilon, Ch .; J.Org.Chem. 57, 5687-5692 (1992), Will DG, Breipohl G., Langner D., Knolle J., Uhlmann E., Tetrahedron 51, 12069 - 12082, 8, 1995) from the amine and glyoxylic acid by catalytic hydrogenation. Of the polybasic secondary amino acids, which also serve as the backbone, only a Co-III complex of N '- (aminoethyl) -N-aminoethylglycine (3,7,11-triazaundecanoic acid) has been described (Watan-abe, Kuroda Nippon Kagaku Kaishi, 1972, 1409-1415, Chem. Abstr. 77, 121610x, 1972), other polybasic secondary amino acids are not known.

Various catechol compounds were linked to ß-lactams, which resulted in a considerable increase in the antibacterial effectiveness of these antibiotics, due to the introduction into the bacterial cell via bacterial iron transport routes (for example Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, RL, Antimicrob. Agents Chemother. 35 (1991), 653). So far, however, no such compounds have been approved for use in humans, inter alia because of unfavorable side effects. To achieve this goal, further new effective synthetic siderophores must be sought which are suitable for conjugate formation with antibiotics and for conjugates with high antibacterial activity, for example against resistant pathogenic problem germs such as Stenotrophomonas maltophilia, and have fewer side effects than the previously known compounds of this type.

The invention serves to find new catecholate-antibiotic conjugates, derived from polybasic secondary amino acids or analogous structures, and to their use. The aim of the invention is to find suitable compounds for introducing active substances, e.g. of antibiotics to develop into the bacterial cell that surpass the compounds of this type described so far. By using acylated catechol compounds or by incorporating the catechol structure into the heterocyclic benzoxazinedione structure, the aim is to give the compounds improved pharmacological properties or to serve as pharmacological forms of transport for the catechol compounds which actually promote penetration.

The invention has for its object to find new antibiotic conjugates of catechol compounds or their acylated or incorporated in benzoxazinedione structures, derived from secondary amino acids or analogous structures, of general formula 1, which have stronger antibacterial activity than comparable known compounds of this type.

The object is achieved according to the invention by providing new antibiotic conjugates, in particular penicillin and cephalosporin conjugates of catechol compounds or their acylated derivatives or derivatives incorporated into benzoxazinedione structures, derived from secondary amino acids or analogous structures, of the general formula I,

in which R ¹ = H, alkyl, substituted alkyl, aryl, substituted aryl,

R ² = H, CO alkyl, COO alkyl,

X = direct bond, (CH ₂ ) _q NH-, CO (CH ₂ ) _q NH- with q = 1-6, or

R together with X is a group _{/ Λι} , I _Λ - (CH ₂ ) _q - N-CO-

or CO- (CH) - N-CO-, where q = 1-6

'2 ^ q

R ^J = H, CO alkyl, COO alkyl,

R ⁴ = H, alkyl, substituted alkyl, aryl, substituted aryl, halogen. Alkoxy, substituted alkoxy, in all possible positions, it being possible for the substituents mentioned to occur more than once,

R ⁵ = H, OH, O alkyl, O acyl, O aryl, alkyl, substituted alkyl, aryl, substituted aryl,

, COOalkyl, form a group with R ⁷ -

or R ⁶ = with o = 1 - 10 = R ¹⁰

or R ⁶ = with o == 11 - 1110 - = OR «

with p = 2-10, or R> 7 - = H, alkyl, substituted alkyl, aryl, substituted aryl or R ⁷ together with R ⁸ = -CO-,

or with R =

_R 13

- (CH ₂ ) _S - N with s = 2 - 4 = R 14

R ⁹ n = 0 - 8, m = 0 - 3,

Y = the rest of a β-lactam antibiotic, e.g. a penicillin derivative, in particular an ampicillin or amoxicillin residue (formula A) or a bacampicillin residue (α-ethoxycarbonyloxyethyl ester of ampicillin) or the residue of a cephalosporin, in particular a cefaclor residue (formula B),

A: R = H: ampicillin residue, R = OH: amoxicillin residue B: cefaclor residue

Z = direct bond, or

Z = - (CH ₂ ) _r - with r = 0 - 10 or

Z = arylene or substituted arylene, preferably

with R ⁵ = H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, alkoxy, substituted alkoxy, in all possible positions

mean, in the above formulas acyl, in particular for C 1 -C ₄ alkanoyl or C 1 -C ₄ alkoxycarbonyl, alkyl and alkoxy, also in word combinations such as alkoxycarbonyl, in particular for C 1 -C ₈ alkyl or alkoxy , substituted alkyl for alkyl substituted by halogen, alkoxy, hydroxy, carboxy and alkoxycarbonyl, substituted alkoxy for alkoxy substituted by halogen, alkoxy, carboxy and alkoxycarbonyl, aryl preferably for phenyl or one substituted by alkyl, halogen, alkoxy, hydroxy, carboxy and alkoxycarbonyl Are phenyl and a substituted ammonium ion preferably means an ammonium ion which is mono- or polysubstituted, such as one to four times, substituted by alkyl, with the proviso that R ⁷ together with R ^{8 is} not = -CO- and / or R ^{5 is} not = H, if Z represents a direct bond or that R ^{7 is} not = R ¹² if R ⁶ = R ⁹ , R ⁵ = H and X and Z = direct bonds.

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.

The compounds of the formula I according to the invention are prepared by compounds of the formula I with Y = OH with a corresponding antibiotic, in particular with a penicillin derivative or cephalosporin derivative, especially with ampicillin, amoxicillin or cefaclor by customary processes, for example by the anhydride process (for example using isobutyl chloroformate) , by the active ester process (for example with N-hydroxysuccinimide and dicyclohexyl-carbodiimide) or by the chloride method to give the compounds of the formula I. Compounds of formula 1 with Y = OH are prepared as follows. In a first step, the secondary amino acids of the formula IV are first synthesized by reacting the corresponding amines II with the α-keto acids III, where R = H or (CH ₂ ) _P -NH ₂ .

R- [NHR-CH ₂ -CHR ⁵ - (CH ₂ ) _n ] m -NH ₂ + R ¹ -CO-Z-COOH ^

II III

R- [NHR-CH ₂ -CHR ⁵ - (CH ₂ ) _n ] _m -NH-CHR ¹ -Z-COOH IV

The compounds IV can be purified by preparing their carbobenzoxy derivatives (Z derivatives), separating them from by-products by chromatography using HPLC, and then splitting off the Z groups again by hydrogenolysis (H ₂ / Pd / C).

In a second step, the secondary amino acids are treated with corresponding catechol derivatives, for example with dihydroxy- or diacyloxybenzoic acids or their acid chlorides or with corresponding spacer compounds, for example with 8-methoxycarbonyloxy-3,4-dihydro-2H-1,3-benzoxazin-3-yl- acetyl chloride, (R ⁶ or R ⁷ ) by customary processes, for example by the anhydride process (for example using chloroformic acid isobut ester), by the active ester process (for example using N-hydroxysuccinimide and dicyclohexylcarbodiimide) or by the chloride method to give the compounds of the formula I with Y = OH implemented.

In individual cases it can be advantageous to first prepare the benzyl ester from IV and then to link it in the usual way with the catechol component and then to split off the benzyl group again by hydrogenolysis.

The compounds of the formula I according to the invention with a carboxy Ig group can be present as free acids, in the form of their salts or as easily cleavable esters, in particular cleavable under physiological conditions. Another cleaning of the connections can be carried out by customary methods known from the prior art, for example by recrystallization or by means of chromatographic methods.

The compounds of the formula I according to the invention show antibacterial activity which exceeds the activity of previously known comparable compounds. The antibacterial activity was tested in a microdilution test according to the National Committee for Clinical Laboratory Standards, 1998, Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, Approved Standard M7-A, NCCLS, Villanova, Pa. The minimum inhibitory concentrations (MIC values) of the compounds were then tested against the following bacterial strains: the gram-negative strains of Pseudomonas aeruginosa SG 137, ATCC 27853, Escherichia coli ATCC 25922, Klebsieila pneumoniae ATCC 10031, Stenotrophomonas maltophilia GN 12873, Serratia marcescens SG 62 as well as against the Gram-positive strain Staphylococcus aureus SG 511. The results of the antibacterial testing are summarized in the table. The corresponding values of azlocillin, ampicillin and meropenem are given for comparison. The results show that the substances according to the invention clearly outperform the activity of azlocillin, in many cases also the activity of the highly effective meropenem, in all Gram-negative bacterial strains and problem germs. Particularly noteworthy is the excellent effectiveness against Meropenem-resistant bacteria of the species Stenotrophomonas maltophilia. Comparably high activities are achieved with Burkholderia tribes. Bacterial resistance can thus be successfully overcome with the compounds according to the invention. With compounds with Z = phenylene, a broad activity was achieved with Gram-negative bacteria and surprisingly also with Gram-positive bacteria compared to previous compounds of this type. In combination with a β-lactamase inhibitor, efficacies in MRSA and mycobacteria have also been demonstrated. Some of the compounds according to the invention show a far greater activity against Gram-negative bacteria than previously known corresponding catecholate-β-lactam conjugates according to the literature mentioned above, including against the problem germ Stenotrophomonas maltophilia. Because of their antibacterial properties, the compounds of the general formula I are suitable for use as medicaments for bacterial infections. In the case of such diseases, the compounds of the formula I can be used either alone or with physiologically tolerable auxiliaries or excipients, it being possible in principle for all customary pharmacological uses and physiologically tolerable dosages.

Examples

Example 1 N- [3J-bis- (2,3-dimethoxycarbonyloxybenzoylV3.7-diaza-octanoyll -ampicillin formula I with R ¹ , R ⁴ , R ⁵ = H; R ² , R ³ = COOCH ₃ , R ⁶ = R ⁹ with R ⁸ = COOCH ₃ , R ⁷ = CH ₃ 'n = 1, m = 1, X and Z = direct bond, Y = Ampicillino.

To a solution of 0.651 g (1 mmol) of 3,7-bis (2,3-dimethoxycarbonyloxybenzoyl) -3,7-diaza-octanoic acid and 0.112 ml of N-methylmorpholine in 10 ml of anhydrous tetrahydrofuran was 0.131 at -20 ° C with stirring ml (1 mmol) isobutyl chloroformate added. The mixture was stirred for one hour at -10 ° C. and then a solution of 0.453 g (1.1 mmol) ampicillin trihydrate and 0.153 ml (1.1 mmol) triethylamine in 5 ml 80% tetrahydrofuran was added at -10 ° C. The mixture was stirred at -10 to 0 ° C for one hour and at 20 ° C for one hour, and then evaporated in vacuo. The residue was dissolved in ethyl acetate / water, the solution was carefully acidified with hydrochloric acid while cooling with ice and shaken. The organic phase was separated, washed acid-free with aqueous sodium chloride solution, dried and evaporated in vacuo. The residue was purified by preparative HPLC on silica gel (Eurospher 100 C18, 7 μm, Knauer, Berlin) with a mixture of acetonitrile / water (37.5 / 62.5) as the eluent. The acetonitrile was distilled off from the corresponding fraction in vacuo and the residue was lyophilized. This gave 0.44 g (45% of theory) of the title compound in the form of a colorless solid. ¹ H NMR (DMSO-d6): 1.40 (s, 3H, CH ₃ ); 1, 53 (s, 3H, CH _3); 1, 75 (m, 2H, CH _2); 2.76 (s, 3H, CH _3); 2.96 -3.40 (m, 4H, 2 x CH ₂ ); 3.77 - 4.20 (m, 14H, 4 x O CH ₃ , 1 x CH ₂ COOH); 4.17 (s, 1H, 3-CH); 5.38 (m, 1H, 7-CH); 5.50 (m, 1H, a-CH); 5.72 (q, 1H, 6-CH); 7.25 - 7.60 (m, 11H, ArH), 8.71, 9.15 (m, 1H, NHCO).

The sodium salt was prepared by adding a solution of 0.02 g of sodium ethylhexanoate in 3 ml of ethyl acetate to a solution of 0.10 g of the title compound in 12 ml of ethyl acetate. The precipitate which had separated out was filtered off after standing for about 10 minutes and washed with petroleum ether. The sodium salt of the title compound was obtained in the form of a colorless amorphous solid in 90% yield. Example 2 N- [3.10.17 -Tris- (2.3-diacetoxybenzoyl) -3.10,17-triaza-heptadecanovπ-ampicillin Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² , R ³ = COCH ₃ , R ⁶ = R ⁹ with R ⁸ = COCH ₃ , n = 4, m = 2, X and Z = direct bond, Y = Ampicillino.

The preparation was carried out analogously to Example 1 from 3,10,17 ~ tris- (2,3-diacetoxybenzoyl) -3,10,17-triaza-heptadecanoic acid and ampicillin, the title compound being obtained in 40% yield in the form of a colorless amorphous solid was obtained. ¹ H NMR (CDCI ₃ ): 1.15; 1.49 (m, 22H, 8x CH ₂ and 2xCH ₃ ); 2.15 - 2.2912 (m, 18H, 6x COCH ₃ ); 3.07 - 3.38 (m, 8H, 4x NCH _2l ); 4.29 (1H, s, CH); 5.40 (1H, d, CH); 5.54 (m, 1H, CH); 6.40, 6.50 (2x d, 1H; CH); 7.14 - 7.30 (m, 14H, aromat).

Example 3 N- (6-Bis r2- (8-methoxycarbonyloxy-benzoxazin-2,4-dion-3-yl) -ethvn-3 -r2,3-di- (methoxycarbonyloxy) -benzoyll-3.6-diaza-hexanoyl) -ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ = H; R ² , R ³ = COOCH3, R ⁶ and R ⁷ = R ² with p = 2, n = 0, m =

1, X and Z = direct bond, Y = Ampicillino.

A mixture of 2.47 g (2.75 mmol) of 6-bis- [2- (8-methoxycarbonyloxy-benzoxazin-

2,4-dion-3-y!) Ethyl] -3- [2,3-di- (methoxycarbonyloxy) benzoyl] -3,6-diaza-hexanoic acid, 0.317 g (2.75 mmol) of N-hydroxysuccinimide and 0.568 mg (2.75 mmol) of dicyclohexylcarbodiimide in 40 ml of anhydrous dioxane were stirred for 45 minutes at 0 ° C. and 1.5 hours at 20 ° C. and then kept at 4 ° C. overnight. The precipitate was filtered off and extracted several times with dioxane. The extract was evaporated and dried in a high vacuum. The solution of the residue in 10 ml of anhydrous tetrahydrofuran was slowly added to a solution of 0.727 g (1.8 mmol) of ampicillin trihydrate and 0.25 ml of triethylamine in 40 ml of 80% tetrahydrofuran at 0 ° C. The mixture was stirred at 0 ° C. for 45 minutes and at 20 ° C. for 1.5 hours and then evaporated in vacuo. The residue was dissolved in ethyl acetate / water, the solution acidified to pH 3 with 1 M hydrochloric acid and shaken. The organic phase was separated off, washed with aqueous sodium chloride solution, dried over sodium sulfate, concentrated and petroleum ether was added to the residue. 1.5 g (45% of theory) of the title compound were in the form of a colorless amorphous Get solid. The compound was purified by means of 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 distilled off from the corresponding fraction in vacuo and the residue was lyophilized, giving 0.5 g (15% of theory) of the purified title compound.

¹ H NMR (DMSO-d6): 1.41; 1.55 (s, 6H, 2xCH _3); 2.51 - 3.12 (m, 6H, NCH ₂ ); 3.75 - 3.91 (m, 18H, 3x NCH ₂ , 4x COOCH ₃ ); 4.24 (s, 1H, CH); 5.37 (t, J = 4.2, 1H, CH); 5.50 (m, 1H, CH); 5.75 (2x d, 1H, CH); 7.24 - 7.47 (m, 10H, aromat); 7.70 (d, 2H, aromat); 7.80 (d, 2H, aromat.), 8.69 (2xd, 1H, NHCO); 9.13 (2xd, 1H, NHCO). The sodium salt was prepared analogously to Example 1.

Example 4 N- [3.10.17-Tris- (2.3-diacetoxybenzovπ -3.10.17-triaza-heptadecanovn-cefaclor Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² , R ³ = COCH ₃ , R ⁶ = R ⁹ with R ⁸ = COCH ₃ , n = 4, m = 2, X and Z = direct bond, Y = cefacloro.

The title compound or its sodium salt was prepared analogously to Example 1 from 3,10,17-tris (2,3-diacetoxybenzoyl) -3,10,17-triaza-heptadecanoic acid and cephaclor in 40% yield in the form of a colorless one amorphous solid. H NMR (DMSO-d6): 1.48-0.80 (m, 16H, 8xCH ₂ ); 2.14 to 2.26 (m, 18H, 6xCH _3); 3.20 (m, 8H, CH ₂ N); 3.45 (dd, 2H, CH _2); 3.75 (m, 2H, CH ₂ N); 4.93 (m, 1H, CH); 5.48 (m, 1H, CH); 5.68 (m, 1H, CH); 7.19 -7.45 (m, 14H; aromatic); 8.30 (m, 1H, NHCO); 8.66 (m, 1H, NHCO); 9.29 (m, 1H, NHCO).

Example 5 N-r3.10.17-Tris- (2.3-diacetoxybenzovπ-3.10.17-triaza-heptadecanoyll-bacampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² , R ³ = COCH3, R ⁶ = R ⁹ with R ⁸ = COCH ₃ , n = 4, m = 2, X and Z = direct bond, Y = Bacampicillino.

The title compound was prepared analogously to Example 1 from 3,10,17-tris (2,3-diacetoxybenzoyl) -3,10,17-triaza-heptadecanoic acid and bacampicillin in 30% yield in the form of a colorless amorphous solid.

¹ H NMR (DMSO-d6): 1.19-1.52 (m, 28H, 8 x CH ₂ , 4 x CH ₃ ); 2.15 - 2.49 (m, 18H, COCH ₃ ); 2.90 - 3.20 (m, 8H, CHN); 4.12 (m, 2H, OCH ₂ ); 4.30 (m, 1H, CH); 5.42 (t, 1H, CH); 5.50 (m, 1H, CH); 5.70 (m, 1H, CH); 6.6.67 (m, 1H, OCH); 7.16 - 7.41 (m, 14H, aromat); 8.22 2xt, 1H, NHCO); 8.66 (m, 1H, NHCO), 9.18 (m, 1H, NHCO).

Example 6 N-r3J.11-tris (2,3-diacetoxybenzoyl) -3J.11-triaza-undecanovπ-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² , R ³ = COCH ₃ , R ⁶ = R ⁹ with R ⁸ = COOCH ₃ , n = 1, m = 2, X and Z = direct bond, Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to Example 1 from 3,7,11-tris (2,3-diacetoxybenzoyl) -3,7,11-triaza-undecanoic acid and ampicillin in 40% yield in the form of a colorless amorphous solid.

¹ HNMR (DMSO-d6): 1, 40 (s, 3H, CH _3); 1.54 (s, 3H, CH _3); 1.68 - 1.70 (m, 4H, 2x

CH ₂ ); 2.14 - 2.27 (m, 18H, 6x COCH3), 2.98 - 3.30 (m, 8H, 4 x NCH ₂ ), 3.80 (s, 2H,,

NCH ₂ COOH); 4.19 (s, 1H, 3-CH); 5.40 (t, J = 3.7 Hz, 1H, 7-CH); 5.50 (m, 1H, α-CH);

5.52 (m, 1H, 6-CH); 7.22 - 7.46 (m, 14H, ArH), 8.25 -8.30 (m, 1 H, NHCO), 8.60 - 8.80 (2x q, 1 H, NHCO), 9, 12-9.20 (q, 1H, NHCO).

Example 7 N-r3J-bis (5-chloro-2,3-dimethoxycarbonyloxybenzovπ-3.7-diaza-octanovn-ampicillin

Formula I with R ¹ , R ⁵ = H; R ² , R ³ = COOCH3, R ⁴ = 5-Cl, R ⁶ = R ⁹ with R ⁸ = OCOOCH ₃₎ R ⁷ = CH ₃ 'n = 1, m = 1, X and Z = direct bond, Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to

Example 1 from 3,7-bis (5-chloro-2,3 ~ dimethoxycarbony-oxybenzoyl) -3,7-diaza-octanoic acid and ampicillin in 40% yield in the form of a colorless amorphous

Solid. ¹ HNMR (DMSO-d6): 1.39 (s, 3H, CH ₃ ); 1, 53 (s, 3H, CH _3); 1, 75 (m, 2H, CH _2); 2.78 (3H, s, CH _3); 2.96 - 3.40 (4H, m, 2 x CH ₂ ); 3.81 (6H, m, 2 x OCH ₃ ); 3.85 (m, 6H, 2 x OCH ₃ );

3.93 (m, 2H, CH ₂ COOH); 4.18 (s, 1H, 3-CH); 5.38 (d, 1H, 7-CH); 5.48 (q, 1H, 6-CH);

5.74 (d, 1H, a-CH); 7.75 - 7.20 (m, 9H, aromat); 8.75 (m, 1H, NHCO); 9.19 (d, 1H,

NHCO). Example 8 N- {3.7-bis-r5-bromo-2.3-di-f-methoxycarbonyloxy) -benzovn-3.7-diaza-octanoyl) -ampicillin Formula I with R ¹ , R ⁵ = H; R ² , R ³ = COOCH ₃ , R ⁴ = 5-Br, R ⁶ = R ⁹ with R ⁸ = COCH ₃ , R ⁷ = CH ₃ 'n = 1, m = 1, X and Z = direct bond, Y = Ampicillino. The title compound or its sodium salt was prepared analogously to Example 1 from 3,7-bis- (5-bromo-2,3-dimethoxycarbonyloxy-benzoyl) -3,7-diaza-octanoic acid and ampicillin in the form of a 50% yield a colorless amorphous solid.

¹ HNMR (DMSO-d6): 1.75 (2H, m, CH ₂ ); 1, 53 (s, 3H, CH _3); 1, 39 (s, 3H, CH _3), 2.78 (3H, s, CH _3); 3.85 (6H, m, 2 x OCH ₃ ); 3.95 (2H, m, CH ₂ COOH), 4.18 (s, 1 H, 3-CH); 2.96 - 3.40 (4H, m, 2 x CH ₂ ); 3.80 (6H, m, 2 x OCH ₃ ); 5.52 (q, 1H, 6-CH); 5.38 (d, 1H, 7-CH); 5.74 (d, 1H, a-CH); 7.85 - 7.25 (9H, m, aromat); 8.75 (m, 1H, NHCO); 9.20 (d, 1H, NHCO).

Example 9

N-r3.7-bis- (2.3-diacetoxybenzoyl ^' ) -3.7-diaza-octanoyll-ampicin

Formula I with R ¹ , R ⁴ , R ⁵ = H; R ² , R ³ = COCH ₃ , R ⁶ = R ⁹ with R ⁸ = COCH ₃ , R ⁷ = CH ₃ , n = 1, m = 1, X and Z = direct bond, Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to Example 1 from 3,7-bis (2,3-diacetoxybenzoyl) -3,7-diaza-octanoic acid and ampicillin in 40% yield in the form of a colorless amorphous solid.

¹ HNMR (DMSO-d6): 1, 40 (s, 3H, CH _3); 1, 53 (s, 3H, CH _3); 1, 75 (2H, m, CH _2); 2.20 (s, 6H, COCH ₃ ); 2.27 (6H, s, COCH ₃ ); 2.75 (s, 3H, CH _3); 2.87 -3.15 (m, 2H, CH ₂ ); 3.98 (m, 2H, CH ₂ COOH), 5.39 (m, 1 H, 7-CH); 5.52 (m, 1H, 6-CH); 5.85 (m, 1H, α-CH); 6.94 - 7.48 (m, 11H, aromat); 8.73 (m, 1H, NHCO); 9.15 (m, 1H, NHCO).

Example 10 N- [3.8-Bis- (2,3-diacetoxybenzovπ-3.8-diaza-octanovn-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² , R ³ , R ⁸ = COCH ₃ , R ⁶ = R ⁹ with R ⁸ = COCH ₃ , n = 1, m = 2, X and Z = direct bond, Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to Example 1 from 3,8-bis (2,3-diacetoxybenzoyl) -3,8-diaza-octanoic acid and ampicillin in 50% yield in the form of a colorless amorphous solid. ¹ HNMR (DMSO-d6): 1.40-1.60 (4H, m, CH ₂ ); 1, 40 (s, 3H, CH _3); 1.54 (s, 3H, CH _3); 2.17 (3H, s, COCH ₃ ); 2.21 (3H, s, COCH3); 2.27 (6H, s, COCH3); 3.30 (3H, s, CH _3); 3.22 (2H, m, CH _2); 3.95 (2H, m, CH ₂ COOH); 4.19 (s, 1H, 3-CH); 5.38 (m, 1H, 7-CH); 5.51 (m, 1H, 6-CH); 5.72 (m, 1H, α-CH); 6.94 - 7.52 (11 H, m, aromat); 8.30 (1H, m, NHCO); 8.70 (m, 1H, NHCO); 8.70 (m, 1H, NHCO).

Example 11 N-r3.8-bis- (2,3-diacetoxybenzovπ-3,8-diaza-octanovn-amoxicillin formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² , R ³ , R ⁸ = OCOCH ₃ , R ⁶ = R ⁹ with R ⁸ = COCH ₃ , n = 1, m = 2, X and Z = direct bond, Y = amoxiciliino.

The preparation was carried out analogously to Example 1 from 3,8-bis (2,3-diacetoxybenzoyl) -3,8-diaza-octanoic acid and amoxycillin, the title compound being obtained in 40% yield in the form of a colorless amorphous solid. ¹ HNMR (DMSO-d6): 1, 40-1, 60 (m, 4H, CH _2); 1, 41 (s, 3H, CH _3); 1, 54 (s, 3H, CH _3); 2.17 (s, 3H, COCH3); 2.21 (s, 3H, COCH3); 2.27 (s, 6H, COCH3); 3.13 (m, 3H, CH _3); 3.03 (m, 2H, CH _2); 3.95 (m, 2H, CH ₂ COOH); 4.18 (s, 1H, 3-CH); 5.38 (m, 1H, 7-CH); 5.55 (m, 2H, α-CH + 6-CH); 6.60 - 7.45 (m, 10H, aromat); 8.32 (m, 1H, NHCO); 8.56 (m, 1H, NHCO); 9.02 (m, 1H, NHCO); 9.38 (s, 1H, OH). The sodium salt was prepared by adding a solution of 0.02 g of sodium ethylhexanoate in 3 ml of ethyl acetate to a solution of 0.10 g of the title compound in 12 ml of tetrahydrofuran. The precipitate which had separated out was filtered off after standing for about 10 minutes and washed with ethyl acetate. The sodium salt of the title compound was obtained in the form of a colorless amorphous solid in 90% yield.

Example 12 N-f3J-bis (2,3-dichloro-5,6-di-methoxycarbonyloxy-benzovπ-3J-diaza-octanoyl) -ampicillin Formula I with R ¹ , R ⁵ = H; R ² , R ³ = COOCH3, R ⁴ = 5,6-Di-CI, R ⁶ = R ⁹ , R ⁷ = CH ₃ 'n = 1, m = 1, X and Z = direct bond, Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to Example 1 from 3,7-bis- (2,3-dichloro-5,6-di-methoxycarbonyloxy-benzoyl) -3,7-diaza- octanoic acid and ampicillin in 30% yield in the form of a colorless amorphous solid.

¹ HNMR (DMSO-6): 1, 39 (s, 3H, CH _3); 1.53 (s, 3H, CH _3); 1, 80 (m, 2H, CH _2); 2.78 (s, 3H, CH _3); 2.96 -3.40 (m, 4H, 2 x CH ₂ ); 3.82 (m, 6H, 2 x OCH ₃ ); 3.85 (m, 6H, 2 x OCH ₃ ); 4.05 (m, 2H, CH ₂ COOH); 4.19 (s, 1H, 3-CH); 5.38 (m, 1H, 7-CH); 5.48 (m, 1H, 6-CH); 5.70 (m, 1H, α-CH); 7.20 - 8.05 (m, 7H, aromat); 8.65 (m, 1H, NHCO); 9.19 (d, 1H, NHCO).

Example 13 N- (r6-Bis-2.3- (diacetoxybenzovπ-2-aminoethvn-3- (2.3-diacetoxybenzoyl) -3.6-diaza-hexanoylr-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ = H, R ² , R ³ = COCH ₃ , R ⁶ and R ⁷ = R ¹³ with p = 2, n = 0, m = 1,

X and Z = direct bond, Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to Example 1 from 6- [bis- (2,3-diacetoxybenzoyl) -2-aminoethyl] -3- (2,3-diacetoxybenzoyl) -

3,6-diazahexanoic acid and ampicillin in 60% yield in the form of a colorless amorphous solid.

¹ H NMR (DMSO-d6): 1.40 (s, 3H, CH ₃ ); 1, 54 (s, 3H, CH _3); 2.19 - 2.28 (m, 18H,

COCH ₃ ); 3.12 - 4.07 (m, 14H, NCH ₂ ); 4.20 (s, 1H, 3-CH); 5.38 - 5.39 (m, 1H, 7-CH); 5.50 - 5.51 (m, 1H, α-CH); 5.72 - 5.75 (m, 1H, 6-CH); 7.07 - 7.81 (m, 14H, aromat); 8.54 - 9.20 (m, 2 x 1 H, NHCO). ^'

Example 14

N- (3- [ε- (8-Methoxycarbonyloxy-3.4-dihydro-2.4-dioxo-2H-1.3-benzoxazin-3-ylVhexanoyl1- 7- (2.3-di-methoxycarbonyloxy-benzoyl) -10- ( ^' 8-methoxycarbonyloxy -3.4-dihydro-2,4-dioxo-

2H-1,3-benzoxazin-3-vO-3,7-diaza-n-decanoylr-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² = CO in connection with -N = of X, R ³ =

COOCH ₃ , R ⁶ = R ⁹ with R ⁸ = COOCH ₃ , R ⁷ = R ¹² with p = 2, ^• n = 1, m = 1, X = CO (CH ₂ ) _q -

N = with q = 5, and Z = direct bond, Y = ampicillino. The title compound or its sodium salt was prepared analogously to

Example 1 from 3- [ε- (8-methoxycarbonyloxy-3,4-dihydro-2,4-dioxo-2H-1, 3-benz-oxazin-3-yl) -hexanoyl] -7- (2,3- di-methoxycarbonyloxy-benzoyl) -10- (8-methoxycarbonyloxy-3,4- dihydro-2,4-dioxo-2H-1, 3-benzoxazin-3-yl) -3,7-diaza-n-decanoic acid and ampicillin in 40% yield in the form of a colorless amorphous solid.

¹ H NMR (DMSO-d6): 1, 35 (s, 3H, CH _3); 1, 50 (s, 3H, CH _3); 1.00 - 2.30 (m, 12H, 8 x CH ₂ ); 3.08 (m, 4H, CH _2); 3.23 (m, 6H, CH _2); 3.80 (s, 3H, COOCH ₃ ); 3.82 (s, 3H, COOCH ₃ ); 3.89 (s, 6H, COOCHg); 3.90 (m, 2H, CH ₂ COOH); 4.15 (s, 1H, 3-CH); 5.34 (d, 1H, 7-CH); 5.42 (m, 1H, 6-CH); 5.73 (m, 1H, α-CH); 7.21 - 7.90 (m, 14H, aromat); 8.78 (d, 1H, NHCO); 9.14 (d, 1H, NHCO).

Example 15

N-f3.7.11-Tris-r2- (8-methoxycarbonyloxy-2.4-dioxo-benzoxazin-3-yl) acetyl-3.7.1 1- triaza-undecanoylj-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H; R ² = CO in connection with -N = of X, R ³ = COOCH ₃ , R ⁶ = R ¹⁰ with o = 1; ^• n = 1, m = 2, X = CO (CH ₂ ) _q -N = with q = 1, and Z = direct bond, Y = ampicillino. , ^l

The title compound or its sodium salt was prepared analogously to Example 1 from 3.7.1 1 -Tris- [2- (8-methoxycarbonyloxy-2,4-dioxo-benzoxazin-3-yl) acetyl] -3.7 , 1 1-triaza-undecanoic acid and ampicillin in 40% yield in the form of a colorless amorphous solid.

¹ H NMR (, DMSO-d6): 1, 22-1,58 (m 10H, CH ₂ and CH ₃ ); 3.0 - 3.5 (m, 8H,); 3.90 (s, 9H, COOCHg); 4.42, 4.45 (s, 2 x 2H, NCH ₂ ); 4.70 (m, 4H, NCH _2); 4.16 (s, 1H, 3-CH); 5.37 (d, 1H, 7-CH); 5.48 (m, 1H, 6-CH); 5.77 (m, 1H, α-CH); 7.31 - 7.90 (m, 14H, aromat); 8.18, (d, 1H, NHCO); 8.33, (d, 1H, NHCO); 9.17 (m, 1H, NHCO).

Example 16

N-r3.7-bis (2,3-dimethoxycarbonyloxybenzovπ-3.7-diaza-5-hvdroxy-heptanoyl1-ampicillin

Formula I with R ¹ , R ⁴ = H, R ⁵ = OH, R ² , R ³ = COOCH ₃ , R ⁶ = R ⁹ with R ⁸ = COOCH ₃ , R ⁷ = H, n = 1, m = 1, X and Z = direct bond, Y = Ampicillino. The title compound or its sodium salt was prepared analogously to

Example 1 from 3,7-bis (2,3-dimethoxycarbonyloxybenzoyl) -3,7-diaza-5-hydroxy- heptanoic acid and ampicillin in 65% yield in the form of a colorless amorphous

Solid.

¹ HNMR (DMSO-d6): 1, 40 (s, 3H, CH _3); 1, 55 (s, 3H, CH _3); 2.80 -3.10

(m, 4H, 2 x CH ₂ ); 3.75 (s, 3H, CH _3); 3.84 (s, 6H, OCH ₃ ); 3.90 (s, 3H, OCH ₃ ); 4.15 (s, 2H,

CH ₂ COOH); 4.19 (s, 1H, 3-CH); 5.38 (m, 1H, 7-CH); 5.50 (m, 1H, α-CH); 5.55 (q, 1H,

6-CH); 7.2-7.95 (m, 1 1 H, aromat); 8.97 (d, 1H, NHCO); 9.12 (d, 1H, NHCO).

Example 17

N- [8- (8-Methoxycarbonyloxy-2.4-dioxo-benzoxazin-3vπ-5- (2,3-dimethoxycarbonyloxy-benzoyl) -5-aza-4-methyl-octanoyll-ampicillin

Formula I with R ¹ = CH ₃ , R ² , R ³ = COOCH ₃ , R ⁴ , R ⁵ = H, R ⁷ = R ¹² with p = 3,, m = 0, n = 1, X = direct bond, Z = (CH ₂ ) ₂ , Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to

Example 1 from 8- (8-methoxycarbonyloxy-2,4-dioxo-benzoxazin-3-yl) -5- (2,3-dimethoxycarbonyloxybenzoyl) -5-aza-4-methyl-octanoic acid and ampicillin in 73% strength Yield in

Form of a colorless amorphous solid. ¹ HNMR (DMSO-d6): 1, 15 (d, 3H, CH _3); 1, 40 (s, 3H, CH _3); 1, 55 (s, 3H, CH _3); 1, 75

(m, 2H, CH ₂ ); 1.8-2.2 (m, 4H, 2 x CH ₂ ); 3.05 (q, 1H, CH); 3.8-4.0 (m, 9H,

3 x OCH ₃ ); 4.19 (s, 1H, 3-CH); 5.37 (m, 1H, 7-CH); 5.51 (m, 1H, α-CH); 5.67 (q, 1H, 6-CH);

7.2-7.9 (m, 1 1 H, aromat); 8.50-9.10 (m, 2 x 1H, NHCO).

Example 18

N- {4-r5- (Bis-N-2.3-diacetoxybenzoyl-2-aminoethvπ-2- (2.3-di-acetoxybenzovπ-2.5-diaza-pentvn-benzoyl-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ = H, R ² , R ³ = COCH ₃ , R ⁶ and R ⁷ = R ¹³ with p = 2, n = 0, m = 1, X

= direct bond, Y = ampicillino, Z = p-phenylene. The title compound or its sodium salt was prepared analogously to Example 1 from 4- [5- (bis-N-2,3-diacetoxybenzoyl-2-aminoethyl) -2- (2,3-diacetoxybenzoyl) -2.5 -diaza-pentyl] -benzoic acid and ampicillin in 47% yield in the form of a colorless amorphous solid. When the reaction solution was acidified, a solid precipitate was formed, which freed from the solvent by decanting, with little Washed water and then dried under high vacuum.

¹ H NMR (DMSO-d6): 1.40 (s, 3H, CH ₃ ); 1, 52 (s, 3H, CH _3); 2.15 - 2.25 (m, 18H,

COCH ₃ ); 2.66 to 3.56 (m, 14H, NCH _2); 4.18 (s, 1H, 3-CH); 5.37 - 5.41 (m, 1H, 7-

CH); 5.50 - 5.56 (m, 1H, α-CH); 5.90 (m, 1H, 6-CH); 7.27 - 8.25 (m, 18H, aromatic); 8.79 - 9.03 (m, 2 x 1 H, NHCO).

Example 19 N- (4-r5- (8-Methoxycarbonyloxy-2,4-dioxo-1.3-benzoxazin-3-yl) -2- (2.3-di-methoxycarbonyloxybenzoyl) -2-aza-pentvπ-benzoyl) - ampicillin formula I with R ¹ , R ⁴ , R ⁵ = H, R ² , R ³ , R ⁸ = COOCH3, R ⁶ = R ⁹ , R ⁷ together with R ⁸ = - CO-, n = 1, m = 1 , X = direct bond, Y = ampicillino, Z = p-phenylene. The title compound or its sodium salt was prepared analogously to Example 1 from 4- [5- (8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazin-3-yl) -2- (2,3-di- methoxycarbonyloxybenzoyl) -2-aza-pentyl] - benzoic acid and ampicillin in 60% yield in the form of a colorless amorphous solid.

¹ HNMR (DMSO-d6): 1, 40 - 1. 51 (2x s, 6H, CH _3); 1 to 70 - 1, 95 (m, 2H, CH _2); 3.07 to 3.36 (m, 4H, NCH _2); 3.70 - 3.91 (m, 11H, NCH ₂ CO and COOCH3); 4.19 (s, 1H, CH); 5.41 (m, 1H, CH); 5.50 - 5.56 (m, 1H, CH); 5.89 (m, 1H, CH); 7.25 - 7.90 (m, 15H, aromat); 8.78 (m, 1H, NHCO); 9.02 - 9.18 (m, 1H, NHCO).

Example 20

N-f4-F2.6-bis (2,3-di-methoxycarbonyloxybenzoyl) -2,6-diaza-heptvn-benzoyl> -ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ = H, R ² , R ³ , R ⁸ = COOCH3, R ⁶ = R ⁹ , R ⁷ = CH ₃ , n = 1, m = 1, X = direct bond, Y = ampicillino, Z = p-phenylene. The title compound or its sodium salt was prepared analogously to

Example 1 from 4- [2,6-bis- (2,3-di-methoxycarbonyloxybenzoyl) -2,6-diaza-heptyl] benzoic acid and ampicillin, the title compound being obtained in 60% yield in the form of a colorless amorphous solid.

¹ HNMR (DMSO-d6): 1.39; 1.46 (2x s, 6H,, CH _3l ); 1, 65 - 1. 85 (m, 4H, _CH2) ;, 2.73 to 2.75 (m, 3H, NCH _3); 3.73 - 3.86 (m, 12H, COOCH ₃ ) ;, 4.17 (s, 1 H, CH) ;, 5.51 - 5.87 (m, 3H,

CH); 7.28 - 7.91 (m, 15H, aromat), 9.07 - 9.09 (m, 2H, NHCO). Example 21 N- {4-r2J-bis (2,3-diacetoxybenzoyl) -2.7-diaza-heptvn-phenoxyacetyl) -ampicillin formula I with R ¹ , R ⁴ , R ⁵ = H, R ² , R ³ , R ⁸ = COCH ₃ , R ⁶ = R ⁹ , n = 2, m = 1, X = direct bond, Y = ampicillino, Z = pC ₆ H ₄ -0-CH ₂ -.

The title compound or its sodium salt was prepared analogously to Example 1 from 4- [2,7-bis (2,3-diacetoxybenzoyl) -2,7-diaza-heptyl] phenoxyacetic acid and ampicillin in 65% yield in the form of a colorless amorphous solid. ¹ H NMR (DMSO-d6): 1.39-1.53 (m, 10H, 2x CH ₃ , 2xCCH ₂ ); 2.16 - 2.27 (m, 12H, 4x COCH ₃ ); 2.90 - 3.15 (4 m, H, 2x NCH ₂ ); 4.18 (s, 2H, OCH ₂ CO); 4.63 (s, 2H,

CONCH ₂ ares); 5.39 (d, J = 4.04, 1H, CH); 5.51 - 5.52 (m, 1H, CH); 5.75 - 5.85 (m, 1H, CH); 6.88 - 7.41 (m, 15H, aromat.); 8.20-8.35 (m, 1H, NHCO); 8.54-8.57 (m, 1H, NHCO); 9.18-9.20 (m, 1H, NHCO).

Example 22

N- (2-R2J-bis (2,3-diacetoxybenzoyl) -2.7-diaza-heptvn-benzooylf-ampicillin.

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H, R ² , R ³ , R ⁸ = COCH ₃ , R ^δ = R ⁹ , R ¹⁴ = H, with n = 2, m = 1,

X = direct bond, Y = ampicillino, Z = o-phenylene.

The title compound or its sodium salt was prepared analogously to Example 1 from 2- [2,7-bis- (2,3-diacetoxybenzoyl) -2,7-diaza-heptyl] -benzoic acid and

Ampicillin in 36% yield in the form of a colorless amorphous solid.

¹ H NMR (DMSO-d6): 1, 16 - 1. 45 (m, 4H, CH ₂ CH _2); 1, 40 (s, 3H, CH _3); 1, 52 (s, 3H, CH _3);

2.15 - 2.26 (m, 12H, COCH ₃ ); 2.95 - 3.23 (m, 6H, NCH ₂ ); 4.19 (s, 1H, 3-CH); 5.39 -

5.40 (m, 1H, 7-CH); 5.48 - 5.59 (m, 1H, α-CH); 5.88 - 5.91 (m, 1H, 6-CH); 7.24 - 7.54 (m, 15H, aromat); 8.16 - 8.32 (m, 1H, NHCO); 8.92 - 9.12 (m, 1H, NHCO).

Example 23 N- (2-r2.6-bis (2,3-diacetoxybenzovπ-2,6-diaza-heptyll-benzoyl> -ampicillin Formula I with R ¹ , R ⁴ , R ⁵ = H, R ⁷ = CH ₃ , R ² , R ³ , R ⁸ = COCH ₃ , R ⁶ = R ⁹ , R ¹⁴ = H, with n = 1, m = 1, X = direct bond, Y = ampicillino, Z = o-phenylene.

The title compound or its sodium salt was prepared analogously to Example 1 from 2- [2,6-bis (2,3-diacetoxybenzoyl) -2,6-diaza-heptyl] benzoic acid and ampicillin in the form of a 20% yield a colorless amorphous solid. ¹ H NMR (DMSO-d6): 1, 45 to 1.82 (m, 2H, CH ₂ CH _2); 1, 40 (s, 3H, CH _3); 1, 52 (s, 3H, CH _3); 2.12 - 2.27 (m, 12H, COCH ₃ ); 2.71 (s, 3H, CH _3); 2.74 to 3.29 (m, 6H, NCH _2); 4.18 (s, 1H, 3-CH); 5.38 - 5.40 (m, 1H, 7-CH); 5.50 - 5.55 (m, 1H, α-CH); 5.84 - 5.93 (m, 1H, 6-CH); 6.88 - 7.49 (m, 15H, aromat.); 8.96 - 9.26 (m, 2H, NHCO).

Example 24 N-14-r2.6.9.13-tetrakis (2,3-diacetoxybenzoyl) -2,6.9.13-tetraazatidecvπ-benzovπ-ampicillin Formula I with R ¹ , R ⁴ , R ⁵ = H, R ² , R ³ , R ⁸ = COCH ₃ , R ⁶ = R ⁹ , R ⁷ = R ¹⁴ with s = 2 and R ¹³ with p = 3; n = 1, m = 1, X = direct bond, Z = p-phenylene, Y = ampicillino

The title compound or its sodium salt was prepared analogously to Example 1 from 4- [2,6,9,13-tetrakis (2,3-diacetoxy-benzoyl) -2, 6,9,13-tetraaza-tridecyl] - benzoic acid and ampicillin in 50% yield in the form of a colorless amorphous solid. ¹ H NMR (DMSO-d6): 1.38; 1, 51 (s, 6H, 2 x CH _3); 1, 40 - 1. 70 (m, 4H, CCH _2); 2.06 - 2.27 (m, 24H, COCH ₃ ); 3.03 to 3.30 (m, 12H, NCH _2); 4.17 (s, 1H, CH); 4.37 - 4.39 (m, 1H, CH); 5.51 - 5.54 (m, 1H, CH); 5.88-5.94 (m, 1H, CH); 7.19-7.51 (m, 21H, aromat); 8.25 - 9.03 (m, 3H, NHCO).

Example 25

N- (6-r2J-bis- (2 ₁ 3-diacetoxybenzovn-2.7-diaza-heptyll-2,3-dimethoxy-benzoylV ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H, R ² , R ³ , R ⁸ = COCH3, R ⁶ = R ⁹ , with n = 2, m = 1, X = direct bond, Y = Ampicillino, Z = o-phenylene with R ¹⁵ = 3,4-dimethoxy. The title compound or its sodium salt was prepared analogously to

Example 1 from 6- [2,7-bis (2,3-diacetoxybenzoyl) -2,7-diaza-heptyl] -2,3-dimethoxybenzoic acid and ampicillin in 11% yield in the form of a colorless amorphous

Solid.

¹ H NMR (DMSO-d6): 1.03-1.90 (m, 4H, CH ₂ CH ₂ ); 1, 40 (s, 3H, CH _3); 1, 53 (s, 3H, CH _3); 2.15 - 2.26 (m, 12H, COCH ₃ ); 2.80 to 3.69 (m, 6H, NCH _2); 3.28 (s, 6H, O CH ₃ ), 4.19 (s,

1H, 3-CH); 5.37 - 5.40 (m, 1H, 7-CH); 5.42 - 5.55 (m, 1H, α-CH); 5.78 - 5.92 (m, 1H, 6-

CH); 6.94 - 7.73 (m, 13H, aromat); 8.18 - 8.29 (m, 1H, NHCO); 8.93 - 9.11 (m, 2H, 2x

NHCO). Example 26 N 2-r2.6-bis (2,3-di-methoxycarbonyloxy-benzoyl) -2.6-diaza-heptvπ-benzoyl) -ampicillin formula I with R ¹ , R ⁴ , R ⁵ = H, R ⁷ = CH ₃ , R ² , R ³ , R ⁸ = COOCH ₃ , R ⁶ = R ⁹ , R ¹⁵ = H, with n = 1, m = 1, X = direct bond, Y = ampicillino, Z = o-phenylene.

The title compound or its sodium salt was prepared analogously to Example 1 from 2- [2,6-bis- (2,3-dimethoxycarbonyloxy-benzoyl) -2,6-diaza-heptyl] benzoic acid and ampicillin in 21%. yield in the form of a colorless amorphous solid. ¹ H NMR (DMSO-d6): 1, 32 - 1. 68 (m, 2H, CH _2); 1, 40 (s, 3H, CH _3); 1, 52 (s, 3H, CH _3); 2.73 (s, 3H, CH _3); 2.68 to 3.04 (m, 4 H, NCH _2); 3.74 - 3.84 (m, 12H, COOCH ₃ ); 4.18 (s, 1H, 3-CH); 4.39 - 4.49 (m, 2H, NCH ₂ ); 5.39 - 5.40 (m, 1H, 7-CH); 5.43 - 5.53 (m, 1H, α-CH); 5.81 - 5.89 (m, 1H, 6-CH); 6.78 - 7.50 (m, 15H, aromat), 9.03 - 9.13 (m, 1H, NHCO).

Example 27 N- (2-r2.6.10-Tris- (2.3-diacetoxybenzoyl) -2,6.10-triaza-decvn-benzoyl> -ampiciHin Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H, R ² , R ³ , R ⁸ = COCH ₃ , R ⁶ = R ⁹ , R ¹⁵ = H, with n = 1, m = 2, X = direct bond, Y = ampicillino, Z = o-phenylene, C6 ₃ H ₆ N ₆ O ₂₀ S (1257), The title compound or its sodium salt was prepared analogously to Example 1 from 2- [2,6,10-tris (2,3-diacetoxybenzoyl) -2,6,10-triaza-decyl ] -benzoe acid and ampicillin in 17% yield in the form of a colorless amorphous solid ¹ H NMR (DMSO-d6): 1, 62 -, 73 (m, 4H, CH _2); 1, 40 (s, 3H. , CH ₃ ); 1, 51 (s, 3H, CH ₃ ); 2.08 - 2.27 (m, 18H, COCH ₃ ); 2.50 - 3.56 (m, 10H, NCH ₂ ); 4 , 18 (s, 1H, 3-CH); 5.39-5.40 (m, 1H, 7-CH); 5.51-5.52 (m, 1H, α-CH); 5.85 - 5.90 (m, 1H, 6-CH); 6.80 - 7.54 (m, 18H, aromat), 8.10 - 8.32 (m, 1 H, NHCO); 8.88 - 9 , 07 (m, 2H, 2x NHCO).

Example 28 N-r3,7-bis (2,3-diacetoxybenzoyl) -3,7-diaza-heptanovπ-ampicillin Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H, R ² , R ³ , R ⁸ = COCH ₃ , R ⁶ = R ⁹ , n = 1, m = 1, X and Z = direct bond, Y = Ampicillino. The title compound or its sodium salt was prepared analogously to Example 1 from 3,7-bis (2,3-diacetoxybenzoyl) -3,7-diaza-heptanoic acid and ampicillin in 30% yield in the form of a colorless amorphous solid , ¹ HNMR (DMSO-d6): 1.40 - 1.60 (m, 8H, CCH ₂ , CH ₃ ); 2.14 - 2.23 (m, 12H, COCH ₃ ); 3.22 (m, 4H, NCH ₂ ), 3.95 (m, 2H, NCH ₂ CO), 4.14 (s, 1 H, 3-CH), 5.33 (m, 1 H, 7- CH); 5.47 (, 1H, 6-CH); 5.85 (m, 1H, α-CH); 7.03 - 7.52 (m, 11H, aromat); 8.25 (m, 1H, NHCO); 8.68 (m, 1H, NHCO); 9.11 (m, 1H, NHCO).

Example 29 N-r3.9-bis (2,3-diacetoxybenzovπ-3.9-diaza-nonanovn-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H, R ² , R ³ , R ⁸ = COCH3, R ⁶ = R ⁹ , n = 3, m = 1, X and Z = direct bond, Y = Ampicillino.

The title compound or its sodium salt was prepared analogously to

Example 1 from 3,9-bis (2,3-diacetoxybenzoyl) -3,9-diaza-nonanoic acid and ampicillin in 40% yield in the form of a colorless amorphous solid.

¹ HNMR (DMSO-d6): 1.40-1.440 (m, 12H, CCH ₂ , CH ₃ ); 2.16 - 2.23 (m, 12H, COCH ₃ );

3.16 - 3.31 (m, 4H, NCH ₂ ); 4.15 (m, 2H, CH ₂ CO); 3.90 (m, 1H, CH); 5.35 (m, 1H, CH);

5.48 (m, 1H, CH); 5.72 (m, 1H, CH); 7.25 - 7.49 (m, 11H, aromat); 8.32 (m, 1H,

NHCO); 8.68 (m, 1H, NHCO); 9, 11 -9, 15 (m, 1H, NHCO).

Example 30

N-R3.6-bis (2,3-diacetoxybenzoyl) -3,6-diaza-hexanoyl1-ampicillin

Formula I with R ¹ , R ⁴ , R ⁵ , R ⁷ = H, R ² , R ³ , R ⁸ = COCH ₃ , R ⁶ = R ⁹ , n = 0, m = 1, X and Z = direct bond, Y = Ampicillino. The title compound or its sodium salt was prepared analogously to

Example 1 from 3,6-bis (2,3-diacetoxybenzoyl) -3,6-diaza-hexanoic acid and ampicillin in

23% yield in the form of a colorless amorphous solid.

¹ HNMR (DMSO-d6): 1.40; 1, 52 (m, 6H, CH _3); 2.05 - 2.27 (m, 12H, COCH ₃ ); 3.10 - 3.40

(m, 6 H, NCH _2); 4.14 (s, 1H, CH); 5.35 - 5.38 (m, 1H, CH); 5.49 - 5.51 (m, 1H, CH); 5.72 (m, 1H, CH); 7.24 - 7.49 (m, 11H, aromat.); 8.25 - 8.35 (m, 1H, NHCO); 8.72 - 8.74

(m, 1H, NHCO); 9.10-9.20 (m, 1H, NHCO). Table. Antibacterial activity of the siderophore-antibiotic conjugates MIC values [μg / ml]

Claims

claims 1. Catecholate-β-lactam conjugates of the general formula R ⁱ wherein R »1 _ = H, alkyl, substituted alkyl, aryl, substituted aryl, R> 2 '_ = H, COalkyl, COOalkyl, X = direct bond, (CH ₂ ) _q NH-, CO (CH ₂ ) _q NH- with q = 1-6, or R ² together with X represents a group (CH) - N-CO " or CO- (CH ₂ ) - N-CO-, where q = 1-6 R ³ = H, CO alkyl, COO alkyl, R ⁴ = H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, alkoxy, substituted alkoxy, in all possible positions, it being possible for the substituents mentioned to occur more than once, R> 5 _ = H, OH, O alkyl, O acyl, O aryl, alkyl, substituted alkyl, aryl, substituted aryl, with R ⁸ = H, COAlkyl, COOalkyl, together with R ⁷ indicates a group or R ⁶ and / or R ⁷ = - D 12 or R ⁷ = H, alkyl, substituted alkyl, aryl, substituted aryl or R ⁷ together with R ⁸ = -CO-, or with R = R ¹³ - (CH ₂ ) _S - N with s = 2 - 4 = R 14 R ⁹ n = 0-8, m = 0-3, Y = OA with A = H, an alkali metal ion, an ammonium ion or a substituted ammonium ion, Z = direct bond or Z = - (CH ₂ ) _r -with r = 0-10 or Z = arylene or substituted arylene, preferably with R ¹⁵ = H, alkyl, substituted alkyl, aryl, substituted aryl, halogen, alkoxy, substituted alkoxy, in all possible positions, mean, in the case of the presence of asymmetric C atoms, the corresponding D and L forms, Enantiomers and diastereomers as well as the racemates or enantiomers and Diastereomeric mixtures of the compounds of formula I and such compounds as free acids, in the form of their salts or as easily cleavable esters, with the proviso that R ⁷ together with R ^{8 is} not = -CO- and / or R ^{5 is} not = H if Z represents a direct bond or that R ^{7 is} not = R ¹² if R ⁶ = R ⁹ , R ⁵ = H and X and Z are direct bonds. 2. Compounds of formula I according to claim 1, wherein R ¹ and R ⁵ = H, R ⁴ = H or halogen, R ⁷ = H or CH ₃ , R ⁶ = R ⁹ or R ⁶ and / or R ⁷ = R ¹² or R ¹³ , n = 1-2, m = 1-2, X and Z = direct bond. 3. Compounds of formula I according to claim 1, wherein R ¹ and R ⁵ = H, R ⁴ = H or,, halogen, R ⁷ = H or CH ₃ , R ⁶ = R ⁹ , or R ⁶ and / or R ⁷ = R ¹² or R ¹³ , n = 1 - 3, m = '1, X = direct bond and Z = phenylene or substituted phenylene. 4. Compounds of formula I according to claim 1, wherein R ¹ and R ⁵ = H, R ⁴ = H or halogen, R ⁷ = H or CH ₃ , R ⁶ = R ⁹ , n = 1-3, m = 1, X and Z = direct bond. 5. Compounds of formula I according to claim 1, wherein R ¹ and R ⁵ = H, R ⁴ = H or halogen, R ⁷ = H or CH ₃ , R ⁶ and R ⁷ = R ¹³ with p = 2, n = 0 , m = 1, X and Z = direct bond. 6. Compounds of formula I according to claim 1, wherein R ¹ = alkyl, R ⁵ = H, R ⁴ = H or halogen, R ⁷ = H or CH ₃ , R ⁶ = R ⁹ , n = 1 - 3, m = 1, X and Z = direct bond 7. Compounds of formula I according to claim 1, wherein R ¹ and R ⁵ = H, R ⁴ = H or halogen, R ⁷ = H or CH ₃ , R ⁶ = R ¹⁰ with o = 1-2, n = 1 - 3, m = 1 - 2, X together with R ^{2 represents} a group _ΛΛ , _Λ1 , J, __ - CO- (CH ₂ ) _q - N-CO— and Z means a direct bond. 8. Use of the compounds of formula I according to claims 1-7 as growth factors for bacteria, especially for mycobacteria. 9. Use of the compounds of formula I according to claims 1-7 as constituents of antibiotics for their active introduction into bacterial cells. 10. Use of the compounds of formula I according to claims 1-7 as therapeutic agents for diseases which are due to a disorder of the iron metabolism. 11. Medicament containing a compound of formula I according to claims 1-7 together with conventional carrier materials.