DE2747350A1 - CLAVULANIC ACID ANALOGS, THEIR SALT AND ESTERS AND PROCESS FOR THEIR PRODUCTION - Google Patents

Description

2 7 A 7 3 -I,

Dr. F. Zumstein Sr. - Dr. E. Assmann - Dr. R. Koenigsberger Dipl.-Phys. R. Holzbauer - Dipl.-Ing. F. Klingseisen - Dr. F. Zumstein jun.

PATENT LAWYERS BOOO München 2 Brauhausstr _e 3e 4 Telefon Semmel Nr 22 5341 Telegramme Zumpat Telex 529Θ79

Antib. 37
14/20

GLAXO LABORATOIRES LIMITED, Greenford, Middlesex, England

Clavulanic acid analogs, their salts and esters and processes for their preparation.

The invention relates to new antibiotics and β-lactamase inhibitors and a method for their production.

In the DT-OS 2 6O4 697 the isolation of the clavulanic acid and of their salts in pure form from fermentations of Streptomyces clavuligerus.

The present invention relates to analogs of clavulanic acid and its salts and esters which have a carbon bond Contain substituents in place of their hydroxyl group. These are, as will be described in more detail below, than Antibiotics or as ß-lactamase inhibitors can be used.

The compounds are referred to herein with reference to "Clavam". This designation became the parent heterocycle of formula A

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(Λ)

ORIGINAL INSPECTED

8th
- * '- 27A735Ü

in analogy to the term "Cepham" which is used in naming the cephalosporin compounds in J.Amer.Chem.Soc., 1962, 84, 3400.

Accordingly, compounds of the formula I

^H -0. CH ₁ -R ¹

created, wherein R

represents a carboxyl or esterified carboxyl group and R the remainder of a carbon nucleophile or product ,.

, esterified thereof, formed by cleavage of any ^ present here Carboxyl groups, is, together with their salts, when a Carboxyl group is present.

The remainder of the carbon nucleophile is most desirably of Formula II

wherein X and Y, which can be the same or different, are groups mean that are able to form a stabilized carbanion, e.g. electron-withdrawing groups, and Z is an alkyl, Means alkenyl, alkynyl, cycloalkyl, aralkyl or aryl group or a hydrogen atom.

Thus, suitable groups capable of:

to stabilize or bring about a negative charge,

2 esterified carboxyl or cyano groups or acyl groups R CO-,

2 wherein R is an alkyl, cycloalkyl, aralkyl or aryl group, which may optionally be substituted, may mean.

Suitable alkyl, alkenyl or alkynyl groups in the

2 radicals Z or R can be straight-chain or branched, unsubstituted or substituted groups with 1 to 8 carbon atoms, for example methyl, ethyl, propyl or isopropyl or butyl, sec-butyl, tert-butyl -, allyl or

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ORlGiNAL INSPECTED

Propargyl group, where desired substituents are for example Alkoxy e.g. methoxy, halogen e.g. fluorine, cyano; Acyloxy, e.g., alkanoyloxy, such as acetoxy; and alkoxycarbonyl, e.g., ethoxycarbonyl are.

Suitable cycloalkyl groups in Z or R can be 5 to 8, preferably have 3 to 6 carbon atoms, e.g. Cyclopentyl or cyclohexyl.

Suitable aryl groups in Z or R can have up to 12 carbon atoms e.g. a phenyl or substituted phenyl group, suitable substituents being halogen, e.g. chlorine, Nitro, cyano; Alkyl, e.g., methyl; or alkoxy, e.g., methoxy.

Suitable aralkyl groups in Z or R can have up to 10 carbon atoms have and are in particular arylmethyl groups, e.g. a benzyl group or a phenethyl group, with suitable Ring substituents are those given above for the aryl groups are.

In general, it is preferred that any alkyl, alkoxy, alkanoyloxy and alkoxycarbonyl groups present in the group R Has 1 to 6 carbon atoms.

Preferred residues of the carbon nucleophiles of the formula II are those who differ from ß-diketones or ß-ketoesters derive, i.e. those where both X and Y are

Acyl group R CO, as defined above> mean or those wherein one of the radicals X and Y is an acyl group R CO, as defined above, or an esterified carboxyl group means.

It is preferred that Z represents a hydrogen atom. Means

X or Y is an acyl group R CO or an esterified carboxyl group as described above, so it is preferred that

R or the hydrocarbon portion of the esterified carboxyl group is a C ₁ _ ^ - alky group is!.

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Compounds in which the group -CXYZ is a pentan-2,4-dion-3-yl group are particularly preferred.

It will be understood that when the group -CXYZ contains an esterified carboxyl group, the product undergoes cleavage , R in the product according to the invention contains one or more carboxyl groups which can be present in the salt form.

The compounds of formula I wherein R represents an esterified carboxyl group can generally be represented as compounds of formula I wherein R represents a group COOR- ⁵ , wherein OR- ^ represents an organic group suitably different from an alcohol (aliphatic or araliphatic), a phenol or a stannanol. Such alcohol, phenol or stannanol used to esterify the carboxyl group preferably contain no more than 24 carbon atoms.

Thus, Fr can mean: a straight-chain or branched, unsubstituted or substituted alkyl or alkenyl group with preferably 1 to 8 carbon atoms, for example a methyl, ethyl, propyl or isopropyl, butyl, sec-butyl, tert.- Butyl or allyl group, where desired substituents are, for example, alkoxy, such as methoxy; Halogen, ie fluorine, chlorine, bromine or iodine; Cyano; Acyloxy, for example alkanoyloxy such as acetoxy or pivaloyloxy or alkoxycarbonyloxy, for example ethoxycarbonyloxy; Acyl, for example p-bromobenzoyl, and alkoxycarbonyl, for example ethoxycarbonyl; an aralkyl group with up to 20 carbon atoms, in particular an arylmethyl group, for example a benzyl or substituted benzyl group, where suitable substituents are either halogen, for example chlorine; Nitro, for example o- or p-nitro; Cyano; Alkoxy, for example p-methoxy or alkyl, for example p-methyl groups; a diphenylmethyl or triphenylmethyl group or a fur-2-ylmethyl, thien-2-ylmethyl or pyrid-4-ylmethyl group, where the heterocyclic groups thereof can also be substituted, for example, by a C ₁ j -alkyl group, preferably methyl;

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an aryl group of up to 12 carbon atoms, e.g. Phenyl or substituted phenyl, suitable substituents being either halogen, e.g., chlorine; Nitro, e.g. o- or p-nitro; Cyano; Are alkoxy, e.g., p-methoxy, or alkyl, e.g., p-methyl groups;

a cycloalkyl group having not more than 12 carbon atoms such as adamantyl;

a heterocyclic group with no more than 12 carbon atoms, wherein the heteroatom is, for example, oxygen, as in the tetrahydropyranyl or phthalidyl group; or a stannyl group having up to 24 carbon atoms, e.g., a stannyl group having three substituents that are the same or different can be selected from alkyl, alkenyl, aryl, aralkyl, cycloalkyl, alkoxy, aryloxy or aralkoxy groups. Such groups include methyl, ethyl, propyl, η-butyl, phenyl and benzyl groups.

Esterified carboxyl groups in the grouping of the formula II

4 4

can also be represented by -COOR, where R is like

is defined for R ^ with the exception of stannyl.

In some cases, the compounds of formula I exist in dlastereomeric forms and the present invention includes them in separate form or in combination. It is obvious that some of the compounds of the formula I are capable of keto-enol tautomerism and in the individual Forms or mixtures thereof.

The salts according to the invention include salts with inorganic ones Bases such as alkali metal salts, e.g. sodium, potassium and lithium salts, Alkaline earth metal salts, e.g. calcium and magnesium salts and ammonium salts as well as salts with organic bases, e.g. Amine salts. If there is more than one acidic group, mono-, di- or even tri-salts are possible.

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For use in pharmaceutical compositions, the salts should be physiologically acceptable.

The compounds according to the invention generally show β-lactamase-inhibiting activity and can be used in the protection of ß-lactam antibiotics that cause ß-lactamase hydrolysis accessible, e.g. from antibiotics such as ampicillin or cephalexin.

The compounds according to the invention also generally show antibiotic activity against Gram-positive organisms and in some cases against Gram-negative Organisms. If the 3-carboxylate ester is metabolically labile, then so the parent acid is formed in vivo. Examples of such esters include the acyloxymethyl esters, e.g. the acetoxymethyl and pivaloyloxymethyl ester and α-alkoxycarbonyloxyalkyl ester such as 1 -A'thoxycarbonyloxyethyl ester.

Will the 3-carboxyl ester group quickly, for example by The esters in particular are hydrolysis or reduction without any noticeable degradation of the remaining part of the molecule can be used as carboxyl-protected derivatives of the parent acids. Certain 3-carboxylate esters can be either at the purification or the characterization of the invention Acids or as carboxyl-protected intermediates for use in the manufacture of other derivatives.

Esters, which work particularly well as carboxyl-protected intermediates Suitable and primarily useful in this context include the aryl methyl esters such as those below are described in more detail, in particular the benzyl, p-nitrobenzyl, benzhydryl and trityl esters and stannyl, e.g. tri-n-butyl stannyl ester.

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The compounds of the present invention for which antibiotic activity was demonstrated were against a range of Gram-positive microorganisms, for example against strains of Staphylococcus aureus and also against strains active by certain Gram-negative organisms such as Haemophilus influenzae. Certain compounds, especially those wherein R in formula II is a pentan-2,4-dion-3-yl group or a 1-carboxyl-propan-2-on-1-yl group, and R represents a carboxyl group in the salt form, have been found against Gram-negative organisms including strains from Escherichia coil, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae, Klebsiella aerogenes, Proteus «Irabllis, Proteus morganii and Proteus vulgaris active.

The new acids and their salts and esters are opposed to the action of ß-lactamases caused by Gram-positive Organisms are formed, for example against those formed by Staphylococcus aureus, and against fi-lactamases produced by gram-negative organisms, stable.

As stated above, the new acids and their salts and esters in general also have the ability to ß-lactamase enzymes, for example, those produced by gram-positive organisms, such as those produced by strains produced by Staphylococcus aureus, and the enzymes produced by Gram-negative bacteria such as strains from Proteus mirabilis, Escherichia coil, Neisseria gonorrhoeae, Klebsiella aerogenes, Salmonella typhimurium and Haemophilus influenzae and are therefore in combination with ß-lactam antibiotics, such as penicillin antibiotics, such as Ampicillin and amoxycillin, can be used.

The compounds according to the invention including those compounds of the formula I in which R is a carboxyl group (in the Salt form) and R is a pentan-2,4-dion-5-yl group, 1-ethoxycarbonyl-propaTi-2-one-i -yl group, 1 -benzoyl-1 -, ethoxycarbonyl-methyl group or i-methoxycarbonylpropan-2-on-i-yl-

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Group means also, as indicated by studies on the Mouse has been shown to be absorbed when administered orally. These compounds are of interest for use in conjunction with both injectable and orally absorbable ß-lactam antibiotics that target ß-lactamases Gram-positive and / or Gram-negative organisms are sensitive.

The new antibiotic acids and their salts and esters can be used alone or in conjunction with a ß-lactam antibiotic, preferably a broad spectrum β-lactam antibiotic, which is conventionally administered orally or parenterally Type can be. The use of the antibiotic acids and their salts is particularly preferred.

Examples of broad spectrum beta-lactam orally absorbed antibiotics include cephalexin, cephaloglycine, ampicillin and amoxycillin and their orally absorbed esters, e.g. acyloxymethyl and a Phthalidyl esters and the orally absorbed esters of carbenicillin and ticarcillin and mecillinam, e.g. the indanyl, phenyl and Pivaloyloxymethyl ester. The broad spectrum ß-lactam antibiotics that are not absorbed orally include carbenicillin, Ticarcillin, Mecillinam, Cephalotin, Cephaloridin, Cefazolin, Cephacetril and Cephaplrin. Examples of narrow-band ß-lactam antibiotics are penicillin G and penicillin V.

The combinations of the compounds according to the invention with, for example, ampicillin are generally synergistic Activity against β-lactamase producing strains of Staphylococcus aureus. In general, the connections show in combination with ß-lactam-sensitive ß-lactam antibiotics, e.g. penicillins or cephalosporins, compared to ß-lactamase-producing strains of Klebsieila aerogenes, Proteus mirabilis, Proteus rettgeri and Proteus vulgaris synergistic activity.

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According to a further feature of the invention, pharmaceutical compositions (including veterinary Compositions) created, the at least one acid, a physiologically acceptable salt or a metabolically contain labile ester of the invention. In view of the protective effect described above, the compositions can advantageously contain other ß-lactam antibiotics. The compositions usually also contain one pharmaceutical (including veterinary) carriers or excipients.

The compositions of the invention include those in one suitable for oral or parenteral use Shape.

The compositions can, for example, in the form of powders, tablets, capsules, troches, solutions and syrups, which are suitable for oral administration are present and can e.g. starch, lactose, talc, magnesium stearate, gelatin, contain distilled water and suspending, dispersing, emulsifying, flavoring and coloring agents.

The compounds can further be formulated as rectal compositions such as suppositories or retention enemas.

The compounds of the invention can be formulated for administration by injection. The connections can thus be formulated into ampoules for reconstitution prior to use.

The active compounds according to the invention are generally administered to humans with a total daily dose of 50 mg to 20 g, administered preferably from 100 mg to 10 g, which can be divided into doses administered one to four times per day will.

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When the composition contains another β-lactam antibiotic, the total amount of β-lactam antibiotic is desirably 100 mg to 20 g, which can be administered in divided doses 1 to 4 times a day. The dose units are generally 12.5 mg to 5 g, preferably 50 mg to 1 g of the active compound of the invention when used alone and 25 mg to 5 g, preferably 100 mg to 1 g Total ß-lactam antibiotic when a compound according to the invention and a further ß-lactam antibiotic are present.

In general, the ratio by weight of the compound according to the invention to the β-lactam antibiotic to be protected is 10: 1 to 1:10, more preferably 5: 1 to 1: 5 and especially 2: 1 to 1: 2. The active compounds of the invention can be used in the treatment of a variety of diseases in humans and animals, such as caused by pathogenic bacteria, such as in the treatment of infections in the respiratory system or in the urinary system.

The compounds of the invention can be prepared by any suitable method. Thus relates to an item the invention a process for the preparation of a compound of the formula I, in which a compound of the formula III

(Ill)

where R is an esterified carboxyl group and E is a rapidly or easily exchangeable substituent, or a compound of formula IV

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2 7 A 7 3 ο ύ

(IV)

in which R denotes an esterified carboxyl group ^{, is reacted with a compound of the formula R 1} H in the presence of a base or with a salt of the compound RH in which R denotes the radical of a carbon nucleophile as defined above. The cation in this salt can be, for example, a monovalent metal ion or an ammonium ion. Suitable cations are alkali metal, tetraalkylammonium or thallium or thallo ions. Thallosalts are particularly preferred when the starting material is a compound of formula III.

The rapidly exchangeable substituent E can, for example, be a halogen atom (for example chlorine, bromine or iodine) or an aromatic or aliphatic sulfonyloxy group which contains, for example, 1 to 20 carbon atoms. The aliphatic or aromatic group of such a sulfonyloxy group can be, for example, an alkyl (e.g. C ₁ q) group which can be substituted by a halogen atom, e.g. fluorine or chlorine, or an aryl (e.g. C ^^ J group, the alkyl , for example methyl, alkoxy, for example methoxy or halogen, for example bromine, substituents. Preferred sulfonyloxy groups include methanesulfonyloxy, tosyloxy or phenylsulfonyloxy. The substituent E is preferably chlorine or bromine.

The reaction with the compound of formula III is desirably is carried out in an aprotic organic solvent at or below room temperature, for example at -80 ° C to +40 ⁰ C. Ether solvents such as 1,2-dimethoxyethane or tetrahydrofuran have proven to be suitable. Other suitable solvents include amides such as dimethylformamide or hexamethylphosphoramide, sulfoxide, for example dimethyl sulfoxide and sulfones, for example sulfolane. If tetraalkylammonium salts are used, halogenated hydrocarbon solvents such as methylene chloride may be suitable.

809817/0894

ORIGINAL INSPECTED

In some solvents, especially in dipolar aprotic solvents like dimethyl sulfoxide and when Z is a Means hydrogen atom, further alkylation can take place to some extent to give a material which contains two clavulanic acid residues or their derivative attached to the remainder of the carbon nucleophile.

The reaction of a compound of the formula III or the diene compound of formula IV with the compound of formula R H can be used in the presence of an inorganic base a crown ether in a suitable aprotic liquid medium, e.g. in a halogenated hydrocarbon solvent, take place. This is a preferred method when the starting material is a diene of Formula IV.

A crown ether is a macrocyclic polyether, such as a number of ethyleneoxy units that are formed to form a Rings are linked, the inner diameter of which is approximately that of a special metal ion, e.g. of sodium or potassium, that is used in the implementation. In general, 6 ethyleneoxy units (18-crown-6) are suitable for a Take up potassium ion, while 5 ethyleneoxy units (i5-crown-5) are suitable for sodium.

Some ethylene groups in such crown ethers can by other divalent units such as o-phenylene or 1,2-cyclohexylene units be replaced.

The inorganic base can, for example, be an alkali or alkaline earth metal hydroxide, carbonate or bicarbonate, e.g. potassium carbonate, be.

The reaction may be in the temperature range from -15 to + 5O ⁰ C, preferably from 0 to + 35 ° C.

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Is one or more of the reactants, for example the base in the solvent in which the reaction takes place, insoluble, the crown ether can transport the reactant or reactants from the solid phase into the effect liquid phase or between two liquid phases *.

A preferred single liquid phase system is methylene chloride with potassium carbonate / "! 8-crown-6.

The diene compounds of the formula IV can be prepared from compounds of the formula III by treatment with a tertiary amine such as Triethylarain can be prepared, a compound of the formula IV being obtained.

The compounds of the formula III in which E is a halogen atom, can, as described in DT-OS 2,657,081, prepared will. Compounds of the formula III in which E is a sulfonyloxy group can, as described in DT-OS 2 616 087, getting produced.

In the above reactions, if the starting product contains an ester group in the group R and / or in the group -CXYZ and the corresponding acid or the corresponding salt it is necessary to subject the compound to ester cleavage. For this purpose, easily cleavable esters are, for example Aryl methyl esters, which can be cleaved by reduction, e.g. by hydrogenative cleavage, are preferred. The split one Aryl methyl ester, e.g., a p-nitrobenzyl ester, can be obtained by hydrative cleavage, for example using a Metal catalyst, e.g. a noble metal such as platinum, palladium or rhodium. The catalyst can be supported on a carrier, E.g. on activated carbon or kieselguhr. A p-nitrobenzyl group can be formed by reducing the nitro group (e.g. using a dissolving metal reducing agent such as zinc in acetic acid or zinc in aqueous tetrahydrofuran or Acetone, which is controlled by adding aqueous hydrochloric acid, for example in the pH range from 3 to 6, preferably 4.0 to 5.5 will; Aluminum amalgam in moist ether, e.g., tetrahydrofuran;

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Iron and ammonium chloride in aqueous ether, e.g. tetrahydrofuran) be removed, followed by hydrolysis either under the reducing conditions or by subsequent treatment with acid. Alternatively, a stannyl ester can be produced by very mild solvolysis, for example by reaction with Water, alcohols, phenols or carboxylic acids, e.g. acetic acid.

If it is desired to form a salt of the compound of formula I, it can initially be in solution in a suitable organic Solvent formed acid with a suitable base, preferably under conditions that favor the precipitation of the salt, implemented. In the formation of the alkali metal salts, for example the sodium or potassium salts, a Alkanoate is a preferred base, such as a 2-ethylhexanoate. The salts can either be on the carboxyl group attached to the ring or on any of the carboxyl groups present in R. can be formed.

If an ester of the formula I is desired which is different from the ester initially formed, the ester group can be added to Methods as described above can be removed and the carboxylic acid product by those described below Methods to be recovered.

The esters of the formula I can be prepared from the corresponding acids or their reactive derivatives by reaction with an alcohol, Phenol or stannanol or a reactive derivative thereof to form the desired ester. The implementation is desirably carried out under mild conditions to prevent disruption of the bicyclic core. The usage neutral or mild acidic or basic conditions at temperatures of e.g. -70 to + 35 ° C is preferred. The alkyl, alkoxyalkyl and simple aralkyl esters can by reacting an acid of the formula I with the appropriate diazoalkane or diazoaralkane, e.g., diazomethane or diphenyldiazomethane. The implementation is generally in an ether, ester or halocarbon solvent, e.g.

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2 7 4 7 3 5

Diethyl ether, ethyl acetate or dichloromethane carried out. In general, reduced temperatures, for example from -15 to +15 ⁰ C, more preferably about room temperature, preferably.

The ester derived from alcohols can be obtained by reacting a reactive derivative of the alcohol, for example a halide such as chloride, bromide or iodide or a hydrocarbon sulfonyl derivative such as a mesyl or Tosyl ester with a salt of an acid of the formula I, e.g. an alkali or alkaline earth metal salt such as a lithium, Sodium, potassium, calcium or barium salt or an amine salt, e.g. triethylammonium salt. These Reaction is preferably carried out in a substituted sulfoxide or amide solvent, e.g., dimethyl sulfoxide, dimethylformamide or hexamethylphosphoramide.

Stannyl esters can suitably by reacting a Carboxylic acid of the formula I or a salt thereof can be formed with reactive tetravalent tin groups. Trialkyl tin oxides are preferred for the synthesis of tin compounds in view of their accessibility and low toxicity.

In the preparation of the compounds of the formula III from esters of clavulanic acid, some of the corresponding E isomers formed and, if desired, isolated, these Ε-isomers using those given above Methods give the Ε-isomers of the compounds of formula I.

The carbanion salts that are used in the process according to the invention are usable, have been described in numerous literature references and the thallo salts of ethyl acetoacetate, acetylacetone and ethyl benzoylacetate are from E.C. Taylor, G.H. Hawks and A. Mckillop, J. Amer. Chem. Soc. (1968), 20, 2421 known. The thallo salts of p-nitrobenzyl acetoacetate and methyl

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acetoacetate were prepared following the procedure described in the reference above.

The following examples illustrate the invention in more detail.

example 1

4-nitrobenzyl (3R, 5R, i 'Z) -2- (3-acetyl-4-oxopentylidene) clavam-j? -Carboxylate

2.7 g of thalloacetylacetonate were added to a suspension of 1.17 g of 4-nitrobenzyl (3R, 5R, Z) -2- (2-chloroethylidene) clavam-3-carboxylate in 25 ml dirnethoxyethane and stirred the mixture 2 hours at room temperature. The reaction mixture was centrifuged and the insoluble thallo salts discarded. the organic liquids were evaporated to dryness and the residue dissolved in 10 ml of ethyl acetate. The solution was diluted (1: 1) with 50 ml of ethyl acetate - petroleum ether (boiling point 60-80 ° C.) and the solid which had separated out was filtered off removed by Kieseiguhr. The filtrate was evaporated to dryness and the residue on preparative silica gel plates using ethyl acetate - petroleum ether (b.p. 60 - 80 C) {1M) Chromatographed as eluant to 0.85 g To give title esters in the form of an oil.

[oc] _D + 19 ° (c 1.0; CHCl), 0 _max (CHBr ₃ ) 1794 (β-lactam), 1750 (ester), 1728 (acetyl), 1694 (enol ether), 1526 and 1J49 cm " ¹ (NO ₂ ), * t (CDCl,) for the predominant (keto) -tautomer 1.76 and 2.50 (doublets, J = 8 Hz, aromatic protons), 4.32 (s, C-5 H), 4.75 (s, -CH ₂ Ar), 4.95 (s, CJ H), 5.44 (t, J = 7 Hz, = CH-), 6.32 (t, J = 7 Hz, C -3'H) 6.48 and 6.94 (doublets, J = 16 Hz, C-6 protons), 7.38 (t, J = 7 Hz, C-2 'protons) and 7.85 ( s, -CH,); resonances due to the lower proportion of the (enol) tautomer were found at 6.98 (d, J = 8 Hz, C-2 ¹ protons) and 7.94 (s, = C.OH .CH,) observed.

Example 2

4-nitrobenzyl (3R, 5R.i'Z.VRS) -2- (3-ethoxycarbonyl-4-oxopentylidene) clavam-3-carboxylate

2.66 g of thallium (I) salt of ethyl acetoacetate * (8 mmol) were added to a suspension of 3.17 g of 4-nitrobenzyl- (JR, 5R, Z) -

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2- (2-chloroethylidene) clavam-3-carboxylate in 25 ml of dimethoxyethane and the mixture was stirred for 1 hour at room temperature.
The reaction mixture was centrifuged to remove insoluble thallium salts. The organic ones were steamed
Liquids to dryness and redissolved the residue in 5 ml of ethyl acetate. The solution was diluted (1: 1) with 50 ml of ethyl acetate-petroleum ether (boiling point 40-60 ° C.) and the precipitated solid was discarded. The organic solution was evaporated to dryness and the residue was chromatographed on preparative silica gel plates, using ethyl acetate-petroleum ether (bp.
40-60 ° C) (1: 1) used as eluant to obtain 0.61 g of the title ester as an oil.

* .. «" (CHBr,) 1800 (ß-lactam), 1746 (ester), 1710 (acetyl),
'max j λ

1528 and 1348 cm "(NO ₂ ), t (CDCl ₅ ) 1.75 and 2.48 (doublets,

J = 8.5 Hz, aromatic protons), 4.33 (d, J = 2 Hz, C-5 H), 4.73 (s, -CH ₂ Ar), 4.95 (s, C-3 H ), 5.38 (t, J = 7 Hz, -CH-), 5.83

(q, J = 7 Hz -COOCH ₂ CH ₅ ), 6.50 and 6.93 (dd, J = 2 and if Hz; and d, J = 17 Hz, C-6 protons), 6.52 ( m, C-3 ¹ H), 7 * 37 (t, J = 7 Hz,

C-2 ¹ protons), 7.80 (s, -COCH ₅ ) and 8.75 (q, J = 7 Hz; -COOCH ₂ CH ₅ ).

The title ester was also under similar conditions from the Sodium salt made from ethyl acetoacetate. The spectral properties of the chromatographed product were the same similar in the previous example.

The suitable potassium salts were converted in an analogous manner

manufactured:

Example 3

4-Ni trobenzyl (3R, 5R, 1'Z, 3'RS) -2- (3-benzoyl-3-ethoxycarbonylpropylidene) clavam-3-carboxylate

In a yield of 31 % \) _Μον (CHBr.,) 1792 (ß-lactam), 1732

max Pj ι

(Ester) 1689 (enol ether), 1522 and 1344 cm (NO ₂ ) Ii (CDCl ₅ ) 1.80, 2.06 and 2.50 (multiplets, aromatic protons),
4.39 (dd, C-5 H), 4.80 (s, -CH ₃ Ar), 4.97 (s, C-3 H), 5.29
(t, J = 7 Hz, -CH-), 5.63 (t, J = 7 Hz, C-3'H), 5.97 (q, J = 7 Hz, -COOCH ₂ CH ₅ ), 6 , 54 and 7.01 (multiplets, C-6 protons), 7.21 (t, J = 7 Hz, C-2 ¹ protons) and 8.88 (t, J = 7 Hz, -COOCH ₂ CH ₅ ).

some peaks were due to the presence of two diastereo-

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meren doubled in terms of C-3 ^1.

Example 4

4-Nitrobenzyl- (3R, 5R, 1'Z, 3'RS) -2- (3-methoxycarbonyl-4- oxopentylidene) -clavam-3-carboxylate In 14% yield) (CHBr,) 18OO (β-lactam ), 1748 (Ester),

ΓΏ3.Χ j

1714 (acetyl), 1698 (enol ether), 1522 and 1346 (nitro), t (CDCl,) 1.78 and 2.51 (aromatic protons), 4.35 (d, J = 2 Hz, C-5 H) , 4.76 (s, -CH ₂ Ar) 4.97 (s, C-3 H), 5.40 (t, J = 7 Hz = CH-), 6.30 (s, -OCH), 6 , 51 (m, Cy H), 6.52 and 6.96 (dd, J = 2 and 17 Hz and d, J = 17 Hz, C-6 protons), 7.39 (t, J = 7 Hz , C-2 'protons) and 7.80 (s, -COCH,).

Example 5 4-nitrobenzyl- (3R, 5R, i'Z, 3 ^f RS) -2-f3- (4-nitrobenz yloxy carbonyl) -4-oxopentylidene-1-clavam-3-carboxylate In 10% yield 5 (CHBr ,) 18OO (ß-lactam), 175O (ester),

HIcLX 0λ

1716 (acetyl), 1520 and 1 ^ 46 cm (nitro), χ (CDCl,) 1.79 and 2.52 (aromatic protons), 4.35 (d, J = 2 Hz, C-5 protons), 4/73 and 4.75 (singlets, -CH ₃ Ar), 4.95 (s, C-3 proton), 5.38 (t, J = 7 Hz, = CH-), 6.38 (m , C-3 ¹ proton), 6.48 and 6.95 (dd, J = 2 and 17 Hz and d, J = 17 Hz, C-6 protons), 7.32 (t, J = 7 Hz , C-2 ¹ protons) and 7.80 (s, -COCH,).

Example 6

Sodium (3R ₁ 5R, 1 ¹ Z, 3 ¹ RS) -2- (3-ethoxycarbonyl-4-o.xopentyldene) clavam-3-carboxylate

0.65 g of palladium on activated carbon (10 %) were added to a solution of 0.67 g of 4-nitrobenzyl- (3R, 5R, 1'Z, 3'RS) -2- (3-ethoxycarbonyl-4-oxopentylidene) -clavam-3-carboxylate in styl acetate and shaken the mixture for several minutes over a hydrogen generator until the hydrogen uptake ceased. The mixture was filtered through kieselguhr and a solution of 0.165 g of sodium 2-ethylhexanoate in 5 ml of ethyl acetate was added to the filtrate. The filtrate was evaporated to a small volume and the concentrate was diluted with 50 ml of diethyl ether. The precipitated solid was filtered off and dried in a vacuum desiccator, giving 0.28 g of the title compound

809817/0894

0.5

received. [<x] _D + 13 ° (c 1.0, H ₃ O), ^ _max (NuJoI) 1786 (ß-lactam), 1754 (ester), 1708 (acetyl) and 1610 cm " ¹ (-CO ₂ " ), τ (D ₂ O) 4.28 (d, C-5 H), 5.11 (s, C-3 H), 5.79 (q, -COOCH ₂ CH ₅ ) 6.12 (t, C-5 ¹ H), 6.40 and 6.92 (dd and d, C-6 protons), 7.55 (m, C-2 ¹ protons), 7.70 (s, -COCH ₃ ) and 8.76 (q, -COOCH ₂ CH ₃ ).

The following were produced in an analogous manner:

Example 7 Sodium (3R, 5R, 1'Z) -2- (3-acetyl-4-oxopentyllden) -

clavam-3-carboxylate

In 48 # yield a _Qv (NuJoI) 1780 (ß-lactam), 172Ο (acetyl),

¹ ITIaX Q

1688 (enol ether) and 16ΟΟ (-CO ₂ ) ^ (D ₂ O) 4.32 (d, C-5 H), 5.15 (s, C-3 H), 6.45 and 6.96 (dd and d, C-6 protons), 7, ^ 2 (d, J = 7 Hz, C-2 ¹ protons) and 7.76 (s, -COCH,).

Example 8 Sodium (3R, 5R, 1'Z, 3'RS) -2- (3-benzoyl-3-ethoxycarbonyl-

propylidene) clavam-5-carboxylate

In 47% yield λ _mov (pH 6 buffer) 250 nm (£ = 9,900),

^v max

^ " _QV (NuJoI) 1790 (ß-lactam), 1732 (ester), 1690 (enol ether) and 1620 cm" (-CO ₂ "), ΐ (D ₂ O) 2.0 - 2.7 (m, aromatic Protons), 4.44 (d, C-5 H), 5.87 (q, J = 7 Hz, -COOCH ₂ CH ₃ ), 6.53 and 7.21 (C-6 protons), 7, 30 (m, C-2 ¹ protons) and 3.86 (q, J = 7 Hz, -COOCH ₂ CH ₃ ).

Example 9 Sodium (3R, 5R, 1 'Z, 3 ^f RS) -2- ^ -methoxycarbonyl ^ -oxopentyl-

iden) clavam-3-carboxylate

In 48 # yield i, _mov (NuJoI) 1790 (ß-lactam), 1740 (ester), 1710 (acetyl) and 1618 cm (CO ₂ ), χ (D ₂ O) 4.33 (d, J = 2 Hz, C-5 protons), 5.16 (s, C-3 protons), 6.26 (s, -OCH,), 6.46 and 6.95 (dd, J = 2 and 17 Hz and d, J = 17 Hz, C-6 protons), 7.39 (m, C-2 'protons) and 7.72 (s, -COCH ₃ ).

Example 10

4-nitrobenzyl - (3P-, 5R, 1 'Z) -2- (3-acetyl-4-oxopentylidene ) -clavam-3-carboxylate

0.33 g of tetra-n-butylammonium salt of acetylacetone was added

809817/0894

a suspension of 0.35 g of 4-nitrobenzyl (3R, 5R * Z) -2- (2-chloroethylidene) clavam-3-carboxylate in 5 ml of dirnethoxyethane. After stirring for 20 minutes at room temperature, the yellow solution was concentrated in vacuo. The residue was chromatographed on preparative silica gel plates using Kthylacetat-petroleum ether - (1: 1) as eluent to give 17 mg Titelester whose spectral properties goods indicated in Example 1 similar (b.p. 60 8O ⁰ C.).

Example 11

Sodium (3R, 5R, 1'Z, 3'RS) -2- (3- carboxy-4-oxopentylidene) -clavaTi-3-carboxylate

0.70 g of palladium on activated carbon (10 %) were added to a solution of 0.73 g of 4-nitrobenzyl- (3R, 5R, 1 'Ζ, 3'Ρ3) -2- [3- (4-η1ίΓθ-benzyloxycarbonyl ) -4-oxopentylidene] clavam-3-carboxylate in 50 ml of ethyl acetate and the mixture was shaken vigorously for 2 minutes over a hydrogen generator. The mixture was quickly filtered through kieselguhr and a solution of 0.14 g of sodium 2-ethylhexanoate in 2 ml of ethyl acetate was added to the filtrate. A precipitate quickly formed which was filtered off, washed with ether and dried in a desiccator to give 0.17 g of the title compound. $ _mQV (NuJoI) 1786 (fl-Lactam), 1702 (acetyl) and 1608 cm " ¹

ΠΙ α X

(-CO ₂ "), τ (D ₂ O) 4.32 (d, c-5 H), 5.13 (s, C-3 H), 6.47 and 6.92 (ABq, J = 17 Hz, C-6 protons 7.35-7.6 (m, C-2 ¹ protons) and 7.75 (-COCH,).

Example 12 Acetoxymethyl- (3R, 5R, Z) -2- (3-acetyl-4-oxopentyllden) -clavam-

3-carboxylate

0.43 ml of chloromethyl acetate was added to a solution of 1.44 g of sodium iodide in 10 ml of anhydrous acetone and the mixture was stirred for 3 hours at room temperature. The mixture was then concentrated in vacuo and the residue partitioned between 10 ml water and 10 ml of petroleum ether (bp. 60 - 8O ⁰ C) distributed. The organic extract was _{dried over Na 3} SO ^ and added to a stirred solution of 0.90 g of sodium (3R, 5R, Z) -2- (3-acetyl-4-oxo-pentylidene) · clavam-3-carboxylate in 7 ml of dimethylformamide were added. After this

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274735Ü

With stirring for 10 min, the mixture was partitioned between 50 ml of brine and 50 ml of ethyl acetate. The organic layer was washed with 3 × 50 ml of water, _{dried over Na 3} SO ^ and concentrated in vacuo. The residue was passed through a column of 25 g of silica gel using ethyl acetate-petroleum ether (b.p. 60-80 ° C.) (2: 1) as the eluent to give 0.60 g of the title ester in the form of a colorless oil.

A _max (0.1 N NaOH) 258 ( _fc 12 800) and 507 nm (£ 4 000), 0 _max (CHBr ₃ ) 1795 (ß-lactam), 1762 (ester) and 1692 cm " ¹ (enol ether), X (CDCl ₃ ) 4.20-4.40 (m, -OCH ₂ O- and C-5 H), 5.00 (C-3 H), 5.46 (t, J = 7 Hz, = CH -), 6.32 (t, J = J Hz, C-3 ¹ H), 6.50 and 6.97 (ABq, J = 17 Hz, C-6 protons), 7.39 (t, J = 7 Hz, C-2 ¹ protons) and 7.8 - 8.0 (m, methyl protons).

Example 13 4-nitrobenzyl- (3R, 5R, Z) -2- (3-acetyl-4-oxopentylidene) -

clavam-3-carboxylate. .... ,

^ * <4 - nitrobenzyl ,

50 mg of potassium carbonate and 0.32 gV (3R, 5R, Z) -2- (2-chloroethylidene) clavam-3-carboxylate were added to a solution of 0.40 ml of acetylacetone and 0.10 g of 18-crown-6 in 5 ml of dry methylene chloride. After stirring for 20 minutes, the solution had cleared and another 90 mg portion of potassium carbonate was added to the mixture. After stirring for a further 15 minutes, the reaction mixture was diluted with 5 ml of methylene chloride and washed with 10 ml of 2N aqueous sulfuric acid. The organic phase was _{dried over Na 3} SO ^ and chromatographed on preparative silica gel plates using ethyl acetate-petroleum ether (bp 60-80 ° C.) (1: 1) as the eluent to obtain 80 mg of the title ester, the spectroscopic properties of which the given in Example 1 were similar.

Example 14

4-nitrobenzyl- (3R, 5R, Z) -2- (3-acetyl-4-oxopentylidene) - clavam-3-carboxylate

50 mg of potassium carbonate were added to a solution of 0, -20 g 4-nitrobenzyl (5R) -2-vinylclav-2-em-3-carboxylate 0.35 g

809817/0894

Acetylacetone and 0.10 g of 18-crown-6 in 5 ml of dry methylene chloride. After stirring for 15 minutes, the mixture was added with 5 ml Diluted methylene chloride and washed with 5 ml of 0.5 N aqueous hydrochloric acid. The organic phase was dried over NapSO ^ and on preparative silica gel plates using ethyl acetate-petroleum ether (Bp 40-60 ° C) (1: 1) chromatographed as the eluent, giving 40 mg of an oil whose IR and NMR spectra were similar to those given in Example 1.

Example 15

4-nitrobenzyl (3R »5R» i'Z, 3 ^f RS) -2- (3-cyano-3-methoxycarbonylpropylidene) clavam-3-carboxylate

50 mg of potassium carbonate were added to a solution of 0.20 g of 4-nitrobenzyl (5R) -2-vinylclav-2-em-3-carboxylate, 0.20 g of methyl cyanoacetate and 0.10 g of 18-crown-6 in 5 ml dry methylene chloride. After stirring for 15 minutes, the mixture was diluted with 5 ml of methylene chloride and washed with 5 ml of 0.5N aqueous hydrochloric acid. The organic phase was dried over Na ₂ SO _1, dried and on preparative silica gel plates using ethyl acetate-petroleum ether -: acetate as eluent to give 35 mg Titelester in the form of an oil (1: 1) (bp 40 6O ⁰ C.) received.

^{(CHBr)) 1} 796 (.beta.-lactam), 1745 (ester), 1692 (enol ethers), 1520 and 1342 cm ^"1 (nitro), Ti _(CDCl3) 1.74 and 2.46 (aromatic protons), 4 , 28 (m, C-5 H), 4.70 (s, benzyl protons), 4.86 (s, C-3 H), 5.28 (t, J = 7 Hz, = CH-), 6, 20 (s, -OCH ₅ ), 6.40 (t, J = 7 Hz, C-3 ¹ proton), 6.46 and 6.88 (m, C-6 protons) and 7.23 (t , J = 7 Hz, C-2 'protons).

609817/0894

Claims (1)

Claims 1.) Compounds of the formula I (D H
MR where R is a carboxyl or esterified carboxyl group, R is the radical a carbon nucleophile or a product thereof, formed by cleavage of any esterified carboxyl groups herein, means, and when a carboxyl group is present, their salts. 2.) Compounds according to claim 1, wherein R is a group of the formula II means in which X and Y, which can be the same or different, Represent groups that can form a stabilized carbanion, and Z is an alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or represents aryl group or a hydrogen atom. 3.) Compounds according to claim 2, wherein the group capable of forming a stabilized carbanion is an esterified one Means carboxyl group, a cyano group or a group R CO, ρ
wherein R represents an optionally substituted alkyl, cycloalkyl, aralkyl or aryl group. 8 0 9 817 / OJJ A ORIGINAL iNSPEC 'i.) Compounds according to claim 2 or>, wherein Z or R is a C ₁ n -alkyl, alkenyl or alkynyl group, optionally substituted by a halogen atom or an alkoxy, cyano, alkanoyloxy or alkoxycarbonyl group; a C 1-6 cycloalkyl group; an aryl group having up to 12 carbon atoms which is optionally substituted by a halogen atom, an alkyl group or an alkoxy group; or an aralkyl group having up to 10 carbon atoms which is optionally substituted by a halogen atom, an alkyl group or an alkoxy group. 5.) Compounds according to any one of claims 2 to 4, wherein X 2 2
an acyl group, R CO, in which R is as defined in claim 3 and Y is an acyl group R CO or an esterified carboxyl group. 1 / ^X 6.) Compounds according to claim 1, wherein R is a group -C-Y as defined in claim 2, in which one or more esterified carboxyl groups are replaced by free carboxyl groups. 7.) Compounds according to any one of claims 1 to 5, wherein R is a pentan-2,4-dion-3-yl group. 8.) Compounds according to any one of the preceding claims, wherein R is a group COOR- ^, in which Tr is an organic group which is derived from an aliphatic or araliphatic alcohol, a phenol or a stannanol. 9.) Compounds according to one of the preceding claims, wherein other esterified carboxyl groups present in the compound of formula I are represented by the formula -COOR where R is a group which is derived from an aliphatic or araliphatic alcohol or phenol. 10. ^ erbindungen according to claim 8 or 9, wherein R and R ^ straight-chain or branched, substituted or unsubstituted 8 0 9817/0894 27473o'j 5 - Alkyl or alkenyl groups with 1 to 8 carbon atoms, aralkyl groups with up to 20 carbon atoms, aryl groups with up to 12 carbon atoms, cycloalkyl groups with up to 12 carbon atoms, optionally containing one or more heteroatoms in the ring system, or R ^ * is a stannyl group with up to to 24 carbon atoms means. 11. ^ erbindungen according to any one of claims 8 to 10, wherein the esterified carboxyl group is metabolically labile. 12. Compounds according to any one of claims 8 to 10, wherein R a benzyloxycarbonyl group, optionally substituted by an o- or p-nitro, p-methoxy or ρ-methyl group means. 13.Verbindungen according to any one of claims 8 to 12, wherein R means a p-nitrobenzyloxycarbonyl group. 14.) Alkali metal, alkaline earth metal, ammonium or substituted Ammonium salts according to one of Claims 1 to 13 15.) Sodium, potassium, lithium, calcium, magnesium or Ammonium salt of a compound according to any one of claims 1 to 13 16.) Salts according to claim 14 or 15 * which are physiologically acceptable are. 17 ·) Compounds according to any one of claims 2 to 16, wherein Z means a hydrogen atom. 18.) Pharmaceutical composition (including a veterinary composition), characterized in that it contains at least one acid, a physiologically acceptable salt or a metabolically labile ester according to claim 1, together with a pharmaceutical carrier or excipient and / or a further ß-lactam Contains antibiotic. 19) Composition according to claim 18, characterized in that 80981 7/0894 ORIGINAL JNSPECfED 27A73bO that it is in the form of dosage units, the 12.5 mg contain up to 5 g of the active ingredient of the invention when this is used alone, and 25 mg to 5 ß total ß-lactam antibiotic, when a compound according to the invention and another β-lactam antibiotic are present. 20.) Composition according to claim 18, characterized in that that it contains a compound of the formula I according to claim 1, in which R is a pentan-2,4-dion-3-yl group or a 1-carboxylpropan-2-on-i-yl group represents and R represents a carboxyl group in the salt form. 21.) Process for the preparation of a compound of formula I according to claim 1, characterized in that a compound is used of formula III (III) MR where R is an esterified carboxyl group and E is an easily exchangeable substituent or a compound of formula IV (IV) wherein R is an esterified carboxyl group, with a compound of the formula R H in the presence of a base or with a salt of the compound of the formula R H, in which R is the radical of a carbon nucleophile, which reacts when a 809817/0894 27473-0 Acid of the formula I is desired, followed by ester cleavage and salt formation, if a salt is desired. 22.) Process according to claim 21, characterized in that the salt of the compound of the formula R ¹ H is an alkali metal, tetraalkylammonium or thallium or thallo salt, and that this is reacted with a compound of the formula III. 25.) The method according to claim 22, characterized in that the easily exchangeable substituent E is a halogen atom or an aromatic or aliphatic sulfonyloxy group. 24.) Method according to claim 23, characterized in that E means a chlorine or bromine atom. 25.) The method according to claim 21, characterized in that a compound of the formula R H is used and this with a Compound of the formula IV in the presence of an inorganic base using a crown ether in an aprotic liquid medium converts. 26.) The method according to claim 21, characterized in that a compound of the formula R H is used and this with a Compound of the formula III in the presence of an inorganic base using a crown ether in an aprotic liquid medium converts. 27.) Method according to claim 25 or 26, characterized in that that the reaction in a halogenated hydrocarbon solvent is carried out. 28.) The method according to any one of claims 25 to 27, characterized characterized in that the inorganic base is an alkali metal hydroxide, carbonate or bicarbonate. 29.) The method according to any one of claims 21 to 28, characterized in that any ester group in the initially formed compound of formula I is cleaved by reduction. 809817/0894 30.) Process according to claim 29, characterized in that the reduction is carried out by catalytic hydrogenative cleavage is carried out. 51.) Process according to claim 29 or J> 0, characterized in that the ester is a p-nitrobenzyl ester. 32.) Method according to one of claims 21 to 30 »thereby characterized in that an acidic product of the formula I is re-esterified.