HK1015763B - Benzoxazindione derivatives, process for their preparation and their use - Google Patents

Description

Err1:Expecting ',' delimiter: line 1 column 350 (char 349)

Benzoxazine derivatives of formula l with the substitutes indicated have not been described in the literature.

Structurally related compounds are salicylic acid derivatives described in DE 11 47 583 which are analgesic. Furthermore, several publications are known from the patent literature aimed at improving antibiotic agents, e.g. β-lactam compounds with certain catechol or hydroxypyridone residues from EP 0 472 062, cephalospores containing an amide or sulphonamide group from EP 0 341 948 or alpha-aminoquinolino- (((3) penicillin from EP 0 496 332.

Err1:Expecting ',' delimiter: line 1 column 193 (char 192)

The N- ((2,3-dihydroxybenzoyl) glycine has been found as a siderophore in B. subtilis (lto, T., Neilands, J.B., J. Amer. Chem. Soc. 80 (1958), 4645), some catechol-substituted amino acid derivatives have already been synthesized, e.g. the N- ((2,3-dihydroxybenzoyl) -L-threonine (Kanai, F., Kaneko, T., Morishima, H., Isshiki, K., Takita, T., Takeuchi, T., Umezawa, H., J. Antibiotic. 38 (1985), 39), the N2,N6-bis-2,3-dihydroxybenzoyl) -L-threonine (Corbin, J.L., Bakterien, B.A., Biochemistry, 75), the S- (((2,3-dihydroxybenzoyl), S- ((2,7-bis-B, K.K., Kaneko, T., Morishima, H., Isshiki, K., Takita, T., Takeuchi, T., T., Umezawa, H., J., J., 28); the N2,N6-bis-methoxybenzoyl-methoxybenzoyl (Bacetyl-methoxybenzoyl), B.Bacethanol, B.Bacethanol, B.Bacethanol, B.A., B.A., B.A., B.A., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B., B

Various catechol compounds have been linked to beta-lactamenes, which have resulted in a significant increase in the antibacterial activity of these antibiotics due to the introduction of bacterial iron transport pathways into the bacterial cell (e.g. WO 97/49670 or Arisawa, M., Sekine, Y., Shimizu, S., Takano, H., Angehrn, P., Then, R.L., Antimicrobial Agents Chemother. 35 (1991), 653). However, no such compounds have so far reached a clinical stage of maturity.

The production of benzoxa derivatives from acyloxybenzoyl chloride and amino components by cleavage of HCI and methanol has not been described to date.

The purpose of the invention is to discover and use new benzoxazine derivatives. The purpose of the invention is to develop compounds suitable for introducing active substances, e.g. antibiotics, into the bacterial cell via bacterial iron transport pathways. The purpose of the invention is to achieve, by incorporating the catechol structure into the heterocyclic benzoxazine structure, that the compounds in their acylated form, in particular their conjugates with antibiotics, have improved pharmacological properties over the free catechol or can actually serve as pharmacological transport modes for the penetration-promoting catechol compounds.

The purpose of the invention is to discover new benzoxazine di-derivatives that can act as siderophores.

The problem is solved according to the invention by providing new benzoxazine di-derivatives of the general formula l, where R1 = H, COAlkyl or COOAlkyl, where alkyl means straight or branched C1-8 alkyl, R2 = H, straight or branched C1-8 alkyl, halogen and R3 are the following substituents: The following information shall be provided for each test chemical: with Z = with R4 = H, straight-chain or branched C1-8 alkyl, phenyl or substituted phenyl substituted by straight-chain or branched C1-8 alkyl, halogen, in particular Cl or F, straight-chain or branched C1-8 alkoxy, hydroxy, carboxy, straight-chain or branched C1-8 alkoxycarbonyl or halogen substituted C1-8 alkyl, in particular hydroxy or acyloxyphenyl, where acyl means straight-chain or branched C1-6 alkyl or straight-chain or branched C1-6 alkoxycarbonyl,or, with R4 = (CH2) nCOX with X = OA, where A = H is a straight chain or branched C1-8 alkyl, a sodium or potassium ion or an ammonium ion or an ammonium ion with one to four alkyl substitutions, or with X = an active substance residue consisting of the residue of an antibiotic which is directly connected to the rest of the structural part of the compound of formula l by a free OH or NH group or by common linker groups, selected from the β-lactam antibiotics, these being in particular penicillins, carbapenic or carbaphalosporins, tetracyclines, quinoglycyls, macroside amines or cephalolones, and with n = 1 to 10, or with R4 = (CH2) n-Y, where Y is a benzoxazidone residue of the form iswhere R1 and R2 are as defined above and both benzoxazidone residues may be equal or different and n = 1 to 10, and R5 = OA, where A is as defined above or means benzyl, or with R5 = an active substance residue as defined above or with R5 = NH-CHR8-COR9, with R8 = H, straight-chain or branched C1-8 alkyl, phenyl or substituted phenyl as defined above and with R9 = OA, where A is as defined above, or with R9 = an active substance residue as defined above or with R5 = R17 = X and Y as above, n = 1 - 10 and where R6 = H,straight or branched chain C1-8-alkyl, halides and with R7 = H, acyl as defined above, and n = 1 - 10 and m = 1 - 2, provided that if R4 does not contain an active substance residue as defined above, R5 or R9 represents or contains an active substance residue as defined above, or if R5 does not contain an active substance residue as defined above, R4 = (CH2) nCOX with X = an active substance residue as defined above, or with R4 and R5 as above or R4 = CH2OH provided that if R4 does not contain an active substance residue as defined above, R5 or R9 is an active substance residue as defined above,or if R5 does not contain an active substance residue as defined above, R4 = (CH2) nCOX with X = an active substance residue as defined above, or R18 = with R10 and/or R11 = H, straight chain or branched C1-8 alkyl, phenyl or substituted phenyl as defined above, n = 1-10, and with COR9 and R12 in all possible positions, R9 = an active substance residue as defined above and R12 = H, straight chain or branched C1-8 alkyl, halogen, hydroxy, straight chain or branched C1-8 alkoxy, a benzoxazine restdione Y or R12 = R = 19 where R1, R2 as above, R14, R15 as R1, R2 and n = 1 - 10 may be,or) R3 = R20 = with R13 and COR9 in all possible positions and with R13 = H, straight chain or branched C1-8 alkyl, halogen, hydroxy, straight chain or branched C1-8 alkoxy or a benzoxazidone residue Y, and R9 = an active substance residue as defined above and p= 0 - 2, or) R3 = = R21 or R3 = = R22 with R9 = an active substance residue as defined above, R16 = H, straight chain or branched C1-8 alkyl, phenyl or substituted phenyl as defined above,

For the purposes of the above and below formulae, acyl means, in particular, straight-chain or branched C1-6-alkanoyl or straight-chain or branched C1-6-alkoxycarbonyl; straight-chain or branched alkyl and straight-chain or branched alkoxy, whether or not in word combinations such as straight-chain or branched alkoxycarbonyl, are, in particular, straight-chain or branched C1-8-alkyl and -alkoxy; a substituted alkyl means a straight-chain or branched alkyl, in particular a halogen, Phen Cl or F, straight-chain or branched alkoxy, hydroxy, carboxy, straight-chain or branched alkoxy, and an alkyl may be substituted by one or more simple alkyl or halogen, such as ammonium alkyl, or an alkyl may be substituted by one or more alkyl or halogen.

'residue' means the residue of a suitable antibacterial agent with a free NH or OH group, whereby the active substance is esterified or amidated via this NH or OH group by the compound of formula 1. The binding between the benzoxazine dihydroxide derivative and the antibiotic may be both directly and via common linker groups, e.g. aminocarbons, hydroxycarbons, diamine or diols. An antibiotic is a corresponding β-lactam containing an NH or OH group, such as an NH or OH group, such as a cephalosporin, e.g. cephaloxine, tetracycline or claforidin, or a cecycline, e.g. a penicillin, an amoxicillin or an oxycodone, an amoxicillin or an amyl amide, or a carboxylide, an amide or a cyclocycline, an amine or a carboxylic acid.

In the case of asymmetric C atoms, the corresponding D and L forms, enantiomers and diastereomers, and the racemates or enantiomer and diastereomer enzyme mixtures are also the subject of the invention.

The compounds mentioned may be present as free acids, as their salts or as easily fissile esters, such as those that are fissile under physiological conditions.

For the preparation of compounds of formula l, compounds of formula l with R5 or R9 = OH are first prepared by condensation of 2,3-diacyloxybenzoyl chloride with appropriate amino components, e.g. amino acids, dipeptides or aminobenzoic acids in sodium bicarbonate solution according to the formula shown in the diagram 1: with R1 = COOAlkyl or H

The following table shows the data:

In the course of the reaction, the COOAlkyl group at R1 can be hydrolysed to form compounds with R1 = H. These can be acylated again, e.g. to compounds with R1 = COAlkyl.

Compounds of formula l with R5 or R9 = OH can be prepared in the same way as in reaction scheme 2 by the reaction of appropriate amides, e.g. 2,3-dihydroxybenzyhydrazone, with chlorophyll alkyl esters in an alkaline medium.

The following table shows the calculation of the calculation:

The compounds of the invention of formula l with R3, R5, R9 or X = an active substance residue as defined above are obtained, for example, by: a. First, a compound of formula l with A = H is converted by conventional means, e.g. by phosphorentachloride in tetrachloric carbon, to the corresponding chloride, and then this is defined by an active substance as above, containing a free OH or NH group and, where appropriate, a common linker group, such as residues of a diamininocarbonate, hydroxycarbonate or diamine or diol, in a suitable solvent, e.g. diamidrofuran, or a compound of formula l with A = H, e.g. by the mixed tetrachloric acid method, first with a free tertiary acid and a suitable triaminethylamine, then with a suitable triaminethylamine and, where appropriate, a free diaminethylamine, e.g. diamidroxylamine, or a suitable diaminethylamine, in a solvent, e.g. a diaminethylamine, or a triaminethylamine, and, where appropriate, a combination of the following three methods, is converted into a solvent, e.g.

Compounds of formula l with a carboxyl group may be present as free acids, as their salts or as esters which are readily fissile, especially under physiological conditions.

The compounds of the invention of formula l show siderophoric activity in various Gram-negative bacterial strains and can therefore be used as growth factors for certain bacterial cultures.

The test for siderophore activity according to DIN 58 940 was performed with different bacterial indicator mutants which do not show growth under the test conditions due to lack of their own fission transport systems. A growth promotion can be observed after addition of the test substances as foreign siderophores. For the indicator mutants, the biosynthesis of the respective siderophore, e.g. pyoverdin, pyochelin, enterobactin, aerobactin, yersiniabactin or e.g. the aromatic biosynthesis is blocked or absent due to lack of receptors for enterobactin, pyokelin or pyovulizium, and other important exponents of the bacterial iron transport (e.g. Epsilon, fioxamine, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon, Epsilon

The growth zones of the indicator mutants (in mm diameter) under the influence of the test substances are given in Table 1.

As a result, compounds of general formula l with R3, R5, R9 and X = one active substance, specifically a β-lactam, have antibacterial activity, including against other antibacterial strains resistant to GN-locactamines, where the pre-electro-accelerated side effects of benzoxazine are minimally dependent on the antibacterial activity of the total strain of Azithromycin. For the determination of the antibacterial activity of Erythromycin, the high antibacterial activity was demonstrated in a comparison test carried out in accordance with the ATC 1282, ATC 10402, ATC 10353, ATC 583, ATC 2732, ATC 273, ATC 273, ATC 283, ATC 283, ATC 273, ATC 273, ATC 273, ATC 273, ATC 283, ATC 273, ATC 273, ATC 283, ATC 273, ATC 273, ATC 273, ATC 283, ATC 283, ATC 273, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 283, ATC 2833, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATC 2832, ATT, ATT22, ATT22, ATT22, ATT22, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32, AT32,

Compounds of general formula l with R3, R5, R9 or X = an active substance residue as defined above, and their salts in the presence of acid groups and esters which are fissile under physiological conditions, are suitable for use as medicinal products against bacterial infections in humans and livestock due to their antibacterial activity.

For the aforementioned diseases, the compounds of formula L may be used either alone or in the form of pharmaceutical preparations with physiologically compatible excipients or carriers known from the state of the art, in principle allowing all usual pharmacological uses.

Examples Example 1

Manufacture of acetic acid (formula I with R1 = COOCH3, R2 = H, R3 = CH2COOH)

A solution of 2.75 g glycine in 175 ml of 0.5M sodium hydrocarbonate solution was cooled in an ultrasonic bath to 0-5°C. At 0-5°C, 10.5 g 2.3-di- (methoxycarbonyloxy) benzoyl chloride, dissolved in 20 ml of absolute tetrahydrofuran, was dripped at stirring. The cloudy solution formed after 1 hour was filtered and the tetrahydrofuran distilled. The resulting substance was diluted and washed with a little cold water. For cleaning, the substance was again diluted in 0.5M sodium hydrocarbonate solution, filtered and painted with concentrated hydrochloric acid. Crystalline bleach with a melting point of 205-208°C was obtained in a 70% solution of the product.

Example 2

The manufacture of (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetylglycine (formula I with R1 = COOCH3, R2 = H, R3 = CH2CONHCH2COOH) is specified in the Annex to this Regulation.

The compound was produced analogously to example 1 from glycylglycine and 2,3-Di- (methoxycarbonyloxy) benzoyl chloride in aqueous sodium bicarbonate solution.

Example 3

The manufacture of (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl-L-alanine (formula I with R1 = COOCH3, R2 = H, R3 = CH2CONH-CH(CH3) -COOH) is specified in the Annex to this Regulation.

The compound was produced analogously, for example, 1 from glycyl-L-alanine and 2,3-Di- (methoxycarbonyloxy) benzoyl chloride in aqueous sodium bicarbonate solution, and colorless crystals with a melting point of 180-185°C were obtained from acetic acid ethyl esters after recrystallization at a yield of 70% of the theory.

Example 4

The manufacture of (8-hydroxy-2,4-dioxo-benzoxazine-3-yl) acetyl-L-alanine (formula I with R1 = H, R2 = H, R3 = CH2CONH-CH(CH3) -COOH) is specified in the Annex to this Regulation.

The compound was obtained from the parent sludge from the isolation of (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl-L-alanine (product from example 3) by HPLC preparation (eluting agent: acetonitrile/water = 1/1 with 0.05% trifluoroacetic acid) and colourless crystals with a melting point of 203-204 °C were obtained from acetic acid ethyl esters recrystallized at a yield of 20% of the theory.

Example 5

The compound was prepared by instant extraction of the acetic acid ester from the acetic acid mixture obtained after acidification with hydrochloric acid (formula I with R1 = COOCH3, R2 = H, R3 = CH2CONH-CH(COOH) - CH2CH(CH3)2) by analogy with example 1 from glycylleucine and 2,3-Di-(methoxycarbonyloxy) benzoyl chloride in aqueous sodium bicarbonate solution. Isolation was obtained by instant extraction of the acetic acid ester from the acetic acid mixture obtained after acidification with hydrochloric acid, repeated washing of the resulting solution with water, drying with sulphur crystals and removal of the solution. Vacuum distillate HPLC (E/W: 0.01%) and the acetic acid crystalline were obtained in water with a concentration of the acetic acid of approximately 180-179 °C.

Example 6

Manufacture from products of heading 2913 or 2913

The compound was isolated by HPLC preparation (eluting agent: acetonitrile/water = 1/1 with 0.05% trifluoroacetic acid) as a second product from the reaction mixture obtained in the manufacture of (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl-L-leucine (product from example 5).

Example 7

Manufacture of 2-L- ((8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) propionic acid (formula I with R1 = COOCH3, R2 = H, R3 = CH(CH3) -COOH)

The compound was prepared analogously to, for example, L-alanine 4 and 2,3-di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium bicarbonate solution.

Example 8

The compound was produced analogously to, for example, 4 from L-phenylalanine and 2,3-Di-methhoxycarbonyloxybenzoyl chloride in aqueous sodium bicarbonate solution. After preparation by HPLC (eluting agent: acetonitrile/water = 1/1 with 0.05 % trifluoroacetic acid) and recrystallization from water, the crystals were obtained colorless at a melting point of 182-184°C at a yield of 50% of the theory.

Example 9

Manufacture from unwrought natural mineral oils of heading 2937

The mixture was stirred for 30 minutes and then acidified with hydrochloric acid. The raw product was dissolved in hot dimethylformamide, the solution was filtered and the product was re-extracted with water. Further purification was carried out by means of a preparation HPLC (eluting agent: acetonitrile/water = 1/1 0.05 Trifluoroacetic acid). Colourless crystals were obtained with a melting point of 232-234 °C.

Example 10

Manufacture of N-[(8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) -acetyl]ampicillin (formula I with R1 = COOCH3, R2 = H, R3 = CH2-CO-R5, R5 = N-ampicillin) (a) Manufacture of (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl chloride. A mixture of 1.07 g (3 mmol) 8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl-acetic acid (substance 1) and 1 g phosphorpentachloride in 5 ml of absolute carbon tetrachloride was heated carefully until the HCI development was completed (30 minutes). The resulting solution was filtered and the filtrate was narrowed. The residue was reconstituted in hot carbon tetrachloride, the acid chloride was precipitated with anhydrous petroleum ether and dried in a high vacuum, resulting in 0.81 g of the product (86% of the theory) with a melting point of 80-82 °C. (b) A solution of 0.78 g ampicillin sodium salt in 12 ml of 80% tetrahydrofuran was cooled to -5°C. 0.63 g 8-methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl-acetyl chloride was added to the solution by stirring. The mixture was stirred for 1 hour at 0°C and 20°C for 1 hour, then evaporated in a vacuum. The residue was distilled with 50 ml of water and 50 ml of acetic acid ethyl ester. Then slightly acidified with 1M saline acid (pH 3) and washed three times with aqueous sodium chloride solution. The organic phase was separated, distilled over sodium sulphate and pressed to a volume of 20 ml. The back was then coated with ammonium nitrate, which was 0,4 g of the white powder (792%) of the ammonium nitrate.

Example 11

Manufacture of N- (((8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) -acetyl) amoxicillin (formula I with R1 = COOCH3, R2 = H, R3 = CH2COR5, R5 = N-Amoxicillin)

A solution of 0.55 g of amoxicillin in 8 ml of 80% tetrahydrofuran was added to 0.22 ml of triethylamine and cooled to -5 °C. 0.45 g (8-methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl chloride (production according to example 8) was added to the solution by stirring. The mixture was stirred at 0 °C and 20 °C for 1 hour and then evaporated in the vacuum. The residue was mixed with 40 ml of water and 40 ml of acetic acid ethyl ester. It was acidified with 1 m of hydrochloric acid (pH 3), shaken and desiccated with a watery sodium chloride solution. The organic phase was thoroughly scrubbed, separated by a steam bath and evaporated with 80 per cent of the amoxic acid in a white powder.

Example 12

Manufacture of N-[(8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) -acetyl-glycyl]ampicillin (formula I with R1 = COOCH3, R2 = H, R3 = CH2-CO-NH-CH2-COR5 R5 = N-ampicillin)

0.352 g (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl glycine (production method see example 2), 140 μl triethylamine and a catalytic amount of dimethylaminopyridine were dissolved in 5 ml of absolute tetrahydrofuran and stirred at -20°C with 126 μl of iron chloride isobutylester. The mixture was stirred for 30 minutes at -20°C. Then 0.357 g of ampicillin sodium salt were added to 5 ml of 80% tetrahydrofuran. It was stirred for 1 hour at -20°C and +20°C, then steamed in a vacuum. The backing was steamed with acetic acid and water and the solution was carefully removed. The solution was filled with 0.05% amethyl acetic acid (Ampicillin) and water (Ampicillin) with sodium tetrahydrofuran, the sodium salt was added to the solution, and the water was treated with sodium nitric acid (Ampicillin) for a period of three hours.

Example 13

Manufacture of N-[(8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) -acetyl-L-alanyl]ampicillin (formula I with R1 = COOCH3, R2 = H, R3 = CH2-CONH-CH(CH3) -COR5, R5 = N-ampicillin)

The compound was prepared by analogy, for example, 12 from (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl-L-alanine (production see example 3) and ampicillin sodium salt, and purified by preparative HPLC (eluting agent: acetonitrile/water = 1/1 with 0.05 % trifluoroacetic acid), resulting in a colourless solid with a yield of 65% of the theory.

Example 14

Manufacture from N- (((8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) -acetyl-L-leucyl) ampicillin (formula I with R1 = COOCH3, R2 = H, R3 = CH2-CONH-CH(COR5) -CH2CH(CH3) 2, R5 = N-ampicillin)

The compound was prepared analogously to, for example, 12 from (8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) acetyl-L-leucine (production see example 5) and ampicillin sodium salt.

Example 15

Manufacture of N- (((8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) -ace-tyl) -O-n-propionyl-amoxicillin (formula I with R1 = COOCH3, R2 = H, R3 = CH2COR5, R5 = N- (((O-n-propionyl) -amoxicillin)), whether or not chemically defined

0,385 g N- (((8-Methoxycarbonyloxy-2,4-dioxo-benzoxazine-3-yl) -acetyl) amoxicillin (production see example 11) were dissolved in 25 ml of tetrahydrofuran and cooled to -78°C. Stirring was done by adding 0,34 ml of triethylamine, then 0,16 ml of propionyl chloride. The reaction mixture was stirred for 30 minutes at -60°C and 1 hour at 20°C. Then the reaction mixture was vaporized in a vacuum and the residual was re-acidified with water and acetic acid ethyl ester. After acidification with 1M of hydrochloric acid (pH 3) the solution was washed with a water-based sodium chloride solution. The organic phase was dissolved, largely separated from the sodium amoxic acid and incorporated in a white powder containing 40% of the amoxic acid.

Example 16

Manufacture of 4- ((8-Methoxycarbonyioxy-2,4-dioxo-benzoxazine-3-yl) benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = C6H4-COOH (p))

The compound was produced analogously, for example, 1 from 4-aminobenzoic acid and 2,3-Di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution, which were recrystallized from acetic acid ethyl esters to colourless crystals with a melting point of 236-240°C at a yield of 80% of the theory.

Example 17

Manufacture of 2L,6-Bis ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) hexane acid (formula I with R1 = COOCH3, R2 = H, R3 = CHR4-COOH, R4 = (CH2) 4Y)

The compound was obtained by analogy, for example, 5 of L-lysine and 2 of 2,3-Di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution as a colourless foam.

Example 18

Manufacture from N-[4-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -benzoyl]-ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = H, COR9 in the 4-position, R9 = N-ampicillin (Na salt), p = 0) (a) Manufacture from 4- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl chloride The compound was produced analogously to substance 10a from substance 16 and phosphor pentachloride in carbon tetrachloride, resulting in a colourless oil with a yield of 65% of the theory. (b) Manufacture of N-[4-[8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin The compound was prepared analogously to substance 10b from 4- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl chloride and ampicillin sodium salt, resulting in a white powder at a yield of 85% of the theory. (c) Sodium salt: A solution of 0.25 g N-[4- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin in acetic acid ethyl ester was refrigerated and stirred with a solution of 0,083 g sodium-2-ethyl hexanoate in acetic acid ethyl ester. After precipitation of the product, it was filtered with petroleum ether. The purification was carried out by means of a preparative HPLC (eluting agent: acetonitrile/water). This produced a white powder with a yield of 0.202 g (79% of the theory).

Example 19

Manufacture of 4-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl-methyl) benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = H, COR9 in the 4-position, R9 = OH, p = 1)

The compound was prepared analogously to substance 5 from 4-aminomethylbenzoic acid and 2,3-di-methoxycarbonyloxybenzoylchloride in aqueous sodium hydrocarbonate solution.

Example 20 Manufacture from N-[4-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl-methyl) benzoyl]-ampicillin sodium salt (formula I with R1 COOCH3, R2 = H, R3 = R20 with R13 = H, COR9 in the 4 position, R9 = N-ampicillin (Na salt), p = 1)

(a) Manufacture from 4- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl-methyl) benzoyl chloride The compound was produced analogously to substance 10a from substance 19 and phosphor pentachloride in carbon tetrachloride, resulting in a colourless oil with a yield of 95% of the theory. (b) Manufacture of N-[4-[8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl-methyl) benzoyl]ampicillin The compound was prepared analogously to substance 10b from 4- ((8-Methoxycarbonyl-oxy-2,4-dioxo-1,3-benzoxazine-3-yl-methyl) benzoyl chloride and ampicillin sodium salt, resulting in a white powder with a yield of 80% of the theory. (c) Sodium salt: produced by analogy with substance 18 from N-[4-[8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl-methyl) benzoyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester, to obtain a white powder at a yield of 60% of the theory.

Example 21

Manufacture of 3,5-bis- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = Y in 3 position, COR9 in 5 position, R9 = OH, p = 0, R1, R2 as above)

The compound was prepared analogously to substance 5 from 3,5-diaminobenzoic acid and 2 molecular equivalents of 2,3-Di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution.

Example 22

Manufacture of N-[3,5-bis- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]-ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = Y in 3 position, COR9 in 5 position, R9 = -N-ampicillin (Na salt), p = 0, R1, R2 as above) (a) Manufacture from 3,5-bis- ((8) -methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl chloride The compound was produced by analogy with substance 10a from substance 21 and phosphor pentachloride in carbon tetrachloride, and obtained as a colourless foam at a yield of 90% of the theory. (b) Manufacture of N-[3, 5-bis-[[8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin The compound was produced analogously to substance 10b from 3,5-bis[(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl chloride and ampicillin sodium salt, obtained as a white powder at a yield of 80% of the theory. (c) Sodium salt: The compound was prepared analogously to substance 18 from N-[3,5-bis- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester, resulting in a white powder at a yield of 40% of the theory.

Example 23

Manufacture from 3-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) propionic acid (formula I with R1 = COOCH3, R2 = H, R3 = (CH2) 2COOH)

The compound was prepared analogously to substance 5 from β-alanine and 2,3-Di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution.

Example 24

Manufacture from N-[3-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionyl]-ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = (CH2) 2CO-N-ampicillin (Na salt)) (a) Manufacture from 3- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) propionyl chloride The compound was produced analogously to substance 10a from substance 23 and phosphor pentachloride in carbon tetrachloride, resulting in a yellowish oil at a yield of 100% of the theory. (b) Manufacture of N-[3-[8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionyl]ampicillin The compound was prepared analogously to substance 10b from 2- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) propionyl chloride and ampicillin sodium salt, resulting in a white powder with a yield of 88% of the theory. (c) Sodium salt: The salt was produced analogously to substance 18 from N-[3- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester, resulting in a white powder at a yield of 41% of the theory.

Example 25

Manufacture of 3,5-bis-[3- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionylamino]benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = R18 with R10, R11 = H, R12 = R19 in 3 position, COR9 in 5 position, R9 = OH, R15, R14 = H, n = 2, R1, R2 as above)

The compound was prepared analogously to substance 5 from 3,5-diaminobenzoic acid and 2 molecular equivalents 3-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionyl chloride (substance 24a) in aqueous sodium hydrocarbonate solution, resulting in colourless crystals with a melting point of 160-165°C at a yield of 50% of the theory.

Example 26

Manufacture of N-{3,5-bis-[3-(8-methoxycarbonyloxy-2,4-benzoxazine-3-yl) -propionylamino]-benzoyl}-ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = R18 with R10, R11 = H, R12 = R19 in 3 position, COR9 in 5 position, R9 = N-ampicillin (Na salt), R15, R14 = H, n = 2, R1, R2 as above) (a) Manufacture from N-{3,5-bis-[3-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionylamino]-benzoyl}-ampicillin The compound was prepared analogously to substance 12 from substance 23 and ampicillin sodium salt, resulting in a white powder with a yield of 80% of the theory. (b) Sodium salt: The compound was prepared analogously to substance 18 from N-{3,5-bis[3-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionylamino]-benzoyl-ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl esters, resulting in a white powder at a yield of 18% of the theory.

Example 27

Manufacture of 3,5-bis[(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-n-3-yl) -acetylamino]benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = R18 with R10, R11 = H, R12 = R19 in the 3 position, COR9 in the 5 position, R9 = OH, R15, R14 = H, n = 1, R1, R2 as above)

The compound was prepared analogously to substance 5 from 3,5-diaminobenzoic acid and its two molecular equivalents (8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) acetyl chloride (substance 10a) in aqueous sodium hydrocarbonate solution.

Example 28

Manufacture of N-{3,5-Bis-[(8-methoxycarbonyloxy-2,4-benzoxazine-3-yl) -acetylamino]-benzoyl}-ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = R18 with R10, R11 = H, R12 = R19 in 3 position, COR9 in 5 position, R9 = N-ampicillin (Na salt), R15, R14 = H, n = 1, R1, R2 as above) (a) Manufacture from N-{3,5-bis-[8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -acetylamino]-benzoyl-ampicillin The compound was prepared analogously to substance 12 from substance 27 and ampicillin sodium salt, resulting in a white powder with a yield of 90% of the theory. (b) Sodium salt: The salt was produced analogously to substance 18 from N-{3,5-bis-[8-methoxycarbonyloxy-2,4-dioxo-1,3-acetylamino-benzoxazine-3-yl]-benzoyl-ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester, resulting in a white powder at a yield of 17% of the theory.

Example 29 Manufacture of 4-Chlor-3- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = Cl in the 2-position, COR9 in the 5-position, R9 = OH, p = 0)

The compound was prepared analogously to substance 5 from 3-amino-4-chlorobenzoic acid and 2,3-di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution.

Example 30

Manufacture of N-[4-Chlor-3-(8-Methoxycarbonyloxy-2,4-Diox-1,3-benzoxazine-3-yl) benzoyl]-ampicillin Sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = Cl in the 2 position, COR9 in the 5 position, R9 = N-ampicillin (Na salt), p = 0) (a) Manufacture of 4-Chlor-3- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl chloride The compound was prepared analogously to substance 10a from substance 29 and phosphor pentachloride in carbon tetrachloride, resulting in a yellowish powder with a yield of 94% of the theory and a melting point of 76-78°C. (b) Manufacture of N-[4-Chlor-3-[[8-methoxycarbonyloxy-2,4-dioxo-1,3- 3benzoxazine-3-yl) benzoyl]ampicillin The compound was prepared analogously to substance 10b from 4-Chlor-3- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl)) benzoyl chloride and ampicillin sodium salt, resulting in a white powder with a yield of 87% of the theory. (c) Sodium salt: It was produced analogously to substance 18 from N-[4-Chlor-3- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester, resulting in a white powder at a yield of 55% of the theory.

Example 31

Manufacture of 2-hydroxy-4- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = OH in the 3rd position, COR9 in the 4th position, R9 = OH, p = 0)

The compound was prepared analogously to substance 5 from 4-amino salicylic acid and 2,3-di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution.

Example 32

Manufacture from N-[2-Hydroxy-4-(8-Methoxycarbonyloxy-2,4-Diox-1,3-benzoxazine-3-yl) benzoyl]-ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = OH in the 3rd position, COR9 in the 4th position, R9 = N-ampicillin (Na salt), p = 0), (a) Preparation of Succinimido-2-hydroxy-4- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoate: 0.224 g substance 31 and 0.069 g N-hydroxy-succimide in 5 ml anhydrous dioxane were obtained by mixing 0.124 g dicyclohexylcarbodiamide in 5 ml anhydrous dioxane under argon atmosphere and stirring at 0°C. The mixture was stirred for 8 hours at 20°C, the precipitation was filtered and the solvent removed in a vacuum. The remaining oil was fixed by rubbing with some isopropanol.23 g (81% of the theory) with a melting point of 145°C to 150°C. (b) Preparation of N-[2-hydroxy-4- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin: 0.191 g of ampicillin trihydrate was suspended in a mixture of 5 ml tetrahydrofuran and 5 ml water under argon atmosphere and dissolved in 138 μl triethylamine. Subsequently, a solution of 0.223 g of succinimide-2-hydroxy-4-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-petroxy-netropic acid was added to 5 ml of the solution and the mixture was maintained at 20°C for 10 hours. The reaction sample was dissolved in water at 20°C. The solution was then dissolved in water and dissolved in an organic solution of amethyl chloride and sodium, and finally the solution was dissolved in water and dissolved in sodium sulphate.The salt was produced by analogy with substance 18 from N-[2-hydroxy-4- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester. A white powder was obtained at a yield of 19% of the theory.

Example 33

Manufacture of 3-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoic acid (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = H , COR9 in the 3-position, R9 = OH, p = 0)

The compound was prepared analogously to substance 5 from 3-aminobenzoic acid and 2,3-Di- ((methoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution.

Example 34

Manufacture from N-[3-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]-ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = R20 with R13 = H, COR9 in 3 position, R9 = N-ampicillin (Na salt), p = 0) (a) Manufacture from 3- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl chloride The compound was prepared analogue to substance 10a from substance 33 and phosphor pentachloride in carbon tetrachloride. A yellowish oil was obtained at a yield of 97% of the theory. The compound was prepared analogously to substance 10b from 3- ((8-Methoxycarbonyl-oxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl chloride and ampicillin sodium salt, resulting in a white powder with a yield of 87% of the theory. (c) Sodium salt: The salt was produced analogously to substance 18 from N-[3-[8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) benzoyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester, resulting in a white powder at a yield of 59% of the theory.

Example 35

For the manufacture of 2L- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -pentandicarbonic acid-1-benzyl ester (formula I with R1 = COOCH3, R2 = H, R3 = CHR4-COR5 with R4 = (CH2) 2COOH, R5 = O-benzyl)

1 g of L-glutamic acid-1 benzyl ester was dissolved in 40 ml of anhydrous tetrahydrofuran under argon atmosphere. Under ice cooling and stirring, 1.24 ml of triethylamine was added first, then a solution of 1.22 g of 2,3-di- ((methoxycarbonyloxy) benzoyl chloride was added to 10 ml of anhydrous tetrahydrofuran. After 20 hours of stirring at 20°C, the tetrahydrofuran was removed in a vacuum and the residue was added to water and acetic acid ethyl ester. Under ice cooling and stirring, the acetic acid ethyl ester phase was separated. It was repeatedly washed with water and saturated sodium chloride solution and finally purified. The result was a conservative solution of 0.2% HPLC per sample (160%) obtained by the purification of the sample.

Example 36

Manufacture from a mixture of hydrocarbons obtained from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of hydrocarbons from the distillation of the distillation of hydrocarbons from the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the distillation of the (a) Manufacture of 4-Chlorcarbonyl-2L- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) butyric acid esters The compound was produced analogously to substance 10a from substance 35 and phosphor pentachloride in carbon tetrachloride, resulting in a yellowish oil with a yield of 97% of the theory. (b) Manufacture of 4-ampicillin-carbamoyl-2L- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) butyric acid esters The compound was prepared analogously to substance 10b from 4-Chlorcarbonyl-2L- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) butyric acid cycloester and ampicillin sodium salt, resulting in a white powder with a yield of 87% of the theory. (c) Sodium salt: It was produced analogue to substance 18 from 4-Ampicillin-carbamoyl-2L- ((8-methoxy-carbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -butanoyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester.

Example 37

Manufacture of 2L-[2L,6-bis-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -hexanoylamino]-6-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -hexane acid (formula I with R1 = COOCH3, R2 = H, R3 = CHR4-COR5 with R4 =(CH2) 4-Y, R5 =R17 with X = OH, n = 4) (a) Preparation of 2L-[2L,6-bis-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) hexanoylamino]-6-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) hexanoacetic acid ester: 1,55 g 6-Amino-2-(2,6-diaminohexanoylamino) hexanoacetic acid ester-tris-p-toluolsulfonate were dissolved in 20 ml of anhydrous dimethylform and reconstituted in argon atmosphere and the solution was reconstituted in a normal solution of dimethyl acetic acid and then dissolved in 0,48 ml of 0,48-methoxycarbonyl-methoxy-1,3-methoxycarbonyl-methoxylamine and then dissolved in a solution of 1,53 g 2,3-dioxycarbonyl-methoxycarbonyl-methoxy-3-methoxycarbonyl-methoxy-3-methoxy-3-methoxycarbonyl-methoxy-3-methoxy-3-methoxy-methoxy-3-methoxy-methoxy-methoxy-3-methoxy-methoxy-methoxy-methoxy-3-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-methoxy-met

Example 38

Manufacture of N-{2L-[2L,6-bis-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -hexanoylamino]-6-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -hexanoyl) -ampicillin sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = CHR4-COR5 with R4 = (CH2) 4-Y, R5 = R17 with X = N-ampicillin (Na-salt), n = 4) (a) Manufacture from N-{2L-[2'L,6'-Bis- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl)) -hexanoylamino]-6- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -hexanoyl)) -ampicillin The compound was prepared analogously to substance 12 from substance 37 and ampicillin sodium salt, resulting in a white powder with a yield of 90% of the theory. (b) Sodium salt: The salt was produced analogously to substance 18 from N-{2L-[2L,6-bis-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -hexanoylamino]-6-(8-methoxycarbonyloxy-2,4-dioxo-1,3-benzo-oxazine-3-yl) -hexanoyl} ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester. A white powder was obtained at a yield of 15% of the theory.

Example 39 Manufacture of 3-hydroxy-2L- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) propanoic acid (formula I with R1 = COOCH3, R2 = H, R3 = CHR4-COR5 with R4 = CH2-OH, R5 = OH)

(a) Manufacture of 2L-N-2,3-dimethoxycarbonyl-benzoyl) serine-benzyl ester The compound was prepared analogously to substance 35 from L-serine benzyl ester hydrochloride and 2,3-di- (methoxycarbonyloxy) benzoyl chloride in tetrahydrofuran, resulting in white foam at a yield of 43% of the theory. (b) 1.3 g 2L-N-(2,3-dimethoxycarbonyloxybenzoyl) serine benzyl ester was suspended in 50 ml of ethanol and 300 mg of palladium carbon catalyst (10%ig) was added. After transfer to a hydrogen atmosphere, the mixture was shaken for 2 hours at 20°C and normal pressure. After filtration by cellite, it was evaporated. Cleaning by HPLC produced a white foam, yield: 599 mg (48% of the theory).

Example 40

Manufacture from N-[3-Hydroxy-2L- ((8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionyl]-ampicillin Sodium salt (formula I with R1 = COOCH3, R2 = H, R3 = CHR4-COR5 with R4 CH2-OH, R5 N-ampicillin (Na salt) (a) Manufacture of N-[3-Hydroxy-2L- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionyl]ampicillin The compound was prepared analogously to substance 12 from substance 39 and ampicillin sodium salt, resulting in a white powder with a yield of 90% of the theory. (b) Sodium salt: It was produced analogously to substance 18 from N-[3-hydroxy-2L- ((8-methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -propionyl]ampicillin and sodium-2-ethylhexanoate in acetic acid ethyl ester, resulting in a white powder at a yield of 10% of the theory.

Example 41

Manufacture of acetic acid (R1 = COOC2H5, R2 = H, R3 = CH2COOH)

The compound was prepared analogously to substance 1 from glycine and 2,3-Di- (ethoxycarbonyloxy) benzoyl chloride in aqueous sodium hydrocarbonate solution.

Example 42

Manufacture from N-{N'-[6-(8-Methoxycarbonyloxy-2,4-dioxo-1,3-benzoxazine-3-yl) -hexyl]-N'-[2,3-di-methoxycarbonyloxy) -benzoyl]-6-aminohexyl}-N-[2,3-di-methoxycarbonyloxy) -benzoyl]-glycine (formulation I with R3 = Z-CHR4-COR5; R1, R7 = COOCH3, R2 = R4 = R6 = H, R5 = OH, n = 6, m = 2 (a) Manufacture of benzyl ester (R5 = OCH2C6H5): To a solution of 880 mg N-[N'-(6-aminohexyl) -6-glycine benzyl ester tosylate and 1.04 ml triethylamine in 20 ml dichloromethane, a solution of 864 mg 2,3-di- ((methoxycarbonyloxy) benzoyl chloride in 5 ml dichloromethane was added at -30°C. The mixture was stirred for 1 hour at -10°C and 1 hour at room temperature and then filtered. The solution was pressed and the residue absorbed in 20 ml acetic acid ethyl ester. The acetic acid ethyl ester solution was washed with 1M of acetic acid, saturated sodium carbonate residue and water. Dry and abrasion of the solution was obtained by a vacuum-dye solid with a salinity of 650 mg (60%) of the theoretical. (b) Production of the acid (R5 = OH): The above benzyl ester was hydrated in methanol at 100 mg Pd/C (10%ig) for 3 hours in a room temperature shaker. Other

After filtration of the catalyst by Celite, the solvent was distilled in a vacuum to obtain a colourless solid with a yield of 70% of the theory. Tabelle 1

	PAO 6609	WAH 5030	AB 2847	enb-7	TA 2700
1	0		15	18	13
2	13		10	22	21
4	0		0	14	0
7	0		0	10	0
9	0	20	24	0	16
Kontrolle	a) 35	a) 40	b) 23	c) 38	c) 20

Tabelle 1

a) Ferrioxamin E,

b) Ferrichrom,

c) Ferrioxamin G

Tabelle 2

Substanz	Pseudomonas aeruginosa			Klebsiella	E.coli	Stenotrop. maltoph.	Staphylococcus
	SG 137	ATCC 27853	NCTC 10662	ATCC 10031	ATCC 25922	GN 12873	SG 511
Azlocillin	3,12	3,12	6,25	6,25	6,25	12,5	0,2
Ampicillin	>100	>100	>100	25	6,25	>100	<0,05
Substanz 10	0,78	6,25	3,12	0,2	6,25	3,12	0,78
Substanz 11	0,78	3,12	3,12		12,5	12,5	0,78
Substanz 12	0,4	3,12	1,56	6,25	3,12	1,56	0,78
Substanz 13	0,2	1,56	3,12	0,1	3,12	3,12	1,56
Substanz 14	1,56	3,12	1,56	0,78	3,12	1,56	1,56
Substanz 15	0,78	1,56	1,56	3,12	12,5	6,25	1,56
Substanz 18	0,4	1,56	1,56	6,25	25	3,12	1,56
Substanz 20	1,56	6,25	12,5	6,25	12,5	6,25	0,78
Substanz 22	0,2	1,56	0,78	6,25	25	0,78	25
Substanz 24	3,12	6,25	12,5	50	25	25	12,5
Substanz 26	0,05	0,2	0,1	0,2	6,25	1,56	6,25
Substanz 28	0,05	1,56	1,56	1,56	25	3,12	25
Substanz 30	<0,05	0,78	0,4	1,56	6,25	0,78	1,56
Substanz 32	0,1	0,78	0,78	3,12	50	0,78	0,4
Substanz 34	<0,05	0,2	0,4	1,56	3,12	1,56	0,78
Substanz 36	0,2	0,78	1,56	1,56	3,12	1,56	0,2
Substanz 38	0,2	0,78	0,78	0,4	6,25	0,4	3,12
Substanz 40	0,4	1,56	1,56	25	12,5	3,12	0,4

In the examples, HPLC means High Performance Liquid Chromatography

Claims (18)

1. Benzoxazinedione derivatives of the formula I in which R¹ = H, COalkyl or COOalkyl, wherein alkyl in each case denotes straight-chain or branched C_1-8-alkyl, R² = H, straight-chain or branched C_1-8-alkyl or halogen and R³ represents the following substituents:

   a) R³ = -Z-CHR⁴-COR⁵ where Z = where R⁴ = H, straight-chain or branched C_1-8-alkyl, phenyl or substituted phenyl, which is substituted by straight-chain or branched C_1-8-alkyl, halogen, in particular Cl or F, straight-chain or branched C_1-8-alkoxy, hydroxyl, carboxyl, straight-chain or branched C_1-8-alkoxycarbonyl or halogen-substituted C_1-8-alkyl, in particular hydroxy- or acyloxyphenyl, wherein acyl denotes straight-chain or branched C_1-6-alkanoyl or straight-chain or branched C_1-6-alkoxycarbonyl, or where R⁴ = (CH₂)_NCOX, where X = OA, wherein A = H, straight-chain or branched C_1-8-alkyl, a sodium or potassium ion or an ammonium ion or an ammonium ion with one to four alkyl substituents, or where X = an active compound radical which denotes the radical of an antibiotic, which is bonded via a free OH or NH group directly or via conventional linker groups to the remaining structural part of the compound of the formula I, chosen from the group comprising β-lactam antibiotics, these being in particular penicillins, cephalosporins or carbapenems, tetracyclines, aminoglycosides, macrolides or quinolones, and where n = 1 - 10, or where R⁴ = (CH₂)_n-Y, wherein Y represents a benzoxazinedione radical of the form wherein R¹ and R² are as defined above, and the two benzoxazinedione radicals can be identical or different, and n can be 1 - 10, and where R⁵ = OA, wherein A is as defined above, or denotes benzyl or where R⁵ = an active compound radical as defined above or where R⁵ = NH-CHR⁸-COR⁹, where R⁸ = H, straightchain or branched C_1-8-alkyl, phenyl or substituted phenyl as defined above and where R⁹ = OA, wherein A is as defined above, or where R⁹ = an active compound radical as defined above or where R⁵ =    = R¹⁷ where X and Y are as above, n = 1 - 10 and where R⁶ = H, straight-chain or branched C_1-8-alkyl or halogen, and where R⁷ = H or acyl as defined above and n = 1 - 10 and m = 1 - 2, with the proviso that if R⁴ contains no active compound radical as defined above, R⁵ or R⁹ represent or contain an active compound radical as defined above, or if R⁵ contains no active compound radical as defined above, R⁴ = (CH₂)_nCOX, where X = an active compound radical as defined above, or

   b) R³ = CHR⁴-COR⁵ where R⁴ and R⁵ are as above or R⁴ = CH₂OH, with the proviso that if R⁴ contains no active compound radical as defined above, R⁵ or R⁹ represent an active compound radical as defined above, or if R⁵ contains no active compound radical as defined above, R⁴ = (CH₂)_nCOX, where X = an active compound radical as defined above, or

   c) R³ =    = R¹⁸ where R¹⁰ and/or R¹¹ = H, straight-chain or branched C_1-8-alkyl, phenyl or substituted phenyl as defined above, n = 1 - 10, and where COR⁹ and R¹² are in all the possible positions, R⁹ = an active compound radical as defined above and R¹² = H, straight-chain or branched C_1-8-alkyl, halogen, hydroxyl, straight-chain or branched C_1-8-alkoxy or a benzoxazinedione radical Y or R¹² =    = R¹⁹ where R¹ and R² are as above, R¹⁴ and R¹⁵ are as R¹ and R² and n can be 1 - 10, or

   d) R³ =    = R²⁰ where R¹³ and COR⁹ are in all the possible positions and where R¹³ = H, straight-chain or branched C_1-8-alkyl, halogen, hydroxyl, straight-chain or branched C_1-8-alkoxy or a benzoxazinedione radical Y, and R⁹ = an active compound radical as defined above and p = 0 - 2, or

   e) R³ =    = R²¹ or R³ =    = R²² where R⁹ = an active compound radical as defined above and R¹⁶ H, straight-chain or branched C_1-8-alkyl, phenyl or substituted phenyl as defined above, or

   f) R³ = an active compound radical as defined above. and esters, which can be split off under physiological conditions, of those compounds of the formula I which contain a free carboxyl group in the radical R³.
2. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ denotes the radical of an antibacterial active compound as defined above.
3. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ is the radical of any desired cephalosporin, which is bonded via an NH or an OH group.
4. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ is the radical of any desired penicillin, which is bonded via an NH or an OH group.
5. Compounds of the formula I according to claim 1 or 4, wherein X or R³ or R⁵ or R⁹ denotes an ampicillin radical.
6. Compounds of the formula I according to claim 1 or 4, wherein X or R³ or R⁵ or R⁹ denotes an amoxicillin or O-acylamoxicillin radical.
7. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ denotes a 6-aminopenicillanic acid radical.
8. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ is any desired tetracycline radical, which is bonded via an NH or an OH group.
9. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ is the radical of any desired macrolide, which is bonded via an NH or an OH group.
10. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ is the radical of any desired quinolone, which is bonded via an NH or an OH group.
11. Compounds of the formula I according to claim 1, wherein X or R³ or R⁵ or R⁹ is the radical of any desired carbapenem, which is bonded via an NH or an OH group.
12. N-(8-Methoxycarbonyloxy-2,4-dioxo-benzoxazin-3-yl-acetyl)-ampicillin according to claim 1, 4 or 5.
13. N-(8-Methoxycarbonyloxy-2,4-dioxo-benzoxazin-3-yl-acetyl)-amoxicillin according to claim 1, 4 or 6.
14. Compounds of the formula I according to one of claims 1 to 13, for use as growth factors for bacteria.
15. Compounds of the formula I according to one of claims 1 to 13 containing an active compound radical as defined above for X or R³ or R⁵ or R⁹, for use as therapeutic agents for bacterial infections.
16. Medicaments comprising a compound of the formula I according to one of claims 1 to 13, together with conventional carrier materials.
17. Compounds of the formula I according to one of claims 1 to 13 for use as a medicament.
18. Use of compounds of the formula I according to claim 1 where R⁵ or R⁹ = OH for the preparation of compounds of the formula I according to one of claims 1 to 13.