DE2949269A1 - Antibacterial and beta-lactamase inhibitor beta-lactam cpds. - which are methyl-substd. 3,7-di:oxo-1-aza-bi:cyclo-(3,2,0)-heptan-2-carboxylic acid derivs. - Google Patents

Abstract

New beta-lactam cpds. are des-thia-penicillonic acid derivs. of formula (I) and their physiologically acceptable salts. R1, R2 and R3 are H or Me, at least one being Me; R4 is H, Cl, Br or OH; R5 is H, 1-4C alkyl, benzyl, nitrobenzyl, methoxybenzyl or a readily hydrolysable residue; and R6 is H, 1-6C alkyl, 1-4C hydroxyalkyl, benzyl or alpha-hydroxybenzyl. (I) are well tolerated cpds. with broad spectrum in vitro and in vivo activity against pathogenic microorganisms such as gram- positive and gram-negative bacteria (including strains resistant to usual cephalosporin and penicillin antibiotics). (I) also have beta-lactamase inhibiting activity against beta-lactamases from gram-positive and gram-negative microorganisms. In addition, (I) are useful as intermediates for other pharmaceuticals (e.g. thienamycin derivs. with beta-lactamase inhibiting and antibacterial activity).

Description

ß-lactam compounds,

Pharmaceutical preparations containing them, and processes for their production, ß-Lactam compounds, pharmaceutical preparations containing them, and processes for their production where F: 1 'R2 and R3 can be the same or different and one of these radicals is CH3, the others are H or CH3, R4 H, C1, Br or OH, R5 H, alkyl with 1 - 4 carbon atoms, benzyl, nitrobenzyl, Methoxybenzyl or an easily hydrolyzable radical and R6 denotes H, r., Alkyl with 1 - C C atoms, hydroxyalkyl with 1 - 4 C atoms, benzyl or α-hydroxybenzyl, and their physiologically harmless salts.

The invention was based on the object of finding new compounds that can be used to manufacture drugs. This task was solved by providing the lactams of the formula I.

It has been found that the compounds mentioned are well tolerated have valuable pharmacological properties. For example, they work in vitro and in vivo against harmful microorganisms, e.g.

gram-positive and gram-negative bacteria, such as Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas, e.g., Pseudomonas aeruginosa and Proteus, e.g., Proteus mirabilis. They are characterized by a broad spectrum of activity the end. These effects can be demonstrated, for example, in the usual way on bacterial cultures show in vitro. Also effects against germs, the common cephalosporin and penicillin antibiotics resistant occur.

The chemotherapeutic efficacy in vivo is preferably measured in mice determined. Pharmacokinetic studies, e.g. determination of concentrations the active substances in the serum, from which the biological half-lives are calculated can also be carried out on dogs. Also attempts at Mice, rats, rabbits or other mammals are possible.

Furthermore, the new compounds show ß-lactamase-inhibiting action against B-lactamases from gram-positive and gram-negative microorganisms.

The compounds can accordingly be used as pharmaceuticals in human and veterinary medicine, particularly to combat bacterial Infections.

They can also be used as intermediate products for the production of other drugs be used. So they can through appropriate conversions in the 3-position are converted into derivatives of thienamycin, which in turn are good Show ß-lactamase-inhibiting and antibacterial effects.

The invention relates to lactams of the formula I and their physiological properties harmless salts.

The radicals R1 to R3 can each be H or CE3, but not all at the same time H mean. The compounds of the formula I can be classified accordingly in 4-methyl-, 5-methyl-, 4,4-dimethyl-, 4,5-dimethyl- and 4,4,5-trimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane -2-carboxylic acids and their derivatives.

The radical R4 preferably denotes H, in the second place preferably OH, also C1 or Br.

The radical R5 preferably denotes H or an easily removable ester group such as tert-butyl, benzyl, o-, m- or p-nitrobenzyl, o-, m- or p-methoxybenzyl.

Furthermore, R5 can be methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or sec-butyl.

In addition, R5 can be used for an easily hydrolyzable, preferably in Vivo hydrolyzable, residue that is naturally pharmaceutically harmless s +> in got to.

Such residues are in the chemistry of penicillins and cephalosporins common, and those skilled in the art know which groups are meant by this.

Preferred easily hydrolyzable radicals are besides tert-alkyl groups especially alkoxyalkyl, alkanoyloxyalkyl, alkanoylamidoalkyl, N-alkyl-alkanoyl-amidoalkyl, Alkoxycarbonyloxyalkyl, phthalidyl (= 2-oxo-3,4-benzo-2,5-dihydro-5-furyl), 2-oxo-tetrahydro-5-furyl, 2-oxo-3-alkyl-tetrahydro-5-furyl, trialkylsilyl, arylalkyl, Alkoxyarylalkyl, Benzhydryl, trichloroethyl or aroylalkyl means, the alkyl, alkoxy and Alkanoyl groups in each case 1 - 6, the aryl groups in each case 6-10 and the aroyl groups Have 7-11 carbon atoms.

Accordingly, R5 is also preferably alkanoyloxymethyl (e.g. Acetoxymethyl, propionyloxymethyl, isobutyryloxymethyl, pivaloyloxymethyl), 1-alkanoyloxyethyl (e.g. l-acetoxyethyl, l-propionyloxyethyl, l-isobutyryloxyethyl, l-pivaloyloxyethyl), Alkanoylamidomethyl (e.g. pivaloylamidomethyl), N-alkyl-alkanoylamidomethyl (e.g. N-methyl-pivaloylamidomethyl), alkoxycarbonyloxymethyl (e.g. ethoxycarbonyloxymethyl), l-alkoxycarbonyloxyethyl (e.g. l-ethoxycarbonyloxyethyl, l-tert.-butoxy-carbonyloxyethyl), further preferred for methoxymethyl, phthalidyl, 2-oxo-3-methyltetrahydro-5-furyl, Trimethylsilyl, benzhydryl, trichloroethyl or benzoylmethyl.

The radical R6 denotes H, alkyl with 1-6, preferably 1-4, in particular 1 or 2 carbon atoms, hydroxyalkyl, preferably 1-hydroxyalkyl, with 1-4, in particular 1 or 2 carbon atoms, benzyl or -hydroxybenzyl. Are H, ethyl and 1-hydroxyethyl preferred; furthermore, R6 preferably represents methyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, hydroxymethyl, 2-hydroxyethyl, 1-, 2- or 3-hydroxypropyl, l-hydroxy-l-methyl-ethyl, l-methyl-2-hydroxy-ethyl, 1-, 2-, 3- or 4-hydroxybutyl, l-hydroxy-2-methyl-propyl, 2-hydroxy-2-methylpropyl, 2-methyl-3-hydroxypropyl, l-hydroxy-l-methylpropyl, l-hydroxymethyl-propyl, l-methyl-2-hydroxypropyl, 1-methyl-3-hydroxypropyl, 1, 1-dimethyl-2-hydroxypropyl, benzyl or -hydroxybenzyl.

Accordingly, the invention particularly relates to those Compounds of the formula I in which at least one of the radicals mentioned is one of the has preferred meanings given above.

Some preferred groups of compounds can be identified by the following Part formulas Ia - Ie are expressed which correspond to the formula I and in which the unspecified radicals have the meaning given for formula I, in which however, in Ia R4 denotes H or OH; in Ib R5 H, alkyl with 1 - 4 carbon atoms, benzyl or denotes nitrobenzyl; In Ic R6 denotes H, ethyl or 1-hydroxyethyl; In Id R4 denotes H or OH, R5 denotes H, alkyl with 1-4 carbon atoms, benzyl or nitrobenzyl and R6 denotes H, ethyl or 1-hydroxyethyl; in le R4 R5 H, alkyl with 1 - 4 carbon atoms' Benzyl or nitrobenzyl and R6 denotes H, ethyl or l-hydroxyethyl.

The compounds of formula I have asymmetric carbon atoms in 2- and 5-position and can have further asymmetric carbon atoms in the 4- and / or 6-position and optionally in the substituents RS and R6. You can therefore use it as a racemic or optically active mixtures or in the form of pure optically active antipodes can be obtained.

All of these possible stereoisomeric forms of the new compounds are included in the formula I and thus in the subject matter of the present invention.

The compounds with a stereochemistry similar to the natural thienamycin are preferred.

The invention also relates to a process for the preparation of the compounds of the formula I, characterized in that a β-lactam of the general formulas IIa or IIb wherein X is O, N2 or (H, Hal) and Hal is Cl, Br or J and K1 to R6 have the meanings given, or one of its functional derivatives is treated with a cyclizing agent or another compound corresponding to formula I, but in which one or more oxo and / or syaroxy groups are present in protected form, these oxo and / or hydroxyl groups are set free by solvolysis nc that one optionally obtained a hydroxy compound of the formula r (R4-0E) by treatment with a halogenating agent in the corresponding chlorine - or bromine compound of the formula I (R4 = Cl or Br) converts unc / or removes the halogen atom from a obtained chlorine or bromine compound of the formula 1 (R4 = C1 or Br) by treatment with a reducing agent (one or more stages) and / or an ester of the formula 1 obtained (in which R5 is different from 11) cleaves and / or a carboxylic acid of the formula I (R5-H) obtained is esterified or by treatment with a B. ase converts it into one of its physiologically harmless salts.

The compounds of the formula I are, moreover, largely according to known methods, as they are in the literature (e.g. in the standard works like Houben-Weyl, Methods of Organic Chemistry, Georg-Thieme-Verlag, Stuttgart, as well as the scientific and patent literature in the field of synthesis of Dethia penam and Dethia penem derivatives, precursors of clavulanic acid and thienamycin) are described, under the reaction conditions for the reactions mentioned are known and suitable. You can also use a file that is known per se, but not here make use of closer tenth variants.

If desired, the starting materials and intermediates can also be used in situ are formed in such a way that they are not isolated from the reaction mixture, but immediately further converts to the bicyclic lactams of the formula I. Those Compounds of the formula I in which the radical R6 denotes H, alkyl or benzyl, are preferably obtained by cyclizing the lactams of the formulas IIa or IIb. The starting materials of the formula IIa are preferred. Those connections of the formula I, in which the radical R6 is hydroxyalkyl or -hydroxybenzyl, are on the other hand preferably off by solvolytic cleavage of a protective group a compound otherwise corresponding to formula I available.

Instead of the compounds of the formulas IIa or IIb, their functional derivatives are cyclized. As functional derivatives of carboxylic acids of the formula IIa are particularly suitable their reactive esters (preferably the esters with N-hydroxysuccinimide), their acid halides (preferably the chlorides and bromides) or their reactive amides (preferably the imidazolides). As functional derivatives of the compounds of the formula lib are, for example, the corresponding enol ethers and enol esters.

The starting materials of the formulas IIa and IIb are new.

They can be obtained, for example, in the following ways (in In the general formulas below, the radicals R1 to k6 X and Hal have the same values as above given meaning, unless otherwise stated): a) (for compounds with R1 = CH3, R6 = H): 3-methyl-3-butenoic acid ester of the formula H2C-C (CH3) -CR2R3-COOR7 (in which R7 is a cleavable, preferably a hydrogenolytically cleavable, ester group, especially benzyl, means) become 4-methyl-4- (CR2R3-COOR7) -acetldin-2-ones with chlorosulfonyl isocyanate (III) implemented. Reaction with balogenacetic acid derivatives of the formula Hal-CH2-COOR5 (in which R5 is preferably different from H) yields 1- (CH2-COOR5) -4-methyl-4- (CR2R3-COOR7) -azetidin-2-one, Cleavage of the radical R7 (e.g. by hydrogenolysis) the corresponding carboxylic acids of the formula IIa (R1 = CH3), which, if desired, can be converted into the corresponding functional Derivatives can be transferred; E.g. by reaction with N-Hydroxy-succinimide / dicyclohexylcarbodiimide the succinimido esters, analogously with N-hydroxyphthalimide the phthalimido esters, with oxalyl chloride, SOCl2, POCl3, PCl5, a Vilsmeier reagent / available from dimethylformamide (DMF) and SOCl2, POCl3 or oxalyl chloride7 in the presence or absence of an inert one Solvent and / or a base, the chlorides, with carbonyldiimidazole, the imidazolides Chloroformic acid alkyl esters or phosphoric acid monochloride dialkyl esters the corresponding Alkylcarbonyloxy or dialkylphosphonyl derivatives (in which the alkyl groups 1 - 6, preferably contain 1 to 4 carbon atoms; corresponding to IIa, but -COO-CO-O-alkyl or -C00-PO (OAlkyl) 2 instead of COOH) or with 1-methyl-2-hydroxypyridinium iodide the esters derived therefrom.

(for compounds with R1 = R6 = h): 4-acyloxyazetidin-2-one (e.g. 4-acetoxy-azetidin-2-one) are with O-silylketene acetalane of the formula R²R³C = C (OSiAlkyl3) (OR8) (where R8 is Any radical is, in particular, however, alkyl having 1 to 6 carbon atoms, preferably Methyl or ethyl, CC13CH2-, CH2Br-CH2-, CC13-C (CH3) 2-, benzyl, chlorobenzyl, bromobenzyl, Nitrobenzyl or methoxybenzyl, in which the alkyl groups are also in the SiAlkyl3 group can be identical or different and preferably contain up to 4 carbon atoms; alkyl3 is preferably trimethyl or tert. -Butyl-dimethyl) in the presence of Lewis acids (such as TiC14, TiCl4 / isopropyl titanate, ZnCl, ZnBr2, Zn (OOCCH3) 2, FeCl3, A1C13, Zn / Cu / CH2J2) implemented.

Subsequent hydrolysis gives 4- (CH²R³-COOR8) -azetidin-2-one (IV) which are reduced to the corresponding 4- (CR²R³-CH2OH) -azetidin-2-ones-, then reacted with Hal-CH2-COOR5 to 1- (CH2-COOR5) -4- (CR²R³-CH2OH) -azetidin-2-ones and can be further oxidized to carboxylic acids of the formula IIa-11).

c) The above-mentioned 4-methyl-4- (CR2R3-COOR7) -azetidin-2-ones (III) or 4- (CR2R3-COOR8) -azetidin-2-one (IV) can by reaction with a compound of the formula R9-Hal (in which R9 is an amino protective group, preferably SiAlkyl3, in which the alkyl groups preferably have 1 - 6 carbon atoms, such as trimethylsilyl or tert-butyldimethylsilyl, also e.g. dimethoxydiphenylmethyl, methoxybenzyl, benzyloxycarbonyl, nitro, bromine, Chloro- or methoxy-benzyloxycarbonylmethyl, tetrahydropyranyl, means) in 1-R9-4-R¹ -4- (CR²R³-COOR10) -azetidin-2-ones (V) (where R10 is R7 or R8). Cleavage of the group R10, e.g. by hydrogenolysis, yields the corresponding l-R9-4-Rl-4- (CR2R3-COOH) -azetidin-2-ones, the active derivatives mentioned under a), e.g. the corresponding chlorides, by reaction with sulfurans of the formula Alkyl2SaCH-COOR5 (in which the alkyl groups Have 1 - 4 carbon atoms; in turn obtainable from dialkyl sulfides and compounds of the formula Hal-CH2-COOR5 in the presence of bases), expediently in an inert solvent in the presence of a base such as triethylamine, pyridine or K2CO3 or an excess of sulfurane at temperatures between about 10 and 100 °, in l-R9-4-Rl-4- / CR2R3-CO-C (= SAlkyl2) -COOR57-azetidin-2-one (VI) can be transferred. Cleavage of the group R9 (e.g. R9 r trialkylsilyl: with tetra-n-butylammonium fluoride; R9 = methoxybenzyl or dimethoxydiphenylmethyl: by oxidative cleavage with K2S208; R9 - (optionally substituted) benzyloxycarbonyl: by hydrogenolysis) leads to 4-R 251¹-4- [CR²-R³-CO-C - (= 5-alkyl2) -COOR5] -azetidin-2-ones, the one hand by ozonolysis (expediently in an inert solvent such as ethyl acetate or CH2Cl2 at temperatures between -100 and + 30 °; then addition a dialkyl sulfide such as dimethyl sulfide or a triaryl phosphine such as triphenylphosphine) in compounds of formula IIb (R6 = H, X = 0), on the other hand by reduction (e.g. with zinc dust / acetic acid) into corresponding 4-R¹-4- (CR²R³-CO-CH2-COOR5) -azetidin-2-ones (VII) can be converted. Halogenation, e.g. bromination with N-bromosuccinimide, provides compounds of the formula IIb / R6 = H, X = = (H, Hal) 7-d) The oxo compounds of formula IIb (R6 - H, X = 0) can also be obtained by using the sulfurans of formula VI first ozonolyzed, using 1-R9-4-R¹-4- (CR²R³-CO-CO-COOR5) -azetidin-2-one receives.

From these, the protective group R9 becomes one of those indicated under c) Methods removed.

e) The diazoketones of the formula IIb (R6 = Ii, X = N2) are available by reacting VII with arylsulfonyl azides (aryl = e.g. tolyl, carboxyphenyl) in an inert solvent such as acetonitrile, preferably in the presence of a Base such as triethylamine at temperatures between about 0 and 400.

f) Starting materials of the formulas IIa or IIb that have a substituent contained in the 3-position (R6 not equal to H) can be obtained analogously, using the substituents R6 is expediently introduced at a suitable preliminary stage.

It can be advisable to use intermediate functional groups by blocking protective groups that are split off again at a later stage will.

For example, the l-R9-4-Rl-4- (CR2R3-COORlO) -azetidin-2-one (V) first with a lithium compound, e.g. a lithium amide such as lithium cyclohexylisopropylamide or lithium hexamethyl disilylamide, convert into 2-lithium enolate, which then with a halide of the formula R6-Hal or (to introduce a l-hydroxyalkyl- or «-hydroxybenzyl group) with an aldehyde of the formula R11-CHO, in which R11 is H, alkyl with 1 - 5 carbon atoms or C6H5 is implemented.

After hydrolysis of the enolate 1-R9-3-R6-4-R¹-4- (CR²R³-COOR10) -azetidin-2-ones are formed, either via the corresponding 3-R6-4-R¹-4- (CR²R³-COOR10) -azetidin-2-ones and 1- (CH2-COOR5) -3-R6-4-R¹-4- (CR²R³-COOR10) -azetidin-2-ones in starting materials of the formula IIa (R6 not equal to H), or analogously to V via l-R9-3-R6-4-Rl-4- [CR²R³-CO-C - (= SAlkyl2) -COOR5] azetidin-2-ones and 3-R6-4-R¹-4- [CR²R³-CO-C (= alkyl2) -COOR5] -azetidin-2-ones in starting materials of Formula IIb (R6 not equal to H) can be converted.

In general, the cyclization of the compounds IIa or ITb succeeds in Presence of an inert solvent at temperatures between about -100 and +1500, a catalyst can be present. Particularly suitable catalysts are Metal connections.

The compounds of the formula IIa are preferably cyclized in the presence of a base in an organic solvent at temperatures between about -100 and + 60 °, preferably between -78 and + ». Above all, serve as bases Lithium amides, which are generally obtained in situ from a lithium alkyl such as n-butyllithium and a secondary amine such as diisopropylamine, isopropylcyclohexylamine, hexamethyldisilazane, Dicyclohexylamine are produced, also e.g. NaOH, KOH, NaH, KH, NaNH2, KNH2, Diaza bicycloundecane, diazabicyclononane or phase transfer catalysts such as tetrabutylammonium iodide or benzyl trimethylammonium chloride. As a solvent are, for example, ethers such as diethyl ether, diisopropyl ether, dimethoxyethane, Tetrahydrofuran (THF), dioxane; Hydrocarbons such as pentane, hexane or toluene; halogenated hydrocarbons such as dichloromethane or chloroform; Amides such as acetamide, DMF or dimethylacetamide. THF is preferred as the solvent. It can be beneficial in this reaction under an inert gas such as nitrogen or argon work.

The ring closure of compounds of the formula IIb (X = H, Hal) succeeds under the same conditions as that of the compounds of formula IIa.

The diazoketones of the formula IIb (X o N2) are cyclized expediently by heating with a metal compound, preferably dirhodium tetraacetate, in an inert solvent such as a hydrocarbon such as benzene or toluene at temperatures between 50 and 150, preferably 70 and 1100.

2,3-Dioxocarboxylic acid derivatives of Formula IIb (X = 0) are preferred produced in situ, e.g. by ozonolysis of the corresponding dialkylsulfurans (corresponding to IIb, but -SAlkyl2 instead of X) under the conditions given above or by Cleavage of a protective group R9 from the corresponding one on the lactam N atom by this Group protected starting materials according to the methods given above. The so obtained 2,3-Dioxo derivatives usually cyclize spontaneously in the presence of the? inert solvent (e.g. CH2C12, ethyl acetate or THF) at temperatures between around -100 and +500.

The lactams of the formula I are also obtainable by being in a otherwise of the formula I corresponding compound, but in which one or more oxo and / or hydroxyl groups are present in protected form, these oxo and / or hydroxyl groups sets free through solvolysis.

The 3-Oxbgruppe (e.g. in the form of a 2-en-3-ol-ether) are preferred and / or a hydroxy group optionally present in the substituent R6 (e.g. in the form of a trialkylsilyl ether) in protected form.

Particularly preferred starting materials which can be converted into I by solvolysis are accordingly those of the general formula VIII wherein Z1 R6, Z-alkyl (in which the alkyl part has 1 - 4 carbon atoms) or α-Z-benzyl, or and Z denote a protected hydroxyl group, but in which z1 - R6 and may be.

The group (s) Z are accordingly preferably alkyl3Si-O groups, in which the alkyl groups preferably have 1-6 carbon atoms, e.g. trimethylsilyloxy or tert-butyl-dimethyl-silyloxy; there are also alkyl (preferably 1-6 Carbon atoms) or arylsulfonyloxy groups (preferably with 6-10 carbon atoms), e.g. methanesulfonyloxy or p-toluenesulfonyloxy.

The starting materials for solvolysis, especially those too of formula VIII are new. As a rule, they are analogous to the compounds of the formula I obtainable by the methods described above.

Some preferred starting materials of Formula VIII can be, for example, as follows obtained: a) The above-mentioned 1- (CH2-COOR5) -3-R6-4-R¹ -4- (CR²R³-COOR10) -azetidin-2-ones (R6 = hydroxyalkyl or α-hydroxybenzyl) are used to introduce a Hydroxy protective group suitable reagent (e.g. a trialkylchlorosilane such as tert-butyldimethylchlorosilane) converted into the corresponding 3-Z-alkyl or 3- (ctZ-benzyl) derivatives, these converted into compounds analogous to the methods given above that correspond to the formula IIa correspond, but instead of the radical R6 a 3-Z-alkyl or. 3- (¢ -Z-benzyl) group wear and these cyclized as indicated above.

The lactams of the formula I are also obtainable by being in a otherwise of the formula I corresponding compound, but in which one or more oxo and / or hydroxyl groups are present in protected form, these oxo and / or hydroxyl groups sets free through solvolysis.

The 3-Oxbgruppe (e.g. in the form of a 2-en-3-ol-ether) are preferred and / or a hydroxy group optionally present in the substituent R6 (e.g. in the form of a trialkylsilyl ether) in protected form.

Particularly preferred starting materials which can be converted into I by solvolysis are accordingly those of the general formula VIII in which z] R6 Z-alkyl (in which the alkyl part has 1 - # C atoms) or [-Z-benzyl], or and Z denote a protected hydroxyl group, but in which Z¹ = R6 and not at the same time may be.

The group (s) Z are accordingly preferably alkyl3Si-O groups, in which the alkyl groups preferably have 1-6 carbon atoms, e.g. trimethylsllyloxy or tert-butyl-dimethyl-silyloxy; there are also alkyl (preferably 1-6 Carbon atoms) or arylsulfonyloxy groups (preferably with 6-10 carbon atoms), e.g. methanesulfonyloxy or p-toluenesulfonyloxy.

The starting materials for solvolysis, especially those too of formula VIII are new. As a rule, they are analogous to the compounds of the formula I obtainable by the methods described above.

Some preferred starting materials of Formula VIII can be, for example, as follows obtained: a) The above-mentioned 1- (CH2-COOR5) -3-R6-4-R1-4- (CR2R3-COOR10) -azetidin-2-ones (R6 = hydroxyalkyl or -hydroxybenzyl) are used to introduce a hydroxy protecting group suitable reagent (e.g. a trialkylchlorosilane such as tert-butyldimethylchlorosilane) converted into the corresponding 3-Z-alkyl or 3 - («» Z-benzyl) derivatives, these converted into compounds analogous to the methods given above that correspond to the formula IIa correspond, but instead of the radical R6 a 3-Z-alkyl or. 3 - (<- Z-benzyl) group wear and these cyclized as indicated above.

b) A compound of the formula I (R2 t R3 e CH3, R4 = R - H) is with a reagent suitable for introducing a hydroxy protecting group (e.g. a trialkylchlorosilane such as tert-butyldimethylchlorosilane into a compound of the formula VIII (R2 = R3 = CH3; -A-B- = CZ-C (C00R5) -, Z1 = H). This is (e.g.

with Li-hexamethyldisilylamide) converted into the 6-en-7-olate, which with carboxylic acid halides, esters or anhydrides of the formula R11-CO-Q (in which R11 alkyl with 1 - 3 carbon atoms or phenyl, Q Cl, Br, O-alkyl with 1 - 4 carbon atoms' -O-CO-R11 or O-SO3R12 and R12 are methyl, phenyl or tolyl) acylated in the 6-position where compounds of the formula VIII (R² = R³ = CH3, -A-B- = -CZ = C (COOR5) -, R11-CO- arise in place of Z¹). Reduction with complex metal hydrides, e.g. with potassium tris-sec-butyl borohydride, leads to compounds of the formula VIII (R2 "R3 = CH3, -A-B- = -Cz = C (COOR5) -, zl = α-hydroxyalkyl with 1 - 4 carbon atoms or α-hydroxybenzyl).

They are preferably solvolyzed by treatment with a tetraalkylammonium halide, e.g. tetra-n-butylammonium fluoride or with tetra-n-butylammonium chloride, bromide or iodide in the presence of KF, or with KF or AgF in the presence of crown ethers (e.g. 18-crown-6-), or with trifluoroacetic acid in the presence or absence an additional inert solvent such as THF in the presence of traces of water, at temperatures between about -10 and +40, preferably between 10 and 300.

If desired, one can optionally contain in a compound obtained existing hydroxyl group in the 2-position by treatment with a chlorination or Convert the brominating agent into the corresponding 2-chloro or 2-bromine compound. Inorganic or organic acid chlorides are expediently used as halogenating agents or bromides such as SOCl2, SOBr2, POC13, PC15, COCl2, Vilsmeier reagent, acetyl chloride, Oxalyl chloride. It is expedient to work in the presence of a base such as triethylamine, Pyridine, lutidine, dimethylaniline in an inert solvent, e.g. dichloromethane, THF, dioxane, benzene or toluene at temperatures between about -70 and 00.

One can also from a 2-chloro or 2-bromine compound obtained remove the halogen atom reductively (in one or more stages). A multi-stage is preferred Method in which one first reacts the halogen compound with the equivalent Amount of a triaryl or trialkyl phosphine, e.g. with triphenyl or tri-n-butyl phosphine converts into the corresponding phosphonium salt. For the production of this phosphonium salt one works in an inert solvent, e.g. in an amide such as DMF, at temperatures between about -10 and + 30 °. The phosphonium salt obtained is easily hydrolyzed, choosing conditions under which the other functional Groups in Compound I are not also attacked. Accordingly the hydrolysis of the phosphonium salt is expediently under approximately neutral conditions, e.g.

in the presence of disodium hydrogen phosphate at a pH of about 7 in a two-phase system (dichloromethane, ethyl acetate, diethyl ether / water) Temperatures between about -20 and 00 are made.

Furthermore, if desired, an obtained ester of the formula I (in which R5 is different from H) saponify to the carboxylic acid (I, R5 = H). It works for example with trifluoroacetic acid (in excess and / or in the presence of a inert solvents such as dichloromethane, chloroform, diethyl ether, THF, benzene, Toluene, acetonitrile at temperatures between about -50 and 00) or with trimethyliodosilane, this also in situ from 3,6-bis-trimethyl-silyl-1,4-cyclohexadiene and iodine or from Hexamethyldisilane and iodine can be formed. The latter reagent becomes useful also in one of the specified solvents at temperatures between about -50 and +300 are used, whereby a trimethylsilyl ester is formed first. This becomes extremely easy, e.g. with aqueous NaHC03 solution at room temperature saponified to free acid.

A obtained ester I (R5 = benzyl, nitrobenzyl or methoxybenzyl) can also be converted hydrogenolytically into the acid I (R5 = H), e.g. by hydrogenolysis on a noble metal catalyst such as palladium-carbon or on Raney nickel in an inert solvent such as ethyl acetate or THF at temperatures between about 0 and 400 and pressures between about 1 and 100 at before-Lyt at room temperature and 1 at. Is used in the presence of a base (e.g. NaOOCCH3, Na2C03, NaHC03, K2C03, 3 Li2CO3, NH4OOCCH3) hydrogenated, the corresponding salts are obtained directly.

Furthermore, one can obtain a carboxylic acid of the formula I (R5 = H) esterify, whereby for the esterification in particular re the esters with one of the easily hydrolyzable ester groups mentioned come into consideration. the Esters are conveniently obtained by reacting a salt of the carboxylic acid, e.g. of the Na or K salt, with a corresponding halogen compound of the formula R5-Hal, where R5 is different from H, e.g. with methyl iodide, n-butyl bromide, benzyl chloride, o-, m- or p-nitrobenzyl chloride, bromide or iodide, o-, m- or p-methoxybenzyl chloride, bromide or iodide, pivaloylcxymethyl chloride, pivaloylamidomethyl chloride, ethoxycarbonyloxymethyl chloride, Bromophthalide, benzhydryl chloride.

This esterification is expediently carried out in the presence of one or more inert solvent at temperatures between about 0 and 30 °, preferably at Room temperature. A mixture of a halogenated one is particularly suitable as a solvent Hydrocarbon such as dichloromethane and DMF.

An acid of the formula I (R5 = H) can be obtained by reaction with a base transferred into one of their physiologically harmless metal or ammonium salts will.

As salts come in particular the sodium, potassium, magnesium, Calcium and ammonium salts into consideration, also substituted ammonium salts, z.fl. the dimethyl, iathyl or [iisopropylammonium, monoethanol, di-ethanol and triethanolammonium, Cyclohe.ylamrroniur, dicyclohexylammonium and dibenzylethylenediammonium salts. The preferred sodium and xalium salts are obtained, for example, by adding the acid of formula I (R5 = sodium or potassium hydroxide solution diluted in the calculated amount, sodium or potassium carbonate solution, sodium or potassium bicarbonate solution and dissolve the solution then evaporated or freeze-dried.

The compounds of the formula I have at least two centers of asymmetry. They are therefore generally obtained in the synthesis as mixtures of racemates, from which the individual racemates, for example by chromatography or can be isolated in pure form by recrystallization from inert solvents. Racemates obtained can, if desired, mechanically by methods known per se or chemically separated into their optical antipodes. Preferably be off the racemate diastereomers by reaction with an optically active resolving agent educated. Suitable as a separating agent for the racemic carboxylic acids I (R5 = H) obtained e.g. optically active bases, e.g. quinine, quinidine, cinchonine, cinchonidine, brucine, Dehydroabietylamine, strychnine, morphine, the D- and L-forms of l-phenyl-methyl, Fenchylamine, menthylamine or basic amino acids, e.g. arginine or lysine, or their esters. The various forms of the diastereomers can be in an separated in a known manner, e.g. by fractional crystallization, and the Optically active compounds of the formula I can be obtained in a manner known per se from the Diastereomers are decomposed in freedom.

{The invention also relates to the use of the compounds of the formula I and their physiologically acceptable salts for the production of pharmaceutical products Preparations, in particular by non-chemical means.

They can be used together with at least one solid, liquid and / or semi-liquid carrier or excipient and optionally in combination with one or more other active ingredient (s) in a suitable dosage form to be brought.

The invention also relates to agents, in particular pharmaceuticals Preparations containing at least one compound of the formula I and / or one their physiologically harmless salts.

These preparations can be used as medicaments in human or veterinary medicine be used. Organic or inorganic substances are used as carriers that are suitable for enteral (e.g. oral), parenteral or topical application are suitable and do not react with the new compounds, for example water, vegetable Oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatine, carbohydrates such as lactose or starch, magnesium stearate, talc, petrolatum. For oral use serve in particular tablets, dragees, capsules, syrups, juices or drops, for rectal use suppositories, for parenteral use solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, for topical application ointments, creams or powders.

The new compounds can also be lyophilized and thus obtained Lyophilisates can be used e.g. for the production of injection preparations. the specified preparations can be sterilized and / or any additives such as lubricants, Preserving, stabilizing and / or wetting agents, emulsifiers, salts for influencing osmotic pressure, buffer substances, coloring, flavoring and / or aromatic substances contain.

If desired, you can also use one or more other active ingredients contain, e.g. one or more antibiotics and / or vitamins. When using them as ß-lactamase inhibitors, they are beneficial, for example, together with a B-lactam antibiotic administered.

The invention also relates to the use of the compounds of formula I in the fight against diseases, in particular bacterial infections, as well as their use in the therapeutic treatment of the human or animal Body.

The substances according to the invention are generally used in analogy to known antibiotics, e.g.

Oxacillin or cefoxitin, and β-lactamase inhibitors, e.g. Clavulanic acid, Thienamycin or CP 45 899, administered, preferably in dosages between about 25 and 1000 mg, in particular between 50 and 500 mg per dosage unit. The daily Dosage is preferably between about 0.5 and 20 mg / kg of body weight. The special one However, dose for any particular patient depends on various factors on, for example, the effectiveness of the special compounds used, age, body weight, general state of health, gender, diet, the time and route of administration, the rate of elimination, drug combination and the severity of the disease to which the therapy applies.

¢ ce of the Verbini yer mentioned in the following examples. the formula I is particularly suitable for the production of pharmaceutical preparations.

In the examples below, "customary work-up" means: Man if necessary, gives water and / or an organic solvent such as benzene, Add ethyl acetate or dichloromethane, separate, and dry the organic phase Sodium sulfate, filtered, evaporated and purified by chromatography (silica gel; Eluent: dichloromethane, then diethyl ether, unless otherwise noted) and / or Crystallization.

IR = bands of the IR spectra (without solvent; cm-1); KR = signals the nuclear magnetic resonance spectra (in CDCl3; ppm).

Example 1 a) From 6.3 ml of hexamethyldisilazane and 21 ml of n-butyllithium in 75 ml of THF, lithium hexamethyldisilylamide is produced at -100. One is still stirring one hour, cools to -75 ° and, while stirring, a solution of 3.68 g of N- [2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) propionyloxy] - succinamide in 20 ml of THF. The temperature is allowed to rise to 00 and after 1.5 hours Add in hydrochloric acid to pH 3.0, work on (ethyl acetate) as usual, and obtain 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester. F.80 °.

IR (in KBr): 1740, 1776, KR: 1.16 (3E, d, J = 7.3 Hz); 1.42 (3S, s); 1.50 (9H, s); 2.4 (1H, q, J = 7.3 Hz); 3.02 (1H, d, J = 15.5 Hz); 3.27 (1H, d, J = 15.5 Hz); 4.63 (1H, s).

The starting material can be obtained as follows: aa) One drips first 16.2 g (0.15 mol) of benzyl alcohol, then 16.8 g (0.166 mol) of triethylamine at -20 ° below Stir to a solution of 18 g (0.152 mol) of 3,3-dimethylacrylic acid chloride in 120 ml of toluene, stirred for 1.5 hours at 200 and 1 hour at 2W °, filtered, works as usual and receives a mixture ("G 1") of 3-methyl-3-butenoic acid benzyl ester and 3,3-dimethylacrylic acid benzyl ester (85:15, estimated from the KMR spectrum).

ab) To a solution of 16 g of lithium diisopropylamide in 150 ml of THF are added at -78 ° 30 g of phosphoric acid hexamethyltriamide, stirred for 30 minutes, and added 30 ° the crude mixture G 1 obtained according to aa) is added, and the mixture is stirred for a further 10 minutes add 17 g of methyl iodide. An oily mixture of isomers (G 2 ") of 2,3-dimethyl-2- and benzyl 2,3-dimethyl-3-butenoate.

ac) 14 g (68.6 mmol) of the crude mixture G 2 are added within 5 hours at 25 ° with 7.2 ml (83 mmol) of chlorosulfonyl isocyanate, stirred into a mixture from 63 g of Na2SO3, 175 g of NaHCO3, 210 ml of water and 210 g of ice, which is mixed with 250 ml of ethyl acetate is covered, works up as usual and receives 2- (4-methyl-2-oxo-azetidin-4-yl) -propionic acid benzyl ester.

ad) A solution of 2.47 g (10 mmol) of crude benzyl 2- (4-methyl-2-oxo-azetidin-4-yl) propionate, 2.14 g (11 mmol) of tert-butyl bromoacetate and 0.37 g (1 mmol) of tetrabutylammonium iodide 10 ml of 32% sodium hydroxide solution are added to 30 ml of CH2C12 while stirring at 0 °. Customary work-up gives oily 2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) propionic acid benzyl ester; IR: 1735, 1741, 17'2, 2800-3000.

ae) A solution of 3.61 g (10 mmol) of the above ester in 55 ml of ethyl acetate is hydrogenated at 1 atom and 200 on 2 g of 5% Pd-C. After filtration, Evaporation and treatment with hexane gives 2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) propionic acid, F. 105-1070.

af) 16 g (78.5 mmol) of dicyclohexylcarbodiimide are added with stirring to a solution of 20 g (73.9 mmol) of the above acid in 500 ml of acetonitrile.

Then 9.05 g (78.5 mmol) of N-hydroxysuccinimide are added. The mixture is stirred for 16 hours at 200, filtered, evaporated, worked up as usual and receives N- [2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) propionyloxy] succinimide, 130-132 ° F. IR (KBr): 1745, 1750, 1790, 1810. KR: 1.40 (3H, d, J = 7 Hz); 1.48 (9H, s); 1.59 (3H, s): 2.85 (4H, s); 2.8 (1H, d, J = 15.5 Hz); 3.2 (1 h, d, J = 15.5 Hz); 3.2 (1H, q); 3.91 (2H, AB q, J = 17 and 1.7 Hz).

b) A solution of 1 g (3.95 mmol) of 4,5-dimethyl-3,7-dioXo-1-aza-bicyclo (3.2,0) heptane-2-carboxylic acid tert-butyl ester in 30 ml of acetonitrile is 1.01 g (4.5 mmol) of 3,6-trimethylsilyl-1,4-cyclohexadiene with stirring at 0 ° mot and 1.01 g (3.98 mmol) of iodine were added. The ice bath is removed and the reaction is followed thin layer chromatography. After the transesterification has taken place, the mixture is cooled again to 0 °. A solution of 336 mg (4 mmol) of NaIsCO3 in 30 ml of water is added dropwise with stirring and wash with diethyl ether. The aqueous phase is freeze-dried. Man receives the sodium salt of 4,5-dimethyl-3,7-dioxo-1-aza-bicyclo (3,2,0) -heptane-2-carboxylic acid.

c) A mixture of 1.97 g of 4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid, 2.16 g of p-nitrobenzyl bromide, 0.7 g of K2CO3 and 30 ml of DMF are stirred at 200 overnight. It is evaporated, worked up as usual, and 4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid p-nitrobenzyl ester is obtained.

Example 2 Analogously to Example la), N- [2- (1-tert-butoxycarbonylmethyl-2-oxo-azetidin-4-yl) -2-methyl-propionyloxy7-succinimide is obtained Obtainable by reacting benzyl 2,2-dimethyl-3-dutenoate with chlorosulfonyl isocyanate to 2-methyl-2- (2-oxo-azetidin-4-yl) -propionic acid benzyl ester and other reactions analogous to Example 1 about 2- (l-tert-butoxycarbonylmethyl-2-oxo-azetidin-4-yl) -2-methylpropionic acid benzyl ester and the corresponding free acid] the 4,4-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester (M.p. 82-84 °) and from it according to Example 1b) the sodium salt of 4t4-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

The starting material can also be obtained as follows: a) Dissolve 5 g (38.8 mmol) of 4-acetoxy-azetidin-2-one in 50 ml of CH2C12 and added dropwise under N2 -78 add a solution of 4.6 ml TiC14 in 50 ml CH2Cl2. After 15 minutes it will be under Stir a solution of 16 9 (85 mmol) 1-ethoxy-1-trimethylsilyloxy-2-methyl-proene added dropwise in 100 ml of Cii2C12. The mixture is stirred for a further 1 hour at -700, then for 18 hours at 200. The mixture is stirred into aqueous Na2dHPO4 solution, filtered through kieselguhr, works as usual on (chromatography with CH2C12 / acetone 7; 3) and receives 2- (2-oxo-azetidin-4-yl) -2-methyl-propionic acid ethyl ester, Oil. IR: 1720, 1760, 2880, 2900, 2945, 2980 and 3260. KR: 1.21 (3H, s); 1.23 (3H, s); 1.28 (3H, t); 2.85 (2H, broad, 16 signals); 3.87 1H, dd, J = 5.1 and 2 Hz); 4.18 (2H, q); 6.5 (1H, broad).

b) 8.3 g (44.9 mmol) of the above ester are dissolved in 250 ml of THF, 2 g (91.8 mmol) of LiBH4 are added at 0 °, the mixture is allowed to come to 200 and is allowed to Stand for 18 hours. It is evaporated, extracted with CH2Cl2, evaporated again and dissolved in acetone, filtered, concentrated the filtrate and obtained 2- (2-oxo-azetidin-4-yl) -2-methyl-propanol, F. 138-1390.

c) Analogously to example lad) is obtained from the above alcohol with Bromoacetic acid tert-butyl ester 2- (1-tert-butoxycarbonylmethyl-2-oxo-azetidin-4-yl) -2-methyl-propane-cl, F. 53-55 °. IR: 740, 850,940, 1050, 1155, 1220, 1360, 1390, 1470, 1720-1760 (broad Band), 2890, 2950, 2990, 3450. KR: 0.89 (3H, s); 0.895 (3H, s); 1.45 (9H, s); 2.32 (1.4, broad); 2.73 (1H, dd, J = 14.9 and 2.8 Hz); 2.93 (1H, dd, J = 14.9 and 5.0 Hz); 3.38 (2H, s); ; 3.94 (1, dd, J = 5.0 and 2.8 Hz); 3.95 (2H, AB q).

u) Dissolve 0.257 g (1 mmol) of the above alcohol in 26 ml of acetone and 0.13 ml Jones reagent (8 N solution of CrO3 in H2S04 / fl20 1: 3.35). after one hour a further 0.13 51 Jones reagent is added. After two hours of stirring, one works up as usual and receives 2- (1-tert-butoxycarbonylmethyl-2-oxo-azetidin-4-yl) -2-methylpropionic acid, 133-135 ° F.

e) Analogously to Example 1 af), the above acid is converted into the corresponding Succinimidoester converted.

Example 3 Analogously to example la) one obtains from N- [2- (1-tert-butoxy carbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) -2-methylpropionyloxy7-succinimide / F. 138-1400; available through Conversion of 2,2,3-trimethyl-3-butenoic acid benzyl ester with chlorosulfonyl isocyanate to form 2-methyl-2- (4-methyl-2-oxo-azetidin-4-yl) propionic acid benzyl ester (IR: 1725, 1760, 3250; KR: 1.23 (3H, s);; 1.27 (3H, s), 1.35 <3H, s) 2.5 (1H, dd, J - 15.5 and 1.9 Hz); 2.99 (1H, dd, J -15.5 and 1.4 Hz); 5.11 (2H, s); 7.33 (5H, s)) and further reactions analogous to Example 1 via 2- (1-tert-butoxycarbonylmethyl-4 -methyl-2-oxo-azetidin-4-yl) -2-methylproFionic acid benzyl ester (KR: 1.29 (3H, s); 1.295 (3H, s); 1.40 (3H, s); 1.45 (9H, s); 2.56 (1H, d, J = 15.0 Hz); 3.11 (1H, d, J = 15.0 Hz); 3.87 (2H, s); 5.11 (2H, s); 7.33 (5H, s)) and the corresponding free acid (m.p. 160-1610) 7 the 4,4,5-trimethyl-3,7-dioxo-1-aza-bicyclo- (3,2.01-heptane-2-carboxylic acid tert-butyl ester (F. 830; IR (KBr): 700, 760, 780, 820, 855, 945, 990, 1030, 1160, 1235, 1255, 1315, 1360, 1370, 1390, 1415, 1460, 1740, 1770, 2995, 3000; KR: 1.07 (3H, s); 1.17 (3H, s); 1.46 (3H, s); 1.48 (9H, s); 3.01 (1H, d, J = 15.5 Hz); 3.22 (1H, d, J = 15.5 Hz); 4.64 (1H, s)) and, according to Example 1b), the sodium salt of 4,4,5-trimethyl-3,7-dioxo-1-aza-bicyclo (3,2,0) heptane-2-carboxylic acid.

Example 4 Analogously to example la) one obtains from N- / 2- (l-tert.

Butoxycarbonylmethyl-2-oxo-azetidin-4-yl) propionyloxy / succinimide / obtainable by a) reaction of 4-acetoxy-azetidin-2-one with 1-methoxy-1-trimethylsilyloxypropene and subsequent hydrolysis to methyl 2- (2-oxo-azetidin-4-yl) propionate, LiBH4 reduction to 2- 2- (2-oxo-azetidin-4-yl) propanol, reaction with bromoacetic acid tert-butyl ester to 2- (1-tert-butoxycarbonylmethyl-2-oxo-azetidin-4 ~ yl) propanol, oxidation to 2 » tert-butoxycarbonylmethyl-2-oxo-azetidin-4-yl) propionic acid and esterification, or b) Reaction of 2-methyl-1-3-butenoic acid benzyl ester with chlorosulfonyl isocyanate to 2- (2-oxo-azetidin-4-yl) -propionic acid benzyl ester and more Reactions analogous to Example 1 using 2- (1-tert-eutoxycarbonylmethyl-2-oxo-azetidin-4-yl-propionic acid benzyl ester and the corresponding free acid7 is 4-ethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester and from it according to Example 1b) the sodium salt of 4-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Example 5 Analogously to Example la), N- [2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) acetoxy7-succinimide is obtained / obtainable by direct reaction of the mixture G 1 with chlorosulfonyl isocyanate to (4-methyl-2-oxo-azetidin-4-yl) -acetic acid benzyl ester (IR: 1725, 175C, 1760, 3250) and further reactions analogous to Example 1 via 2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) benzyl acetate and the corresponding free acid] tert-butyl 5-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylate and from it according to example lb) the sodium salt aer 5-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-curbonic acid ..

Example 6 a) Analogously to Example 1, N- / 2- <1-benzyloxycarbonylmethyl-2-oxo-azetidin-4-yl) -2-methyl-propionyloxy7-succinimide is obtained [obtainable by reacting 3,3-dimethyl-1,4-pentadiene with chlorosulfonyl isocyanate to 3- 3- (2-oxo-azetidin-4-yl) -3-methyl-1-butene (KR: 1.01 (6H, s); 2.62; 2.86 (2H, AB, split further, J = 15.4 or 2.8 or 0.84 Hz and J = 15.4 or 4.8 or 1.7 Hz); 3.5 (1H, dd, J = 2.8 and 4.8 Hz); 4.97; 5.12; 5.82 (3H, ABX), reaction with benzyl bromoacetate in the presence of NaH in THF to give 3- (1-benzyloxycarbonylmethyl-2-oxo-azetidin-4-yl) -3-methyl-1-butene, Oxidation with KMnO4 to give 2- (1-benzyloxycarbonylmethyl-2-oxo-azetidin-4-yl) -2-methylpropionic acid and esterification with N-hydroxysuccinimide7 the 4,4-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzyl ester.

b) Hydrogenation of 1 g of the above ester on 200 mg of 5% Pd-C in 15 ml of ethyl acetate at 200 and lat gives 4,4-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Example 7 Ar.alog Example la) is obtained from N- / 2- (1-tert-butoxycarbonylmethyl-2-oxo-3-ethyl-4-methyl-azetidin-4-yl) propionyloxy7-succinimide Obtainable by reacting 2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -propionic acid benzyl ester (cf. Example 41a), below) with LiN / Si (CH3) 372, reaction of the Li enolate formed with ethyl iodide to form 2- (1-tert-butyl-dimethylsilyl-2-oxo-3-ethyl-4-methyl-azetidin-4-yl) propionic acid benzyl ester, Cleavage with tetrabutylammonium fluoride to benzyl 2- (2-O>: o-3-ethyl-4-methyl-azetidin-4-yl) propionate, Reaction with bromoacetic acid tert-butyl ester to give 2- <l-tert-butoxycarbonylmethyl-2-oxo- Benzyl 3-ethyl-4-methyl-azetidin-4-yl) propionate, hydrogenolysis for free Propionic acid and esterification with N-hydroxysuccinimide7 6-ethyl-4,5-dimethyl-3,7-dioxo-1-aza-bicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester and from this analogously to Example 1b) the sodium salt of 6-ethyl-4,5-dimethyl-3,7-dioxo-1-aza-bicyclo (3,2,0) heptane-2-carboxylic acid.

Example 8 Analogously to Example 1a), N- [2- (1-tert-butoxyzarbonylmethyl-2-oxo-3,4-dimethyl-azetidin-4-yl) propionyloxy7-succinLmide is obtained / Obtainable by reaction of the lithium enolate of 2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -propionic acid benzyl ester with methyl iodide and further reactions analogous to Example 17, 3,4,5-trimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester and from this analogously to Example 1b) 3,4,5-trimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2- carboxylic acid Example 9 Analogously to Example la), N- [2- (1-tert-butoxycarbonylmethyl-2-oxo-3-hexyl-4-methyl-azetidin-4-yl) propionyloxy7-succinimide is obtained Obtainable by reaction of the lithium enolate of benzyl 2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) propionate with hexyl bromide and further reactions analogous to Example 27, 6-hexyl-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carbonic acid tert-tutyl ester and therefrom, analogously to Example 1b), 6-hexyl-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) -heptane-2-carboxylic acid.

Example 10 Analogously to Example la), N- [2- (1-tert-butoxycarbonyXmethyl-2-oxo-3-benzyl-4-methyl-acetldln-4-yl) propionyloxX7-succinimide is obtained Obtainable by reaction of the lithium enolate of 2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -propionic acid benzyl ester with benzyl bromide and further reactions analogous to Example 27 6-Benzyl-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) -heptane-2-carboxylic acid tert-butyl ester and from this analogously to Example 1b) 6-benzyl-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Example 11 A suspension of 2.71 g of 2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) propionic acid is added (Example lae) in 25 ml of benzene with 0.9 ml of oxalyl chloride, stirred for 12 hours at 200, evaporates and dissolves the crude acid chloride obtained (2.9 g) in 25 ml of THF. Under Exclusion of moisture 6.4 ml of hexamethyldisilazane are dissolved in 75 ml of THF and at -10 ° with 21 ml of a 1.6 molar solution of butyllithium in hexane. After stirring for 15 minutes, the acid chloride solution is added. One stirs 1 hour at -70t, warmed to 00 and added 2N HCl to pH 3. According to the usual Working up gives 4,5-dimethyl-3,7-dioxo-1-a-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester (oily mixture of isomers, partially crystallizes).

Example 12 Analogously to Example 11, 2- (1-tert-butoxycarbonylmethyl-2-oxo-azetidin-4-yl) -2-methyl-propionic acid (Example 2d) via the corresponding acid chloride 4,4-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester. F. 82-840.

Example 13 Analogously to Example 11, 2- <1-tert-butoxycarbonylmethyl-4-methyl-azetidin-2-on-4-yl) -2-methyl- propionic acid (Example 3) via the corresponding chloride 4,4,5-trimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester. F. 83 °.

Example 14 Analogously to Example 11, 2- (l-tert-butoxycarbonylmethyl-2-oxo-azetidin-4-yl) propionic acid is obtained (Example 4) via the corresponding chloride 4-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Example 15 Analogously to Example 11, from 2- (l-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) acetic acid (Example 5) via the corresponding chloride 5-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Examples 16 to 20 Analogously to Example 11, one obtains from the corresponding 2- (1-R5-oxycarbonylmethyl-4-methyl-2-oxo-azetiGin - <- yl) propionic acids via their Acid chlorides: 16. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo <3.2,0) -heptane-2-carboxylic acid methyl ester.

17. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid ethyl ester.

18. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzyl ester.

19. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid pmethoxybenzyl ester.

20. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) -heptane-2-carboxylic acid pivaloyloxymethyl ester.

Example 21 1 g of 2- (1-tert-butoxycarbonylmethyl-4-methyl-2-oxo-azetidin-4-yl) propionic acid is dissolved (cf. Example 1 ae) under N2 in 15 ml of THF, mixed with 0.57 g of carbonyldiimidazole and stir overnight. This solution, which contains the imidazolide of the acid, becomes too a cooled to -78 ° solution of 2.18 ml of hexamethyldisilazane, 6.6 ml of a 1.6 molar solution of butyllithium in hexane and 15 ml of THF were added dropwise. Within The mixture is warmed to 0 ° for 2 hours and 2N HCl is added to pH 3.

The THF is distilled off and worked up as usual with ethyl acetate and receives 4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

F. 800.

Examples 22 to 30 Analogously to Example 21, one obtains from the corresponding acids via the corresponding imidazolides given in Examples 2 to 10 3,7-Dioxo-1-azabicyclo- (3,2,0) heptane-2-carboxylic acid ester.

Example 31 a) 3.0 g of α- [2- (4-methyl-2-oxo-azetidin-4-yl) propionyl] -α-tert-butoxycarbonyl-methylene-dimethylsulfuran are dissolved (Isomer from the mp 169 °) in 150 ml CH2Cl2 and conducts at 700 ozone up to the beginning Blue discoloration. Then 5 ml of dimethyl sulfide are added.

The cleavage product formed from the ozonide formed, 4- (4-methyl-2-oxo-azetidin-4-yl) -2,3-dioxopentanoic acid-tert. -butyl ester, is not isolated.

It is evaporated and the residue is chromatographed on silica gel (Merck 60; Grain size 0.063 - 0.2 mm).

First, with ethyl acetate, dimethyl sulfone, then with diethyl ether 2-Hydroxy-4,5-dimethyl-3,7-dioxol-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester (Isomer of m.p. 114 - 1180) eluted.

KR: 1.36 (3H, d, J - 8.4 Hz); 1.5 (9H, s); 1.58 (3H, s); 2.58 (1H, q, J - 8.4 Hz); 2.9 (1H, d, J -16.3 Hz); 3.26 (1H, d, J = 16.3 Hz); 4.48 (1H, broad, OH).

Analogously, one obtains from the other isomer (mp 151 ° see below, paragraph c) α- [2- (4-Methyl-2-oxo-azetidin-4-yl) -propionyl] -α-tert-butoxycarbonyl-methylenedimethylsulfurans the isomeric 2-hydroxy-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) -heptane-2-carboxylic acid tert-butyl ester, Mp 128-130 ° C. KR: 1.21 (3h, d, J 3 7.2 Hz); 1.38 (3H, s), 1.50 (9H, s); 2.81 (1H, q, J w 7.2 Hz); 3.10 (2H, s); 4.44 (1H, s). According to the XR spectrum, this is isomer the 2ß-Hydroxy-4ß, SB-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) -heptane-2α-carbonylsäuretert. -butyl ester.

The starting materials are available as follows: aa) A solution of 24.6 g (0.1 mol) of 2- (4-methyl-2-oxo-azetidin-4-yl) propionic acid benzyl ester (Example lac) in 900 ml of ethyl acetate is hydrogenated on 6 g of 5% Pd-C at 1 atm and 200. Man receives 2- 2- (4-methyl-2-oxo-azetidin-4-yl) -propionic acid, F. 1090. KR (in acetone): 1.22 (3H, d, J - 7.5 Hz); 1.44 (3H, s); 2.6 (1H, dd, J = 14.8 and 1.8 Hz); 2.76 (1H, q, J = 7.5 Hi); 3.06 (1H, d, J = 14.8 Hz).

ab) A solution of 15.6 g (0.1 mol) of this acid in 200 ml of dichloromethane is tert with stirring with 16.6 g (0.11 mol). -Butyldimethylchlorosilane, then with 15 g (0.22 mol) of imidazole were added and the mixture was stirred at 200 for a further 16 hours. According to usual Working up gives 27 g of crude oily 2- (4-methyl-2-oxoazetidin-4-yl) propionic acid (tert-butyldimethylsilyl ester, which is dissolved in 350 ml of dichloromethane.

14 g (9.5 ml) of oxalyl chloride and 0.5 are added while stirring ml of dimethylformamide, stirred for a further 1 hour at 0 ° and 30 minutes at 200, evaporated and receives crude 2- 2- (4-methyl-2-oxo-azetidin-4-yl) propionyl chloride. IR: 1780, 1810.

ac) A solution of 4.25 g (24.2 mmol) of tert-butoxycarbonyl-methylenedimethylsulfurane is added dropwise in 20 ml of benzene with stirring at 0 ° in a solution of 2.1 g (12 mmol) of the above Acid chloride in 20 ml of benzene and lets the temperature continue to lead over Come to 20 ° at night. The precipitated sulfonium chloride is filtered off and evaporated a, the filtrate works up and obtained by chromatography (silica gel); Dichloromethane / ethanol 9: 1, then ethanol alone) two isomers of the desired α- [2- (4-methyl-2-oxo-azetidin-4-yl) propionyl] -α-tert. -butoxycarbonylmethylene-dimethylsulfurana, F. 1690 (KE: 1.10 (3H, d, J = 7 Hz); 1.48 (3H, s); 1.50 (9H, s); 2.48 (1H, d, J = 14 Hz); 2.89; 2.90; 3.08 (1S, dd, J a 14 and 2.5 Hz); 4.05 (1H, q, J = 7 Hz); 6.32 (1H, NH)) and m.p. 151 ° (KR: 1.18 (3H, d, J "7 Hz); 1.51 (3H, s); 1.53 (9H, s); 2.61 (1H, dd, J = 15.5 and 2 Hz); 2.91 (6H, s); 4.06 (1H, q, J = 7 Hz); 6.1 (1H, NH)).

b) Analogously to example Ib) one obtains from those described in paragraph a) isomeric tert-butyl esters, the sodium salts of the two isomeric 2-hydroxy-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acids.

Example 32 Analogously to Example 31, «- / 2-Methyl-2- (2-oxoazetidin-4-yl) propionyl] -α-tert-butoxycarbonyl-methylenedimethylsulfuran is obtained / obtainable from 2-methyl-2- (2-oxo-azetidin-4-yl) -propionic acid benzyl ester (example 2) via 2-methyl-2- (2-oxo-azetidin-4-yl) -propionic acid and 2-methyl-2- (2-oxo-azetidin-4-yl) propionyl chloride] 2-Hydroxy-4,4-dimethyl-3,7-dioXo-1-azabicyclo (32tO) heptane-2-carboxylic acid tert-butyl ester by ozone splitting and cyclization and therefrom according to example lb) the sodium salt of 2-hydroxy-4,4-dimethyl-3,7-dioxo-1-azabicyclo- (3,2,0) heptane-2-carboxylic acid.

EXAMPLE 33 Analogously to Example 31, α- [2-methyl-2- (4-methyl-2-oxo-azetidin-4-yl) propionyl] -α-tert-butoxycarbonyl-methylene-dimethylsulfuran is obtained / obtainable from 2-methyl-2- (4-methyl-2-oxo-azetidin-4-yl) benzyl propionate (Example 3) via 2-methyl-2- (4-methyl-2-oxo-azetidin-4-yl-propionic acid and 2-methyl-2- (4-methyl-2-oxo-azetidin-4-yl) - propionyl chloride] Ozone splitting and cyclization of 2-hydroxy-4,4,5-trimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester and from it according to Example lb) the sodium salt of 2-hydroxy-4,4,5-trimethyl-3,7-dioxol-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Example 34 Analogously to Example 31, α- [2- (2-oxo-azetidin-4-yl) -propionyl7-d-tert-butoxycarbonyl-methylene-dimethylsulfuran is obtained [Obtainable from benzyl 2- 2- (2-oxo-azetidin-4-yl) propionate (Example 4) via 2- (2-Oxo-azetidin-4-yl) -propionic acid and 2- 2- (2-Oxo-azetidin-4-yl) -propionyl chloride 7 by ozone splitting and cyclization, tert-butyl 2-hydroxy-4-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylate and from it according to Example lb) the sodium salt of 2-hydroxy-4-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Example 35 Analogously to Example 31, α- [2- (4-methyl-2-oxoazetiain-4-yl) acetyl7 -> - tert-butoxycarbonyl-methylenedimethylsulfuran is obtained from / obtainable from (4-methyl-2-oxo-azetidin-4-yl) -acetic acid benzyl ester (see example 5) via 4-methyl-2-oxo-azetidin-4-yl) acetic acid (m.p. 110 °; X; R in DMSO: 1.40 (3h, s); 2.58 (1H, d, J = 14.7 Hz); 2.60 (2H, s); 3.02 (1H, d, J = 14.7 Hz), 8.03 (1H, NH); 9.68 (1H, COOH) and 4-methyl-2-oxo-azetidin-4-yl) acetyl chloride7 by splitting ozone and cyclization of 2-hydroxy-5-methyl-3,7-dioxo1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester and from it according to Example lb) the sodium salt of 2-hydroxy-5-methyl-3,7-dioxol-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Example 36 Analogously to Example 31, α- [2- (4-methyl-2-oxoazetidin-4-yl) -propionyl7-X-benzyloxycarbonyl-methylenedimethylsulfuran is obtained / obtainable from 2- (4-methyl-2-oxo-azetidin-4-yl) propionyl chloride and benzyloxycarbonylmethylene dimethylsulfuran7 by ozone splitting and cyclization, 2-hydroxy-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzyl ester.

Example 37 Analogously to Example 31, [- / 2- (3-ethyl-4-methyl-2-oxo-azetidin-4-yl) -propionyl-α-tert-butoxycarbonyl-methylene-dimethylsulfuran is obtained / obtainable from 2- (2-oxo-3-ethyl-4-methyl-azetidin-4-yl) propionosurebenzyl ester (Example 7) by hydrogenolysis to the free acid, conversion to chloride and reaction with tert-butoxycarbonyl-methylene-dimethyl-sulfuran] by decomposing ozone and cyclization 2-Hydroxy-4,5-dimethyl-6-ethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Examples 38 to 40 analogous to Example 37 are obtained from the corresponding Dimethylsulfurans: 38. 2-Hydroxy-4,5,6-trimethyl-3,7-dioxo-1-azabicyclo- (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

39. 2-Hydroxy-4,5-diemthyl-6-hexyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

40. 2-Hydroxy-4,5-dimethyl-6-benzyl-3,7-dioxo-1-azabicycloX3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Example 41 1.5 g of tert-butyl 2-bromo-3-oxo-4- (4-methyl-2-oxo-azetidin-4-yl) pentanoate are dissolved in 100 ml of absolute THF, add 218 mg of NaH with stirring and cool to 0 °. 4.6 ml of hydrochloric acid are added dropwise with stirring. After the usual work-up (Silica gel; chloroform / diethyl ether) gives 4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester, Mixture of isomers.

The starting material can be obtained as follows: a) A solution of 14 g (56.7 mmol) of 2- (4-methyl-2-oxoazetidin-4-yl) propionic acid benzyl ester (Example 1 ac) in 250 ml of diethyl ether is tert with 7 g of triethylamine, then with 10 g. -Butyldimethyl-chlorosilane offset.

After the conversion has taken place (thin-layer chromatographic control) it is washed with saturated NaCl solution, worked up as usual (silica gel; toluene / diethyl ether) and get 2- (1-tert-butyl-dimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -propionic acid benzyl ester (Mixture of isomers). IR: 1725, 1745, KR: 0.17 (3H, s); 0.23 (3H, s); 0.24 (3H, s); 0.31 (3H, s); 0.97 (9H, s); o.99 (9H, s); 1.22 (3H, d, J = 7 Hz); 1.25 (3H d, J = 7 Hz); 149 (3H, s); 1.51 (3H, s) 2.58 (1H, d, J - 15.3 Hz); 2.62 (1H, d, J = 16.7 Hz), 2.88 (1H, q, J - 7 Hz); 3.35 (1H, d, J æ 16.7 Hz), 3.55 (1H, d, J - 15.3 Hz); 5.10 (2H, s); 5.12 (2H, s), 7.36 (SH, s).

b) A solution of 14 g (38.8 mmol) of this ester in 500 ml of ethyl acetate is hydrogenated on 7 g of 5% Pd-C at 1 atm and 200. 2- (1-tert-butyl-dimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) propionic acid is obtained. F. 1040. KR: 0.17 (3H, s); 0.25 (6H, s); 0.32 (3H, s); 0.98 (9H, s); 0.99 (9H, s); 1.23 (3H, d, J = 7.8 Hz), 1.3 (3H, d, J = 7.8 Hz), 1.52 (3H, s); 1.57 (3H, 5), 2.60 (1H, d, J - 16 Hz), 2.67 (1H, d, J = 16 Hz); 2.80 (1H, q, J - 7.8 Hz); 2.85 (LH, q, J = 7.8 Hz); 3.31 (1H, d, J - 16 Hz).

c) 4.4 ml of triethylamine and then 2 ml (58.4 mmol) of oxalyl chloride are added to a solution of 5.42 g (20 mmol) of this acid in 100 ml of diethyl ether at -50 ° with stirring, stir for 1 hour at -50 ° and 1 hour at 00, filtered, evaporated a, dissolves in 150 ml of hexane and cools to 00. Add to this solution of the crude acid chloride 7.2 g (41 mmol) of tert-butoxycarbonylmethylenedimethylsulfuran in 50 ml of benzene added dropwise with stirring. After the usual work-up (silica gel; ethyl acetate / acetone) one obtains [2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azet-azetidin-4-yl) -propionyl7-tert-butoxycarbonyl-methylene-dimethylsulfuran, 2 isomers, m.p. 1110 and 1260.

d) A solution of 4.3 g (10 mmol) of the above dimethylsulfurans (M.p. 111 °) in 50 ml of acetic acid is mixed with 3.26 g (50 mmol) of zinc dust at 100 and stirred at 200 for 2 hours. It is filtered off, washed with acetone and evaporated and stir the residue with an aqueous solution of sodium dihydrogen phosphate with the simultaneous addition of ethyl acetate. Preserves after concentration and drying man the oily 4- (l-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -3-oxo-pentanoic acid tert-butyl ester.

e) A solution of 3.4 g (9.22 mol) of this ester in 50 ml of tetrahydrofuran is at 20 ° for one hour with 3.15 g (10 mmol) of tetrabutylammonium fluoride trihydrate touched. Customary work-up gives oily tert-butyl 4- (4-methylen-2-oxo-azetidin-4-yl) -3-oxo-pentane acid.

f) A solution of 1.3 g (5.2 mmol) of the above ester in 100 ml Carbon tetrachloride is admixed with 0.925 g (5.2 mmol) of N-bromosuccinimide. Man stir in the exclusion of light for 2 hours at 200, filtered off, evaporated and receives 2-bromo-3-oxo-4- <4-methyl-2-oxo-azetidin-4-yl) pentanoic acid tert-butyl ester.

Example 42 Analogously to Example 41, tert-butyl 2-bromo-3-oxo-4-methyl-4-t2-cXo-azetidin-4-yl) pentanoate is obtained [Obtainable from 2-methyl-2- (2-oxo-azetidin-4-yl) -propionic acid benzyl ester via 2- (1-tert-butyldimethylsilyl-2-o>: o-azetidin-4-yl) -2-methyl -propionic acid benzyl ester, the free acid, (2- (1-tert-butyldimethylsilyl-2-oxoazetidin-4-yl) - 2-methyl-propionyl) -Tert. -butoxycarbonylmethylene-dimethylsulfuran, 4 (l-tert-butyldimethylsilyl-2-oxo-azetidin-4-yl) -4-methyl-3-oxo-pentanoic acid-tert-butyl ester and tert-butyl 3-oxo-4-methyl-4- (2-oxo-azetidin-4-yl) pentanoate 7 with NaH 4,4-Dimethyl-3,7-dioXo-1-aza-bicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Example 43 Analogously to Example 41, tert-butyl 2-bromo-3-oxo-4-methyl-4- (4-methyl-2-oxo-azetidin-4-yl) pentanoate is obtained [Obtainable from 2-methyl-2- (4-methyl-2-oxo-azetidin-4-yl) propionic acid benzyl ester via 2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -2-methyl-propionic acid benzyl ester (Base used: 4-dimethylaminopyridine instead of triethylamine; KR: 0.29 (3H, s); 0.3 (3H, s); 1.02 (9H, s); 1.38 (6H, s); 1.55 (3H, s); 2.66 (1H, d, J - 15.5 Hz); 3.38 (1H, d, J = 15.5 Hz); 5.16 (2H, s), 7.4 (5H, s)), 2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -2-methyl-propionic acid (KR: 0.3 (6H, s); 1.04 (9H, s); 1.39 (3H, s); 1.395 (3H, s) 1.63 (3H, s); 2.73 (1H, d, J = 16.5 Hz); 3.4 (1H, d, J - 16.9 Hz); 9.08 (1H, COOH)), (2- (l-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -2-methylpropionyl) -tert-butoxycarbonylmethylene-dimethylsulfuran, 4- (1-tert-Butyldimethylsllyl-4-methyl-2-oxo-azetidin-4-yl) -4-methyl-3-oxo-pentanoic acid tert. butyl ester and 4-methyl-4- (4-methyl-2-oxo-azetidin-4-yl) -3-oXo-pentanoic acid tert. -butylester7 with NaH 4,4,5-trimethyl-3,7-dioXo-1-azabicyclot3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Example 44 Analogously to Example 41, 2-bromo-3-oxo-4- (2-oxo-azetidin-4-yl) tert-butyl pentanoate derived from benzyl 2- (2-oxo-azetidin-4-yl) propionate via 2- (1-tert-butyldimethylsilyl-2-oxo-azetidin-4-yl) -propionic acid benzyl ester, 2- (1-tert-Butyldimethylsilyl-2-oxo-azetidin-4-yl) -propionic acid, (2- (1-tert-butyldimathylsilyl-2-oxo-azetidln-4-yl) -propionyl) -tert. - butoxycarbonylmethylene-dimethylsulfuran, 4- 4- (1-tert-Butyldlmethylsilyl-2-oxo-azetidin-4-yl) -3-oxo-pentanoic acid-tert. -butyl ester and 3-oxo-4- (2-oxo-azetidin-4-yl) pentanoic acid tert-butyl ester] with NaH 4-methyl-3,7-dioxo-l-azabicyclo (3,2,0) tert-butyl heptane-2-carboxylate.

Example 45 Analogously to Example 41, 2-bromo-3-oxo-4- (4-methyl-2-oxo-azetidin-4-yl) -butanoic acid tert-butyl ester [obtainable from (4-methyl-2-oxo-azetidin-4-yl) -acetic acid benzyl ester via benzyl (l-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -acetate (KR: 0.35 (6H, s); 1.1 (9H, 5); 1.63 (3H, s); 2.90 (2H, s); 2.92 (1H, d, J = 15 , 5 Hz) S 3.40 (1H, d, J I 15.5 Hz); 5.26 (2H, s); 7.5 (5H, s)), (l-tert-butyldimethylsilyl-4-methyl- 2-oxo-azetidin-4-yl) acetic acid (m.p. 120-1210; KR: 0.35 (6H, s); 1.05 (9H, s); 1.65 (3H, s); 2.85 (2H, s); 2.91 (1H, d, J æ 16.2 Hz); 3.38 (1H, d, J s 16.2Hz); 10.3 (1H, s)), ((l-tert-butyldimethylsilyl-4-methyl-2-oxo-azetldin-4-yl) acetyl) -tert-butoxycarbonylmethylene-dimethylsulfuran, (IR: 785, 820, 835, 850 1040, 1075, 1180, 1260, 1320, 1275, 1580, 1678, 1740 (broad), 2860, 2930, 2970) 4- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -3- oxo-butanoic acid tert-butyl ester (F. 88 - 890) and 4- (4-methyl-2-oxo-azetidin-4-yl) -3-oxo-butanoic acid tert-butyl ester / with NaH 5-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid-tert-butylic acid examples 46 to 50 Analogously to Example 41, the corresponding 2-bromo-3-oxo-4- (2-oxo-azetidin-4-yl) butane or pentanoic acid esters with NaH: 46. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid p-nitrobenzyl ester.

47. 4,4-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzyl ester.

48. 4,4,5-trimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzyl ester.

49. 4-Methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzyl ester.

50. 5-Methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzyl ester.

Example 51 A solution of 281 mg of 2-diazo-3-oxo- (4-methyl-2-oxoazetidin-4-yl) pentanoic acid tert. -butyl ester and 50 mg Rh2 (COCCH3) 4 in 8 ml benzene is 4 hours cooked. It is filtered, evaporated, the residue is chromatographed and 4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester is obtained. F. 80 °.

The starting material can be obtained as follows: a) To a solution of 3.69 g of 4- (l-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -3-oxo-pentanoic acid tert-butyl ester (Example 41d) in 100 ml of acetonitrile are added 1.1 g of triethylamine, then 2 g of p-toluenesulfonyl azide and stir overnight at 20 °. Obtained after evaporation and chromatography (chloroform) 4- (X-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -2-diazo-3-oxo-pentanoic acid tert-butyl ester.

b) 3.95 g (10 mmol) of the above ester are dissolved in 80 ml of TUF, 3.15 g (10 mmol) of tetrabutylammonium fluoride trihydrate are added and the mixture is stirred over Night at 20 °. Customary work-up gives 2-diazo-4- (4-methyl-2-oxo-azetidin-4-yl) -3-oxo-pentanoic acid-tert.

butyl ester.

Example 52 Analogously to Example 51, tert-butyl 2-diazo-3-oxo-4-methyl-4- (2-oxo-azetidin-4-yl) pentanoate is obtained Obtainable from 4- (l-tert-butyldimethylsilyl-2-oxo-azetidin-4-yl) -4-methyl-3-oxo-pentanoic acid-tert-butyl ester (Example 42) via 2-diazo-3-oxo-4-methyl-4- (1-tert.-butyldimethylsilyl-2-oxo-azetidin-4-yl) tert-butyl pentanoate7 with Rh2 (OOCCH3) 4 denotes 4,4-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane 2-carboxylic acid tert. -butyl ester. F. 82-840.

Example 53 Analogously to Example 51, tert-butyl 2-diazo-3-oxo-4-methyl-4- (4-methyl) -2-oxo-azetidin-4-yl) pentanoate is obtained Obtainable from 4- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -4-methyl-3-oxo-pentanoic acid tert-butyl ester (Example 43) via 2-diazo-3-oxo-4-methyl-4- (1-tert.-butyldimethylsilyl-4omethyl-2-oxoazetidine 4-yl) pentanoic acid tert. -butylester7 with RH2 (OCOCCH3) 4 the 4,4,5-trimethyl-3,7-dioxo-1-azabicyclo- (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Example 54 Analogously to Example 51, tert-butyl 2-diazo-3-oxo-4- (2-oso-azetidin-4-yl) pentanoate is obtained [obtainable from 4- (1-tert-butyldimethylsilyl-2-oxo-azetidin-4-yl) -3-oxo-pentanoic acid tert-butyl ester (Example 44) via 2-diazo-3-oxo-4- (1-tert.-butyldimethylsilyl-2-oXoazetidin-4-yl) pentanoic acid tert. -butylester7 with Rh2 (OOCCH3) 4 the 4-methyl-3,7-dioxo-1-azabicyclo (3,2,0) -heptane-2-carboxylic acid tert-butyl ester.

Example 55 Analogously to Example 51, 2-diazo-3-oxo-4- (4-methyl-2-oxo-azetidin-4-yl) -butanoic acid tert. butyl ester [obtainable from 4- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) - 3-oxo-butanoic acid tert. butyl ester (Example 45) via 2-diazo-3-oxo-4 - (l-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -3-oxo-butanoic acid tert-butyl ester ; 76-78 °; Cleavage of the tert-butyl-dimethylsilyl group with KF / 18-Krone-67 with Rh2 (OOCCH3) 4 the 5-methyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Example 56 a) Analogously to Example 51, 2-diazo-3-oxo-4- (4-methyl-2-oxo-azetidin-4-yl) -butane-xurebenzyl ester is obtained / Obtainable by reacting (l-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -acetic acid (Example 45) with carbonyldiimidazole in THF to (not isolated) imidazolide, Reaction with the Mg salt of the malonic acid momo-benzyl ester to give 3-oxo-4- (1-tert.-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) -butanoic acid benzyl ester, Cleavage of the amino protective group with tetrabutylammonium fluoride in TUF with formation of 3-oxo-4- (4-methyl-2-oxo-azetidin-4-yl) -butanoic acid benzyl ester and reaction with 4-carboxybenzenesulfonyl azide / triethylamine in acetonitrile at 0 to 20 °] with Rh2 (OOCH3) 4 the 5-methyl-3,7-dioxo-1-azabicyclo (3,2,0) -heptane-2-carboxylic acid benzyl ester.

b) Hydrogenation of this ester analogously to Example 6b) gives 5-M thyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Examples 57 to 60 Analogously to Example 51 are obtained from the corresponding 2-Diazo-3-oxo-4- (4-methyl-2-oxo-azetidin-4-yl) pentanoic acid esters with Rh2 (OOCCH3) 4: 57. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid pivaloylamidomethyl ester.

58. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid ethoxycarbonyloxymethyl ester.

59. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid phthalidyl ester.

60. 4,5-Dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid benzhydryl ester.

Example 61 a) A solution of 1.3 g (3.4 mmol) of 2,3-dioxo-4- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) is stirred -pentanoic acid tert-butyl ester L-F. 102-1040; obtainable by introducing ozone into a solution for half an hour of [2- (1-tert-butyldimethylsilyl-4-methyl-2-oxo-azetidin-4-yl) propionyl] -tert-butoxycarbonylmethylene-dimethylsulfuran (cf. Example 41c) in CH2C12 at -30 ° and addition of dimethyl sulfide7 and 1.1 g (3.5m0ol) tetrabutylammonium fluoride trihydrate in 20 ml THF for one hour at 200, evaporates (the intermediate 2,3-dioxo-4- (4-methyl-2-oxoazetidin-4-yl) pentanoic acid tert-butyl ester is not isolated) work on as usual and obtain 2-hydroxy-4,5-dimethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

cyclohexylisopropylamide (made from 3.1 g cyclohexylisopropylamine and 13.8 ml of butyl Li (15%, 1.6 molar) solution in THF) in 70 ml of THF, gives way 40 minutes add 2.57 ml of acetaldehyde, stir for a further 15 minutes and acidify with 2N HC1 up to pH 3.5. Customary work-up (ethyl acetate) gives 2-tert. g Butyl-dimethylsilyl-3- (1-hydroxyethyl) -4-methyl-2-oxo-azetidin-4-yl] -propionic acid benzyl ester.

ab) Treating this ester with tetrabutylammonium fluoride provides 2- [3- (1-Hydroxycarbonylethyl) -4-methyl-2-oxo-azetidin-4-y17-propionic acid benzyl ester.

ac) The following reaction with tert.-butyl bronacetate leads to 2- [1-tert-butoxycarbonylmethyl-3- (1-hydroxyethyl) -4-methyl-2-oxo-azetidin-4-yl7-propionic acid benzyl ester.

ad) A solution of 4.05 g of the above ester is added 60 ml of ether with a solution of 1.6 g of tert-butyldimethylchlorosilane in 20 ml of ether, a solution of 1.2 g is added dropwise with ice cooling, exclusion of moisture and stirring Triethylamine in 12 ml of ether is added and the mixture is stirred at 20 ° overnight. After that it will be several times washed with saturated NaCl solution, dried and evaporated. The received crude 2- [1-tert-butoxycarbonylmethyl-3- (1-tert-butyl-dimethylsilyloxyethyl) -4-methyl-2-oxo-azetidin-4-yl] propionic acid benzyl ester is hydrogenolyzed analogously to Example lae) to give free propionic acid, which is esterified with N-hydroxysuccinimide analogously to Example laaf).

ae) The N-- (1-tert-butoxycarbonylmethyl-3- (1-tert-butyl-dimethylsilyloxy-ethyl) -4-methyl-2-oxo-azetidin-4-yl) propionyloxy] succinamide obtained is cyclized analogously to Example la).

b) Analogously to example lb) one obtains from the ester prepared according to a) 4,5-dimethyl-6- (1-hydroxyethyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Examples 72-75 From those given in Examples 42-45 Starting materials are 4,4-dimethyl-, 4,4,5-trimethyl-, 4-methyl- and 5-methyl-6- (1-tert-butyl-dimethylsilyloxyethyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester and obtained therefrom analogously to Example 71: 72a) 4,4-dimethyl-6- (1-hydroxyethyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 4,4-Dimethyl-6- (1-hydroxyethyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

73a) 4,4,5-trimethyl-6- (1-hydroxyethyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 4,4,5-trimethyl-6- (1-hydroxyethyl-3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

74a) 4-methyl-6- (1-hydroxyethyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carconic acid tert: butyl ester; b) 4-methyl-6- (1-hydroxyethyl) -3,7-dioxo-1-azabicyclo- (3,2,0) heptane-2-carboxylic acid.

75a) 5-methyl-6- (1-hydroxyethyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 5-methyl-6- (1-hydroxyethyl) -3,7-dloxo-1-azabicyclo- (3,2,0) heptane-2-carboxylic acid.

Examples 76 to 80 Analogous to Examples 71 to 75, but with benzaldehyde instead of acetaldehyde, the following is obtained: 76a) 4,5-dimethyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 4,5-Dimethyl-6- (α-hydroxybenzyl) -3,7-dioxo-lazabicyclo (3,2,0) heptane-2-carboxylic acid.

77a) 4,4-Dimethyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 4,4-Dimethyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

78a) 4,4,5-trimethyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 4,4,5-trimethyl-6- (rthydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

79a) 4-methyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 4-methyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

80a) 5-methyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester; b) 5-methyl-6- (α-hydroxybenzyl) -3,7-dioxo-1-azabicyclo (3,2,0) heptane-2-carboxylic acid.

Example 81 Analogously to Example 71a), 3-tert-butyldimethylsilyloxy-4,4-dimethyl-6- (1-hydroxyethyl) -7-oxo-1-azabicyclo (3,2,0) hept-2-ene is obtained 2-carboxylic acid tert-butyl ester /available by reaction of 4,4-dimethyl-3,7-dioxol-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester with tert-butyldimethylchlorosilane in the presence of 4-dimethylaminopyridine in THF at 20 ° and implementation of the 3-tert obtained. -Butyl-dimethylsilyloxy-4,4-dimethyl-7-oXo-1-azabicyclo (3,2,0) hept-2-en-2-carboxylic acid tert-butyl ester with lithium bis-trimethylsilylamide / acetaldehyde similar to Example 61aa)] with tetrabutylammonium fluoride trihydrate the 4,4-dimethyl-6- (1-hydroxyethyl) -3,7-dioxol-azabicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

Example 82 Analogously to Example 81, 3-tert-butyldimethylsilyloxy-4,4,5-trimethyl-6- (1-hydroxyethyl) -7-oxo-1-azabicycloe3,2,0) hept-2-en-2 is obtained -carboxylic acid tert-butyl ester the 4,4,5-trimethyl-6- (1-hydroxyethyl) -3,7-dioxo z ^ -bicyclo (3,2,0) heptane-2-carboxylic acid tert-butyl ester.

The following examples relate to pharmaceutical preparations, the compounds of the formula I or their physiologically acceptable salts contain: Example A: Tablets A mixture of 1 kg of 4,5-dimethyl-3,7-dioxo-1-azabicyclo- (3,2,0) heptane-2-carboxylic acid pivaloyloxymethyl ester, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is used compressed into tablets in the usual way, in such a way that each tablet contains 200 mg of active ingredient contains.

Example B: Dragees Analogously to Example A, tablets are pressed which then in the usual way with a coating of sucrose, potato starch, Talc, tragacanth and dye are coated.

Example C: Capsules 10 kg of the sodium salt of 4,5-dimethyl-3,7-dioxol-aza-bicyclo (3,2,0) heptane-2-carboxylic acid are filled usually in hard gelatin capsules, so that each capsule contains 500 mg of active ingredient.

Example D: Analysis A solution of 1 kg of the sodium salt of 4,5-dimethyl-3,7-dioxo-1-aza-bicyclo (3,2,0) heptane-2-carboxylic acid in 30 l of double-distilled water is sterile filtered, filled into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 5 mg of active ingredient.

Similarly, tablets, coated tablets, capsules or ampoules are available, the one or more of the other active ingredients of the formula I and / or their physiological contain harmless salts.

Claims (5)

Claims 1) ß-lactam compounds of the general formula I where R1, R2 and R3 can be identical or different and one of these radicals CH31 the other H or CH3, R4 H, C1, Br or OH, R5 H, alkyl with 1-4 C atoms, benzyl, nitrobenzyl, methoxybenzyl or a easily hydrolyzable radical and R6 denotes H, alkyl with 1-6 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, benzyl or α-hydroxybenzyl, as well as their physiologically harmless salts. 2. a) 4-Methyl-3-, 7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. b) 4,4-Dimethyl-3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. c) 4,5-dimethyl-3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. d) 4,4,5-trimethyl-3,7-dioxo-1-azabicyclo / 3 heptane-2-carboxylic acid. e) 5-methyl-3,7-dioxo-1-azabicyclo [3.2.0] heptane-2-carboxylic acid. 3. Process for the preparation of B-lactam compounds of the general formula I. where R1, R2 and R3 can be the same or different and one of these radicals is CH3, the others are H or CH3, and H or CH3, R4 is H, C1, Br or OH, R5 is H, alkyl with 1-4 carbon atoms, benzyl , Nitrobenzyl, methoxybenzyl or an easily hydrolyzable radical and R6 signify H, alkyl with 1-6 carbon atoms, hydroxyalkyl with 1-4 carbon atoms, benzyl or o (rhydroxybenzyl, as well as their physiologically harmless salts, characterized in that one a ß-lactam of the general formula IIa or IIb wherein X is 0, N2 or (H, Hal) and Hal is Cl, Br or J and R1 to R6 have the meanings given, or one of its functional derivatives is treated with a cyclizing agent or that one otherwise corresponds to the formula I, in which However, one or more oxo and / or hydroxyl groups are present in protected form, these oxo and / or hydroxyl groups are set free by solvolysis and that, if appropriate, a hydroxyl compound of the formula I (R4 = OH) obtained is converted into the corresponding one by treatment with a halogenating agent Chlorine or bromine compound of the formula I (R4 = Cl or Br) and / or the halogen atom is removed from a obtained chlorine or bromine compound of the formula I (R4 = C1 or Br) by treatment with a reducing agent (one or more stages) and / or an ester of the formula I obtained (in which R5 is different from H) cleaves and / or a carboxylic acid of the formula I (R5 = H) obtained is esterified or by treatment with a Converts base into one of their physiologically harmless salts. 4. Process for the production of pharmaceutical preparations, thereby characterized in that a compound of the formula I and / or one of its physiologically in salt of concern together with at least one solid, liquid or semi-liquid Carrier or auxiliary substance and optionally in combination with one or more brings further active ingredient (s) into a suitable dosage form. 5. Pharmaceutical preparation, characterized by a content on at least one compound of the formula I and / or one of its physiologically acceptable compounds Salts.