FR2512027A1 - PENEME-3-CARBOXYLIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE AS ANTIMICROBIAL AGENTS - Google Patents

Abstract

The subject of the invention is 2- (2-fluorophenyl) -6- (1-hydroxyethyl) -penomethyl-3-carboxylic acid and its salts and esters which have been found to have excellent anti-biotic activity, including activity on them. PENICILLINO-RESISTANT MICROORGANISMS WHOSE RESISTANCE RESULTS FROM THE PRODUCTION OF B-LACTAMASE. ESPECIALLY, ESTER (5-METHYL-2-OXO-1,3-DIOXOLENE-4-YL) METHYLICALLY PROVIDES REMARKABLY GOOD RESULTS FROM THE POINTS OF VIEW CONCENTRATION IN THE BLOOD AND RATE COLLECTED IN URINE.

Description

The present invention relates to a new penem-3- acid

  carboxylic acid, its salts and esters, to a process

  for the preparation of these compounds, as well as their use

  as antimicrobial agents.

  Penicillins form a well-known class of antibiotics which have been widely used for many

  years in therapeutics, in humans and animals.

  Chemically, penicillins share a common structure

  F-lactam, commonly called "penam", which can be

by the following formula: s

S 5 12

  Many of the interesting penicillin derivatives have a carbon-carbon double bond between positions 2 and 3 and the structure with this double bond is known as "penem"; these structures pename and peneme form the basis of the semi-systematic nomenclature of the derivatives of

  penicillin, and this nomenclature is, in general,

  It is accepted by those skilled in the art world-wide and is used here. The numbering system used here is that indicated on the formula above. Although known penicillins are a valuable weapon in the pharmaceutical arsenal, the appearance of new, and often penicillin-resistant strains,

  of pathogenic bacteria makes it more and more

  to search for new antibiotics.

  follows that various penem type compounds have been prepared

  by synthesis in an attempt to achieve antibacterial activity.

  more potent, broader antibacterial spectrum and / or improved efficacy against penicillin-resistant microorganisms. For example, U.S. Patent No. 4,260,618 discloses

  a class of penem compounds that can be

ter by the formula:

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(D) n Rb

S RI

  in which Ra and Rb represent hydrogen atoms or various organic groups, N is 1 or 2 and Rc is, inter alia, a C1-C6 alkylthio group,

  which may be substituted by one or more chloro atoms

re, bromine or fluorine.

  European Patent No. 3960 discloses a similar class of compounds, which can be represented by the formula: ## STR1 ## wherein Rd represents various organic groups, Rf represents a hydroxy group or various organic groups, and Re represents among others, a haloethylthio group, pr

  for example a chloroethylthio or bromoethylthio group.

  In addition, the Japanese Kokai patent application (i.e.

  Published but not reviewed) No. 153789/80 discloses 2- (2-bromoethylthio) -6- (1-hydroxyethyl) penme-3-carboxylic acid which can be represented by the formula: OH 11 3 C SSCH 2 CH 2 Br

N C

a H COOH

  The Applicant has now discovered a compound

  particular, as well as its salts and esters, which, although

  to the known compounds defined above, has significant advantages from the point of view of its antimicrobial activity (both in vitro and in vivo), its chemical stability, its behavior when metabolized, and

  of its absorption in the bloodstream.

  The compounds according to the present invention are

  2- (2-fluoroethylthio) -6- (1-hydroxyethyl) penem-3-carbohydrate

  xyl, which can be represented by the formula: OH

HSC S-CH 2 CH 2 F

R 3 C (1)

O COOH

  as well as its pharmaceutically acceptable salts and esters.

  Although all the pharmaceutically acceptable salts and esters of the compound of formula (I) are of interest, the Applicant has discovered, very surprisingly, that a particular ester makes it possible to obtain much better results from the point of view of concentration in the blood. and rate collected in the urine than those provided by others

  salts and esters (as is conventional in this field, the Deman-

  deresse prefers to administer a salt or ester, rather than

  free acid, in order to improve the water solubility or ab-

  In fact, with this ester, the rate collected in the urine as well as the concentration in the blood can be several times higher than those of other salts and esters. This remarkable ester is the ester.

  (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl.

  The compound of formula (I) can be used in the form of a pharmaceutically acceptable salt. Examples of these salts are those formed with metals (such as

  lithium, sodium, potassium, calcium or magnesium

  sium), those formed with ammonia or an organic amine

  (such as ammonium, cyclohexylammonium, diisocyanate

  propylammonium or triethylammonium), and those formed with

  basic amino acids (such as lysine or arginine).

  Among them, the sodium and potassium salts are preferably

  rable. When the compound according to the invention is used in the form of an ester, it is preferable that it be an ester which can be activated in vivo by the metabolism; examples of suitable esters are the esters

  acetoxymethyl, pivaloyloxymethyl, 1-ethoxycarbonyl-

  oxyethyl, phthalidyl and (5-methyl-2-oxo-1,3-dioxo)

  lene-4-yl) methyl, the ester (5-methyl-2-oxo-1,3-dioxo)

  methylen-4-yl) being particularly preferred.

for the reasons mentioned above.

  The compounds according to the invention are represented here by a planar formula; however, it is understood that the compounds according to the invention can be presented under

  the shape of various optical isomers, because of the presence

  of a certain number of asymmetric carbon atoms, and that they may also be in the form of

  various geometric isomers As well as the isomers dis-

  their mixtures, that is to say the racemic compounds

  are concerned by the present invention. However,

  preferable compounds are those having the same configuration

  than thienamycin, that is to say the

(5 R, 6 S) and 6- / 1- (R) 7.

  The compounds according to the invention can be prepared by reacting a compound of formula (II):

H 3 C 3:

o N R 2

  (in which R 1 represents a protecting group of hy-

  and R 2 represents a protected carboxy group) with a compound of formula (III):

X-CH 2 CH 2 F (III)

  (wherein X is a leaving group), thereby obtaining a compound of formula (IV): OR 1

C, - ,, S S-CH 2 CH 2 F

0 I IR ()

o NR 2

  wherein R 1 and R 2 have the abovementioned meanings.

  The protecting group represented by R 1 is then removed leaving a free hydroxy group and, if necessary, the protected carboxy group represented by R 2 is converted to

  a free carboxy group (before, after or during the elimination

  the hydroxyl protecting group represented by R 1),

  which gives the compound sought according to the invention.

  When preparing the free acid of formula (I), it can then be salified or esterified or, when the compound is isolated from the reaction mixture in the form of a salt, it can be converted into the free or esterified acid,

  by procedures well known in the art.

  The leaving group represented by X in the compound of formula (III) can be, for example, a hydroxy group,

  a halogen atom (for example a bromine atom or io-

  de), an alkanesulfonyloxy group (for example a group

  methanesulfonyloxy or ethanesulfonyloxy), a halogen group

  alkanesulfonyloxy (for example a trifluoromethane-

  sulfonyloxy), or an arenesulfonyloxy group (e.g.

  benzenesulfonyloxy or p-toluenesulfonyloxy).

  The reaction of the compound of formula (II) with the compound of formula (III) (wherein X is any of

  groups defined above, with the exception of one hydro-

  xy) to obtain the compound of formula (IV) is preferably

  The nature of the solvent used in this reaction is not critical so long as it does not have a deleterious effect on the reaction.

  Examples of these solvents are:

  halogenated hydrocarbons such as chloroform, methylene chloride or ethylene dichloride; ethers such as diethyl ether or tetrahydrofuran; nitromethane;

251202?

  a mixture of one or more of these solvents and water or other organic solvent; or a mixture of two or more of any of these solvents The nature of the

  the basis used is not,

  as long as it does not affect other parts of the compound, in particular the nucleus> -Lactam The base acts as

  acid binding agent and any

  known as fulfilling this function.

  organic bases such as triethylamine, pyridine, 2,6-lutidine or N, N-dimethyl

  aniline; alkali and alkaline carbonates

  earthquake (such as sodium carbonate, carbonate of

  tassium or calcium carbonate); as well as bicarbo-

  alkali metal compounds such as sodium bicarbonate.

  Although the reaction temperature is not critical

  that the Applicant prefers to carry out the reaction at a

  relatively low temperature, in order to limit the

  The time required for the reaction depends mainly on the reaction temperature and the nature of the starting materials, but

  generally, from several minutes to 200 hours is enough.

  Once the reaction is complete, the desired compound of formula (IV) can be separated from the reaction mixture; by

  For example, a separation sequence

  It is suitable to dilute the reaction mixture with a water immiscible organic solvent; wash the mixture with water; and distilling the solvent to obtain the desired compound If necessary, the solvent can then be purified by conventional means, for example

  by recrystallization, reprecipitation or chromatography.

  When the compound of formula (IV) obtained as described

  above is in the form of the 5S isomer, it can easily

  be converted into the R isomer by heating it, either alone or in the presence of an organic solvent such as toluene,

  xylene, N, N-dimethylformamide or N, N-dimethyla

  amide In order to limit the side reactions, this reaction can, if necessary, be carried out in the presence

  a polymerization inhibitor such as hydroquinone.

  When a compound of formula (III) in which X is hydroxy is used, it is preferable to carry out the reaction by reacting the compound of

  formula (II) with the compound of formula (III), that is,

  say 2-fluoroethanol, in the presence of triphenylphosphine and a dialkyl ester of azodicarboxylic acid,

  for example diethyl azodicarboxylate.

  It is preferable to carry out this reaction in advance.

  the presence of an inert solvent, the nature of which is not critical.

  until it has a deleterious effect on the reaction.

  Examples of suitable solvents are: ethers (such as diethyl ether, tetrahydrofuran or

  dioxane) and aromatic hydrocarbons (such as benzene

  ne or toluene), as well as mixtures of two or more

of these solvents.

  Although the reaction temperature is not critical either, the Applicant prefers to perform the

  reaction at a relatively low temperature in order to limit

  ter or avoid side reactions, and this is how a temperature of -200 C at room temperature test

  The time required for the reaction depends mainly on

  the reaction temperature and the nature of the starting substances, but a lapse of time

  minutes to 100 hours is sufficient in general.

  Once the reaction is complete, we can separate the

  of formula (IV) of the reaction mixture by conventional means, for example by the separation sequence described above. If desired, when the compound is

  isomer 5S, it can be converted into the 5R isomer

while heating.

  If necessary, the carboxy protecting group of the resulting compound of formula (IV) is then removed by

  conventional means, in order to obtain the free carboxylic acid.

  It goes without saying that the nature of the reaction used to remove the carboxy protecting group depends on the nature of the group itself. The carboxy protecting group is

  preferably an aralkyl group (for example benzyl or

  nitrobenzyl, particularly a p-nitrobenzyl group),

  because these groups are easily eliminated by reduction.

  A variety of reducing agents are available for this reaction, but the Applicant prefers to use a catalytic reduction mode using hydrogen and

  a suitable catalyst (preferably palladium coal).

  This reaction is normally carried out in the presence of a solvent, the nature of which is not critical as long as it has no adverse effect on the reaction. The preferred solvents are: alcohols (such as methanol or ethanol) ), ethers (such as tetrahydrofuran or dioxane), fatty acids (such as acetic acid), and mixtures

  one or more of these solvents and water or a solution

  phosphate buffer The reaction temperature is not

  not particularly limited, although it is

  between 00 C and room temperature, approximately The time required for the reaction depends on the nature of the

  starting materials and reducing agents, but the reaction

  tion is usually finalized within a period of

  time from several minutes to 100 hours.

  Once the reaction is complete, the resulting compound can be separated from the reaction mixture by means

  For example, a separation sequence

  to: filter insoluble substances; to wash the solution

  organic solution obtained as filtrate, with water; to dry

  organic solution; and to distill the solvent, in order to obtain

  identify the desired compound that may possibly be

  purify by conventional means, such as recrystallization

  preparative thin-layer chromatography or

column chromatography.

  Similarly, the hydroxyl protecting group represents

  R is eliminated in a conventional manner before, after

  during removal of the carboxy protecting group,

  described above The nature of the hydroxyl protecting group represented by R 1 is not particularly

  limited, and any suitable group may be used

  However, it is preferable that the protecting group is a group

  aralkyloxycarbonyl (for example benzyloxycarbonyl

  bonyle or p-nitrobenzyloxycarbonyl) or a trialkyl group

  silyl (eg trimethylsilyl or t-butyl-

  dimethylsilyl), and most preferably a t-butyldimethylsilyl group. When R 1 represents an aralkyloxycarbonyl group (for example a p-nitrobenzyloxycarbonyl group), it can be removed by contacting the corresponding compound with a reducing agent. The nature of the reducing agent as well as the reaction conditions used for the elimination of this protecting group of hydroxy are the same as those already described for the elimination of

  carboxy protecting group contained in the group

  R 2 and, therefore, the carboxy protecting group and the hydroxy protecting group may be

eliminated simultaneously.

  When R 1 represents a trialkylsilyl group (by

  a t-butyldimethylsilyl group), it can be eliminated

  by treating the compound with a fluoride ion generating compound (such as tetrabutylammonium fluoride)

  or with an acid (such as hydrochloric acid, sulfuric acid,

  furic acid or acetic acid), preferably with a

  generating the fluoride ions The reaction is preferably

  in the presence of a solvent, the nature of which is not critical as long as it has no adverse effect on the reaction. The Applicant prefers to use an ether

  (such as tetrahydrofuran or dioxane) as the solvent.

  It is better to use a reaction temperature

  between room temperature and 60 C, and the

  The time required for the reaction can vary from a few minutes

at 100 hours.

  After removal of the protective group (or groups), the resulting compound of formula (I) can be separated from the reaction medium in a conventional manner, and, if necessary, IS

  then purified by technicians and technicians.

  preparation, thin-layered preparative chromatography or

column chromatography.

  When the protected carboxy group represented by R in the compound of formula (IV) is an esterified carboxy group, and particularly where the ester group is one of the preferable groups described above for the compounds of the invention and especially when it is a (5-methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonyl group

  it may not be necessary to eliminate the protection group

  carboxy and the desired ester can be prepared

  In this case, the reaction selected to remove the hydroxy protecting group represented by R Pl shall

  be such that it leaves the carboxy group intact.

verifies.

  If desired, the resulting compound of formula (I) or its salt or ester, when in configuration 55,

  can be converted to the corresponding isomer in

  5 R, by heating, in the presence or absence of an organic solvent, as described in connection with

formula (IV).

  The compounds can also be prepared according to

  by heating a compound of formula (V):

OR 1 'H

S sS-CH 2 CH 2 F OK ___N S

R 2

  (wherein R 1 and R 2 have the abovementioned meanings and Z represents a trialkylphosphonio group, for example a tributylphosphonio group, a triarylphosphonio group,

  example a triphenylphosphonio group or a phospho-

  diesterified accompanied by the cation, for example a diethylphosphon O group accompanied by a lithium ion or

  sodium) to obtain a compound of formula (IV); eliminated

  the protecting group of hydroxy represented by R 1

  and, if necessary, by converting the carboxy group pro-

  tegé represented by R in a free carboxy group.

  This reaction is described in British Patent No. 2,048,261 and the compound of formula (V), which is the starting material for this reaction, can also

  be prepared as described in this patent, the sequence

  whole paratory being represented by the following reaction scheme: CR Il OR 1

FCH 2 CH 2 SCR S -SCHC 2 F

_H 3 CH c

01 C 52, RL OM C) O 1 H S

OR 1

At OHC-CR 2 SNSHC 2

S, C / SCH 2 CH 2 F

  D.OHC-CR 2H 3 C + Agent 1 I> {} C halogenation (lIlr} R 2 OR 1 S c SCH 2 CH 2 F H 3 C It phosphine or S phosphite HÉ R 2

OR 1 OR 1

  H 3 CS c SCH 2 CH 2 F -H 3 CS 2 CF H 3 CI heating IN / Ze fage TNR 2 {V) c (m) R 12 OR 1 H 3 C __S y SCH 2 CH 2 F {la) In the above formulas, Y represents an alkanoyloxy group (for example an acetoxy or propionyloxy group), an alkanesulfonyl group (for example a methanesulphonyl or ethanesulfonyl group), an arenesulfonyl group (for example a benzenesulphonyl or p-toluenesulfonyl group).

  nyl) or a halogen atom (for example a chlorine atom

  bromine or iodine), preferably an acetoxy or methanesulfonyl group or a chlorine atom, and more preferably an acetoxy group M represents an alkali metal, for example sodium, potassium or lithium, preferably sodium R represents an alkyl group (for example a methyl, ethyl, propyl, isopropyl or butyl group) or

  an aryl group (for example a phenyl group), preferably

  Where R is a methyl group R represents an alkyl group (for example a methyl, ethyl, propyl, isopropyl or butyl group), preferably a methyl group Hal represents a halogen atom, for example a chlorine, bromine or hydrogen atom. iodine R represents a hydrogen atom or a

  esterified carboxy group Z +, R 1 and R 2 have the

mentioned above.

  The above reaction sequence is known from British Patent No. 2,048,261, as indicated above, and all the details of the reactions are as described in this patent. However, it is important in this particular reaction sequence that in the first stage / that is, in the reaction of the compound of formula (VI) with carbon disulfide and the compounds of formula (VII) and (VIII) to obtain the compound of formula (IX) 7 the

  compounds of formula (VII) and (VIII) and the disulphide of

  have been reacted simultaneously, in advance, in order to provide an intermediate compound of formula (XIII) which is fairly stable: ## STR5 ## in which M has the abovementioned meaning, compound is then reacted with the compound of formula (VI) in the

  reaction described in the aforementioned British patent, the

posed of formula (VII), the compound of formula (VIII) and carbon disulphide are added little by little, in this order, to the compound of formula (VI) but, if one thus operates in the particular case present, the compound of formula (IX) is obtained in a very poor yield, because the compound of formula (VII) and the compound of formula (VIII) will react to give an unstable intermediate compound, i.e. a metal salt of 2-fluoroethanethiol which, for its part,

  decomposes rapidly giving ethylene sulfide.

  The esters of the compound of formula (I) can be prepared by a standard esterification mode, starting from the compound of formula (I) (the free acid) or a salt thereof or by a conventional transesterification process starting from a other ester For example, in the case of the very ester

  preferable, ie the ester (5-methyl-2-oxo-1,3-dioxo)

  lene-4-yl) methyl, it can be prepared by a reaction

  conventional esterification, for example a 4-halomethyl-

  1-methyl-1,3-dioxolene-2-one (eg 4-bromomethyl-1,3-methyl-diol-2-one) with the free acid or one of

  its salts (preferably an alkali metal salt)

  This reaction is particularly carried out using a salt of the acid of formula (I) although, if the free acid is used for this reaction, the same

  effect can be obtained by using the free acid in

sence of a base.

  These esterification reactions are normally

  in the presence of a solvent, the nature of which is not

  critical as long as it has no adverse effect on the reaction

  Examples of suitable solvents are N, N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, nitromethane, acetonitrile, acetone, tetrahydrofuran, dioxane, methanol,

  chloroform, methylene chloride, benzene or toluene

  luene, preferably N, N-dimethylformamide, N-N-

  dimethylacetamide or dimethylsulfoxide.

  As indicated above, if the esterification reaction

  tion is carried out using the free acid of formula (I) and a 4-methyl-5-methyl-1,3-dioxolene-2-one, the reaction

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  is preferably performed in the presence of a base Ce can

  be an organic base (such as triethylamine or dicy-

  clohexylamine) or a mineral base, in particular a car-

  alkali or alkaline earth metal carbonate or bicarbonate (such as sodium bicarbonate, sodium carbonate,

  potassium carbonate or calcium carbonate).

  The reaction temperature is not critical either.

  that although it is better to carry out the reaction to

  a relatively low temperature in order to limit the

  secondary conditions, preferably a temperature of 0 to

  1000 C The time required for the reaction depends on the temperature

  reaction and the nature of the reagents, but the reaction is normally finalized within a

  time from several minutes to 200 hours.

  Once the reaction is complete, we can separate the

  of the reaction mixture by conventional means.

  For example, the reaction mixture may be suitably added to a water immiscible solvent; wash the entire mixture with water; dry the mixture; and distilling off the solvent to obtain the desired compound which can then be purified, if necessary, by conventional means such as recrystallization or

  various chromatographic techniques.

  The compounds of the invention have potent antibacterial activity on various varieties of bacteria, including gram-positive bacteria and Gram-negative bacteria, as well as on anaerobic bacteria and thus are useful for the treatment of induced diseases.

by these bacteria.

  The activities of the compounds according to the invention on

  Bacteria are shown in the following table, in

  terms of minimum inhibitory concentrations (micrograms -

  mes per ml) In addition, results obtained are reported

  with a number of known compounds of similar structure

  The compounds are identified in the following table by the numbers assigned to them in the following list:

  (5R, 6S) -2- (2-Fluoroethylthio) -6- [1- (R) -hydroxyethyl] -7-

  Sodium-3-carboxylic acid 2 (5 R, 6 S) -2- (2-fluoroethylthio) -6- (1) (R) -hydroxyethyl) 7

  -5-methyl-2-oxo-1,3-dioxolene-3-carboxylate

no-4-yl) methyl

  (5 R, 6 S) -2- (2-chloroethylthio) -6- [1- (R) -hydroxy)

  ethyl 17 sodium penem-3-carboxylate

  (5 R, 6 S) -2-ethylthio-6- [1- (R) -hydroxyethyl] penem-

Sodium 3-carboxylate

  (5R, 6S) -2- (2-bromoethylthio) -6 - [- (R) -hydroxyethyl] -

sodium penem-3-carboxylate.

  Compounds Nos. 1 and 2 are compounds according to the invention

  which are respectively the sodium salt and the ester (5-

  methyl-2-oxo-1,3-dioxolene-4-yl) methyl of the compound of formula (I), while compounds 4 and 5 are known compounds having a similar structure and compound 3 is a compound described in Generally speaking, in the prior art, two results, A and B, are given for the compound No. 2. The first, A, is the result when the compound is used as such, while the second, B, is that obtained after have incubated the compound with rabbit serum for one hour at 37 C in order to simulate

the effects obtained in vivo.

BOARD

  Compounds n Microorganisms Compounds n

1 2 3 4 5

A B

  Staphylococcus 0.01 0.05 0.01 0.02 0.02 0.05 aureus 209 P Staphylococcus aureus 56 0.02 0.05 0.02 0.02 0.05 0.05 Escherichia coli NIHJ 0.1 0 , 4 0.1 0.2 0.4 0.4 Escherichia coli 609 0.1 0.4 0.1 0.6 0.8 0.4 Klebsiella pneumoniae 8060.1 0.4 0.1 0.4 0 , 4 0.4 Klebsiella pneumoniae 8460.8 3.1 0, 8 Proteus vulgaris 0.8 1.5 0.8 A number of important factors emerge from this table First of all, a rough comparison between the compound n ' 1 and compounds Nos. 3 to 5, which are all

  sodium salts, shows that the compound 1, the compound

  In addition, it is known that Escherichia coli strain 609 produces an enzyme, S-lactamase, which is capable of breaking the nucleus-lactam and to destroy the activity of many derivatives

  penicillin; it follows that it is a penile strain

  cillino-resistant, whereas Escherichia coli NIHJ is generally considered penicillin-sensitive then

  that the compound is equally effective on both

  the compounds according to the previous techniques

  Feel less activity on the resistant strain.

  Finally, although compound N 02 as such is less effective

  in this in vitro test that the compound n'1, when the compound

  was treated with rabbit serum, the product is all

as effective as the compound n'1.

  In addition to their excellent in vitro activity, the compounds according to the invention are also very effective in vivo and have proved more effective than similar known compounds.

  groups of mice with Staphylococcus aureus 56 or Escherichia

  chia coli 704, and then treated by subcutaneous injection of a solution of the compound nl or N 04 in physiological saline The ED 50 of the compound n1 vis-a-vis Staphylococcus aureus 56 and Escherichia coli 704 were found to be 0.9 and 2.9 mg / kg, respectively, whereas the corresponding values for the compound N 04 were

  2.6 and 10.7 mg / kg, respectively.

  Although, as highlighted by the results below,

  above, the compounds according to the invention have a

  generally a good activity and are therefore

  considered to have considerable therapeutic value,

  the compound N 02, that is to say the ester (5-methyl-2-oxo-1,3-

  dioxolene-4-yl) methyl, very surprisingly

  other properties which should give it considerable practical importance. In particular, this ester makes it possible to achieve much better results.

  points of view concentration in the blood and rate collected

  in urine than those obtained with all the other esters tested as well as with the free acid and its salts. For example, whereas the level of the sodium salt collected in the urine was only 7%, the The collected level of the (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl ester was 46%, indicating that the compound was degraded substantially more slowly to inactive metabolic products. the compound N 02 should remain active in the blood for substantially longer than the other esters, the acid

  free form or its salts, and would make it possible to

  concentration in the blood; therefore, the N02 compound could be administered at a lower dose than the other compounds (with correspondingly less risk of side effects and at a lower cost) or, if administered at the same dose , would have a significantly greater effect

powerful and fast.

  In addition, the compounds according to the invention have a very low toxicity. In order to evaluate the acute toxicity, 3000 mg / kg of compound 1 was injected intramuscularly per mouse into a group of 3 mice; no deaths followed

  this dose, thus demonstrating the low toxicity of the compound.

  The compounds according to the invention may be administered

  very oral or parenteral to obtain excellent effects However, the Applicant has discovered that, while it is better to administer the free acid and its salts

  parenterally (for example in the form of an injection

  intravenous, intramuscular or subcutaneous

  that they pass into the blood at a high concentration, the

  esters, and particularly the ester (5-methyl-2-oxo-1,3-

  dioxolene-4-yl) methyl, are preferably administered orally, when they also pass 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 dose of compound according to the invention varies according to the age, the weight and the state of the patient, as well as the form and nature of the administration However, in general, in adults the daily dosage is 200 to 3000 mg of the compound, which can be administered in a single dose

or in several partial catches.

  The following nonlimiting examples are given by way of illustration of the invention. The preparation of some of the starting substances is also illustrated.

in the Preparations below.

EXAMPLE 1

  (5R, 6S) -2- (2-fluoroethylthio) -6- / T- (R) -hydroxyethyl 7-

sodium penem-3-carboxylate

  (a) (55,6 S) -6- / 1- (R) -t-butyldimethylsilyloxyethyl 2-

  P-nitrobenzyl (2-fluoroethylthio) penem-3-carboxylate

  To a solution of 447 mg of (5 S, 6 S) -6 - [- (R) -t-butyl]

  dimethylsilyloxyethyl / -2-thioxopenam-3-carboxylate from p-

  nitrobenzyl in 5 ml of nitromethane is added, under nitrogen gas and while cooling on ice, a solution of 171 mg of 1-bromo2-fluoroethane in 1 ml of

  nitromethane and 138 μl of triethylamine. The mixture is stirred

  at room temperature for 3 days after which the reaction mixture is concentrated by evaporation under reduced pressure and the residue is extracted with methylene chloride. The extract is washed with a saturated aqueous solution of sodium chloride and It is dried over anhydrous magnesium sulphate. The solvent is distilled off and subjected

  the residue on silica gel column chromatography

  This gives the desired product, in crude form, by elution with a mixture of 20/1 by volume of benzene and

  ethyl acetate is then purified by chromatography.

  on a silica gel column, eluting with a 5/1 mixture by volume of hexane and ethyl acetate,

  thus obtaining 110 mg of the compound named in the title.

  -1 Absorption Spectrum I R (liquid film) -max cm:

1790, 1680.

  Spectrum of R M N (CDCl 3) δ 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, quadruplet AB, J = 14.0 Hz); , 70 (1H, doublet, J = 4.0 Hz);

  7.62, 8.23 (4H, A 2 B 2, J = 9.0 Hz).

  (b) (5R, 6S) -6 - [(R) -t-butyldimethylsilyloxyethyl-2 (2-

  p-nitrobenzyl fluoroethylthio) penem-3-carboxylate 2.0 mg of hydroquinone is added to a solution of

  mg of (5S, 6S) -6 - [- (R) -t-butyldimethylsilyloxyethyl] -2-

  P-nitrobenzyl (2-fluoroethylthio) -penem-3-carboxylate in 18 ml of xylene, and the mixture is heated on an oil bath at 135 ° C. under a stream of nitrogen gas for 3 hours. The solvent is then distilled off and the residue is purified by Lobar column chromatography (supplied by Merck & Co., Inc, silica gel, size B) eluting with a 25/1 by volume mixture of benzene and sodium acetate. thereby obtaining, in separate fractions, the title compound and the starting material. The recovered starting material is then heated as

  described above, thereby obtaining an additional quantity

  The total yield is 82 mg

(74.5%).

  Absorption spectrum I R (liquid film) i max cm:

1790, 1690, 1605.

  Spectrum of R M N (CDCl 3) ppm: 0.90 (9H, singlet); 1.35 (3H, doublet, J = 6.0Hz); 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); 4.70 (2H, doublet of triplets, J = 47.0 and 6.0 Hz); , 25, 5, 50 (2H, quadruplet AB, J = 14.0 Hz); , 72 (1H, doublet, J = 2, 0 Hz);

  7.68, 8.24 (4H, A 2 B 2, J = 9, 0 Hz).

  (c) (5 R, 6 S) -2- (2-Fluoroethylthio) -6- [t-R] -hydroxyethyl-7-penem-3-carboxylate p-nitrobenzyl 86 μl of acetic acid and 0.604 ml of ethyl acetate are added. a tetrahydrofuran solution containing 1 mole of fluoride

  from tetrabutylammonium to a solution of 82 mg of (5 R, 65) -

  6- / T (R) -t-butyldimethylsilyloxyethyl / -2- (2-fluoroethyl)

  thio) p-nitrobenzyl penem-3-carboxylate in 2 ml of tetrahydrofuran, and the mixture is stirred overnight at room temperature and then for 10 hours on an oil bath at 30 ° C. After this time, the mixture is diluted the mixture with ethyl acetate and washed, in turn, with a saturated aqueous solution of sodium chloride, using a 5% w / v aqueous solution of bicarbonate sodium and with a saturated aqueous solution of

  sodium chloride Then the solvent is distilled off and

  the residue by Lobar column chromatography (furnace

  denoted by Merck & Co, Inc., silica gel, size A), eluting with a 65/35 by volume mixture of benzene and ethyl acetate, thereby obtaining 40 mg of the product.

  named in the title, melting at 168-170 C.

  U V (ethanol) absorption spectrum> max nm:

261, 339.

  Spectrum of R M N (hexadeuterated dimethyl sulfoxide) ppm: 1.18 (3H, doublet, J = 6.0Hz); 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, doublet of triplets, J = 47.0 and 6.0 Hz); 19 (1H, doublet, J = 4.0 Hz); , 30, 5.48 (2H, quadruplet AB, J = 14.0 Hz); 5.77 (1H, doublet, J = 2.0 Hz);

  7.72, 8.25 (4H, A 2 B 2, J = 9.0 Hz).

  (d) (5R, 6S) -2) (2-Fluoroethylthio) -6- / 1- (R) -hydroxyethyl 7-

p Eneme-3-sodium carboxylate

  39 mg of (5R, 6S) -2- (2-fluoroethylthio) -6-

  P-nitrobenzyl 1- (R) -hydroxyethyl / penem-3-carboxylate in 3 ml of tetrahydrofuran; to the resulting solution was added 3 ml of a pH 7.1 phosphate buffer solution containing sodium ions and 78 mg of palladium

  % wt / wt. The mixture is stirred under nitrogen gas at a temperature of

  room temperature for 2.5 hours after which

  the catalyst is removed by filtration and the

  The resulting aqueous layer is concentrated to about 2 ml by evaporation under reduced pressure. The residue is subjected to column chromatography of Diaion HP-20 AG (produced by Mitsubishi Chemical Industries). using a solution

  Aqueous acetone at 5% vol / vol is concentrated by evaporation.

  under reduced pressure and freeze-dried, which gives

  17 mg of the desired compound in the form of a white powder

  che. Absorption spectrum I R (K Br) max cm 1: max

3425, 1765, 1600.

  U V (H 20) / max nm absorption spectrum:

252.5, 321.5.

  Spectrum of R M N (D 2 O) ppm: 1.30 (3H, doublet, J = 6.0Hz); 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 = 2.0Hz).

EXAMPLE 2

  (5R, 6S) - (2-fluoroethylthio) -6 - [- (R) -hydroxyethyl] acid -

  Penem-3-carboxylic acid A sample of the sodium salt, prepared as described in Example 1, is acidified by adding a solution

  The aqueous solution of citric acid at 5% w / v

  resultant methylene chloride and wash

  the extract with a saturated aqueous solution of chlorine

  sodium chloride, then dried over anhydrous magnesium sulphate

  methylene chloride is distilled, thus obtaining

  the free acid, with a quantitative yield.

  U V (ethanol) absorption spectrum Amax nm:

256, 333.

EXAMPLE 3

  (5 R, 6 S) -2- (2-Fluoroethylthio) -6- (1- (R) -hydroxyethyl) penime 3-carboxylate (5-methyl-2-oxo-1,3-dioxolene-4-yl) methyl A 200 mg solution is cooled on ice

  (5R, 6S) -2- (fluoroethylthio) -6- / T- (R) -hydroxyethylpenem-

  Sodium 3-carboxylate in 4 ml of N, N-dimethylacetamide;

  135 mg of 4-bromomethyl-5-methyl-1,3-dioxolene are added

  2-one and shake the mixture, which is then

  The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. after which the solvent is distilled off, which precipitates crystals. They are washed with a 1: 1 mixture.

  volume of benzene and ethyl acetate, and they are

  by filtration, thus obtaining 180 mg of the desired compound

  in the form of white crystals melting at 138-140 C.

  Absorption spectrum I R (K Br) -max cm-

max

3450, 1825, 1770, 1685, 1485.

  U V (Ethanol) Absorption Spectrum Nmax nm (E):

258.6 (6925), 338.9 (9124).

  Spectrum of R M N (at 100MHz in hexadeuterated dimethylsulfoxide) ppm: 1.20 (3H, doublet, J = 6.0Hz); 2.20 (3H, singlet); 3.10-3.65 (2H, multiplet); 3.82 (1H, doublet of doublets, J = 6.0 and 2.0 Hz); 3.85-4, (1H, multiplet); 4.68 (2H, doublet of triplets, J = 47.0 and 6.0 Hz); 10 (2H, singlet); , 75 (1H, doublet, J = 2.0 Hz).

PREPARATION 1

  (3S, 4R) -3-Il- (R) -t-Butyldimethylsilyloxyethyl-4- (5-

  Fluoro-2-thioxo-1,3-dithiapentyl) azetidine-2-one 4 ml of a methanolic solution of 0.5 M sodium methylate are added dropwise over a period of 15 minutes to a solution of 268 mg of thioacetate. of 2-fluoroethyl and 132 μl of carbon disulfide in 4 ml of anhydrous methanol, which solution was cooled to -15 ° C. The mixture is stirred for 30 minutes at -15 ° C., after which time it is added.

  604 mg of (3S, 4R) -3- / 1- (R) -t-butyldimethylsilyloxyethyl 17-

  4-acetoxyazetidin-2-one and the mixture is stirred for a further hour at -15 to -10 ° C. At the end of this time, crystals of the desired compound begin to precipitate. The mixture is allowed to stand overnight. C., then 0.21 ml of acetic acid is added and the mixture is extracted with ethyl acetate. The extract is washed with saturated aqueous sodium chloride solution and dried over sulphate. anhydrous magnesium The solvent is distilled off and the residue is purified by column chromatography on silica gel, eluting

  with a mixture of 10/1 by volume of benzene and

  ethyl acetate, thereby obtaining 536 mg of the desired compound,

melting at 106-107 C.

  Absorption spectrum I R (K Br) X cm-1 max

3050, 1765, 1725.

  Spectrum of R M N (at 60 MHz, CDCl3) ppm: 0.89 (9H, singlet); 1.21 (3H, doublet, J = 6.0Hz); 3.20 (1H, triplet, J = 2.0Hz); 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); 65 (1H, doublet, J = 2.0 Hz);

6.65 (1H, broad singlet).

PREPARATION 2

  {(3S, 4R) -3- (R) -t-Butyldimethylsilyloxyethyl 7-4- (5-

  fluoro-2-thioxo-1,3-dithiapentyl) azetidine-2-one-1-ylt

  p-nitrobenzyl glycolate 29.85 g of the product obtained in Preparation 1 and 35.33 g of p-nitrobenzyl glyoxylate hydrate are dissolved in 1.4 liters of dry benzene; then the benzene is distilled off by heating the mixture on a C oil bath. The residue is stirred for 4 hours at about

  same temperature of the bath, after which it is purified by chroma-

  silica gel columnography, eluting with the aid of

  of a 10/1 mixture by volume of benzene and ethyl acetate

  the, thus obtaining 38.15 g of the desired compound, under the form of

me of an oil.

  Absorption spectrum I R (liquid film) max cm: Max

3550, 1770, 1605, 1520 -

  Spectrum of R M N (at 60 MHz, CDCl3) at ppm: 0.86 (9H, singlet); 1.20, 1.23 (3H, doublet, J = 6.0Hz); 3.21-4.45 (6H, multiplet); 4.59 (2H, doublet of triplets, J = 47.0 and 6.0 Hz); , 20, 5.33 (2H, quadruplet AB, J = 14.0 Hz); 6.17, 6.21 (1H, doublet, J = 2.0Hz);

  7.49, 8.20 (4H, A 2 B 2, J = 9.0 Hz).

PREPARATION 3

  (3S, 4R) -3- / T- (R) -t-Butyldimethylsilyloxyethyl 7-4- (5-

  fluoro-2-thioxo-1,3-dithiapentyl) azetidin-2-one-1-yl;

  p-nitrobenzyl triphenylphosphoranylacetate 38.15 g of the product obtained are dissolved in the preparation

  2 in 350 ml of tetrahydrofuran, and the solution is cooled

  at a temperature of -20 to -15 ° C.

  8.95 ml of 2,6-lutidine, then slowly added

  5.14 ml of thionyl chloride, while maintaining the temperature

  below -15 ° C. The resulting mixture is stirred for 30 minutes at -20 to -15 ° C.

  pour the reaction mixture on a glacial aqueous solution

  sodium chloride and extracted with ethyl acetate

  The extract is washed with a saturated aqueous solution

  sodium chloride and dried over magnesium sulphate

  anhydrous solution, after which the solvent is distilled off

  which leaves a raw sample of o-1 (3 S, 4 R) -3-

  N- (R) -t-butyldimethylsilyloxyethyl / 7-4- (5-fluoro-2-thioxo)

  P-nitrobenzyl 1,3-dithiapentyl) azetidine-2-one-1-yl 1-chloroacetate The whole of this product is dissolved in 500 ml of tetrahydrofuran and the solution is added.

  11.93 ml of 2,6-lutidine and 27.02 g of triphenylphosphonate

  The mixture is stirred for 42 hours on an oil bath, at a bath temperature of 75-80 ° C, and then

  pour on an ice-cold aqueous solution of sodium chloride.

  The resulting mixture is extracted with ethyl acetate, the extract is washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulphate.

  Anhydrous solvent is distilled off and it is purified

  the residue was chromatographed on a silica gel column, eluting with an 8: 1 by volume mixture of benzene and ethyl acetate, thereby obtaining 26.82 g of the title product, in the form of a yellow powder. Absorption spectrum I R (K Br) cm 1 max

1750, 1620, 1600, 1510.

PREPARATION 4

  (5R, 6S) -6- / 1- (R) -t-butyldimethylsilyloxyethyl 7-2- (2-

  p-nitrobenzyl fluoroethylthio) penem-3-carboxylate 3.35 g of the product obtained as described in Preparation 3 are dissolved in 220 ml of anhydrous xylene, and 1 mg of hydroquinone is added. The mixture is stirred for 12 hours.

  on an oil bath at a bath temperature of 120-125 C.

  The solvent is distilled and the residue is purified by chromatography.

  silica gel columnography, eluting with the aid of

  a 10/1 mixture by volume of benzene and ethyl acetate.

  The elution product is concentrated by evaporation under

  reduced pressure and the residue is further purified by

  Lobar column matography (supplied by Merck & Co Inc, silica gel, two columns of size B in series) eluting with a 25/1 by volume mixture of benzene and ethyl acetate, thus obtaining 810 mg of the title compound, melting at 118-120 C, and 318

* mg of (5S, 6S) -6- / 1- (R) -t-butyldimethylsilyloxyethyl / -2-

  P-nitrobenzyl (2-fluoroethyl) penem-3-carboxylate, the compounds being shown by C C M, U V, I R spectroscopy and R M N being identical to the compounds obtained respectively.

  1 (b) and (1 (a).

Claims (14)

  1 2- (2-Fluoroethylthio) -6- (1-hydroxyethyl) -   Penem-3-carboxylic acid and its pharmaceutically acceptable salts and esters. ceutically acceptable.   (5 R, 6 S) - (2-Fluoroethylthio) -6- / 1- (R) -hydroxyethyl) penem-3-carboxylic acid, and its salts and   pharmaceutically acceptable esters.   2- (2-Fluoroethylthio) -6- (1-hydroxyethyl) penem-   (5-methyl-2-oxo-1,3-dioxolen-4-yl) 3-carboxylate methyl.   (5 R, 6 S) -2- (2-fluoroethylthio) -6- (1) (R) -hydroxy-   (5-methyl-2-oxo-1,3-dioxolene) ethyllpenem-3-carboxylate 4-yl) methyl.   A process for the preparation of 2- (2-fluoroethylthio) -6- (1hydroxyethyl) -penem-3-carboxylic acid, or a salt or ester thereof, characterized in that (a) a compound of formula (II): OR 1 H 3 (3 C O O R 2   wherein R 1 represents a protecting group of the   and R 2 represents a protected carboxy group, with a compound of formula (III): X-CH 2 CH 2 F (III)   in which X represents a leaving group, in order to obtain a compound of formula (IV): 3 3 OR 1 S S-CH 2 CH 2 F H 3 Ct j () N R 2   in which R 1 and R 2 have the abovementioned meanings, the reaction being carried out either, when X represents a group other than a hydroxyl group, in the presence of a base, or, when X represents a hydroxyl group, in the presence of triphenylphosphine and a dialkyl ester of azodicarboxylic acid;   (b) the hydroxyl protecting group is removed.   R 1 and, if necessary, the protected carboxy group represented by R 2 is converted into a free carboxy group; (c) optionally salifying the product of step (b); and (d) optionally esterifying the product of step (b) or (C).   Process according to Claim 5, characterized in that X represents a halogen atom, an alkane sulphonyloxy group, a haloalkanesulfonyloxy group or an arenesulfonyloxy group.   Process for preparing 2- (2-fluoroethyl) acid   thio) -6- (1-hydroxyethyl) -penem-3-carboxylic acid or a salt or ester thereof, characterized in that: (a) a compound of formula (V) is heated: OR 1 H 1 Cs S S- CH 2 CH 2 FS / ze 2 R 2   wherein R1 represents a protecting group of the   droxy, R 2 represents a protected carboxy group and Z + represents   a trialkylphosphonio group, a triaryl group   phosphonio or a di-esterified phosphono group accompanied by a cation, to obtain a compound of formula (IV): OR 1 S P S-CH 2 CH 2 F O R 2   wherein R and R have the aforementioned meanings;   (b) the hydroxyl protecting group is removed.   R 1 and, if necessary, converting the protected carboxy group represented by R 2 into a free carboxy group; (c) optionally salifying the product of step (b); and (d) the product of step (b) is optionally esterified or (c).   Process according to any one of the claims   5, 6 and 7, characterized in that in step (d) it is made to react   the product of stage (b) or (c) with a 4-halomethyl-5-   methyl-1,3-dioxolene-2-one in order to obtain 2- (2-fluorinated   ethylthio) -6- (1-hydroxyethyl) penem-3-carboxylate of (5-   methyl-2-oxo-1,3-dioxolen-4-yl) methyl.   9 A pharmaceutical composition comprising an antibiotic   mixed with a pharmaceutical vehicle or diluent   acceptable, characterized in that the antibiotic is   2- (2-fluoroethylthio) -6- (1-hydroxyethyl) penem-3- acid   carboxylic acid or a salt or ester thereof.   Composition according to claim 9, characterized   in that the antibiotic is 2- (2-fluoroethylthio) -   Sodium 6- (1-hydroxyethyl) penem-3-carboxylate.   11. A composition according to claim 10, characterized   in that the antibiotic is (5 R, 6 S) -2- (2-fluoro)   sodium ethylthio) -6- / T- (R) -hydroxyethyl-7-penem-3-carboxylate.   Composition according to claim 9, characterized   in that the antibiotic is 2- (2-fluoroethylthio) -   6- (1-Hydroxyethyl) penem-3-carboxylate (5-methyl-2-oxo) 1,3-dioxolen-4-yl) methyl.   13 Composition according to claim 12, characterized   in that the antibiotic is (5 R, 6 S) -2- (2-fluoro)   ethylthio) -6- / 1- (R) -hydroxyethyl 7 penem-3-carboxylate   (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl.   The composition of claim 10 or 11, wherein   sent for parenteral administration.   Composition according to Claim 12 or 13,   sent for oral administration.