DE2555626A1 - ISOCLAVULANIC ACID, ITS SALTS AND ESTERS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

"Isoclavulanic acid, its salts and esters" · *, process for their Manufacture and medicinal preparations containing these compounds "

Priority: December 18, 197 ¹ J, Great Britain, No. "5 ^ 788/7 ^ April 14, 1975, Great Britain, No. 15211/75

The invention relates to new compounds with a ß-lactam ring, which inhibit ß-lactamase and are also antibacterial to a certain extent.

In BE-PS 827 926, among other things, the clavulanic acid of the formula O _1, its salts and esters is described.

CO ₂ H

CH ₂ OK

(0)

609 82 7/0970

This compound inhibits ß-lactamase and is also an antibacterial agent.

The invention relates to compounds of the formula I, their salts and esters,

(I)

-N.
0 "; CHoOR

in which R is a hydrogen atom or an acyl radical.

An acyl radical with up to 16 carbon atoms is suitable for pur R. However, the hydrogen atom is preferred.

If R is an acyl radical, this is preferably a radical as it occurs in the acylamino side chain of the known antibacterially active penicillins or cephalosporins, e.g. a {y-aminoacetyl-, 0 (-aminophenylacetyl-, Ctf-amino-JJ-hydroxyphenylacetyl-, Phenylacetyl-, phenoxyacetyl-, 2-thienyl- acetyl-, 3-thienylacetyl-, OC-hydroxyphenylacetyl-, 0 (-Carboxypheny! Acetyl-, (X-carboxy-3-thienylacetyl, 0 (-azidopheny, acetyl or p-hydroxyphenylacetyl radical. In the presence of an amino group, it can be protected in a conventional manner, for example by a Carboxybenzyl group.

A radical of the following formula is suitable for the acyl radical R

609827/0970

CO-CH-, 1

Cl

- R '

in which η denotes 0 or an integer from 1 to 6, R denotes a hydrogen atom or a phenyl or phenoxy radical, R denotes a hydrogen or halogen atom, an alkyl or alkoxy radical having 1 to 4 carbon atoms or a radical of the formula CO-R- ⁵ in which R is a hydrocarbon radical having 1 to 8 carbon atoms.

Preferably η denotes 0 or an integer from 1 to 3, R

ρ is the hydrogen atom or the phenyl or phenoxy radical and R

4 the hydrogen atom or a radical of the formula CO ₃ R, in which R is the phenyl or benzyl radical.

The salts or esters of the compounds of the formula I in which R is an acyl radical correspond to the salts or esters of those according to the invention Compounds of the formula I in which R is the hydrogen atom.

Particularly suitable compounds of the formula I according to the invention are compounds of the formula II and their pharmacologically acceptable salts and esters.

CH ₂ OH

(ID

609827/0 970

Suitable salts are the sodium, 'potassium, calcium, Magnesium, aluminum salts and conventional substituted ammonium salts.

Particularly suitable salts of the compounds according to the invention of formula II are salts of formula III

J>

«V ^

(in)

co «rf»

A.

in which M is a sodium or potassium ion.

These salts can form hydrates.

Particularly useful compounds of the formula according to the invention I are compounds of the formula IV

(IV)

CH ₂ OH

in which A is an inert organic radical with up to 16 carbon atoms, especially with up to 12 carbon atoms.

Suitable for A are alkyl, alkenyl, alkynyl, aryl or aryl

e.g.
alkyl radicals, optionally with / at least one halogen atom,

609827/0970

. · Preferably

an alkoxy-j acyloxy or aryloxy radical with / up to 7 carbon atoms or substituted with at least one hydroxyl or nitro group or optionally substituted amino group are.

Examples of A are methyl, ethyl, n-propyl, isopropyl, straight-chain or branched butyl, pentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, allyl , Butenyl, cyclopropyl-jCyQlobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohexyl, benzyl, benzhydryl, phenylethyl, naphthylmethyl, naphthylmethyl, phenyl , Tolyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, acetylmethyl, benzoylmethyl, ^{2- M} ethoxyethyl, 2-dimethylaminoethyl, 2-doethylaminoethyl, 2 -Piperidinoäthyl-, 2-Morpholinoäthyl-, 3-Dimethyl-

aminopropyl-, p-chlorobenzyl-j.p-methoxybenzyl-i p-nitrobenzyl-, p-bromobenzyl-, m-chlorobenzyl-, D-methoxynaphthyl-2-methyl-, p-chlorophenyl- or p-methoxyphenyl residues.

Preference is given to radicals of the formulas a to d

A ₂ - X ^ CO - A ₃ (a)

CH-Z
Ii - (b)

- CHA ₄ A ₅ (c)

609827/0970

in which A. the hydrogen atom or the methyl group j A "the hydrogen atom or an alkyl radical, with. 1 to ¹ I. carbon atoms, a phenyl or benzyl radical, A a lower alkyl, aryl or C - ^ - arylalkyl radical, X the oxygen or sulfur atom, Z'a "divalent organic radical, A. the hydrogen atom · or a - ,.; - '· inert aryl residue, a is an inert Ärylrest ,, ^ a is a hydrocarbon radical having 1 to 9 carbon atoms, optionally substituted with at least one halogen atom oder'einem.' lower alkyl ^or: acyl or is substituted with a low ethereal or acylated. "■ hydroxyl group.

In the formulas a to d, preferably for A _- . is the hydrogen atom, for Α the hydrogen atom or the methyl radical, for A the methyl, tert -butyl or phenyl radical, for X the oxygen atom, for Z the ethylene or ethenyl radical or a radical of the following formulas

OCH,

for Aj, and A ₁ . each the phenyl, tolyl, halophenyl or methoxyphenyl radical and for A ^ also the hydrogen atom and for Ag a hydrocarbon radical with 1 to 6 carbon atoms, optionally with at least one chlorine, bromine or iodine atom, a trifluoromethyl, tert.- Butyl, methoxy, acetyl, benzoyl or acetoxy radical is substituted.

For A in formula IV, radicals of the formulas e are particularly preferred and f

-CO-CO-A ₉ . (e)

^A 8

"fl2 '(f)

^A lö ~ ^C -

609827/0970

in which A _{7 is} the hydrogen atom or the methyl radical, Aq is the hydrogen atom, the methyl, ethyl or phenyl radical, A is an alkyl radical with 1 to 6 carbon atoms or a phenyl or benzyl radical, A _ is the ethylene, ethenyl, o-phenylene, 4,5-dimethyl-o-phenylene or 4,5-dimethoxy-o-phenylene radical, A ₁₁ and A _{12 are} each the oxygen or sulfur atom.

In formulas e and f, Ag is preferably the hydrogen atom, A_ the methyl-ethyl, propyl, butyl or phenyl radical, A _

of o-phenylene or 4,5-dimethoxy-o-phenylene radical, A. and A _ each the oxygen atom.

Esters of the compounds of the formula I in which the ester radical is converted into the free carboxyl group or its salt are important intermediate compounds in the preparation of the compounds of the formula II or their salt.

Particularly suitable compounds according to the invention are compounds of Formula V

.La

(V)

σ;. Ck ₂ OR

in which R is defined as in formula I and the CO-R radical is an ester radical which can be easily converted into the free carboxylic acid group or its salt by hydrogenation.

609827/0370

5
The benzyl, naphthylmethyl, benzhydryl, trityl, 4-bromobenzyl, 3, lJ-dimethoxybenzyl, 6-methoxy-2-naphthylmethyl, ^, ^ - dimethoxybenzhydryl or 2-nitrobenzyl radical are suitable for R.

The invention further relates to a process for the preparation of the compounds of the formula I, their salts or esters, which is characterized in that a compound of the formula VI, their salt or ester, is isomerized _;

H CH ₂ OR

(VI)

CO ₂ H

in which pure is hydrogen or an acyl radical.

The process according to the invention is preferably carried out along with it a compound of the formula VI by "in which R is the hydrogen atom means.

The isomerization of the compound of the formula VI is generally carried out using a transition metal catalyst in the presence of hydrogen.

If the isomerization is carried out with an ester of the compound of the formula VI in which the ester radical is a radical of

609827/0970

Formula CO ₃ R ⁵ , which is defined according to formula V, the end product often obtained is a compound of formula I or its salt.

A particularly suitable method according to the invention for production of compounds of the formula II or their salt, characterized in that a compound of the formula

P CH ₂ OH

N / ( ^VII >

in which R is defined as in formula V, with a transitional

brings into contact / metal catalyst in the presence of hydrogen /

the reaction being carried out in the presence of a base to prepare a salt of the compound of the formula II.

Palladium, e.g. 10 percent palladium on carbon, is particularly suitable as a transition metal catalyst.

In the isomerization according to the invention, the weight ratio of transition metal catalyst to compound is Formula VI or VII generally below 1: 3, e.g. 1: 2.5 to 1: 3. That too is in the weight of the transition metal catalyst Contain weight of the support necessary for the catalyst.

B09827 / 097Ö

If the reaction is carried out with 1 atmosphere of hydrogen, then 'It usually takes less than 10 hours to complete. Particularly long reaction times should be avoided as they lead to an undesirable reduction in the exocyclic double bond Lead compound of formula I or II.

The isomerization is carried out at non-extreme temperatures, for example at -20 to 10C ⁰ C, such as -5 to 40 ° C, especially at 0 to 20 ⁰ C.

The reaction is generally carried out in an inert organic solvent such as lower alkanols, e.g. ethanol, low-boiling halogenated hydrocarbons, e.g. chloroform or dichloromethane, or ethers such as tetrahydrofuran.

The compounds of formulas VI and VII are not always complete converted into the corresponding compounds of the formulas I or II, an equilibrium mixture of compounds is often obtained of the formulas VI and I or VII and II. These mixtures are optionally in a conventional manner, ζ .B. by chromatography, separated.

The invention relates to a further process for the preparation of the compounds of the formula I, their salts or esters, which thereby is characterized in that a compound of the formula VI, its salt or ester, is isomerized by UV irradiation.

609827 / 097ü

- Il -

This UV irradiation is best carried out with a benzyl ester of a compound of the formula VI, e.g. with the benzyl ester of Compound of formula VI in which R is hydrogen.

The reaction is generally carried out in a degassed organic solvent such as benzene, carbon tetrachloride or acetonitrile in an inert atmosphere such as argon or nitrogen. In general, the isomerization takes place at room temperature, but any non-extreme temperature can be used, for example -20 to 80 ° C., although medium temperatures, for example 0 to 30 ^° C., are preferred.

You can add a photosensitizer to the mixture in a conventional manner, such as dibenzyl, iodine, acetophenone or benzophenone, add.

For the photolytic isomerization of the compound of the formula VI you can use a wide or narrow UV spectrum. It has been found that Hanovia mercury lamps are medium or give satisfactory results at low pressure. You can use these lamps with a water-cooled quartz jacket or glass.

When the compound of the formula VI is irradiated with UV light, a mixture of the compound of the formula I with Starting material and other compounds. This mixture can be separated in a conventional manner, for example by chromatography. Column chromatography, e.g. with silica gel and ethyl acetate / cyclo

609827/0070

hexane, as the eluant, is generally used for separation , the compounds of the formula I are suitable.

The carboxylic acid group in position 2 of the compound of the formula I can conventionally be converted into a different carboxylic acid group being transformed. A free carboxylic acid group in position 2 can therefore by reacting with an alcohol of the formula AOH, in the A is as defined in formula IV, in the presence of a condensing agent such as dicyclohexylcarbodiimide, or by Reacting with a diazo compound, e.g. diazomethane, into a Esters are converted. By treating with a base, e.g. sodium or potassium bicarbonate, this free carboxylic acid group can be removed convert into a salt.

A salt of the compound of formula I can also be converted into an ester by conventional nucieophilic substitution, i.e. by reaction with a compound of the formula AQ., in which A is as defined in formula IV and Q is an easily cleavable radical,

/ Methylsulfonyl as a chlorine, bromine or iodine atom, a / or tolylsulfo-

nyl radical _; is.

The compounds of the formula I according to the invention in which R is a Acyl radical can be selected from the corresponding compounds of the Formula I, where R is hydrogen, can be prepared by conventional acylation reactions such as reacting with a compound of the formula ROH in which R is an acyl radical. This reaction is generally carried out in the presence of a Condensing agents such as dicyclohexylcarbodiimide. Suitable

609 ^ 27/0970

Acylation reactions are described in GB patent application 45738/74.

The invention also relates to medicinal preparations which contain a compound of the formula I, its salt or ester, characterized as an active ingredient in combination with customary pharmacologically acceptable carriers and / or diluents are.

The pharmaceutical preparations according to the invention are generally administered to humans and mammals, for example in a conventional manner for the treatment of infections of the urinary tract, the respiratory tract and the soft tissues as well as for the treatment of otitis media and mastitis.

Suitable forms of the medicinal preparations according to the invention are tablets, capsules, creams, syrups, suspensions, solutions, dry preparations and sterile forms suitable for injections or infusions.

As pharmacologically acceptable carriers and / or diluents binders, dyes, flavorings are suitable, Preservatives and disintegrants.

The compounds of the formula I, their salts or esters, can be the only ones in the medicinal preparations according to the invention that are therapeutic Active ingredient present or together with other therapeutic

60 88 27/0370

/ an em
Agents such as ^ penicillin or cephalosporin. Suitable penicillins or cephalosporins which can be incorporated into the medicinal preparation according to the invention are benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, hetacillin, ampicillin, amoxycillin, ticarcillin, cephaloridine,

Cefoxitin, Cephalothin, Cephalexin, Cephamandol, Cephaloglycine, / Cefuroxime and in vivo hydrolyzable esters of these compounds such as Phenyl and indanyl esters of carbenicillin and ticarcillin, the Acetoxymethyl ester of benzylpenicillin and the trimethylacetoxymethyl and phthalidyl esters of ampicillin and amoxycillin.

There is also a penicillin in the medicinal preparation according to the invention or cephalosporin is present, the ratio of compound of formula I to penicillin or cephalosporin is 10: 1 up to 1: 3, e.g. 5: 1 to 1: 2, in particular 3: 1 to 1: 1. -

The total amount of antibacterial agents in a single dose is generally 50 to 1500 mg, in particular 100 to 1000 mg. However, injections or infusions can contain larger amounts of active ingredient, e.g. 4 g or more.

In general, the daily dose of medicinal preparation according to the invention is 50 to 6000 mg, in particular 500 to 3000 mg. at Severe body infections or infections of an organism that is particularly difficult to influence can be in accordance with higher doses may be used in clinical practice.

The examples illustrate the invention.

609827/09

example 1

CH ₂ OH

CO ₂ CH ₂ COC ₆ H ₅

(D

h-o

CHpOH CO ₂ CH ₂ COC ₆ H ₅

(2)

(D

A dilute solution of phenacyl clavulanate (1) in dry benzene is placed in a quartz vessel with a 450 watt Medium pressure Hanovia mercury lamp for 3 hours under nitrogen irradiated (lamp by Engelhard Hanovia Lamps, Bath Road, Slough, Buckinghamshire, England. The solvent is removed the residue is thin-layer chromatographed. You get two components separated by silica gel chromatography. The more polar component is spectroscopically examined, it is identical to the starting material. The less polar component is identified by high pressure liquid chromatography studied, it consists of a mixture of two compounds identified by preparative high pressure liquid chromatography be separated. The second eluted compound is a colorless oil and, according to spectroscopy, has the structure (2).

IR (film): 3 ^ 80, 1790, 1750, 1690 cnf ¹ .

NMR / (CDCl ₃ ): 3.02 (1H, dd, J = 17 Hz, J ^f = 1 Hz, 6 [beta] -H); 3.52 (IH, dd, J = 17Hz, J '= 3Hz, 6θς-Η); 4.27 (2H, d, J = 9Hz, CH ₀ OH); 5.43 (IH, s, CHCO-R); 5.48 (1H, m, 1CHCHCH ₀ OH); 5.52 (2H, s, CH _n COPh); 5.73 (IH,

609827/0970

dd, J = 3Hz, J «= 1Hz, 5-H) and 7.7 (5H, m, aromatic proton)

Example 2

CH ₂ OH

CO ₂ CH ₂ C ₆ H ₅

(3)

h *>

ι I

¹ H ₂ OH

CO ₂ CH ₂ C ₆ H ₅

A solution of clavulanic acid benzyl ester (3) in dry benzene is irradiated in a quartz vessel with a Hanovia photochemical "Reading Reactor" under protection from nitrogen. Isoclavulanic acid benzyl ester (4) is obtained as a colorless oil in a yield of 40 % according to column chromatography. The lamp (from Engelhard Hanovia Lamps, Bath Road, Slough, Buckinghamshire, England) contains two low-pressure UV lamps with 45 watts, each with an energy maximum at 254 ^nm

IR (CH ₂ Cl ₂ ): 3550, 1795, 17 ¹ IO, 1685 cm " ¹ .

NMR (Z (CDCl3): 1.85 (IH, s, CH ₂ OH); 2.98 (IH, dd, J = 17 Hz, J '= 1 Hz,

6β-H); 3.45 (IH, dd, J = 17Hz, £ · = 2.5Ηζ, 6 <χ-Η); 4.05 (2H, d, J = 7Hz, CH ₂ OH); 5.18 (2H, s, CH ₂ CGH); 5.32 (IH, s, CHCO ₂ CH ₂ C ₆ H ₅ );

5.35 (IH, m, obscured by a signal at 5.32, CHCH ₂ OH);

5.63 (IH, dd, J = 2.5 Hz, J '= 1 Hz, 5 ~ H); 7.36 (5H, s, aromatic proton). The mass spectrum of the product shows a molecular ion at m / e = 289.09 ^ 9 (calculated for ^C ₁₅ ^H ₁₅ ^NO 5 ^: 289.0950).

609827/0970

Example 3

CH ₂ OH

H ι

-N

CH ₂ OH

ff

-O,

CH ₂ OH

(3)

¹ CO ₂ CH ₂ C ₆ H ₄ Br

(5)

CO ₂ CH ₂ C ₆ H ₄ Br

(6)

94 mg of benzyl clavulanate (3) in 8 ml of ethanol are hydrogenated for 60 minutes in the presence of 30 mg of 10 percent palladium on carbon and 28 mg of sodium hydrogen carbonate. The catalyst is washed abfiitriert ^m ^ water and ethanol. The combined filtrates are evaporated. The residue is dissolved in 2.5 ml of dry dimethylformamide containing 245 mg of p-bromobenzyl bromide and left to stand at room temperature for 2 hours. The solution is fractionated over silica gel with ethyl acetate / hexane in a ratio of 1: 1 and finally with ethyl acetate as the eluent. Fractions 16 to 19 are evaporated, giving 11 mg of isoclavulanic acid p-bromobenzyl ester / as thin rods, melting point 134 to 134.5 ° C. (from methylene chloride / carbon tetrachloride). Fractions 21 to 24 are evaporated to obtain 52 mg of clavulanic acid p-brombenzylester (6) as needles, mp. 103 to 104 ⁰ C (from methylene chloride / carbon tetrachloride).

The structures and the absolute stereochemistry of the two products (5) and (6) are confirmed by X-ray analysis .

609827 / 097J

example

-O

-N-

(7)

CH "OH

si. £.

H ι ι

-N-

j CH ₂ OH

CO ₂ CH ₂ C ₆ H ₅ Br

(5)

19.5 mg of sodium salt of isoclavulanic acid (7) are treated for 3 hours with 22.5 mg of p-bromobenzyl bromide in dry dimethylformamide. After this time, thin-layer chromatography with butanol / ethanol / water in a ratio of 16: 4: 7 _{3 shows} that the reaction is almost complete. The solvent is removed under reduced pressure, the residue is chromatographed over silica gel with ethyl acetate / cyclohexane in a ratio of 1: 1. 1 * 1.5 mg of the desired product (5), pp. 132 to ^{0, are obtained}

Example

-0

CiH ^ CHCO ₉ H 6 5, 2 __ ^

CH ₂ OH

CO ₂ CH ₂ C ₆ H ₅

CO ₂ CH ₂ C ₆ H ₅

0 '

CH ₂ OCCHC ₆ H ₅

CO ₂ CH ₂ C ₆ H ₅

(4)

(8th)

609827/0970

255S626

82 mg Isoclavulansäure-benzyl-ester (4) is dissolved in dry methylene chloride and treated with J6 mg phenylmalonic-monobenzyl ester. The solution is ^{cooled to 0 °} C. and 57.7 mg of dicyclohexylcarbodiimide are added. The mixture is stirred at 0 ° C. for 1 hour and then left to stand at room temperature overnight. The mixture is filtered and the piltrate is concentrated. The crude product (8) is obtained, which is purified by fractionation over silica gel and gradient elution with ethyl acetate / cyclohexane. Yield; 42 mg (32 % ) of a gummy colorless product (8).

IR (film): 1805, 17 ¹ IS, 1695 cm " ¹ .

NMR (^ (CDCI,): 2.95 (IH, dd, J = 17Hz, J '= 1Hz, 6β-H); 3.42 (IH,

j - * - *

dd, J = 17Hz, J ^f = 3Hz, 6 (XH); 4.57 (2H, m, C = CHCH ₀ ); 4.59 (IH, s, OCOCHPh); 5.08 (2H, s, CHPhCO ₂ CH ₂ Ph) ;. 5.12 (IH, m, obscured, C = CHCH _0); 5.14 (2H, s, NCHCO-CH _n Ph); 5.35 (IH, bs, NCHCO.CH ^ CH ^);

- c. c.— ~ "a c ά υ J>

5.63 (IH, dd, J = 3Hz, J ^f = 1Hz, 5-H) and 7.28 (15H, s, aromatic proton), molecular weight (mass spectrometry): 541 ..

Example 6

CH ₂ OH CO ₂ CH ₂ C ₆ H ₅

(4)

(7)

CH ₂ OH

609827/0970

A mixture of 60 mg Isoclavulahsäure benzyl ester, 17 "6 mg sodium bicarbonate and 20 mg of palladium on carbon is hydrogenated lOprozentigem hydrogen pressure minutes at 20 ⁰ C and one atmosphere. After this time, thin-layer chromatography with ethyl acetate / cyclohexane in a ratio of 1: 1 shows that the reaction is complete. The catalyst is filtered off and washed with water. The piltrate and the combined wash water are evaporated. The residue is washed twice with ethanol and evaporated, then washed with acetone and evaporated and finally treated with acetone / ether. 30 mg of isoclavulanic acid sodium salt (7) are obtained as a whitish powder.

NMR (Z (D ₂ O): 3.10 (IH, d, J = 17.5 Hz, 6β-CH); 3.64 (IH, dd, J = 17.5 Hz, J '= 3.0 Hz) 4.18 (2H, d, J = 7.5Hz, CH ₂ OH); 5.22 (2H, m, = CH-CH ₂ OH, 3 ~ CH); 5.86 (IH, d, J = 3.0Hz, 5-CH).

The minimum inhibitory concentrations, given in jig / ml, of Isoclavulanic acid sodium salt, ampicillin and combinations of isoclavulanic acid sodium salt with ampicillin against certain Organisms producing β-lactamase are summarized in the table. The results were obtained by microtitration a 1/500 inoculation of an overnight cultured broth.

609827/0970

Tabel

Minimum inhibitory concentration, given in μκ / ml, of isoclavulanic acid, ampicillin and mixtures of these compounds Regen Staphylococcus aureus Russell and Klebsiella aerogenes EJO

CD O (O OO K)

organism links Ampicillin
(µg / ml) Ampicillin +
1 jig / ml iso-
clavulanic acid
sodium salt Ampicillin +
5 jag / ml iso-
clavulanic acid
sodium salt Ampicillin +
20 jig / ml iso-
clavulanic acid
sodium salt Isoclavulane
acid -
sodium salt
(> ig / mi; Staphylococcus
aureus russell
Klebsiella
aerogenic E70 500
500 3.9
15.6 0.78
12.5 0.39
6.2 125
500

KJ cn cn CTi cn Nj CD

-N

Example 7

C ₆ H ₅ CH ₂ OCONHCH ₂ Co ₂ H

Ή ₂ 0Η

CO ₂ CH ₂ C ₆ H ₅

₂ OOCH ₂
(9) COpCH ₂ C ₆ H ₅

! C ⁷ OCHoCiH

120 mg Isoclavulansäure-benzyl ester (4) with 84 mg benzyloxycarbonylglycine, 32 mg of pyridine and 82 mg of dicyclohexylcarbodiimide in methylene chloride are added at 0 ⁰ C. The solution is stirred overnight at room temperature and then filtered. By
Chromatography over silica gel gives the desired product (9) as a colorless, gummy product in 72 percent yield.

IR (film): 3370, 1810, .1700-1760, 1665 cm " ¹ .

NMR (Z (CDCl ₃ ): 3.02 (IH, dd, J = 17.5 Hz, J '= 1 Hz, 6β-H); 3.49 (IH,

dd, J = 17.5Hz, J '= 3Hz, 6c \ -H); 3.9 (2H, d, J = 6Hz,

; 4.67

(2H, m, C = CH. CH ₂ ), • 5.14 (2H, s, NCHCO ₂ CH ₂ Ph); 5.21 (2H, s,

NHCOCH ₂ C ₆ H ₅ ); 5.46 (IH, bs, NCH.CO ₂ CH ₂ CgH ₅ ); 5.72 (IH, dd, J = 3Hz, J '= 1Hz, 5-H); 7.38 (1OH, s, aromatic proton).

609827/0970

Claims (1)

Claims '1J compounds of the formula I and their salts or esters (D 'CH ₂ OR-COoH in which R is a hydrogen atom or an acyl radical. 2. Compounds according to claim 1 of the formula II and their pharmacologically acceptable salts and esters. (II) CH _n OH 3. Compounds according to claim 1, formula I, in which R is an acyl radical having up to 16 carbon atoms. ¹ I. Compounds according to claim 1 and 3 * characterized in that R is an acyl radical of the following formula 609 8 27/0070 CO-CH- (CH_) 2 η in which η is 0 or an integer from 1 to 3, R is a Hydrogen atom, the phenyl or phenoxy radical, R an aqueous 4 is a material atom or a radical of the formula COpR in which R denotes Denotes phenyl or benzyl radical. 5. Salts according to claim 1 of the formula III in which M is a sodium or potassium ion 6. Esters according to claim 1 of formula IV -0 (III) (IV) in which A is an alkyl, alkenyl, alkynyl, aryl or arylalkyl radical, which optionally has at least one halogen atom, Alkoxy, acyloxy or aryloxy radicals with up to 7 carbon 6098 2 7/0970 atoms or at least one hydroxyl or nitro group or optionally substituted amine group is substituted. 7. Esters according to claim 1 and 6, characterized in that A is the methyl, ethyl, n-propyl, isopropyl, straight-chain or branched butyl, pentyl, heptyl, octyl, nonyl, Decyl, undecyl, dodecyl, vinyl, allyl, butenyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, Cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohexyl, Benzyl, benzhydryl, phenylethyl, naphthylmethyl, phenyl, naphthyl, propynyl, tolyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, acetylmethyl, benzylmethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-dimethylaminopropyl, p-chlorobenzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, m-chlorobenzyl-, 6-methoxynaphthyl-2-methyl-, is p-chlorophenyl or p-methoxyphenyl radical. 8. Esters according to claim 1 and 6, characterized in that A is a residue of formulas a to d CHA ₂ - 0 - CO - A ₃ (a) - CH- - Z - CHA ₄ A ₅ (c) 609827/0970 in which A "is a hydrogen atom or the methyl radical, A is the methyl, butyl or phenyl radical, Z is the ethylene, ethenyl, o-phenylene or 4,5-dimethoxy-o-phenylene radical, A ^ and A ₅ one phenyl, tolyl, halophenyl or methoxyphenyl radical each and Ah is also a hydrogen atom / and Ag is a hydrocarbon radical with 1 to 6 carbon atoms, optionally with at least one chlorine, bromine or iodine atom, a trifluoromethyl, tert-butyl, methoxy, acetyl, benzoyl or acetoxy radical is substituted. 9. Esters according to claim 1 of formula V ■ I 0; CH ₂ OR CO ₂ R ⁵ in which R is defined according to claim 1 and R is a benzyl, naphthylmethyl, benzhydryl, trityl, 4-bromobenzyl, 3, k -direthoxybenzyl, 6-methoxy-2-naphthylmethyl or 4,4-dimethoxybenzhydryl radical. 10. Esters according to claim 1 and 9, characterized in that R is the hydrogen atom. 11. A process for the preparation of the compounds according to claim to 10, characterized in that a compound of the formula VI, its salt or ester is isomerized, 609827/0970 CH ₂ OR (VI) in which R is a hydrogen atom or an acyl radical, and optionally in a conventional manner the carboxylic acid residue in position 2 into another carboxylic acid residue and / or Remainder R converts into another remainder R. 12. The method according to claim 11, characterized in that the isomerization is carried out by contacting the compound · the Formula VI carries out with a transition metal catalyst in the presence of hydrogen. 13. The method according to claim 11 for the preparation of compounds of the formula II or their salt, characterized in that that a compound of the formula VII CH ₂ OH (VII) 609827/0970 in which R is defined according to claim 9, with a transition metal catalyst brings into contact in the presence of hydrogen, thereby producing a salt of the compound of formula II carries out the reaction in the presence of a base. Ik. Process according to Claim 11, characterized in that the isomerization is carried out by UV irradiation of the compound of the formula VI. 15. The method according to claim 11 and I ¹ J, characterized in that the benzyl ester of the compound of formula VI is -.-. shine. according to claim 11. 16. Process / for the preparation of the compounds of the formula I, in which R is an acyl radical, characterized in that one a compound of the formula I in which R is the hydrogen atom, their salt or ester, acylated in a conventional manner. according to claim 11 17. Process / for the preparation of the esters of the compounds of Formula I, characterized in that a compound of the formula I or its salt is esterified in a conventional manner. 18. Medicinal preparations, characterized by a content of one Compound according to claim 1 to 10 as an active ingredient in combination with customary pharmacologically acceptable carriers and / or diluents. 19 · Medicinal preparation according to claim l8, characterized by a additional content of a penicillin or cephalosporin. 609827/0970 20. Medicinal preparation according to claim 18 and 19 _}, characterized in that it is benzylpenicillin, phenoxymethylpenicillin, carbenicillin, methicillin, propicillin, hetacillin, ampicillin, amoxycillin, ticarcillin, cephaloridine, as ß-lactam antibiotic Cephaloglycine, Cefuroxime Cephalothin, Cephalexin, Cefoxitxn, / Cephamandol, the acetoxymethyl ester of benzylpenicillin, the trimethylacetoxymethyl or phthalidyl esters of ampicillin or amoxycillin or the Contains phenyl or indanyl esters of carbenicillin or ticarcillin. 21. Medicinal preparation according to claim 18 to 20, characterized in that that the ratio of the compound of the formula I, its salt or ester, to the β-lactam antibiotic is 5: 1 to 1: 2 amounts to. 22. Medicinal preparation according to claim 18 to 21, characterized in that that the total amount of anti-bacterial agents per unit dose is 100 to 1000 mg. 609827/0970