CH638522A5 - Therapeutically active 6-(alpha-hydroxyethyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid derivatives, and processes for their preparation - Google Patents

Description

The invention relates to therapeutically active compounds of formula III

20th

(III)

coxh wherein the dotted line indicates the unsaturated 2,3-dehydro or saturated 2,3-dihydro compound,

R 'is hydrogen, phenyl, C1-C6-alkyl, alkoxyalkyl having 1 to 6 carbon atoms in the alkoxy group and 1 to 6 carbon atoms in the alkyl group, C2-C6-alkenyl, aralkyl and nucleus-substituted aralkyl having 1 3o to 3 carbon atoms in the alkyl and 6 to 10 carbon atoms in the aryl group and the core substituent being chlorine, fluorine, bromine, iodine, hydroxy, amino or Cj-Qj-alkyl, alkylthioalkyl having 2 to 12 carbon atoms or acyl and X being oxygen or sulfur, 35 and their pharmaceutically acceptable salts and esters. These compounds are valuable antibiotics. The invention further relates to processes for the preparation of these compounds and to pharmaceutical preparations.

40 A preferred compound of the invention is represented by the following structural formula I oh or!

45

A

(VII)

_n_

(I)

cooh o

50

wherein R1 is hydrogen or acyl, is split by hydrogenation.

9. A process for the preparation of a compound of the formula III saturated in the ring system according to claim 1 and its pharmaceutically acceptable salts and esters, wherein R 'and X have the meaning given in claim 1, characterized in that in a corresponding compound of the formula VI, in which R1 is hydrogen or acyl, the hydrogen-bonded side chain is removed by hydrogenative cleavage and the double bond is hydrogenated to a single bond.

10. The method according to claim 9 for the preparation of a compound of the formula IV saturated in the ring system according to claim 3, wherein R ', R and X have the meaning given in claim 3, and pharmaceutically acceptable salts thereof, characterized in that a corresponding compound of formula VII where R1 is hydrogen

These compounds according to the invention are related to the new antibiotic thienamycin. Thienamycin is known by the following structural formula

55

60

Oh

A,

_N_

sch2ch2nh2

cooh

(II)

Thienamycin is described in U.S. Patent 3,950,357 (April 13, 1976). It can serve as a starting product for the preparation of the compounds of the present invention by removing the 3-aminoethylthio side chain.

Thienamycin and its isomers (in pure form and as mixtures) are also obtainable by total synthesis,

638522

4th

which is described in US patent application Ser. No.

833 210 (September 15, 1977). This patent application makes the isomers of II accessible as starting products for the preparation of the compounds of the invention I.

There is a constant need for new antibiotics. Unfortunately, because antibiotics do not have a constant selective activity, resistant strains and pathogens emerge. Furthermore, known antibiotics have the disadvantage that they are only effective against certain types of microorganisms. Therefore, further research into new io antibiotics is required.

Unexpectedly, it has been found that the compounds according to the present invention are broad spectrum antibiotics that are used for human, animal and inanimate systems in the artery. 15

The aforementioned antibiotics are active against a wide range of pathogens, which include gram-positive bacteria such as S. aureus, S. pyogenes and B. subtilis and gram-negative bacteria such as E. coli., Proteus morganii, Klebsiella, and Pseudomonas. 20th

The compounds of the formula I according to the invention are expediently prepared by hydrogenating thienamycin (formula II above) or derivatives thereof, in accordance with the following reaction equation:

or '

O

JSt

VI

sch2ch2nhr coxh

H2 / cat.

)

OR "

A.

I 1}

-jk Ii „coxh

III '

wherein R2 and Rs are independently hydrogen or acyl.

In the above reaction scheme the starting product is preferably an N-acylated thienamycin derivative in which the acyl portion contains an aromatic ring such as e.g. N-phen-oxyacetyl-thienamycin:

35

40

A

-îj o ii

SCH ^ H ^ raC-CH-j-O COOH

- <0

45

50

55

These N-acylated thienamycins, in which the acyl portion is an aromatic ring system, are preferred in the preparation of the compounds according to the invention,

since the desired product after hydrogenation can be easily separated by chromatographic separation of the reaction mixture over such a polystyrene resin which has an affinity for the aromatic nucleus, by cleavage of the cysteaminyl side chain, while the resin has little or no affinity for the decysteaminyl-thienamycin Derivatives according to the invention.

Suitable catalysts for the aforementioned hydrogenation are platinum metals and oxides thereof, such as palladium, platium, rhodium and the like, and Raney nickel. As mentioned above, the thienamycin substrate is preferably an N-acylated thienamycin derivative, the acyl portion being an aromatic residue. The hydrogenation is preferably carried out in a hydrogenation tank, the thienamycin substrate to be reduced being dissolved in water or an aqueous mixture of water and a polar organic solvent such as dioxane, tetrahydrofuran, dimethylformamide (DMF) or the like. The unsaturated derivative, Ia, is obtained in essentially quantitative yield by hydrogenation, as described above, at 0 to 50 ° C. under 1 to 2 atmospheres of hydrogen within 0.5 to 3 hours. The 2,3-dihydro derivative, Ib, is obtained by hydrogenation as described above at 0 to 70 ° C at about 1 to 10 atmospheres of hydrogen within 3 to 10 hours.

As mentioned above, the desired product obtained is obtained from the raw material and from the cystaminyl residue by chromatography on a polystyrene resin such as an XAD-2 resin (manufactured by Rohm & Haas). The separation process is carried out, for example, by entering the reaction mixture into an XAD-2 resin column and then eluting with water. The identification of the desired fractions is carried out by registering the labeled fractions by ultraviolet absorption and liquid high pressure chromatography, HPLC (Waters Associates). Because of the affinity of the aromatic acyl portion for the XAD-2 resin, the separation of the products of the present invention from the starting material and the by-products of the hydrogenation is easily performed. The evaluation of the fractions from the XAD-2 resin is carried out by introducing an aliquot sample (1 jxl) of the fraction in question into the HPLC system, which is equipped with a 254 nm UV detector and a 2 ft. X 1/8 inch id Column loaded with a C18 Bondapak phase reversal absorbent (supplied by Waters Associates). The column is eluted with an aqueous 10% tetrahydrofuran (THF) solution at a flow rate of 0.5 ml / min.

The compounds according to the invention are valuable antibiotics which are active against various gram-positive and gram-negative bacteria and are therefore used for

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638522

in human and veterinary medicine as well as in lifeless systems. The products according to the invention can therefore be used as antibacterial drugs for the treatment of infections caused by gram-positive or gram-negative bacteria, e.g. Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae, Bacillus subtilis, Salmonella typhosa, Pseudomonas and Bacterium proteus. The antibacterial compounds of the invention can also be used as additives for animal foods, for the preparation of animal feed and as disinfectants. For example, they can be used in aqueous preparations in concentrations of about 0.1 to 100 ppm to prevent harmful bacterial growth in medical or dental instruments and as bactericides for industrial applications, e.g. in water-based dyes and in the white water in paper mills.

The compounds according to the invention can be used alone or in combination as an active substance in a large number of pharmaceutical preparations. These antibiotics and their corresponding pharmaceutically acceptable salts, esters and amides can be used in the form of capsules, tablets, powders or liquid solutions such as suspensions or elixirs. They can be administered orally, intravenously or intramuscularly. The pharmaceutically acceptable derivatives are salts of the free amino group, such as, for example, the phosphate, chloride, Ci-trete, and salts, esters and amides of suitable functional groups which carry the substituents R or R '

are.

These pharmaceutical forms of preparation can be prepared by methods that are common in the industry.

The preparations are preferably produced in a form which is suitable for absorption by the gastrointestinal tract. Tablets and capsules for oral administration may be in unit dosages and may contain common excipients such as binders e.g. Syrup, acacia, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone, fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, lubricants for example magnesium stearate, talc, polyethylene glycol, Si02, disintegrants, for example potato starch or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated by known methods. Oral liquid preparations can be in the form of aqueous or oily suspensions, solutions, emulsions, syrups, elixirs etc. or they can be prepared as a dry product, for example for dissolution with water or other suitable carriers. These liquid preparations can contain conventional additives such as, for example, suspending agents, for example sorbitol, syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate, gel or hydrogenated edible oils, e.g. Almond oil, fractionated coconut oil, oily esters, propylene glycol or ethylene glycol, preservatives, e.g. Methyl or propyl p-hydroxybenzoate or sorbic acid. Suppositories can contain common base materials, e.g. Cocoa butter or other glycerides.

Preparations for injection can be in single doses in the form of ampoules or in multiple doses with added preservatives. The preparations can be in the form of suspensions, solutions, emulsions in oil or aqueous vehicles or can contain formulating agents such as suspending, stabilizing and / or dispersing agents. On the other hand, the active substance can be in powder form for preparation with a suitable carrier, e.g. sterile, pyrogen-free water, before use.

The preparations can also be in a suitable form for absorption by the mucosal membrane of the nose and the respiratory or bronchial tissues and can preferably be prepared in the form of powders or liquid sprays or inhalants, lozenges, etc. For the treatment of the eyes and ears, the preparations can be in capsules , in liquid or semi-solid form or they can be used as drops. Topical application forms can be formulated in hydrophobic or hydrophilic bases, such as ointments, creams, lotions, paints or powders.

In addition to the carrier, the preparations can also contain stabilizers, binders, antioxidants, preservatives, lubricants, suspending agents, viscosity-influencing agents and flavoring agents. Further active substances can also be added in order to achieve a broader antibiotic spectrum.

For veterinary use, for example, the preparation can be formulated for intramamma administration of either long-acting or quick-releasing base materials.

The dosage to be administered depends largely on the conditions of the subject to be treated and the weight, frequency of administration, the parenteral route for general infections and the oral route for intestinal infections being preferred. In general, a daily oral dose contains about 15 to 600 mg of the active ingredient per kg. Body weight in one or more administrations per day. A preferred daily dosage for adults is in the range of about 80 to 120 mg of active substance per kg of body weight.

The preparations can be administered in several unit dosages, for example in solid or liquid, orally ingestible doses. The preparations can contain about 0.1 to 99% active substance, preferably 10-60% active substance, per unit dose, either liquid or solid. The preparations generally contain 15 to 1500 mg of the active substance, but it is preferred to use a dosage in the range from about 250 mg to 1000 mg. For parenteral administration, the unit dose is generally the pure compound in a slightly acidified sterile water solution or is in the form of a soluble powder for the preparation of a solution.

The invention is explained in more detail in the following examples.

example 1

Sodium 6- (a.-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept - 2-en-2-carboxylate by hydrogenation of N-phenoxyacetyl-thienamycin sodium salt

Level A

Preparation of the sodium salt of N-phenoxyacetyl-thienamycin

In a 250 ml flask containing thienamycin (190 mg), 30 ml of water, 0.6 g of sodium bicarbonate and 30 ml of dioxane are added. While the mixture was stirred and kept at 0 ° C, phenoxyacetyl chloride (170 mg) was added dropwise over 10 minutes. The solution is stirred for a further 10 minutes and then acidified to pH 4.5 with 30% phosphoric acid. To remove excess reagent and hy-

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

638522

6

drolized product, the phenoxyacetic acid, the acidified solution is quickly extracted with 50 ml of ether. The aqueous layer obtained is further acidified with 30% phosphoric acid to a pH of 2.0 and then extracted with 50 ml of ethyl acetate. The organic layer containing the free N-phenoxyacetyl thienamycin is separated and extracted with 30 ml of an aqueous solution containing 60 mg of sodium bicarbonate. The aqueous layer is freeze-dried and gives 120 mg of N-phenoxyacetyl-thienamycin sodium salt. Electrophoresis (0.5 M, pH 7.0, phosphate buffer, 2KV, 20 minutes): Single bioactive zone that moves 45 mm against the anode.

302 nm.

UV:

Level B

Preparation of the sodium salt of 6- (a-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept-2-ene-2-carboxylate

In a 250 ml hydrogenation container containing 1.4 palladium oxide and 5 ml of water, 73 mg of N-phenoxyacetyl thienylamycin sodium salt in 27 ml of water are added. The mixture is stirred under an atmosphere of hydrogen at 25 ° C. for three hours, after which the catalyst is separated off by filtration. The filtrate is concentrated to 5 ml and charged to an 80 ml XAD-2 resin column. The column is eluted with water in 3 ml fractions and evaluated by UV absorption. The fractions containing the title compound are identified, combined, freeze-dried and give 12 mg of sodium 6- (a-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carb- oxylate. Electrophoresis (0.5 M pH 7.0 phosphate buffer, 2 kv, 20 minutes): single bioactive zone that moves 70 mm against the anord.

UV:

1 H2 °

A max

265 nm.

100 MHz NMR (D20): 1.29 (d), 2.86 (m), 3.39 (q), 4.24 (quintet), 4.26 (dt) and 6.27 ppm (q). The antibacterial activity of this compound is inhibited by β-lactamase.

Example 2

Sodium 6- (a, -hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] heptane - 2-carboxylate by hydrogenation of N-phenoxyacetyl-thien-amycin sodium salt

5

The reaction described in Example 1, Step B is repeated except that the reaction time is extended to 6 hours. Fractionation of the reaction mixture in the XAD-2 column and elution with io water gives 3 ml fractions. Fractions No. 15 to No. 60, which were identified by UV absorption, are combined and determined as the unsaturated product according to Example 1. Fractions Nos. 1 to 14, which show no UV absorption, are tested bio-15 on MB-108 plates and show that the activity begins with Fraction No. 6, with a peak in Fraction 9 and decreased in Fraction No. 13. The antibacterial activity of these fractions is inhibited by ß-lactamase. Fractions No. 9 to No. 13 are evaporated to dryness 20 and give 0.5 mg of the title compound.

Example 3

Sodium 6- (a, -hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept - 2-en-2-carboxylate by hydrogenation of thienamycin sodium salt

25th

Following the procedure of Example 1, Step B, except replacing N-phenoxyacetyl-thienamycin 30 with an equivalent amount of thienamycin, the title compound is obtained from the reaction mixture by preparative thin layer chromatography using 20% methanol in water as Eluent is obtained on silica gel plates (silica gel GF, Analtech Inc.).

Example 4

Production of benzyl-6- (a-hydroxyethyl) -7-oxo-l-azabi-40 cycto- [3.2.0] -hept-2-en-2-carboxylate (IIa)

OH

A.

CO 2 ^ a

(la)

->

(IIa)

R = CH2C6H5

Sodium 6- (a-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] -ss -hept-2-en-2-carboxylate (Ia) 5 mg is mixed with benzyl bromide (0.2 ml) in hexamethylphosphoramide (0.5 ml) stirred at 25 ° C for 30 minutes. 5 ml of ethyl acetate are added to the mixture. After the mixture has been thoroughly washed with water, the organic layer is separated off, dried over sodium sulfate and concentrated to 0.2 ml. The desired product (3.0 mg) is isolated by TLC, silica gel GF plates (Rf 0.31, 20% ethyl acetate / chloroform). The product shows an IR absorption at 1780 cm-1 (β-lactam), UV absorption at 276 nm, mass spectrum 65 at m / e 287 (molecular ion) and NMR resonance at 3.18 ppm (q, J = 3 , 0 and 6.0 Hz), which data correspond to the assumed structure (II, R = CH2-C6H5).

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638522

Example 5

Preparation of benzyl-6- (a-acetoxyethyl) -7-oxo-l-azabi-cyclo [3.2.0] -hept-2-en-2-carboxylate (Hb)

OH

A

/ 7_N_Ü

o ac 2 ° / py

XC02CH2.

• 0

(Ib)

Benzyl 6- (a-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] -hept-2-en-2-carboxylate (Ib) (18 mg) are dissolved in 1 ml of pyridine (Py) and 0. 2 ml of acetic anhydride (AczO) dissolved. The mixture is stirred for 3 hours at 25 ° C. and then evaporated to dryness, an oily residue being formed. The residue is dissolved in 0.2 ml of chloroform and chromatographed on two 20 X 20 cm, 250 N silica gel TLC plates (Rf 0.56, 20% ethyl acetate / chloroform) and gives 4 mg of the desired product (IIb). NMR (CDC13, 60 MHz) resonances at 2.02 (s, OAc) and 6.48 (t, vinyl proton) and 7.40 ppm (m, aromatic protons) and IR (CHCI3) carbonyl vibrations at 1780 (ß-lactam) and 1740 cm-1 (ester).

OAc co2ch

-. (IIb)

20th

25th

Example 6

Production of sodium 6 - (<x-acetoxyethyl) -7-oxo-l-azabi-cyclo [3.2.0] -hept-2-en-2-carboxylate (Ile)

OAc

30th

C02CH2

(Ic)

Benzyl-6- (a-acetoxyethyl) -7-oxo-l-azabicycIo [3.2.0] -hept-2-en-2-carboxylate (Ic) (4 mg) are dissolved in 2 ml of dioxane and 2 ml of phosphate powder (0 , 1 M, pH 7.0). The mixture is stirred at 25 ° C. under 1 atmosphere of hydrogen in the presence of a 10% Pd / C catalyst (10 mg) for 10 minutes. The mixture is then filtered off from catalyst and extracted with five times 2 ml of ether. The aqueous layer is separated, freeze-dried and gives 1 mg of the title compound, which is biologically active against Staphylococcus. The product has UV absorption at 268 nm and an HPLC retention time of 6.5 minutes compared to 3.2 minutes for the 6- (a-hydroxy) analog (2 ft. X 1/8 in. C18 Bondapak column , eluted with an aqueous 10% THF solution at a flow rate of 0.5 ml / min).

Example 7

According to the procedure of Example 4, with the exception that for benzyl bromide according to Example 5 an equivalent amount of bromomethyl pivalate, l-bromo-3-methyl-2-butene, l-chloro-2-methylpropane, p-tert. Butylbenzyl bromide and 3-bromophthalide are used, the corresponding esters are obtained:

OAC

.A / X

Kö>

.ft

C02 ° Na®

45

50

-the)

R

Pivaloyloxymethyl, 3-methyl-2-buten-1-yl, 2-methyl-2-propen-l-yl, p-tert-butyl-benzyl and phthalidyl.

Example 8

It is processed according to the method of Example 5 gear-55, with the acetic anhydride / pyridine of Example 5 being replaced by:

an equivalent amount of ethyl chloroformate in the presence of an equivalent amount of triethylamine in the presence of methylene chloride as solvent, 60 methyl iodide in the presence of an equivalent amount of lithium diisopropylamide in the presence of dimethylformamide,

Methanesulfonyl chloride in the presence of an equivalent amount of triethylamine with methylene chloride as the solvent, and

Dimethyl phosphorochloridate in the presence of an equivalent amount of triethylamine with methylene chloride as solvent,

638522

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the following compounds (O-R ') are obtained: O-ethoxycarbonyl, O-methyl, O-methanesulfonyl and O-dimethoxyphospinyl derivatives of benzyl-6- (a-hydroxy-ethyl) -7-oxo -1-azabicyclo [3.2.0] hept-2-en-2-carboxylate.

Example 9

The procedure of Example 6 was followed, with benzyl-6- (a-acetoxyethyl) -7-oxo-l-azabicyclo [3.2.0] - hept-2-ene-2-carboxylate being replaced by: an equivalent Amount of O-ethoxycarbonyl, O-methyl, and O-dimethoxyphosphinyl derivatives of benzyl-6- (a-hydroxyethyl) - 7-oxo-l-azabicyclo [3.2.0] -hept-en-2 carboxylate. The following compounds were obtained: O-ethyloxycarbonyl, O-methyl and O-dimethoxyphosphinyl derivatives of sodium 6- (a-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] -hept-2 --en-2-carboxylate.

Example 10

Manufacture of pharmaceutical preparations

A unit dosage form is made by mixing 120 mg of pivaloyloxymethyl-6- (a-hydroxyethyl) - 7-oxo-l-azabicyclo [3.2.0] -hept-2-ene-2-carboxylate with 20 mg of lactose and 5 mg of magnesium stearate and placing the mixture (145 mg) in a No. 3 gelatin capsule. Similarly, but using more of the active ingredient and less lactose, other dosage forms can be processed in No. 3 gelatin capsules and optionally more than 145 mg of the Mixed ingredients, larger capsules like compressed tablets and pills are made. The following examples illustrate the manufacture of pharmaceutical formulations:

tablet

Per tablet

Pivaloyloxymethyl-6- (a-hydroxyethyl) - 7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate

125

mg

Grain Starch, U.S.P.

6

mg

Dicalcium phosphate

192

mg

Lactose, U.S.P.

190

mg

The active substance is mixed with calcium phosphate, lactose and about half the grain strength. Then the mixture is granulated with 15% starch paste (6 mg) and sieved raw. It is dried at 45 ° C and 5 sieved through No. 16 sieves. The remaining grain starch and the magnesium stearate are added and the mixture is compressed into tablets approximately 0.5 inches in diameter and 800 mg in weight.

io Parenteral solution

Ampoule:

Sodium 6- (a-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] hept-2-en-2-carboxylate 500 mg

15 Diluent: sterile water for injection 2 cc

Ophthalmic solution

Sodium 6- (a-hydroxyethyl) -7-oxo-l-azabicy-20 clo [3.2.0] hept-2-ene-2-carboxylate 100 mg

Hydroxypropylmethyl cellulose 5 mg

Sterile water to 1 ml

Otic solution 25 sodium 6- (a-hydroxyethyl) -7-oxo-l-azabicy-

clo [3.2.0] hept-2-en-2-carboxylate 100 mg

Benzalkonium chloride 0.1 mg

Sterile water to 1 ml

30 topical ointment

PivaIoyloxymethyI-6- (a-hydroxyethyl) -7-oxo-l-azabicyclo [3.2.0] -hept-2-en-2-carboxylate 100 mg

Polyethylene Glycol 4000 U.S.P. 400 mg

Polyethylene Glycol 400 U.S.P. 1.0 g

35

The active substance in the above formulations can be used alone or in combination with other biologically active substances, for example with other antibacterial agents such as lincomycin, a penicillin, strepto-40 mycin, novobiocin, gentamicin, neomycin, kolistin and kanamycin or with other therapeutic agents such as probenecid will.

45

v

Claims (9)

638522 2nd PATENT CLAIMS 1. Compound of Formula III (iii) coxh where the dotted line indicates the unsaturated 2,3-dehydro or saturated 2,3-dihydro compound, R 'is water, phenyl, CrC6-alkyl, alkoxy-alkyl with 1 to 6 carbon atoms in the alkoxy group and 1 to 6 carbon atoms in the alkyl group, C2-C6 - alkenyl, aralkyl and nucleus-substituted aralkyl with 1 to 3 carbon atoms in the Alkyl and 6 to 10 carbon atoms in the aryl group and the core substituent being chlorine, fluorine, bromine, iodine, hydroxyl, amino or CrCG-alkyl, alkylthioalkyl having 2 to 12 carbon atoms, acyl, thioacyl, sulfo or alkali metal sulfonate group or dimethoxyphosphinyl and X is oxygen or sulfur, and their pharmaceutically acceptable salts and esters. 2. Compound according to claim 1 of formula I. (I) cooh 3. Compound of formula IV according to claim 1 OR ' COXR atoms, aryloxy with 6 to 10 carbon atoms, aralkoxy and nucleus-substituted aralkoxy, the alkoxy group having 1 to 3 carbon atoms and the nucleus substituent nitro, Chlorine, bromine, fluorine, iodine and alkyl having 1 to 6 carbon atoms, aryl having 6 to 10 carbon atoms, alkenyl having 2 to 6 carbon atoms, benzyl, haloalkyl and perhaloalkyl, in which the halogen is chlorine, bromine or fluorine, and the alkyl has 1 to 6 carbon atoms, X is oxygen or sulfur, io R is hydrogen, benzhydryl, phthalidyl, alkyl having 1 to 10 carbon atoms, phenacyl and nucleus-substituted phenacyl, where the substituents are chlorine, bromine, fluorine and alkyl having 1 to 6 carbon atoms, alkoxyalkyl having 1 to 6 carbon atoms in the alkoxy and 1 to 6 carbon atoms in the alkyl group, alkanoyloxyalkyl with 2 to 12 carbon atoms, halogen and perhaloalkyl, the halogen being chlorine, bromine or fluorine and the alkyl chain having 1 to 6 carbon atoms, alkenyl having 2 to 6 carbon atoms, aralkyl having 1 to 3 carbon atoms 20 in the alkyl and 6 to 10 carbon atoms in the aryl radical, heteroalkyl, where the heteroatom is oxygen, sulfur or nitrogen, nucleus-substituted aralkyl and heteroaralkyl, where the substituent is chlorine, fluorine, bromine, iodine and alkyl with 1 to 6 carbon atoms, alkoxy with 1 to 6 Koh-25 lenstoffatomen, heterocyclyalkyl, where the heterocycle has 4 to 10 carbon atoms and the heteroatom is oxygen, sulfur or nitrogen and the alkyl group has 1 to 6 carbon atoms, indanylmethyl, aryl and nucleus-substituted aryl with 6 to 10 ring carbon atoms, with 30 of the core substituent hydroxy, 5- Is indanyl, alkyl having 1 to 6 carbon atoms, chlorine, fluorine, bromine, alkylthioalkyl having 2 to 12 carbon atoms, cycloalkylthioalkyl having 4 to 12 Carbon atoms, acylthioalkyl, the acyl radical Has 2 to 10 carbon atoms and the alkyl radical has 1 to 6 carbon atoms, and pharmaceutically acceptable Salts thereof. 4. A compound according to claim 3 of formula V. OR ' 40 (IV) 45 (V) C0XR wherein the dotted line indicates the unsaturated 2,3-dehydro or saturated 2,3-dihydro compound, R 'is hydrogen, phenyl, QQ-alkyl, alkoxyalkyl having 1 to 6 carbon atoms in the alkoxy group and 1 to 6 carbon atoms in the Alkyl group, C2-C6-alkenyl, aralkyl and nucleus-substituted aralkyl with 1 to 3 carbon atoms in the alkyl and 6 to 10 carbon atoms in the aryl group and wherein the nucleus substituent is chlorine, fluorine, bromine, iodine, hydroxy, amino or Cj-Q-alkyl is alkylthioalkyl having 2 to 12 carbon atoms or a group of the formula X ' -CR "or -SO, S M © wherein M + is hydrogen or an alkali metal cation, X 'is oxygen or sulfur and R "is hydrogen, amino, mono- or dialkylamino, in which the alkyl group has 1 to 6 carbon atoms, alkyl with 1 to 6 carbon atoms, phenylthio and nucleus-substituted phenylthio, where the nucleus substituent Alkyl with 1 to 6 carbon atoms, chlorine, Is fluorine, bromine or iodine, alkoxy with 1 to 6 carbon wherein R ', R and X have the meaning given in claim 3. so 5. A compound according to claim 4, characterized in that R 'is hydrogen, alkyl having 1 to 6 carbon atoms, allyl, 2-methyl-2-propenyl, benzyl, p-bromobenzyl, p-tert-butylbenzyl, alkylthioalkyl having 2 to 8 carbon atoms, a group of the formula: 55 O II -CR "or -SO30 M © 60 wherein R "is hydrogen, amino, mono- and dialkylamino, with 1 to 6 carbon atoms in the alkyl moiety, alkyl with 1 to 6 carbon atoms, phenylthio, alkoxy with 1 to 6 carbon atoms, phenoxy, benzyloxy, p-nitrobenzyloxy, phenyl, allyl, 2 Methyl 2-propenyl, benzyl, halogen or 65 perhaloalkyl having 1 to 6 carbon atoms, the halogen being chlorine, fluorine or bromine R is hydrogen, alkyl of 1 to 6 carbon atoms, phenacyl, p-bromophenacyl, pivaloyloxymethyl, halogen 3rd 638522 or perhaloalkyl having 1 to 6 carbon atoms, the halogen being chlorine, fluorine or bromine, alkenyl having 2 to 6 carbon atoms, benzyl, benzylhydryl, p-tert-butyl-benzyl, p-bromobenzyl, phthalidyl, 5-indanylmethyl, phenyl, 5-indanyl, acetylthiomethyl, acetylthioethyl, pivaloylthio-methyl, alkylthioalkyl of 2 to 6 carbon atoms, and X is oxygen. 6. A compound according to claim 4, characterized in that R 'is hydrogen, methyl, allyl, phenyl, benzyl, methylthiomethyl, formyl, sulfoacetyl, carbamoyl, bromoacetyl, ethoxycarbonyl, p-nitrobenzyloxycarbonyl, X oxygen, R is hydrogen, methyl, tert-butyl, phenacyl, p-bromophenacyl, pivaoyloxymethyl, 2,2,2-trichloroethyl, allyl, 3-methyl-2-butenyl, 2-methyl-2-propenyl, benzyl, Benzylhydryl, p-tert-butylbenzyl, phthalidyl, phenyl, 5-indanyl, acetylthiomethyl, acetylthioethyl, pivalylthiomethyl, methylthiomethyl. 7. A process for the preparation of a compound of the formula III which is monounsaturated in the ring system and its pharmaceutically acceptable salts and esters, in which R 'and X have the meaning given in claim 1, characterized in that in a corresponding compound of the formula VI or ' SCH2CH2NHfT (Vi) coxh in which R1 is hydrogen or acyl, the hydrogen-bonded side chain is removed by hydrogenation. 8. The method according to claim 7 for the preparation of a ring system monounsaturated compound of formula IV according to claim 3, wherein R ', R and X have the meaning given in claim 3, and pharmaceutically acceptable salts thereof, characterized in that a corresponding compound of Formula VII or is acyl, is hydrogenated and cleaved and the double bond is hydrogenated. 11. Antibiotic, pharmaceutical preparation containing in a unit dose a therapeutically effective amount of a compound according to claim 1 in combination with a pharmaceutical carrier. 12. Antibiotic, pharmaceutical preparation according to claim 11, containing a compound according to claim 3. 10th