BE897162A - CEPHALOSPORINS WITH ANTIBIOTIC ACTIVITY - Google Patents

Description

       

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  Description attached to a request for
BELGIAN PATENT filed by the so-called company: GLAXO GROUP LIMITED having for object: Cephalosporins with antibiotic activity Qualification proposed: INVENTION PATENT

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The present invention relates to improvements relating to cephalosporins. The invention relates more particularly to new cephalosporins and their derivatives which have an interesting antibiotic activity.



   The compounds of the nature of the cephalosporins which will be discussed in the present thesis are called with reference to the "cephaloma" according to the work J. Amer. Chem. Soc., 1962, 84, 3400, the term `` cephem '' referring to the basic cephalic structure which comprises a double bond.



   Antibiotics of the cephalosporin type are widely used for the treatment of diseases caused by pathogenic bacteria in humans and animals and are particularly useful for the treatment of diseases caused by bacteria which are resistant to other antibiotics, as compounds of the nature of penicillins and for the treatment of patients sensitive to penicillins. In many circumstances, it is desirable to employ a cephalosporin-type antibiotic which exhibits activity against both Gram-positive and Gram-negative microorganisms, and considerable research has been devoted to the development of various types of broad spectrum cephalosporin antibiotics.

   Thus, for example, the specification of British Patent No. 1,399,086 describes a new class of
 EMI2.1
 cephalosporins which contain a group 7P- etherified) -acylamido, the oximino group having the syn configuration. This class of antibiotic compounds is characterized by a high antibacterial activity against a whole series of Gram-positive and Gram-negative organisms, associated with a particularly high stability with respect to the p-lactamases generated by various Gram-negative organisms.



   The discovery of this class of compounds has stimulated further research in the same field, aimed at discovering compounds with improved properties, for example, vis-à-vis particular classes of organisms,

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 especially Gram-negative organisms. The specification of British Patent No. 1,453,049 describes, among others, the compound that is (6R, 7R) -3-carbamoyloxy-methyl-7- / rz) -2- (fur-2-yl) acid -2-methoxyimino ac étamido7céph-3- ème-4-carboxylic, which we know under the recognized name of "cefuroxime".



   The specification of British Patent No. 1,604,971 reveals the existence of a whole series of antibiotics of the genus cephalosporins where the side chain in position 7ss can be chosen from, among others, a 2- (2-aminothiazole) radical -4-yl) -2- (etherified oxyimino) acetamido where the etherifying group, among many other possibilities, may be an alkyl radical substituted by a cycloalkyl group, although there is no specific illustration of compounds containing such a group. The group in position 3 can also be chosen from a large number of possible radicals and a substituent in position 3 is an optional substituted carbamoyloxymethyl radical.

   Other compounds of the cephalosporin nature, which have a 2- (2-aminothiazole-4-yl) -2- (oxyimino etherified) acetamido radical in position 7ss are described, for example in the descriptions of the British patents NO 5,584,398 and 2,029,824.



   The Applicant has now discovered that by choosing a (Z) -2- (2-aminothiazole-4-yl) -2-cyclopropyl-methoxyiminoacetamido radical in position 7ss, combined with certain particular radicals in position 3, to obtain compounds of the genus of cephalosporins having a particularly advantageous activity (which will be described in more detail later in this memo) against a whole range of pathogenic organisms which are commonly encountered.



   The present invention therefore more particularly relates to antibiotics of the nature of cephalosporins which correspond to the formula of general structure (I)

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 EMI4.1
 in which R1 represents a hydrogen atom or a methyl or 2-chloroethyl radical, as well as the non-toxic salts and the metabolically labile and non-toxic esters of these compounds.



   The compounds according to the present invention are
 EMI4.2
 syn isomers. The syn isomer form is defined by the confi-
 EMI4.3
 guration of the group -
 EMI4.4
 with respect to the carboxamido radical. In this memo, the syn configuration is represented in structure by the following formula:
 EMI4.5
 
It should be understood that since the compounds according to the present invention are geometric isomers, some mixture with the corresponding anti-isomer may occur.



   The scope of the present invention also extends to solvates (more particularly hydrates) of the compounds of formula (I) and their non-toxic salts. The scope of the present invention also extends to non-toxic salts and to solvates of metabolically labile and non-toxic esters

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 compounds of formula (I). It can easily be understood that the solvates must be pharmacologically compatible.



   The compounds according to the present invention can exist in tautomeric forms (for example with regard to the 2-aminothiazolyl radical) and it is obvious that the scope of the present invention also extends to these tautomeric forms, for example form 2 -iminothiazolinyl.



   The compounds according to the present invention exhibit broad spectrum antibiotic activity, both in vitro and in vivo. These compounds exert a high activity against both Gram-negative and Gram-positive organisms among which numerous strains producing ss-lactamases. The compounds in question are also endowed with a high stability towards ss-lactamases generated by a whole range of Gram-negative and Gram-positive organisms.



   It has been found that the compounds according to the present invention exert a high activity against strains of Staphylococcusaureus, Staphylococcus epidermidis and Streptococcus species comprising the penicillinase producing strains of these Gram-positive bacteria. This activity is associated with a high effect against various organisms belonging to the enterobacteriaceae class (for example strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis and Indole-positive Proteus, such as Proteus vulgaris, Proteus morganii and Providence species), and strains of Haemophilus influenzae and Acinetobacter calcoaceticus, as well as good activity against Pseudomonas species.

   This combination of high activity against Gram-positive organisms and high activity against Gram-negative organisms possessed by the compounds according to the present invention is particularly unusual.



   The non-toxic salts which can be formed by the reaction of the carboxyl group present in the compounds of formula (I), include salts obtained with inorganic bases,

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 such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts), salts obtained with amino acids (e.g. lysine and arginine salts) salts obtained with organic bases (for example next salt, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglucosamine).

   Other non-toxic salts include acid addition salts, for example those formed with hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, formic and trifluoroacetic acids. The salts can also be in the form of resinates obtained, for example, with a polystyrene resin or a resin in a copolymer of divinylbenzene and crosslinked polystyrene, containing sulfonic acid groups or quaternary amino groups, or a resin containing carboxyl groups, for example a polyacrylic acid resin. Salts with soluble bases (for example alkali metal salts, such as sodium salts) of the compounds of formula (I) can be used in the therapeutic field, due to the rapid distribution or distribution of these salts in the 'Qrp5 near their administration.

   However, when it is desired to obtain insoluble salts of the compounds of formula (I) for a particular application, for example for the manufacture of depot preparations, these salts can be obtained in a conventional manner, for example at using suitable organic amines.



   Metabolically labile and non-toxic esters which can be formed by esterification of the carboxyl group of the related compound of formula (1) include acyloxyalkyl esters, for example alkanoyloxy-methyl or ethyl esters, such as acetoxy-methyl esters or - Ethyl or pivaloyloxymethyl and alkoxycarbonyloxy-alkyl esters, for example (lower alkoxy) -carbonyloxy-ethyl esters, such as ethoxycarbonyloxy-ethyl esters.

   Besides derivatives of the type

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 ester mentioned above, the scope of the present invention also extends to the compounds of formula (I) in the form of other physiologically compatible equivalents, that is to say physiologically compatible compounds which, like the metabolically labile esters , transform in vivo into the related antibiotic compound of formula (1).



   These salts and esters and other derivatives, such as the salts obtained with toluene-p-sulfonic and methane-sulfonic acids and the esters with t-butyl or diphenylmethyl esterifying radicals, can be used as intermediates for the preparation and / or purification of the compounds of formula (I) in accordance with the present invention, for example, during the implementation of the methods described below.



   A preferred compound according to the present invention is (6R, 7R) -7-Lrz) -2- (2-aminothiazole-4-yl) - 2-cyclopropylmethoxyiminoacetamido73-carbamoyloxymethyl-ceph- acid
 EMI7.1
 3-th-4-carboxylic acid, as well as the non-toxic salts and the metabolically labile and non-toxic esters of this compound.



   The compounds according to the present invention can be used for the treatment of various diseases caused by pathogenic bacteria in humans and animals, such as respiratory tract infections and urinary tract infections.



   According to another of its particularities, the present invention relates to a process for the preparation of an antibiotic compound corresponding to the general formula (I) as defined above or of an atoxic salt or of a metabolically labile and atoxic ester d '' such a compound, characterized in that a compound of the formula is formed:

   
 EMI7.2
 

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 EMI8.1
 9 1 which represents the group as defined above or a radical protecting the N function, for example a labile group, such as an acyl radical, more particularly a lower alkanoyl group, such as acetyl, an alkanoyl radical less than halogenated substitution, such as a mono-, di- or tri-chloroacetyl, chlorosulfonyl or bromosulfonyl group, or a halogenated alkoxycarbony radical, such as 2,2, 2-trichlorethoxycarbonyl, R3 represents a hydrogen atom or a radical blocking the carboxyl function, for example the residue of an esterogenic araliphatic or aliphatic alcohol or of an esterogenic stannanol, silanol or phenol of phenol, silanol or stannanol alcohol mentioned above, preferably containing

   from 1 to 20 carbon atoms), R4 represents an amino group or a protected amino group, B represents> S or> S- 0 (a or P) and the line in broken lines which establishes a bridge between the positions 2,3 and 4 indicates that the compound is a substance of the ceph-2-th type
 EMI8.2
 or ceph-3-th7 a salt of such a compound, eh e, by (A) acylation of a compound of the formula
 EMI8.3
 
 EMI8.4
 p (in which, B and the dashed line or have the meanings assigned to them above) or a salt, for example an acid addition salt (generated, for example, with a mineral acid, such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid or with an organic acid, such as methane sulfonic or toluene-p-sulfonic acid) or a 7-N-silyl derivative of such a compound,

   with an acid of the formula

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 EMI9.1
 (in which R4 has the meanings which have been previously assigned to it) or a salt of such a compound, or with an acylating agent which corresponds to it, or. (B) the reaction of a compound of the formula
 EMI9.2
 
 EMI9.3
 3 4 (in which R4, B and the dashed line R3, have the meanings which have been previously assigned to them) or a salt of such a compound, on an acylating agent.

   serving to generate the group -CH2OCONHR2 (where R2 has the meanings which were previously assigned to it) in position 3, then, if this proves necessary and / or desirable in each circumstance, any of the reactions are carried out which follow, in any suitable order, i) conversion of an isomer to the desired isomer # 3,
 EMI9.4
 ii) reduction of a compound in which B represents> S- to form a compound in which B represents> 8, iii) conversion of a carboxyl group into a metabolically labile and non-toxic ester function,

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 iv) formation of an atoxic salt, and v) removal of any groups blocking the carboxyl function and / or protecting the N function.



   The above-mentioned reactions i) to v) can be carried out in a conventional manner.



   In the above-mentioned process (A), the starting material of formula (II) is preferably a compound in which B represented and the line in dashed lines represents a substance of the ceph-3-th type.



   The acylating agents which can be used for the preparation of compounds of formula (I) include acid halides, more particularly acid bromides or chlorides. These acylating agents can be prepared by the reaction of an acid (III) or a salt thereof on a halogenating agent, for example phosphorus pentachloride, thionyl chloride or oxalyl chloride.



   Acylations using acid halides can be used in aqueous and non-aqueous reaction media, conveniently at temperatures from -50 to + 50oC, preferably from -40 to + 30oC, if desired, in the presence of a acid fixing agent. Suitable reaction media include aqueous ketones, such as aqueous acetone, aqueous alcohols, such as aqueous ethanol, esters, such as ethyl acetate, halogenated hydrocarbons, such as methylene chloride, amides, such as dimethylacetamide, nitriles, such as acetonitrile or mixtures of 2 or more of 2 of these solvents.

   As suitable binding agents, there may be mentioned tertiary amines (for example triethylamine or dimethylaniline), inorganic bases (for example calcium carbonate or sodium bicarbonate) and oxyranes, such as 1,2-lower alkylene oxides (eg ethylene oxide or propylene oxide), which bind the hydrogen halide released during the acylation reaction.



   The acids of formula (III) themselves can be used as acylating agents for the preparation of

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 compounds of formula (I). Acylations which use acids (III) are advantageously carried out in the presence of a condensing agent, for example a carbodiimide, such as N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-y-dimethylaminopropylcarbodiimide , a carbonyl compound, such as carbonyldiimidazole, or an isoxazolium salt, such as N-ethyl-5-phenylisoxazolium perchlorate.



   It is also possible to carry out the acylation with other amidogenic acid derivatives of formula (III), such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (for example generated with pivalic acid or with a haloformate, such as a lower alkyl haloformate). Mixed anhydrides can also be formed with phosphorus acids (e.g. phosphoric or phosphorous acids), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. toluene-p-sulfonic acid). An activated ester can conveniently be formed in situ using, for example 1-hydroxybenzotriazole in the presence of a condensing agent, as previously described. You can also preform the activated ester.



   Acylation reactions which involve the free acids or their amidogenic derivatives mentioned above, are advantageously carried out in an anhydrous reaction medium, for example methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile.



   Another activation method consists, for example, in reacting an acid of formula (III) on a preformed solution or suspension by adding a carbonyl halide, more particularly phosgene or oxalyl chloride, or a halide of phosphorylated, such as phosphorus oxychloride, to a solvent, such as a halogenated hydrocarbon, for example methylene chloride, containing a tertiary (lower acylacamide, such as N, N-dimethylformamide. The activated form of the acid of formula (III) can then be reacted with a compound of the 7-amino type of formula (II)

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 in a suitable solvent or in a suitable mixture of solvents, for example a halogenated hydrocarbon, for example dichloromethane.

   The acylation reaction can conveniently be carried out at temperatures which fluctuate from -50 to + 50oC, preferably from -40 to + 30oC, if desired in the presence of an acid-fixing agent, for example of nature. described above (for example dimethylaniline).



   If desired, the above acylation reactions can be carried out in the presence of a catalyst, such as 4-dimethylaminopyridine.



   If desired, the acids of formula (III) and the corresponding acylating agents can be prepared and used in the form of their acid addition salts. Thus, for example, it is convenient to use the acid chlorides in the form of their hydrochloride type salts and the acid bromides in the form of their hydrobromide type salts.



   The carbamoylation of 3-hydroxymethyl compounds of formula (IV) can be carried out by implementing conventional methods using appropriate carbamoylating agents. These suitable carbamoylating agents include
 EMI12.1
 c c isocyanates of formula R5. NCO (in which represents a methyl or 2-chloroethyl radical or a labile substituent group), so as to obtain a compound containing a
 EMI12.2
 substituent in position 3 which corresponds to the formula CH2O. e & (in which R5 the meanings which have been previously assigned to it CONHR5). The labile group R5 can subsequently be split, for example by hydrolysis, to generate a 3-carbamoyloxymethyl group.



   As examples of labile radicals5 which can easily be split by subsequent treatment, mention may be made of:
 EMI12.3
 labile radicals previously cited as examples of the 2 radical These labile groups can generally be
R. split by acid or base catalyzed hydrolysis (e.g. base catalyzed hydrolysis using sodium bicarbonate).

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 EMI13.1
 



  The reaction product can be separated from the reaction mixture which may contain, for example, a starting material of the unmodified cephalosporin type and other substances, by means of a whole series of processes including recrystallization, iontophoresis. , column chromatography and the use of ion exchangers (for example by using chromatography or ion exchange resins) or macroreticular resins.
 EMI13.2
 



  0 A derivative of the ester type of Acephalosporin can be transformed, obtained by implementing the method according to the present invention. the corresponding corresponding derivative A, for example 2, by ster a base, such as pyridine or triethylamine.



   It is also possible to oxidize a reaction product of the ceph-2-th type to obtain the corresponding 1-oxide of ceph-3-th, for example by the reaction on a peracid, for example peracetic acid or m -chloroperbenzolque, it is possible subsequently to reduce the sulphoxide thus obtained in the manner described in the remainder of this specification, with a view to obtaining the desired corresponding ceph-3-th sulphide.



   When a compound is obtained in which B represents; > S 0, this compound can be transformed into the corresponding sulfide, for example, by reduction of the acyloxysulfonium or corresponding alkoxysulfonium salt, prepared in situ, by the reaction on, for example acetyl chloride in the case of 'an acetoxysulfonium salt, the reduction being effected by, for example,. sodium dithionite or with an iodide ion, as in a solution of potassium iodide in a water-miscible solvent, for example acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature which varies from -20 to + 50oC.



   The metabolically labile esters of the compounds of formula (I) can be prepared by the reaction of a compound of formula (I) or a salt or a protected derivative of this compound, with the appropriate esterifying agent, such as a halide

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 of acyloxyalkyl or an alkoxycarbonyloxyalkyl halide (for example iodide), the reaction being carried out conveniently in an inert organic solvent, such as dimethylforma-
 EMI14.1
 mide or acetone, this reaction being followed, when necessary, by the removal of any protective groups.



   The salts with bases of the compounds of formula (I) can be formed by reacting an acid of formula (1) on a suitable base. Thus, for example, the sodium or potassium salts can be prepared by using the salt of the 2-ethylhexanoate type or of the respective bicarbonate type.



  Acid addition salts can be prepared by reacting a compound of formula (I) or a metabolically labile ester of such a compound with the appropriate acid.



   When a compound of formula (I) is obtained in the form of a mixture of isomers, the syn isomer can be obtained, for example, by implementing conventional methods, such as by crystallization or by chromatography.



     As starting materials. for the preparation of ¯ compounds of formula (I) in accordance with the present invention, use is preferably made of compounds of general formula (III) and their amidogenic derivatives, such as the acid halides and the anhydrides which correspond to them , in their syn isomer form or in the form of mixtures of syn isomers and corresponding anti isomers containing at least 90% of syn isomers.



   The acids of formula (III) and their derivatives can be prepared by etherification of a compound of the formula
 EMI14.2
 

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   (in which R4 has the meanings which have been previously assigned to it and R represents a hydrogen atom or a group blocking the carboxyl function) or a salt of such a compound, by selective reaction on a compound of the general formula
 EMI15.1
 (in which T represents a halogen, such as chlorine, bromine or iodine, a sulfate or sulfonate group, such as tosylate), this reaction being followed by the elimination of any R group blocking the carboxyl function . Isomers can be separated either before or after the etherification reaction of this kind.

   The etherification reaction is conveniently carried out in the presence of a base, for example potassium carbonate or sodium hydride and it is preferably carried out in an organic solvent, for example dimethyl sulfoxide, a cyclic ether, such as tetrahydrofuran or dioxane, or an N, N-disubstituted amide, such as dimethylformamide. Under these conditions, the configuration of the oxyimino group remains substantially unmodified by the implementation of the etherification reaction. When the compound of formula (VI) is used in the form of a free acid or a salt with a base, the etherification reaction is generally carried out in the presence of a strong base, for example the potassium t-butoxide, a sufficient amount of strong base being added to form a bi-anion.

   In addition, the reaction must be carried out in the presence of a base if an acid addition salt of a compound of formula (VI) is used, the amount of base sufficient to quickly neutralize the acid in question.



   Acids of formula (III) can also be prepared by reacting a compound of the formula:

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 EMI16.1
 (in which R4 and R6 have the meanings previously indicated) on a compound of the formula
 EMI16.2
 followed by the removal of any RU radical blocking the carboxyl function and, if necessary, the separation of the syn and anti isomers.



   The acids of formula (III) can be converted to the corresponding acid anhydrides and halides and to the acid addition salts by means of conventional methods, for example, as described above.



   The starting materials of formula IV can be prepared by the use of methods analogous to those described in British Patent No. 1,474,519 and in United States Patent No. 3,976,546. these starting materials by carrying out the acylation of the corresponding 7-amino-3-hydroxymethyl type compounds, for example, in a manner analogous to the process (A) described above.



   It is necessary. understand that, in the case of the abovementioned transformations, it may prove necessary to protect any sensitive radicals present in the molecule of the compound in question, in order to avoid the appearance of undesirable side reactions. For example, during the implementation of any of the reaction sequences listed above, it may prove necessary to protect the NH 2 radical from the aminothiazolyl group, for example by tritylation, acylation (for example chloracetylation or formylation), protonation or by using any other conventional method.

   The protecting group can subsequently be removed via any convenient method which does not cause degradation or decomposition of the desired compound, for example

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 in the case of a trityl radical, by the use of an optionally halogenated carboxylic acid, for example acetic acid, formic acid, chloracetic acid or trifluoroacetic acid, or by using a mineral acid, for example hydrochloric acid, or mixtures of these acids, preferably in the presence of a protic solvent, such as water or, in the case of a chloroacetyl group, by treatment with thiourea.



   The radicals blocking the carboxyl function used for the preparation of compounds of formula (I) or for the preparation of necessary starting materials) are advantageously radicals which can easily be separated during an appropriate stage from the following reactions, conveniently in the last step. However, under certain circumstances it may be convenient to use metabolically labile and non-toxic carboxyl blocking groups, such as acyloxymethyl or acyloxyethyl (e.g. acetoxymethyl or acetoxyethyl or pivaloyloxymethyl) or alkoxycarbonyloxyalkyl (e.g. -ethoxycarbonyloxyethyl) radicals. and keeping these groups in the final product so as to obtain a suitable ester of a compound of formula (I).



   Suitable carboxyl blocking groups are well known to those skilled in the art, an illustrative list of blocked carboxyl groups in the specification of British Patent No. 1,399,086. The preferred blocked carboxyl groups are aryl (lower alkoxy) carbonyl radicals , such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl, (lower alkoxy) carbonyl radicals, such as t-butoxycarbonyl and halo (lower alkoxy) carbonyl radicals, such as 2, 2, 2-trichlorethoxycarbonyl.

   The carboxyl blocking radical can subsequently be removed by using any of the appropriate methods described in the technical literature, thus, for example, hydrolysis can be applied in many cases.

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 catalyzed by an acid or a base, just as enzymatic catalysis hydrolysis can be carried out.



   The antibiotic compounds according to the present invention may be presented for administration in any suitable form, by analogy to the administration forms used for other antibiotics and, therefore, the scope of the present invention is also extends to pharmaceutical compositions which comprise at least one antibiotic compound in accordance with the present invention, suitable for use in human or veterinary medicine. With a view to their use, these compositions can be prepared in conventional manner using any necessary pharmaceutical excipients or vehicles.



   The antibiotic compounds according to the present invention may be presented in the form of compositions suitable for injection and these preparations may take the form of unit doses, be introduced into ampoules or into containers which contain multiple doses thereof, if necessary with an additional preservative. The compositions may also adopt forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain composing agents, such as suspending, stabilizing and / or dispersing agents. The active ingredient can also be in the form of a powder suitable for reconstituting the desired pharmaceutical composition using a suitable vehicle, for example sterile pyrogen-free water, before its use.



   If desired, these powder compositions may contain a suitable non-toxic base, in order to improve the water solubility of the active ingredient and / or to ensure that when the powder is added to the reconstitution water, the pH of the aqueous composition thus obtained is physiologically compatible. The base can also be present in the water used to reconstitute the pharmaceutical composition with the powder. The base can be, for example, a

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 inorganic base, such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base, such as lysine or lysine acetate.



   The compositions can also be presented in a form suitable for absorption from the gastrointestinal tract, for example tablets, capsules, syrups or suspensions suitable for oral administration and suppositories.



   The compositions intended for use in veterinary medicine may, for example, be in the form of intramammary preparations in bases with rapid or delayed release of the drug substance.



   The compositions may contain from 0.1%, for example from 0.1 to 99%> of the active material, depending on the mode of administration. When the compositions are in the form of unit doses, each unit dose preferably contains from 100 to 3000 mg of active ingredient, for example from 200 to 2000 mg of this active ingredient. The daily dose intended for the treatment of adult humans varies, preferably, from 200 to 12,000 mg, for example from 1,000 to 9,000 mg of active ingredient per day, depending, inter alia, on the nature of the infection and the mode and frequency of administration. Overall, administration may be administered intravenously or intramuscularly, for example using 400 to 4000 mg per day of the active ingredient for the treatment of adult humans.

   For the treatment of Pseudomonas infections, higher daily doses may be necessary. It will be perfectly understood that, in certain circumstances, for example for the treatment of newborns, it may be desirable to use only unit doses and reduced daily doses.



   The antibiotic compounds according to the present invention can be administered in combination with other therapeutic agents, such as antibiotics, for example penicillins or cephalosporins.

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   The following examples illustrate the present invention.



  All the temperatures indicated in these examples appear in degrees Celsius. Sorbsil U30 is a silica gel manufactured by the company Joseph Crosfield and Son of Warrington, Lancashire, England. The abbreviation DMSO denotes dimethyl sulfoxide.



    Preparation 1 (Z) -2-Cyclopropylmethoxyimino-2- (2-tritylaminothiazole-4-yl) - ethyl acetate
(Z) -2-hydroxymino-2- (2-tritylaminothiazole-4-yl) ethyl acetate, hydrochloride salt (30 g)) was stirred with cyclopropylmethyl bromide (13.5 g) in sodium sulfoxide dimethyl (150 ml) containing potassium carbonate (30 g) at 210, under a nitrogen atmosphere, for 7 hours. The mixture was partitioned between methylene chloride and water. The aqueous layer was extracted with additional methylene chloride and the combined organic solutions were washed with water. After drying using magnesium sulphate, the solution was concentrated and introduced into a column of Sorbsil U30 silica gel (200 g).

   The contents of the column were eluted with ethyl acetate (10-30%) in petroleum ether (P.E. 40-600).



  Evaporation of the appropriate fractions made it possible to obtain the
 EMI20.1
 compound indicated in the title (20.9 g); ^ max (ethanol) 1% cm'03); 254.5nm (E 302) 259.5nm 1 lcm inf. 1 lcm 20 icm 190) and lcm% lcm lcm 294nm 3398 (NH), 1730 (ester), 1593 and 1491cm '(aromatic double bond). 1%. Preparation 2 Acid (Z) -2-cyclopropylmethyl) -7- (thiene-2- 4-yl) acetic
The product of Preparation 1 (20 g) was dissolved in ethanol (200 m) and to it was added hydroxide.
 EMI20.2
 1

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 sodium (2.12 g) in water (40 ml). The mixture was brought to reflux for 45 minutes, during which the precipitation took place. Some of the ethanol (about 150 ml) was removed by distillation and the residue was cooled.

   The mixture was partitioned between methylene chloride and water containing 2N hydrochloric acid (70 ml). The organic layer was washed with water, each aqueous layer being reextracted with an additional amount of methylene chloride. The combined organic layers were dried using magnesium sulfate and evaporated to give the title compound (20 g);
 EMI21.1
 Ainf. (ethanol) 234.5nm (E 383); 266, 5nm lcm lcm cm 226) and (Nujol) 3260 (NH) and lcm lcm max (acid).



    Preparation 3 (a) (6R, 7R) -3- (N-ethylcarbamoyloxymethyl) -7- (thiene-2-yl) acetamidceph-3-th-4-carboxylic acid
A solution of (6R, 7R) -3-hydroxymethyl- was stirred
 EMI21.2
 7- (thiene-2-yl) acetamidocéph-3-th-4-carboxylic (3.54 g) in dry N, N-dimethylformamide (150 ml) at 0-50 it was treated with triethylamine ( 2, ml) and then with methyl isocyanate (5.0 ml). The solution was stirred at et40 for 3.25 hours, then poured into a 3% solution of sodium bicarbonate (1.0 L) which was washed with ethyl acetate. The aqueous fraction was covered with ethyl acetate and the pH was lowered to 2.0 using orthophosphoric acid.

   The layers were separated and the aqueous fraction was further extracted with ethyl acetate. The organic extracts were washed with 0.5 N hydrochloric acid and saturated brine, dried and evaporated to give the title compound (1.39 g); max) 3420 and 3270 (NH), 2600 and 1728 (C02H), 1760 (ss-lactam) 1702

  <Desc / Clms Page number 22>

 
 EMI22.1
 and 1530 cm-1 (CONH); 0.81 (d, J9Hz, NH), that 2.50 (somatic protons) 24 (dd, J5 and 9Hz, C7- "TI (DMSO-d6) H); 6.16 (s, CH2CONH); 6, 41 (C2-CH2) and 7.37 (d, J5Hz, CH3NH).
 EMI22.2
 



  (b) (6R. diphenylmethyl acetamidceph-3-th-4-carboxylate A suspension of (6R, 7R) -3-N-methylcarbamoyloxymethyl-7-acetamidceph-3-th-4-carboxylic acid was stirred (2 0.0 g) in tetrahydrofuran (50 ml) to 20 and a solution of diphenyldiazomethane in dichloromethane (15 ml; 0.28 M) was added thereto. The mixture was stirred at 200. An additional amount of diphenyldiazomethane was added. in dichloromethane (1.0 ml, 1.44 M) for 2 hours and the addition of dichloromethane was repeated after an additional 1 hour, the reaction mixture was evaporated after a total of 4 hours, the residue was triturated with diethyl ether, it was stirred and filtered.

   The solid obtained was washed with a little diethyl ether and was
 EMI22.3
 dried so as to collect the compound indicated in the title (2, g); max (Nujol) 3354 and 3310 (NH), 1790 (P-lactam), max 1704 and 1536 (NHC02R), 1656 and 1536 cm-1 (amide; (DMSO-d6) 0, J9Hz, CH2CONH), approx. 2, 2 to approx. 2, 9 (thie- and diphenyl + NOCH3 protons); 3.00 (s, ÇH (CH)) and 7.39 (d, J5Hz, NHCH,).



  EXAMPLE (a) (6R, 7R) -3-Carbamoyloxymethyl-7- / r7-2-cyclopropylmethoxyL
Diphenylmethyl 75th-4-carboxylate
Oxalyl chloride (0.37 ml) was added to a solution of N, N-dimethylformamide (0.38 ml) in methylene chloride (10 ml) at -200, with stirring. After 5 minutes at 00, the mixture was cooled to -200 and added to it (Z) -2-cyclopropylmethoxyimino-2- (2-tritylaminothiazole-4-yl) acetic acid (1.94 g ).

   The solution was stirred at 00 for 10 minutes before cooling to -200. A suspension of (6R, 7R) -7-amino-3-carbamoyloxymethyl-ceph-3-th-4-carboxylate of diphenylmethyl (1.75 g) was added in

  <Desc / Clms Page number 23>

 methylene chloride (17 ml) containing N, N-dimethylaniline (1.26 ml). The solution was allowed to warm to 210 and stirred for 1.5 hours. After diluting with methylene chloride, the solution was washed with dilute hydrochloric acid and water, each time being extracted with methylene chloride. The combined organic layers were dried (magnesium sulfate) and concentrated.

   The solution was introduced into a column of Sorbsil U30 (70 g) which was eluted with a gradient of ethyl acetate (10 to 100%) in petroleum ether (e.g. 40-600). Evaporation of the appropriate eluate provided the title compound (3.03 g) as a foam;
 EMI23.1
 21 5nm (E 1% ta +10, (c (1.03, CHC13) i 278); 258.5227); 264, 5 (Elcm 1% 1 lcm 5 (El% 88). Lcm (E 186) and 296, (b) Acid (6R, 7R) -7- / IZ) -2- methoxyiminoacetamido7-3-carbamoyloxymethylceph-3- th-4-
X fi 2381 lcmcarboxylic, trifluoroacetate salt
The compound from step (a) (2.86 g) was dissolved in anisole (6 ml) and trifluoroacetic acid (24 ml) was added to 21, with stirring. After 1.25 hours, water (1.5 ml) was added.

   After 5 minutes, the solution was evaporated to half its volume and diisopropyl ether (about 100 ml) was added. The precipitate was collected by filtration, washed with diisopropyl ether and air dried. The solid thus obtained was dissolved in formic acid (7 ml) and water (3 ml) was added.



  After 1.5 hours, the solution was evaporated until an oil was obtained which was triturated with diisopropyl ether so as to obtain the compound indicated in the title.
 EMI23.2
 



  10 (150 + 7; chloroform; lmax io (11 1% D 5 1% and 293 5nm 235nm (El% 308). Nm (El (cm 117). Lcm

  <Desc / Clms Page number 24>

    g), EXAMPLE 2 (a) Acid 6R, 7R) -7 - / (z) -2 cyclopropylmethoxyimino-2- (2-tri-tylaminothiazole-4-yl) acetamido7-3-hydroxymethyl ceph-
3-th-4-carboxylic
Under a nitrogen atmosphere, oxalyl chloride (0.50 ml) was added to a solution of N, N-dimethylformamide (0.48 ml) in dichloromethane (13 ml) at -200. The mixture was stirred at 00 for 10 minutes and cooled to
 EMI24.1
 - (2) 2-acetic acid (2, g) was added and the solution was stirred at 00 for 20 minutes.

   This solution was added to a solution of (6R, 7R) -7-amino-3-hydroxymethyl- ceph-3-th-4-carboxylic acid (1,110 g) in industrial alcohol denatured with methanol (20 ml) of water (2 ml) and triethylamine (5 ml) at 00. This mixture was stirred at 00 for 30 minutes and evaporated. The solid was stirred with water (20 ml), ethyl acetate (20 ml) and methyl isobutyl ketone (20 ml). The pH of this mixture was adjusted to 3.0 with a 20% aqueous solution of phosphonic acid. The solid was washed with water, ethyl acetate, then ether and dried to collect the title compound, containing 0.67
 EMI24.2
 mole of triethylamine (1.736 g) + in 9); ZF7D + 390 DMSO); u. v.

   (ethanol): nm (E 327) and At 259 nm (E1cm 250). lcm (b) (6R, 7R) methoxyimino-2-acetamido7 acid; 27 ceph-3-th-4-carboxylic, sodium salt
A solution of chlorosulfonyl isocyanate (150 mg) in acetone (1 ml) at -100 was added to a solution of the product of preparation 3 (565 mg) in acetone (5 ml) at- 200, under a nitrogen atmosphere. After 15 minutes, the suspension was stirred at 00. After 1 hour, a solution of chlorosulfonyl isocyanate (150 mg) in ethyl acetate (1 ml) was added and the mixture was stirred for

  <Desc / Clms Page number 25>

 
1 additional hour.

   An additional fraction of chlorosulfonyl isocyanate (150 mg) was added, followed by that of water (1 ml) at 0. The suspension was stirred at a temperature of 10 to 200 for 1 hour, so as to obtain a suspension, the pH of which was adjusted to 2.5 by the addition of an aqueous solution of sodium hydroxide.



   The solution thus obtained was extracted with ethyl acetate, an extract which was washed, dried over concentrated sodium sulfate, so as to obtain a solid (62 mg) which was separated by filtration. and from which the filtrate was evaporated so as to obtain a foam (0.47 g). Part (0.42 g) of the foam was stirred in acetone with a solution of sodium 2-ethylhexanoate (0.57 ml of a 1 M solution diluted to 2 ml), so as to get the indicated compound
 EMI25.1
 in the title in the form of a powder (225 mg), u. v. posi i <attractive to infections at 236 nm (E..

   jcm (c) (6R, 7R) -7 - / (z) -2- (2-aminothiazole-4-vl) -2-cyclo-propylmethoxyiminoacetamido7-3-carbamoyloxymethyl ceph-
3-th-4-carboxylic
A solution of the product of the above-mentioned step (a) (136 mg) was diluted in formic acid (1.5 ml) with water. (0.5 ml) and stirred at 20 "for 1 hour. The mixture was filtered and the solid was washed with a mixture of formic acid and water (3: 1). the filtrate so as to obtain a gum which has been triturated with
 EMI25.2
 ether so as to obtain the title compound (74 mg); u. v. (ethanol) with? 1% Xmax lcm infl 257 nm (B 256) 3700 to 2500 and water), 1768 (ss-1actam), 1710 (C02H and carbamate) and 1560 and 1530cm * (amide).



  EXAMPLE 3 (a) (6R. 7R) -3-carbamoyloxymethyl-7 - / (z) -2-cyclopropyl-methoxyimino-2- (2-tritylaminothiazole-4-yl) acetamido7 ceph-3-th-4-carboxyic

  <Desc / Clms Page number 26>

 
Oxalyl chloride (0.37 ml) was added to a solution of N, N-dimethylformamide (0.38 ml) in methylene chloride (10 ml) with stirring and under a nitrogen atmosphere at -200 . After approximately 10 minutes of cooling with ice water, the mixture was cooled to -200 and (Z) -2-cyclopropylmethoxyimino-2- (2-trityl-) acid was added to it.
 EMI26.1
 aminothiazole-4-yl) (1.94 g) and the solution was then stirred under cooling with ice water for 10 minutes.

   The solution was cooled to -20 and added to a solution of (6R, 7R) -7-amino-3-carbamoyl-oxymethylceph-3-th-4-carboxylic acid (1.09 g ) in industrial alcohol denatured with methanol (12 ml) and water (3 ml) containing triethylamine (2.4 ml) at -100 and with vigorous stirring. After 5 minutes, the solution was partitioned between water and methylene chloride. Diluted hydrochloric acid was added to adjust the pH of the aqueous layer to less than 2. The aqueous layer was extracted with an additional amount of methylene chloride and the combined organic layers were washed with
 EMI26.2
 - they were dried over magnesium sulfate and evaporated.

   JOn was triturated the residue with diethyl ether, so as to obtain the compound indicated in the title (2.32 g); / S7 + (NH, NH2, OH, and water), 1785 (ss-lactameb, 1720 (acid and carbamate) and 1683 and 1510 cm "(amide).



  (b) (6R, 7R) 1-acetoxy-1-ethyl imino-2- th-4-carboxylate Acid (6R, LTZ) yl) acetamido7-ceph-3-th-4-carboxylic was stirred (1.1 g) with potassium carbonate (105 mg) in N, N-dimethylformamide (5 ml) under nitrogen and cooling with ice water. After 5 minutes, 1-acetoxy-1-ethyl bromide (300 mg) was added. After 1 hour at ice bath temperature

  <Desc / Clms Page number 27>

 and 2.5 hours to 21, the mixture was partitioned between ethyl acetate and aqueous hydrochloric acid. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and evaporated to a foam .

   This foam was chromatographed on Sorbsil U30 (50 g) in ethyl acetate (10 to 70%) in petroleum ether (P. E. 40-60) so as to collect the
 EMI27.1
 title compound (840 mg); J (CHBr3) mSLX 3538, 3403 (NH and NH2); 1785 (6-lactam), 1730 (ester and carbamate); 1688 and 1513 cm (amide); includes 3, (NH and OCHCH-); 3, (proton thiazole), 419 and 4,6-H); 4, to 5 .. and NH2); and 590 (c) (1 methoxyimino-2- T (CDC13) ceph-3-th-4-carboxylate of 1-acetoxy-1-ethyl, 1-oxide
The product from step (b) (2.7 g) was stirred with 3-chloroperbenzolque acid (734 mg) in methylene chloride (20 ml), under cooling in ice water, for 30 minutes.

   The solution was washed with an aqueous solution of sodium bicarbonate and water, each time carrying out a re-extraction with an additional quantity of methylene chloride. The combined organic layers were dried with magnesium sulfate and concentrated. The residue was purified by chromatography on Sorbsil U30 (50 g) in a mixture of ethyl acetate and petroleum ether (pe 40-600) (1: 1), then in acetate. pure ethyl, so as to obtain the indicated compound
 EMI27.2
 in the title (2.26 g; IE7 47,; CHCL D v 3700-3100 (NH and NH2); 1789 ($ -lactam); max 1729 (ester); 1705 (carbamate); 1698 and 1520 (amide) and 1069 cm-1 (sulfoxide).

  <Desc / Clms Page number 28>

 



  (d) (6R. 7R) -3-Carbamoyloxymethyl-7 - / (Z) -2-cyclopropylmetoxy-imino-2- (2-tritylaminothiazole-4-yl) acetamido7ceph-3-th-
1-acetoxy-1-ethyl 4-carboxylate
The product from step (c) (2.1 g) was dissolved in N, N-dimethylformamide (35 ml) and potassium iodide (1.63 g) was added with stirring and cooling to ice water. Acetyl chloride (0.35 ml) was added. After about 1 hour, an additional amount of acetyl chloride (0.17 ml) was added. After an additional 30 minutes, the solution was partitioned between ethyl acetate and an aqueous solution of sodium metabisulfite.



  The aqueous layer was extracted with an additional amount of ethyl acetate and the combined organic layers were successively washed with dilute hydrochloric acid and brine (2 times). After drying with magnesium sulfate, the solution was concentrated and chromatographed on Sorbsil U30 (50 g) in ethyl acetate (50 to 70%) in ether. petroleum (PE 40-600)
 EMI28.1
 so as to obtain the compound indicated in the title (1.73 g); l +23, (NH and NH --D 3 Max 3 2 17. 1752 and 1732 (esters) 1720 (carbamate) and 1689 and 1517 cm-1 (amide).



  (e) (6R, 7R) -7- / Tz) -2- methoxyiminoacetamido7-3-1-acetoxY-1-ethyl carbamoyloxymethylceph-3-th-(6R, Z) -2cyclopropylmethoxyimino- 2- 4-yl) acetamid27 ceph-3-th-4-carboxylate of 1-acetoxy-1-ethyl! 7- (1.5 g) in formic acid (15 ml) and water (7.5 ml) was then added. After 1.5 hours at 210, the mixture was filtered and the filter cake was leached using a mixture of formic acid and water (2: 1). The combined filtrates were concentrated and the residue was mixed with isopropanol so as to obtain a solution. This solution was evaporated to dryness and the residue was divided between

  <Desc / Clms Page number 29>

 ethyl acetate and an aqueous solution of sodium bicarbonate.

   The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with brine and dried with magnesium sulfate. After evaporation, the residue was triturated with isopropanol (5 ml) so as to obtain
 EMI29.1
 91 the compound described in the title (540 mg) Ceci3);

   x (ethanol 238, fl 256nm 3 Max lcm infl (El% 249) and X 280nm (E1m 179). lcm infl lcm EXAMPLE 4 (a) (6R, 7R) -3-Carbamoyloxymethyl-7 - / (z) -2 -cyclopropylmethoxy-
 EMI29.2
 1-ethoxycarbonyloxy-1-ethyl imino-2- 4-carboxylate
(6R, 7R) -3-carbamoyloxymethyl-7- [(Z) -2-cyclopropylmethoxyimino-2- (2-tritylaminothiazole-4yl) acetamido] ceph-3-th-4-carboxylic acid was dissolved (1 , 1 g) in N, Ndimethylformamide (5 ml) and the solution thus obtained was stirred with potassium carbonate (105 mg) under a nitrogen atmosphere and cooling with ice water. 1-Ethoxycarbonyloxy-1-ethyl bromide was added after 10 minutes.



  After 1 hour, the mixture was allowed to return to 210 and stirred for 3 hours. The mixture thus obtained was distributed between ethyl acetate and aqueous hydrochloric acid. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed with brine, dried with magnesium sulfate and concentrated. The residue was chromatographed on Sorbsil U30 (50 g) in ethyl acetate (10 to 60%) in petroleum ether (P.

   E. 40 to 60), so as to obtain the compound indicated in the title (930 mg); / 7 + 44.00 (c 1.36, CHCl3); #max 1% - 1% max (ethanol) 230 nm (E1cm 312), #infl 236 nm (ED 295) and
 EMI29.3
 x 226). infl lcm

  <Desc / Clms Page number 30>

 
 EMI30.1
 (b) (6R, 7R) -7- / rZ) -2- methoxyiminoacetamido7-3-1-ethoxycarbonyloxy-1-ethyl-carbamoyloxymethylceph-3-th-4-carboxylate The product of step (a) was dissolved (810 mg) in formic acid (8 ml) and water (4 ml) was added with stirring at 210. After 1.25 hours, the precipitate was filtered off and the product was leached. filter cake with a mixture of formic acid and water (2: 1).

   The combined filtrates were concentrated and the residue was triturated with diethyl ether so as to obtain the indicated compound
 EMI30.2
 in the title (340 mg); 7 + - D 3 1 drop of ax 3700-3100 (NH2 + NH), 1768 nicx (ss-lactam), 1722 (ester), 1704 (carbamate), and 1678 and 1535 <t cm "(amide).



  EXAMPLE (a) (6R, 7R) -7- / rZ) -2-Cyclopropylmethoxyimino-2-thiazole-4-yl) acetamido7-3- ceph-3-th-4-carboxylate Diphenylmethyl solution A solution of ( 6R, moyloxymethyl) acetamidceph-3-th-4-carboxylate of diphenylmethyl (500 mg) in methylene chloride (26 ml), at 50, under a nitrogen atmosphere and pyridine was added (0.11 ml) this addition being followed by that of phosphorus pentachloride (0.28 g). The mixture was stirred at 50 for 1 hour and an additional amount of phosphorus pentachloride (51 g) and pyridine (0.02 ml) was added. After stirring for an additional 3 minutes, the mixture was transferred to 50 in a solution of butane-1,3-diol (0.87 ml) in methylene chloride (8.7 ml) also at 50, under an atmosphere of nitrogen.

   The solution was stirred at 50 for 40 minutes and water (8.7 ml) was added. The mixture was stirred at 100 for 50 minutes and then the organic layer was separated. The aqueous phase was extracted with an additional amount of methylene chloride. The combined organic layers were dried and

  <Desc / Clms Page number 31>

 concentrated them to a small volume, so as to obtain a solution of (6R, 7R) -7-amino-3- (N-methylcarbamoyloxymethyl) ceph-3-th-4 = diphenylmethyl carboxylate (solution.



   Oxalyl chloride (0.09 ml) was added to a solution of N, N-dimethylformamide (0.09 ml) in methylene chloride (2.3 ml) at -200. The mixture was stirred at -20 for 1 minute and then immersed in an ice bath for 10 minutes, before cooling to -200.



  (Z) -2-cyclopropylmethoxyimino-2- (2tritylaminothiazole-4-yl) acetic acid (440 mg) was added and the resulting solution was stirred in an ice bath for 10 minutes before cooling to 'to-20 (solution B). Solution A (about 5 ml) was treated with N, N-dimethyl-aniline (0.28 ml) and quickly added to solution B-20. The mixture was stirred at 00 for 10 minutes and then allowed to warm to room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with dichloromethane and washed with an aqueous solution of 2N hydrochloric acid and then with water. The organic layer was separated, dried and evaporated to obtain a crude product.

   This product was chromatographed on silica gel in a mixture of ethyl acetate and petroleum ether (40-600) so as to obtain the indicated compound
 EMI31.1
 in the title in the form of a foam (0.413 g); [alp +28, DMSO); vmax (CHBr3) 3456 and 3400 (NH), 1790 (6-lactam), 1728 (ester), 1688 (OCONHCH3) '1683 and 1516 and 739 (b) Acid (6R. propylmethoxyiminoacetamido7-3- (N-methylcarbamoyloxymethyl) ceph -3-th-4-carboxYlique The product from step (a) (0.44 g) was dissolved in trifluoroacetic acid (3.6 ml) and stirred at 50 for 5 minutes and it was then cooled to the temperature

  <Desc / Clms Page number 32>

 room for 35 minutes. The solution was diluted with diisopropyl ether. The solid thus obtained was collected by filtration, washed with diisopropyl ether and dried.

   This product was dissolved in 98% formic acid (2 ml) and water (1.0 ml) was added.



  After stirring for 30 minutes, the precipitate thus formed was separated by filtration and the filter cake was washed with a mixture of formic acid and water. The filtrate was concentrated and diisopropyl ether was added. The solid thus obtained was then collected, washed with diisopropyl ether and dried so as to collect the title compound in the form of a solid
 EMI32.1
 (93 mg); a / D + 25, O,;

   DMSO); v 2100 (NH + NH + 1776 (P-lactam), 1660 and 1543 (amide) and 1720 to 1600 + C02 + C02H).
00 (EXAMPLE A Dry powder for injection
Glass vials must be aseptically filled with
 EMI32.2
 (6R, 7R) -7-TZ) -2- iminoacetamid27-3-carbamoyloxymethylceph-3-th-4-carboxylate (2-aminothiazole-4-yl) -2-cyclopropylmethoxy-sodium, so that each vial contains one amount of product equivalent to 1.0 g of antibiotic acid. The upper spaces of the flasks must be purged with sterile nitrogen and the flasks closed using discs or rubber stopper and cover: metallic applied by crimping. The product should be prepared shortly before administration by dissolving it in water for injection or in any other suitable sterile vehicle.



   The aforementioned sodium salt can be prepared in a conventional manner, for example, by reacting the compound of Example 2 on an appropriate basis.



  EXAMPLE B Dry powder for injection

  <Desc / Clms Page number 33>

   Acid (6R, 7R) -7- / TZ) -2- (2-aminothiazole-4-yl) - 2-cyclopropylmethoxyiminoacétamido7-3- carbamoyloxymethylceph-3-th-4- - 1.00 g carboxylic Sodium carbonate (anhydrous ) 0.140 g.



   Sterile antibiotic cephalosporin must be aseptically mixed with sodium carbonate using a powder mixer. The mixture should be aseptically introduced into glass vials so that each vial contains an amount of product equivalent to 500 mg of the antibiotic cephalosporin. The upper spaces of the flasks must be purged with sterile nitrogen and the flasks closed with rubber discs or stoppers and metal covers applied by crimping. The product should be prepared shortly before administration by dissolving it in water for injection or in any other suitable sterile vehicle.


    

Claims (6)

CLAIMS 1. Antibiotics of the cephalosporin nature, corresponding to the general formula  EMI34.1  (in which R1 represents a hydrogen atom or the methyl or 2-chloroethyl radical), as well as the non-toxic salts and the metabolically labile and non-toxic esters of these compounds.  EMI34.2   2. (6R, 7R) propylmethoxyiminoacetamido7-3-carbamoyloxymethylceph-3-th-4-carboxylic acid and its non-toxic salts.  3. Metabolically labile and non-toxic esters of the compound according to claim 2.  4. Forms with protected N function and with blocked carboxyl function of the compounds according to claim 1.  5. Process for the preparation of a compound according to claim 1, characterized in that (A) a compound of the formula is acylated  EMI34.3    EMI34.4  9 1 (in which represents the group as defined in claim 1 or a radical protecting the N function,  <Desc / Clms Page number 35>    EMI35.1  represents a hydrogen atom or a radical blocking ** 'S or'4-S0 0 and the carboxyl function, B represents S S- dashed line establishing a bridge between positions 2, 3 and 4 indicates that the compound is a substance of the ceph-2-th or ceph-3-th type) or a salt or 7-N-silyl derivative of such a compound, with an acid of the formula  EMI35.2  (in which R4 represents a protected amino or amino radical), or with a salt of such a compound, or with an acylating agent which corresponds to it, or (B)  we react a compound of the formula  EMI35.3  (in which R "p R, B and the dashed line have the meanings which have been previously assigned to them) or a salt of such a compound, on an acylating agent  EMI35.4  9 used to form the group -CHpOCONHR (whereR the? Meanings which have been previously assigned to it) in position 3, then, if it proves necessary and / or desirable in each circumstance, any of the reactions are carried out which follow, in any suitable order:    <Desc / Clms Page number 36>    EMI36.1  2 5 i) conversion of an isomer into an isomer ii) reduction of a compound in which B represents> to form a compound in which B represents> S, iii) transformation of a carboxyl group into a metabolically labile and non-toxic ester function , iv) formation of an atoxic salt and v) elimination of any groups blocking the carboxyl function and / or protecting the N function.    6 Pharmaceutical compositions, containing, as active ingredient, at least one compound according to any one of claims 1 to 4 or obtained by carrying out the process according to claim 5, in association with a suitable pharmaceutical excipient or vehicle.