CH654308A5 - PENEM-3-CARBONIC ACID DERIVATIVES AND THEIR PRODUCTION. - Google Patents

Description

The present invention relates to a new Pe-nem-3-carboxylic acid, salts thereof and esters thereof, furthermore to processes for the preparation of these compounds and their use as antimicrobial agents.

The penicillins form a well-known class of antibiotics, which have proven their worth in human and animal therapy for many years. Chemically, the penicillins have a ß-lactam structure, commonly referred to as "penam", in common, which corresponds to the following general formula:

■ s-

0 ^

6

5 1

2nd

-H

4th

3rd

COOH

io in which Ra and Rb are hydrogen atoms or various organic groups, n is 1 or 2 and Rc is, inter alia, an alkylthio group having 1 to 6 carbon atoms, it being possible for these compounds to carry one or more chlorine, bromine or fluorine atoms as substituents.

i5 European Patent Specification No. 3960 represents a similar class of compounds, which compounds have the following general formula:

rd>

20th

r

0 ^

• CORf

25th

30th

where Rd is different organic groups, Rf is the hydroxyl group or various organic groups and R3 is, inter alia, a haloethylthio group, e.g. a chloroethyl-thio or a bromoethylthio group.

Furthermore, Japanese patent application Kokai (published, but not yet examined) No. 153.789 / 80 discloses 2- (2-bromoethylthio) -6- (1-hydroxyethyl) penem-3-carboxylic acid of the following formula:

35

40

H3C

OH

A

SV./SCH2 CH2 Br

0 ^ "

• COOH '

Some of the valuable penicillin derivatives have a carbon-carbon double bond between the 2 and 3 positions, the structure having such a double bond being referred to as “penem”. These pe-nam and penem structures form the basis for the semi-systematic nomenclature of penicillin derivatives. This nomenclature is generally accepted by the person skilled in the art and is also used in the present text. The numbering system used is illustrated by the above formula.

Although the known penicillins are a valuable control agent in pharmacy, the development of new and often penicillin-resistant strains of pathogenic bacteria has increasingly shown that the search for new antibiotics is necessary. As a result, various penem compounds have been synthesized in order to achieve a stronger antibacterial activity, a broader antibacterial spectrum and / or a better activity against penicillin-resistant pathogenic microorganisms.

For example, U.S. Patent No. 4,260,618 discloses a class of penem compounds of the following general formula:

Another specific compound with its salts and esters has now been found which, although very closely related to the 45 known compounds mentioned above, has significant advantages in terms of their antimicrobial activity both in vitro and in vivo, in terms of their chemical resistance, and in their behavior in a metabolized state and with regard to their absorption into the bloodstream.

The compounds according to the invention are 2- (2-fluoroethylthio) -6- (1-hydroxyethyl) penem-3-carboxylic acid of the following formula:

50

S-CH2CH2F

COOH

(I)

and their pharmaceutically acceptable salts and esters.

Although all pharmaceutically acceptable salts and esters of the compound of formula I are valuable, it was surprisingly found that a very specific specific ester has a much better blood concentration and recovery rate in the urine than the other salts and esters. As is well known, one is in this field

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it is better to administer a salt or an ester than the free acid to ensure improved solubility or absorption through the digestive tract. It should also be noted that the recovery of this ester in the urine and the blood concentration can be several times better than when using other salts and esters. This excellent ester is the (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl ester.

The compound of formula I can be used in the form of a pharmaceutically acceptable salt. Examples of such salts include those with metals such as e.g. Lithium, sodium, potassium, calcium and magnesium, those with ammonia or an organic amine, e.g. the ammonium, cyclohexylammonium, diisopropylammonium or triethylammonium salts, and those with basic amino acids such as e.g. Lysine or arginine. Of these salts, the sodium and potassium salts are preferred.

If the compound according to the invention is used in the form of an ester, the ester used is preferably one which can be activated in vivo by metabolism. Examples of such esters are the acetoxymeth-yl, pivaloyloxymethyl, 1-ethoxycarbonyloxyethyl, phthalidyl and (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl esters, the latter of which are derived from most preferred esters for the above reasons.

The compounds according to the invention are represented by a flat formula. It should be borne in mind that the compounds according to the invention can exist in the form of various optical isomers due to the presence of a certain number of asymmetric carbon atoms and, moreover, also in the form of various geometric isomers. Both the individual isomers and the mixtures, e.g. Racemates of such compounds are encompassed by the present invention. The preferred compounds, however, are those with the same configuration as thienamycin, i.e. the (5R, 6S) and 6- [l- (R)] configurations.

The compounds according to the invention can be obtained by using a compound of the following general formula:

H3c ori

A

0 ^

(II)

\ R2

wherein R1 is a group protecting the hydroxyl group and R2 is a protected carboxyl group, with a compound of the following general formula:

X-CH2CH2F

(iii)

wherein X represents a removable group, to give a compound of the following general formula:

s-ch2ch2f

(IV)

wherein R1 and R2 have the above meanings. The protecting group represented by the symbol R1 is then removed to obtain a free hydroxyl group by converting the protected carboxyl group represented by R2 to a free carboxyl group before, after or simultaneously with the removal of the group protecting the hydroxyl group represented by R1 in this way to obtain 5 of the desired compound according to the invention. If the free acid of the formula I is obtained, it can then be converted into a salt or esterified, or in those cases in which the compound is isolated from the reaction mixture in the form of a salt, these salts can be used in a manner known per se convert to free acid or esterify.

The cleavable group represented by the symbol X in the compound of formula III can be, for example, the hydroxyl group a halogen atom, e.g. a bromine or iodine atom, an alkanesulfonyloxy group, e.g. a methansulfonyloxy or ethanesulfonyloxy group, a haloalkanesulfonyloxy group, e.g. a trifluoromethanesulfonyloxy group or an arylsulfonyloxy group, e.g. a benzenesulfonyloxy or p-toluenesulfonyloxy group. 20 The reaction of a compound of formula II with a compound of formula III, wherein X represents any of the groups defined above except for the hydroxyl group, to form a compound of formula IV is preferably carried out in an inert solvent and in the presence of a base. The nature of the solvent to be used in this reaction is not important, provided that the solvent does not adversely affect the reaction. Examples of such solvents are halogenated hydrocarbons, e.g. Chloroform, methylene-3o chloride or ethylene dichloride, ether, such as e.g. Diethyl ether or tetrahydrofuran, nitromethane, a mixture of one or more of these solvents with water or with another organic solvent or a mixture of two or more of any of these solvents. The nature of the base to be used is also not restricted to certain limits, provided that the base does not adversely affect other parts of the compound, in particular the β-lactam ring. The base reacts as an acid-binding agent, so that any compound that is suitable and known for this purpose can be used. Examples of such organic bases are triethylamine, pyridine, 2,6-lutidine or N, N-dimethylaniline, alkali metal and alkaline earth metal carbonates such as e.g. Sodium carbonate, potassium carbonate or calcium carbonate, and alkali metal bicarbonates such as 45 sodium bicarbonate.

Although the reaction temperature is also of no importance, the reaction is preferably carried out at a relatively low temperature in order to avoid side reactions. For this purpose, a temperature in the range between -10 ° C and +100 ° C is preferred. The time required for the reaction depends mainly on the reaction temperature and the nature of the starting materials. In general, the reaction is completed within a few minutes to 200 hours. After the reaction has ended, the desired compound of the formula IV can be obtained from the reaction mixture in a manner known per se. A suitable recovery sequence is, for example, the following. The reaction mixture is diluted with a water-immiscible organic solvent, the mixture is washed with water and the solvent is distilled off to obtain the desired compound. This compound can then be further purified if necessary in the customary manner, for example by recrystallization, by falling over or by chromatography.

In those cases in which the compound of the formula IV, as has been obtained according to the above information, is obtained in the form of the 5S isomer, this isomer can be obtained

5 654 308

Heating either alone or in the presence of an organic but the reaction is usually carried out within several

Solvents such as e.g. Toluene, xylene, N, N-dimethylformers should be finished in minutes to 100 hours.

amide or N, N-dimethylacetamide, in the corresponding 5R- After completion of the reaction, the resulting

Transfer isomer. To prevent side reactions, compound can be prepared in a manner known per se from the reaction

if necessary, this reaction can be obtained in the presence of a polymer. For example, you can use this merization inhibitor, e.g. Hydroquinone. Purpose as follows, namely by filtering the

In those cases in which a compound of the insoluble constituents is used, washing the mei III obtained as filtrate, in which X represents the hydroxyl group, an organic solution with water, drying the organic solution, the reaction is preferably carried out by reacting the Solution and then distilling off the solvent compound of formula II with the compound of formula III, io tels, whereby the desired compound is obtained, ie 2-fluoroethanol, in the presence of triphenylphosphine if desired in a known manner, e.g. by recrystallized and an azodicarboxylic acid dialkyl ester, e.g. Azodicarizing, by preparative thin layer chromatography or ethyl bonsate. by column chromatography, can further purify.

This reaction is preferably carried out in the presence of a similarly protecting the hydroxyl group.

inert solvent, the nature of which is not of 15 Group R1 known, before, after or at the same time

interpretation is provided that this solvent does not adversely affect the immediate elimination of the carboxyl group-protecting setting. Examples of suitable Lö group removed in the manner described above. Thieves-

agents include ethers such as e.g. Diet ether, tetrahy- ability of the group R1 protecting the hydroxyl group

drofuran or dioxane, as well as aromatic hydrocarbons is not important by using any such substances, e.g. Benzene or toluene, and finally also Mi- group, as is usually used for such reactions of these mixtures of two or more of this type of solution. But you get medium. preferably an aralkyloxycarbonyl

Although the reaction temperature is not particularly grapple, e.g. is a benzyloxycarbonyl or p-nitrobenzyloxy meaning, the reaction is preferably carried out with an e-carbonyl group, or a trialkylsilyl group, e.g. Carry out a triner at a relatively low temperature in order to prevent secondary re-methylsilyl or tert-butyldimethylsilyl groups, and completely actions. It is therefore preferred to use a tert-butyldimethylsilyl group, a reaction temperature in the range between −20 ° C. and.

Use dangerous ambient temperature. If R1 is an aralkyloxycarbonyl group, e.g. a time required mainly depends on the reac- nitrobenzyloxycarbonyl group, means the same temperature can be depended on and the nature of the aus by treating the corresponding compound in a raw material, but in general a reac reducing agent will be removed. The type of reducing agent lasts from several minutes to 100 hours and the reaction conditions for removing a sol-rich one. The groups protecting the hydroxyl group are diesel. After the reaction has ended, the verbs obtained can, as already described in connection with the binding of the formula IV, in a manner known per se, for example on the side of the group protecting the carboxyl group, which way according to the recovery sequence described above, which is contained in the group represented by R2, can be obtained from the reaction mixture. If desired, the group protecting the carboxyl group and the compound obtained, provided that the 5S group protecting the hydroxyl group is removed at the same time, can be heated by heating it to the corresponding 5R iso.

mer convict. 40 In those cases where R1 is a trialkylsilyl group, e.g.

If it is still present, which means that the carboxyl group is a tert-butyldimethylsilyl group, the protective group can then be removed in a manner known per se by treating the compound in question from the resulting compound of the formula IV with a fluoride ion-generating compound Connection, e.g. Tetra-whereby the free carboxylic acid is obtained. The butylammonium fluoride to be used, or with an acid such as e.g. Salt reaction conditions for removing the carboxylic acid, sulfuric acid or acetic acid, but preferably a group protecting group depend, of course, on the fluoride ion-producing compound. The reac- the type of group used. The carboxyl group ion is preferably carried out in the presence of a solvent, the protecting group is preferably an aralkyl group, the nature of which is not particularly important, for example a benzyl or p-nitrobenzyl group, in particular provided that there is no disadvantageous one with regard to the reaction p-nitrobenzyl group, because these groups easily exert such effects. An ether is preferably removed by reduction. For this implementation e.g. Tetrahydrofuran or dioxane, various reducing agents can be used as solvents, but turn.

preferably a catalytic reduction is carried out.

Use hydrogen and a suitable catalyst between ambient temperature and 60 ° C, where

tors, preferably palladium-on-carbon. This ss the working time for this implementation between several

Implementation usually takes place in the presence of a Lö minutes and can fluctuate for 100 hours.

after the removal of the protective group or protective group.

provided that there is no disadvantage for the reaction, the resulting compound of the formula I will be effective. Preferred solvents include alcohols, which are known to be obtained from the reaction mixture,

such as. Methanol or ethanol, ether such as e.g. Tetrahydro and if necessary, they can be used in a manner known per se, such as furan or dioxane, fatty acids, e.g. Acetic acid, e.g. by recrystallization, preparative thin-layer chromatography

Further purify mixtures of one or more of these organic lematography or column chromatography,

solvent with water or with a phosphate buffer solution. In cases where the specified by R2

The reaction temperature is also not limited to certain carboxyl groups in a compound of the formula IV

zen bound, although usually represents an esterified carboxyl group at temperatures 65, and in particular from 0 ° C to about ambient temperature, when the ester group is one of the preferred groups

The required reaction time largely depends on how it is described above in connection with the

Kind of the starting materials and the reducing agents, fertilize the invention have been described, and quite

654 308

especially when it is a (5-methyl-2-oxo-1,3-di-oxolen-4-yl) methoxycarbonyl group, it may not be necessary to remove the group protecting the carboxyl group by the desired one Ester can be obtained directly. In this case, the reaction chosen to remove the group R1 protecting the hydroxyl group should be controlled so that the esterified carboxyl group remains untouched.

If desired, the compound of formula I obtained, or a salt or ester thereof, in the presence of the 5S configuration, can be heated by the presence or absence of an organic solvent in the manner described in connection with the compound of formula IV has been converted to the corresponding isomer with the 5R configuration.

According to a further process, the compounds according to the invention can be obtained by using a compound of the following general formula:

orl h3c

ORl

A

he-

0 ^

(II

^ SG ^ CHjF

R2

H3C

ORl

A

heat

0 ^

in the)

scfy chjf

R2

h3c

ORl

X

0 ^

T

SCH2CH2F

[U)

h3c

A

.S

0 ^

C II

N S \ Q / Z ©

R2

s-ch2ch2f wherein R1 and R2 have the meanings described above and Z + is a trialkylphosphono group, e.g. a tributylphosphono group, a triarylphosphono group, e.g. a triphenylphosphono group, or a doubly esterified phosphono group combined with a cation, e.g. a di-ethylphosphono group combined with a lithium or sodium ion means heated, whereby a compound of formula IV is obtained, whereupon the group protecting the hydroxyl group represented by R1 is removed and, if the protective group is still present, the protected group represented by R2 Carboxyl group converted into a free carboxyl group.

This implementation is described in British Patent No. 2,048,261. The compounds of the formula V, as are suitable as starting materials for this reaction, can also be prepared in accordance with that patent, the entire course of the reaction being illustrated by the following reaction scheme:

In the above formulas, the symbol Y represents an alk-anoyloxy group, e.g. an acetoxy or propionyloxy-15 grappe, an alkanesulfonyl group, e.g. a methanesulfonyl or ethanesulfonyl group, an arylsulfonyl group, e.g.

a benzenesulfonyl or p-toluenesulfonyl group, a halogen atom, e.g. a chlorine, bromine or iodine atom, but preferably an acetoxy or methanesulfonyl group or a chlorine atom and more preferably an acetoxy group. The symbol M means an alkali metal, e.g. Sodium, potassium or lithium and preferably sodium. The symbol R3 means an alkyl group, e.g. a methyl, ethyl, propyl, iso-propyl or butyl group, or an aryl group, e.g. a '25 phenyl group, and preferably the methyl group. The symbol R4 represents an alkyl group, e.g. represents a methyl, ethyl, propyl, isopropyl or butyl group, and preferably the methyl group. Shark means a halogen atom, e.g. a chlorine, bromine or iodine atom. The symbol R is the hydrogen atom or an esterified carboxyl group. The symbols Z +, R1 and R2 have the above meanings.

The above-mentioned reaction sequence is known from British Patent No. 2,048,261, as has already been mentioned. All details of the reaction are described in the patent. It is important in this particular reaction scheme, however, that in the first stage of work, i.e. in the reaction of a compound of the formula VI with the carbon disulfide and the compounds of the formulas VII and VIII in order to form a compound of the formula EX, the compounds of the formulas VII and VIII and the carbon disulfide are simultaneously reacted in advance to give a largely stable intermediate of get the following formula:

30th

35

S

II

[MS-C-

S-CH2CH2F]

(XIII)

'sch2ch2f

♦ ohc'cr? III

h3c

ORl

A

m]

Y

• a n oh where M has the meaning given above, whereupon this compound is reacted with a compound of formula VI. According to the reaction disclosed in the above-mentioned British patent, the compound of formula VII, the compound of formula VIII and the carbon disulfide are gradually added in this order to a compound of For-55 mei VI, but it has been found that if this order is followed in the present case, the compounds of the formula IX are obtained in extremely poor yield because the compound of the formula VII and the compound of the formula VIII form one another with an unstable intermediate product, ie a metal salt of 2-fluoroethane

thiol, react and this latter metal salt quickly subsides

Formation of ethylene sulfide decomposes.

The esters of the compound of the formula I can be obtained by conventional esterification processes, starting from a compound phosphine or from the formula in the form of the free acid or a salt

- 'v thereof, or by conventional transesterification, starting from another ester. In the case of the most preferred ester, i.e. des (5-methyl-2-oxo-l, 3-

-SCH2CH2F halogenating agent

SCH2CH2F

Phosphite ester

dioxolen-4-yl) methyl ester, the same can, for example, by a conventional esterification reaction, for example of a 4-halomethyl-5-methyl-1,3-dioxolen-2-one, e.g. 4-bromo-methyl-5-methyl-l, 3-dioxolen-2-one, with the free acid or a salt thereof, preferably an alkali metal salt. Such a reaction using a salt of the acid of formula I is particularly convenient, but when using the free acid for this reaction the same effect can be achieved by using the free acid in the presence of a base.

Such esterification reactions usually take place in the presence of a solvent, the nature of which is not particularly important, provided that the solvent does not adversely affect the reaction. Examples of suitable solvents include N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, Ni-tromethane, acetonitrile, acetone, tetrahydrofuran, dioxane, methanol, ethanol, chloroform, methylene chloride, benzene or toluene, but preferably N, N- Dimethylformamide, N, N-dimethylacetamide or dimethyl sulfoxide.

As has already been mentioned, the reaction takes place in those cases in which the esterification reaction is carried out using the free acid of the formula I and a 4-Ha-logenmethyl-5-methyl-1,3-dioxolen-2-one, preferably in the presence of a base. An organic base, e.g. Use triethylamine or dicyclohexylamine, or an inorganic base and in particular an alkali metal or alkaline earth metal carbonate or bicarbonate, for example sodium bicarbonate, sodium carbonate, potassium carbonate or calcium carbonate.

The reaction temperature is also not particularly important, although the reaction is preferably carried out at a relatively low temperature in order to minimize side reactions. The preferred temperature is 0 ° C to 100 ° C. The time required for the reaction depends on the reaction temperature and the nature of the reactants, but the reaction will normally be completed within several minutes to 200 hours.

When the reaction has ended, the product obtained can be obtained from the reaction mixture in a manner known per se. For example, according to a suitable procedure, one can proceed as follows: adding a water-immiscible solvent to the reaction mixture, washing the entire mixture with water, drying the mixture and finally removing the solvent by distillation, the desired compound being obtained if necessary usual measures, such as recrystallization or various chromatographic techniques, can further purify.

The compounds according to the invention have strong antibacterial effects against various varieties of bacteria, including both gram-positive and gram-negative bacteria, and anaerobic bacteria, and are therefore very valuable for the treatment of diseases caused by such bacteria.

The activities of the compounds according to the invention against different bacteria can be found in the following table, stating their minimum inhibitory concentrations (micrograms per milliliter). In addition, a number of known compounds of similar structure with their results are shown. The compounds are identified in the following table by the numbers given below:

1. Sodium (5R, 6S) -2- (2-fluoroethylthio) -6- [l- (R) -hydr-oxyethyl] -penem-3-carboxylate

2. (5-methyl-2-oxo-l, 3-dioxolen-4-yl) - methyl- (5R, 6S) -2-

7 654 308

(2-fluoroethylthio) -6- [l- (R) -hydroxyethyl] -penem-3-carb-oxylate

3. Sodium (5R, 6S) -2- (2-chloroethylthio) -6- l- (R) -hydr-oxyethyl] -penem-3-carboxylate s 4. Sodium (5R, 6S) -2-ethylthio -6- [l- (R) -hydroxyethyl] -penem-3-carboxylate

5. Sodium (5R, 6S) - 2-bromoethylthio) -6- [l- (R) -hydroxyethyl] -penem-3-carboylate

Compounds Nos. 1 and 2 are compounds according to the invention, namely the sodium salt and (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl ester of the compound of the formula I, while compounds No. 4 and 5 known compounds having a similar structure, and Compound No. 3 is a prior art compound in general. Two values A and B are given for compound No. 2. The first wet A is the value obtained when the compound is used as such, while the value B is the value obtained after incubating the compound with Kaninchense-20 rum at 37 ° C for a time of 1 Hour achieved for the purpose of simulating the effects achieved in vivo.

Table 25 Microorganism

Connection no.

1 2 3 4 5

A B

Staphylococcus 0.01 0.05 0.01 0.02 0.02 0.05 30 aureus 209 P Staphylococcus 0.02 0.05 0.02 0.02 0.05 0.05 aureus 56

Escherichia 0.1 0.4 0.1 0.2 0.4 0.4

coli NIHJ

35 Escherichia 0.1 0.4 0.1 0.6 0.8 0.4

coli 609

Klebsiella 0.1 0.4 0.1 0.4 0.4 0.4

pneumoniae 806

Klebsiella 0.8 3.1 0.8 -

40 pneumoniae 846

Proteus 0.8 1.5 0.8 - - -

vulgaris

A review of this table shows some important factors. First, it can be seen in a rough comparison between compound no. 1 and compounds no. 3 to 5, which are all used as sodium salts, that compound no. 1, namely the compound according to the invention, is at least as effective as and in is generally more effective than the known compounds. It is also known that Escherichia coli strain 609 produces the enzyme ß-lactamase, which is able to break the ß-lactam ring and destroy the activity of some penicillin derivatives. It is therefore a penicillin-resistant strain, 55 while Escherichia coli NIHJ is generally regarded as a penicillin-sensitive strain. While Compound No. 1 is equally effective against both strains, the prior art compounds are less effective against the resistant strain. Finally, although compound No. 2 as such is less effective than compound No. 1 in this in vitro test, it is found that when compounded with rabbit serum, the compound is as effective as compound No. 1 is.

In addition to the excellent activity in vitro, the compounds according to the invention are also extremely effective in vivo and have proven to be more effective than similar known compounds. With experimental infection

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NEN from groups of mice with Staphylococcus aureus 56 or Escherichia coli 704 and then treated by subcutaneous injection with a solution of either Compound No. 1 or Compound No. 4 in saline were the ED50 values for Compound No. 1 against Staphylococcus aureus 56 and Escherichia coli 704 0.9 and 2.9 mg / kg, respectively, while the corresponding values for compound no. 4 were 2.6 and 10.7 mg / kg, respectively.

Although it is demonstrated by the above results that the compounds according to the invention generally show good activity and can therefore be assumed to be of considerable value as therapeutic agents, it was surprisingly found that compound no. the (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl ester has other properties which therefore make this compound particularly important for practical purposes. This ester specifically shows a much better blood concentration and recovery in urine than all the other esters tested and than the free acid or salts. For example, while the recovery rate of the sodium salt in urine was only 7%, the corresponding value for the (5-methyl-2-oxo-l, 3-dioxo-len-4-yl) methyl ester was 46%, indicating that that this compound had been broken down to inactive metabolic products much more slowly. It follows that compound no. 2 remains active in the blood for a considerably longer time than the other esters, the free acid or its salts and thus achieves a higher blood concentration. As a result, compound no. 2 could be administered in smaller doses than the other compounds with correspondingly lower risks of side effects and at lower costs, or it can be seen from this that when this compound was administered in the same dose amount, a much stronger and faster effect should be achieved.

In addition, the compounds according to the invention have an extremely low toxicity. To assess acute toxicity, three mice were each intravascularly treated with 3000 mg / kg of compound No. 1 by injection. Not a single mouse died at this dose level, demonstrating the low toxicity of this compound.

The compounds according to the invention can be administered orally or parenterally to achieve very excellent effects. However, it was found that the free acid and its salts are advantageously parenterally, e.g. by intravenous, intramuscular or subcutaneous injection, whereby they are transferred into the blood at a high concentration, while the esters and in particular the (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl ester are preferably administered orally, whereby they are also introduced into the blood at a high concentration.

For oral administration, the compounds are preferably administered in the form of tablets, granules, capsules, powders or syrups. The dosage amount of the compounds according to the invention varies depending on the age, body weight and condition of the patient, as well as on the form and the mode of administration. In general, however, adults will be given daily doses of 200 to 3000 mg of the active substance, the administration being possible in a single dose or in multiple doses.

The invention is illustrated by the following examples. The preparation of some starting materials is also illustrated in the following preparations.

example 1

Sodium (5R, 6S) -2- (2-fluoroethylthio) -6- [l- (R) -hydroxyethylphenylene-3-carboxylate

(a) p-Nitrobenzyl- (5S, 6S) -6- [l- (R) -tert.-butyldimethylsil-oxyethyl] - 2- (2-fluoroethylthio) -penem-3-carboxylate

A solution of 447 mg of p-nitrobenzyl- (5S, 6S) - 6- [l- (R) -tert.-butyldimethylsilyloxyethyl] -2-thioxopenam-3-carboxylate in 5 ml of nitromethane under a stream of nitrogen and with ice cooling Solution of 171 mg of l-bromo-2-fluoroethane, 1 ml of nitromethane and 138 ml of 1 triethylamine were added. The mixture was then stirred at room temperature for 3 days. After this period, the reaction mixture was concentrated by evaporation under reduced pressure and the residue extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. Then the solvent was distilled off and the residue was subjected to column chromatography on silica gel. The desired compound was obtained in crude form by elution with a 20: 1 by volume mixture of benzene and ethyl acetate. This product was further purified on silica gel by column chromatography eluting with a mixture of hexane and ethyl acetate in a volume ratio of 5: 1. In this way, 110 mg of the above-mentioned compound was obtained.

Infrared absorption spectrum (liquid film) vmaxcnr ':

1790,1680.

Nuclear Magnetic Resonance Spectrum (CDC13) 5 ppm:

0.90 (9H, singlet);

1.45 (3H, doublet, J = 6.0Hz);

3.30 (2H, doublet of triplets, J = 19.0 and 6.0 Hz);

3.90 (1H, doublet of doublets, J = 10.0 and 4.0 Hz);

4.20-4.60 (1H, multiplet);

4.65 (2H, doublet of triplets, J = 47.0 and 6.0 Hz);

5,20,5,50 (2H, AB-quartet, J = 14.0 Hz);

5.70 (1H, doublet, J = 4.0 Hz);

7,62,8,23 (4H, A2B2, J = 9.0 Hz).

(b) p-Nitrobenzyl- (5R, 6S) -6- [l- (R) -tert.-butyldimethylsilyloxyethyl] - 2- (2-fluoroethylthio) - penem-3-carboxylate

2.0 mg of hydroquinone were added to a solution of 110 mg of p-nitrobenzyl- (5S, 6S) - 6- [l- (R) -tert.-butyldimethylsilyloxy-ethyl) - 2- (2-fluoroethylthio) - penem-3- Carboxylate in 18 ml of xylene was added and the mixture was heated in an oil bath at 135 ° C. in a stream of nitrogen gas for 3 hours. Thereupon the solvent was distilled off and the residue was purified by chromatography on a Lobar column from Merck & Co., Inc., silica gel, size B) by elution with a mixture of benzene and ethyl acetate in a volume ratio of 25: 1, the mixture being separated Fractions received the compound mentioned above and the starting material. The recovered starting material was then heated in the same manner as described above to obtain additional amounts of the desired compound. The total yield was 82 mg (74.5%).

Infrared absorption spectrum (liquid film) vmaxcm ~ 1-. 1790, 1690, 1605.

Nuclear Magnetic Resonance Spectrum (CDC1) 3 8 ppm:

0.90 (9H, singlet);

1.35 (3H doublet J = 6.0 Hz).

3.32 (2H, doublet of triplets, J = 19.0 and 6.0 Hz);

3.80 (1H, doublet of doublets, J = 4.0 and 2.0 Hz);

4.00 - 4.60 (1H, multiplet);

8th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

654308

4.70 (2H, doublet of triplets, J = 7.0 and 6.0 Hz);

5.25.5.50 (2H, AB-quartet, J = 14.0 Hz);

5.72 (1H, doublet, J = 2.0 Hz).

7.68.8.24 (4H, A2B2, J = 9.0 Hz).

(c) p-Nitrobenzyl- (5R, 6S) -2- (2-fluoroethylthio) - 6- [I- (R) -hydroxyethyl) - penem-3-carboxylate

86 (xl acetic acid and 0.604 ml of a tetrahydrofuran solution containing 1 mol of tetrabutylam monium fluoride were added to a solution of 82 mg of p-nitrobenzyl- (5R, 6S) -6- [1- (R) -tert.-butyldimethylsilyloxyethylethyl] - 2- (2nd -fluoroethylthio) - pe-nem-3-carboxylate in 2 ml of tetrahydrofuran and the mixture was stirred overnight at room temperature and then for 10 hours in an oil bath at 30 ° C. After this period, the mixture was diluted with ethyl acetate and successively with a saturated aqueous sodium chloride solution, an aqueous 5% (w / v) sodium bicarbonate solution and a saturated aqueous sodium chloride solution, the solvent was distilled off and the residue was chromatographed on a Lobar column from Merck & Co., Inc., Silica gel, size A) while eluting with a mixture of benzene and ethyl acetate in a volume ratio of 65:35, whereby 40 mg of the above-mentioned compound of melting point 168 to 170 ° C. were obtained t.

Ultraviolet absorption spectrum (ethanol) Â.maxnm:

261.339.

Magnetic nuclear magnetic resonance spectrum (in hexadeuterated dimethyl sulfoxide) S ppm:

1.18 (3H, doublet, J = 6.0 Hz);

2.90-3.70 (2H, multiplet);

3.86 (1H, doublet of doublets, J = 6.0 and 2.0 Hz);

3.80 - 4.15 (1H, multiplet);

4.66 (2H, DubTett from triplets, J = 47.0 and 6.0 Hz).

5.19 (1H, doublet, J = 4.0 Hz);

5.30, 5.48 (2H, AB-quartet, J = 14.0 Hz);

5.77 (1H, doublet, J = 2.0 Hz);

7.72.8.25 (3H, A2B2, J = 9.0 Hz).

(d) Sodium (5R, 6S) -2- (2-fluoroethylthio) -6- [l- (R) -hydroxyethyl] penem-3-carboxylate

39 mg of p-nitrobenzyl- (5R, 6S) - 2- (2-fluoroethylthio) -6- [l- (R) -hydroxyethyl] - penem-3-carboxylate were dissolved in 3 ml of tetrahydrofuran and the resulting solution with 3 ml a phosphate buffer solution of pH 7.1, which contained sodium ions, and 78 mg of 10% strength by weight palladium on carbon. The mixture was then stirred in a hydrogen gas stream at room temperature for 21/2 hours. At the end of this period, the catalyst was removed by filtration and the filtrate was washed with ethyl acetate. The resulting aqueous layer was concentrated to approximately 2 ml by evaporation under reduced pressure. The residue was then treated by column chromatography on Diaion HP-20AG from Mitsubishi Chemical Industries. The fraction eluted with a 5 vol% aqueous acetone solution was concentrated by evaporation under reduced pressure and freeze-dried to obtain 17 mg of the desired compound in the form of a white powder.

,cm

xnm:

Infrared absorption spectrum (KBr) v ^ 3425.1765.1600.

Ultraviolet absorption spectrum (H20) X "252.5.321.5.

Nuclear Magnetic Resonance Spectrum (D20) 8 ppm: 1.30 (3H, doublet, J = 6.0 Hz);

2.90-3.50 (2H, multiplet);

3.90 (1H, doublet of doublets, J = 6.0 and 2.0 Hz).

4.00-4.45 (1H, multiplet);

4.70 (2H, doublet of triplets, J = 47.0 and 6.0 Hz);

5.69 (1H, doublet, J = 2.0 Hz).

5

Example 2

(5R, 6S) -2- (2-fluoroethylthio) -6- [l- (R) -hydroxyethyl) -penem-3-carboxylic acid

A sample of the io sodium salt obtained according to the information in Example 1 was acidified by adding a 5% (w / v) aqueous citric acid solution. The resulting solution was then extracted with methylene chloride and the extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous i5 magnesium sulfate. The methylene chloride was distilled off to obtain the free acid in quantitative yield.

Ultraviolet absorption spectrum (ethanol) Àmaxnm:

256,333.

20th

Example 3

(5-Methyl-2-oxo-l, 3-dioxolen-4-yl) - methyl- (5R, 6S) -2- (2-fluoroethylthio) -6- [1- (R) -hydroxyethyl] - penem- 3-carb oxylate

25 A solution of 200 mg of the sodium salt of (5R, 6S) -2- (2-fluoroethylthio) -6- [1- (R) - hydroxyethyl] - pe-nem-3-carboxylic acid in 4 ml of N, N-dimethylacetamide was cooled with ice and 135 mg of 4-bromomethyl-5-methyl-l, 3-dioxolen-2-one were added, and the resulting mixture was stirred 3o and then left to stand overnight. The reaction mixture was then diluted with water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate, after which the solvent was removed by distillation. In this way, a precipitate consisting of crystals was obtained. These crystals were washed with a 1: 1 by volume mixture of benzene and ethyl acetate and then collected by filtration. In this way, 40 180 mg of the desired compound were obtained in the form of white crystals of melting point 138 to 140 ° C.

Infrared absorption spectrum (KBr) vmax cm

3450.1825.1770.1685 1485.

Ultraviolet absorption spectrum (ethanol) Xm.K nm (s): «258.6 (6915), 338.9 (9124).

Magnetic nuclear magnetic resonance spectrum (at 100 MHz in hexadeuterated dimethyl sulfoxide) 8 ppm:

1.20 (3H, doublet, J = 6.0 Hz).

2.20 (3H, singlet);

so '3.10-3.65 (2H, mutliplet).

3.82 (1H, doublet of doublets, J = 6.0 and 2.0 Hz).

3.85-4.20 (1H, multiplet);

4.68 (2H, doublet of triplets, J = 47.0 and 6.0 Hz);

5.10 (2H, singlet);

«5 5.75 (1H, doublet, J = 2.0 Hz).

Preparation 1

(3S, 4R) -3- [1- (R) -tert.-Butyldimethylsilyloxyethyl] -4- (5-60 fluoro-2-thioxo-l, 3-dithiapentyl) azetidin-2-one

4 ml of a 0.5 molar solution of sodium methoxide in methanol was added dropwise over a 15 minute period to a solution of 268 mg of 2-fluoroethyl thioacetate and 132 nl of carbon disulfide in 4 ml of anhydrous methanol which had been cooled to 65-15 ° C. The mixture was stirred at -15 ° C. for 30 minutes and then 604 mg (3S, 4R) -3- [l- (R) -tert.-butyldimethylsilyloxyethyl] 4-acetoxyazetidin-2-one was added and the Select mixture

654 308

stirred for a further hour at a temperature of -15 ° C to -10 ° C.

After this period, crystals of the desired compound began to separate out. The mixture was therefore left at -20 ° C overnight, whereupon 0.21 ml of acetic acid was added and the mixture was then extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation and the residue was purified by column chromatography on silica gel, eluting with a 10: 1 by volume mixture of benzene and ethyl acetate. In this way, 536 mg of the desired compound of melting point 106 to 107 ° C. were obtained.

Infrared absorption spectrum (KBr) vmax cm-1: 3050.1765.1725.

Magnetic nuclear magnetic resonance spectrum (at 60 MHz, CDCI3) 8 ppm:

0.89 (9H, singlet);

1.21 (3H, doublet, J = 6.0 Hz);

3.20 (1H, triplet, J = 2.0 Hz);

3.68 (2H, doublet of triplets, J = 21.0 and 6.0 Hz);

4.00-4.50 (1H, multiplet);

4.59 (2H, doublet of triplets, J = 47.0 and 6.0 Hz); 5.65 (1H, doublet, J = 2.0 Hz).

6.65 (1H, broad singlet).

Preparation 2

p-nitrobenzyl-a-j (3S, 4R) -3- [l- (R) -tert.-butyldimethylsil-yloxyethyl] -4- (5-fluoro-2-thioxo-l, 3-dithiapentyl) azetidine- 2-on-1-yl [glycolate

29.85 g of product 1 obtained and 35.33 g of p-nitrobenzylglyoxylate hydrate were dissolved in 1.4 liters of dry benzene. The benzene was then distilled off by heating the mixture to 110 ° C. in an oil bath. The residue was then stirred for 4 hours at practically the same bath temperature, after which it was purified by column chromatography over silica gel, specifically by elution with a mixture of benzene and ethyl acetate in a volume ratio of 10: 1. In this way, 38.15 g of the desired compound were obtained in the form of an oil. Infrared absorption spectrum (liquid film) vmax cm-1: 3550.1770.1605.1520

Magnetic nuclear magnetic resonance spectrum (at 60 MHz, CDCI3) 8 ppm:

0.86 (9H, singlet);

1.20.1.23 (3H, doublet, J = 6.0 Hz);

3.21-4.45 (6H, multiplet);

4.59 (2H, doublet of triplets, J = 47.0 and 6.0 Hz);

5,20,5,33 (2H, AB-quartet, J = 14.0 Hz);

6.17.6.21 (1H, doublet, J = 2.0 Hz);

7.49.8.20 (4H, A2B2, J = 9.0 Hz).

Preparation 3

p-nitrobenzyl-a-j (3S, 4R) -3- [1- (R) -tert.-butyldimethylsilyloxyethyl] -4- (5-fluoro-2-thioxo-l, 3-dithiapentyl) -aceti din-2-one-l-yl \ -a-triphenylphosphoranylacetate

38.15 g of the product obtained according to preparation 2 were

10th

which is dissolved in 350 ml of tetrahydrofuran and the solution cooled to a temperature of from -20 ° C to -15 ° C. 8.95 ml of 2,6-lutidine was then added to this solution and 5.14 ml of thionyl chloride was slowly added while maintaining a temperature below -15 ° C. The resulting mixture was then stirred at a temperature of from -20 ° C to -15 ° C for 30 minutes. The reaction mixture was then poured into an ice-cooled aqueous solution of sodium chloride and extracted with 10 ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was then distilled off, giving a crude sample of p-nitrobenzyl-a- {(3S, 4R) -3- [l- (R) -tert.-butyl-is dimethylsilyloxyethyl] - 4- (5-fluoro- 2-thioxo-l, 3-dithiapentyl) -azetidin-2-one-l-yl) - a-chloroacetate. This entire product was dissolved in 500 ml of tetrahydrofuran and then 11.93 ml of 2,6-lutidine and 27.02 g of triphenylphosphine were added to the solution. The mixture was then stirred in an oil bath at a bath temperature of 75 to 80 ° C. for 42 hours and then poured into an aqueous sodium chloride solution cooled with ice. The resulting mixture was extracted with ethyl acetate and the extract washed with a saturated aqueous sodium chloride solution 25 and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation and the residue was purified by column chromatography on silica gel while eluting with a mixture of benzene and ethyl acetate in a volume ratio of 8: 1. In this way, 26.82 g of the above-mentioned compound was obtained in the form of a yellow powder.

Infrared absorption spectrum (KBr) vmax cm-1: 1750.1620.1600.1510.

35 preparation 4

p-Nitrobenzyl- (5R, 6S) -6- [l- (R) -tert.-butyldimethylsilyloxyethyl] -2- (2-fluoroethylthio) -penem-3-carboxylate

3.35 g of the product obtained according to preparation 3 were dissolved in 220 ml of anhydrous xylene, whereupon 65 mg of 40 hydroquinone were added. Then the mixture was stirred for 12 hours in an oil bath at a bath temperature of 120 to 125 ° C. The solvent was then distilled off and the residue was purified by column chromatography on silica gel while eluting with a mixture of 45 benzene and ethyl acetate in a volume ratio of 10: 1. The eluate was concentrated by evaporation under reduced pressure and the residue was again chromatographed over a Lobar column from Merck & Co. Inc., Kiselgel, two Size B-50 columns connected in series, while eluting with a mixture of benzene and Ethyl acetate in a volume ratio of 25: 1, 810 mg of the above-mentioned compound having a melting point of 118 to 120 ° C. and 318 mg of p-nitrobenzyl- (5S, 6S) - 1- [1- (R) -tert.-butyldimethylsilyloxyethyl) 2- (2-fluoroethyl) - penem-3-55 carboxylate. Thin-layer chromatography and ultraviolet, infrared and magnetic nuclear magnetic resonance spectroscopy proved that these compounds were identical to the compounds according to Examples 1 (b) and 1 (a).

C.

Claims (15)

654 308 PATENT CLAIMS 1.2- (2-Fluoroethylthio) -6- (1-hydroxyethyl) - penem-3-carboxylic acid of the formula: S-CH2CH2F COOH CO and their pharmaceutically acceptable salts and esters. 2. (5R, 6S) -2- (2-fluoroethylthio) -6- [1- (R) -hydroxyethyl] -penem-3-carboxylic acid and its pharmaceutically acceptable salts and esters according to claim 1. 3. (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl-2- (2-fluoro-ethylthio) - 6- (1-hydroxyethyl) -penem-3-carboxylate of the formula: S-CH2CH2F a base or in those cases where X represents the hydroxyl group, in the presence of a triphenylphosphine and an azodicarboxylic acid dialkyl ester, (b) the hydride represented by the symbol R1 5 oxyl group protecting group removed and simultaneously, before or after the protected carboxyl group represented by the symbol R2 into a free carboxyl group, and (c) optionally converting the product from step (b) into a salt. 6. The method according to claim 5, characterized in that X represents a halogen atom, an alkanesulfonyloxy group, a haloalkanesulfonyloxy group or an arylsulfonyloxy group. 15 7. Process for the preparation of esters of 2- (2-fluoro-ethylthio) -6- (l-hydroxyethyl) - penem-3-carboxylic acid, characterized in that the carboxylic acid already mentioned is prepared by the process according to claim 5 and the latter esterified. 20 8. Process for the preparation of 2- (2-fluoroethylthio) -6- (1-hydroxyethyl) - penem-3-carboxylic acid or a salt thereof, characterized in that (a) a compound of the general formula: c00— ch2- 25th H3c ORl A according to claim 1. 4. (5-methyl-2-oxo-l, 3-dioxolen-4-yl) - methyl- (5R, 6S) -2- (2-fluoroethylthio) -6- [1- (R) - hydroxyethyl] - penem-3-carb-oxylate according to claim 1. 5. A process for the preparation of 2- (2-fluoroethylthio) -6- (1-hydroxyethyl) -penem-3-carboxylic acid or salts thereof, characterized in that (a) a compound of the following general formula: 30th 35 0 ^ 11 \ ® / Z® R2 s — ch2 ch2f (V) wherein R1 is a hydroxyl group protecting group, R2 is a protected carboxyl group, and Z + is a trialkylphosphono group, a triarylphosphono group or a double esterified phosphono group combined with a cation, heated to give a compound of the following general formula reach: wherein R1 is a group protecting the hydroxyl group and R2 is a protected carboxyl group, with a compound of the following general formula: ch2ch2f (IV) X-CH2CH2F wherein X represents a removable group, to give a compound of the following general formula: ch2ch2f wherein R1 and R2 have the meanings given above, (b) the group protecting the hydroxyl group represented by the symbol R1 is removed and at the same time, (III) whether or not the protected carboxyl group represented by the symbol R2 is converted into a free carboxyl group, and (c) optionally converting the product from step (b) into a salt. 9. A process for the preparation of esters of 2- (2-fluoro-ethylthio) -6- (1-hydroxyethyl) -penem-3-carboxylic acid, characterized in that the carboxylic acid already mentioned is prepared by the process according to claim 8 and the latter esterified. 55 (IV) wherein R1 and R2 have the meanings given above, the reaction being carried out either in the presence in which X is a group other than the hydroxyl group 10. The method according to any one of claims 7 and 9, characterized in that the product from step (b) or (c) 65 with a 4-halomethyl-5-methyl-l, 3-dioxolen-2-one under Formation of (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl-2- (2-fluoroethylthio) -6- (1-hydroxyethyl) - penem-3-carboxylate. 654 308 11. Pharmaceutical preparation containing an antibiotic in a mixture with at least one pharmaceutically acceptable carrier or diluent, characterized in that the antibiotic is the 2- (2-fluoroethylthio) -6- (1-hydroxyethyl) - penem-3-carboxylic acid or Is salt or an ester thereof. 12. A preparation according to claim 11, characterized in that the antibiotic is sodium 2- (2-fluoroethylthio) -6- (l-hydroxyethyl) - penem-3-carboxylate. 13. A preparation according to claim 12, characterized in that the antibiotic is sodium (5R, 6S) - 2- (2-fluoroethylthio) -6- [l- (R) -hydroxyethyl] - penem-3-carboxylate. 14. Preparation according to claim 11, characterized in that the antibiotic is the (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl-2- (2-fluoroethylthio) -6- (1-hydroxyethyl ) - pe-nem-3-carboxylate. 15. A preparation according to claim 14, characterized in that the antibiotic is the (5-methyl-2-oxo-l, 3-dioxolen-4-yl) methyl (5R, 6S) -2- (2-fluoroethylthio) - 6- [l- (R) -hydr-oxyethyl] - penem-3-carboxylate. 16. A preparation according to claim 12 or 13, characterized in that it is formulated for parenteral administration. 17. A preparation according to claim 14 or 15, characterized in that it is formulated for oral administration.