DE2921344A1 - CEPHALOSPORINE ANTIBIOTICS - Google Patents

Description

CE 255 - 4 -

GLAXO GROUP LIMITED, London VMY 8DH

Cephalosporin antibiotics

Desc eibung

The invention relates to cephalosporin compounds having valuable antibiotic properties.

The present cephalosporin compounds are incorporated herein by reference to "Cepham" according to J. Amer. Chem. Soc, 1962, 84, 5400, where the term "cephem" refers to the basic cepham structure with a double bond.

Cephalosporin antibiotics are used extensively in treatment used by diseases that are caused by pathogenic bacteria in humans and animals, and are particularly used in the Valuable treatment of diseases caused by bacteria that oppose other antibiotics such as penicillin compounds are resistant, as well as in the treatment of penicillin-sensitive patients. In many cases it is desirable use a cephalosporin antibiotic that has activity against both Gram-positive and Gram-negative microorganisms and there has been extensive research on the development of various types of cephalosporin antibiotics aimed at a broad spectrum of activity.

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As will be described 1,399,086 a new class of cephalosporin antibiotics having a 7ß- ^(a -verätherten oximino) -acylamidogruppe for example, in GB-PS, wherein the oximino group has the syn configuration. These. ■ Class of antibiotic compounds is characterized by a high antibacterial activity against a range of Gram-positive and Gram-negative organisms combined with a particularly high stability against ß-lactamases, which are formed by various Gram-negative organisms.

Finding this class of compounds has stimulated further research in the same area to find compounds that the improved properties e.g. against special classes of organisms, especially against gram-negative organisms, own.

In GB-PS 1 4 ^ 6 757 cephalosporin antibiotics with a 7β-acylamido group of the formula

R.C.CO.NH-

^) C (CH ₂ ) _n C00H
R ^B

(where R denotes a thienyl or furyl group} R and R can vary widely and can be, for example, C _1-2 ^ alkyl groups or, together with the carbon atom to which they are attached, form a C, " cycloalkylidene group and m and η are in each case 0 or 1, so that the sum of m and η is 0 or 1), the compounds being syn isomers or mixtures of syn and au isomers with at least 90 % syn isomers. The 3-position of the cephalosporin molecule can be unsubstituted

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or can have one or a wide variety of possible substituents contain. It was found that these compounds have particularly good activity against gram-negative organisms.

Other compounds of similar structure were made from these compounds in further attempts to find antibiotics with an improved broad spectrum of antibiotic activity and / or improved high activity against gram-negative organisms. Such developments not only led to changes with regard to the 7β-acylamido group in the above formula, but also to introduce special groups in the ^ -position of the cephalosporin molecule.

For example, in BE-PS 852 427 cephalosporin antibiotic compounds which fall within the general scope of GB-PS 1,599,086 and wherein the group R in the above formula (A) can be replaced by a wide variety of organic groups including 2-aminothiazol-4-yl and that Oxygen atom in the oxyimino group is bonded to an aliphatic hydrocarbon group, which in turn, e.g. by carboxy can be substituted. In such compounds, the substituent in the 3-position is an acyloxymethyl, hydroxymethyl, Formyl or optionally substituted Heteroeyclisch-thiomethylgruppe limited.

Furthermore, BE-PS 8 ^ 6 81 j5 describes cephalosporin compounds, wherein the group R in the above formula (A) can be replaced by, for example, 2-aminothiazol-4-yl and the oxyimino group a hydroxyimino or blocked hydroxyimino group, e.g. Is methoxyimino. In such connections the 3-position is of the cephalosporin molecule substituted by a methyl group, which in turn may be caused by residues of a large number of nucleophilic compounds such as those described there, can be substituted. In the aforementioned patent

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—Τ—

is such compounds that are only used as intermediates for the preparation of the antibiotics described in the patent mentioned, no antibiotic activity is ascribed .

BE-PS 853 5 ^ 5 describes cephalosporin antibiotics in which the 7β-acylamido side chain is primarily a 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetaraido group and the substituent in the 3-position is similar to that in the aforementioned BE-PS 856 813 is broadly defined.

It has now been found that by suitable selection of a small number of special groups in the 7 [beta] division in coordination with a methyl group in the 3-position cephalosporin compounds having particularly advantageous activity (described in more detail below) over a wide range of conventional occurring pathogenic organisms can be achieved.

The. Invention provides cephalosporin antibiotics of the general formula

HH SN ϊ! _ς

λ - C.CO.NH Γ f ^ l

» _R a oJ N ^ GH ₃ . (D

^coaH

R ^b

(where R ^a and R, which can be the same or different, each represent a C ^ u alkyl group (preferably a straight-chain alkyl group, i.e. a methyl, ethyl, n-propyl or n-butyl group and especially

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from special a methyl or ethyl group) or R and R together with the carbon atom to which they are bonded form a C, ₇ cycloalkylidene group, preferably a C, - cycloalkylidene group), as well as their non-toxic and non-toxic salts metabolically labile esters.

The compounds according to the invention are syn isomers. The syn-isomer Form is determined by the configuration of the group

R ^a '

O.G.COOH

i ^b

defined with reference to the carboxamido group. In the present case, the syn configuration is structurally defined as

NH ₀

A ²

S N

^U - ^ - C.CO.NH

NR ^a

O.C.COOH

Obviously, since the compounds according to the invention are geometric isomers, an admixture with the corresponding anti isomers occur.

The invention also encompasses the solvates (in particular the hydrates) of the compounds of the formula (i). It also includes salts of esters

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of the compounds of formula (I).

The compounds of the invention can be in tautomeric forms (with regard to the 2-aminothiazoIy! group) are present and understand it that such tautomeric forms e.g. the 2-iminothiazolinyl form, fall within the scope of the invention.

comprises from Evidently, in the above formula different C. when R and R u alkyl groups, the carbon atom to which they are attached, a center of asymmetry. Such compounds are diastereomers and the invention includes individual diastereomers of these compounds, as well as mixtures thereof.

The compounds according to the invention show a broad range of antibiotic properties Spectrum of activity. The activity against gram-negative organisms is unusually high. The high activity extends refer to numerous ß-lactamase-binding Gram-negative strains. The compounds also have a high stability towards ß-lactamases produced by a range of Gram-negative organisms are formed.

It was found that the compounds according to the invention have high activity opposite numerous members of the Enterobacteriaceae (e.g. strains of Escherichia coli, Klebsiella pneumpniae, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae, Serratia marcescens, Providence species, Proteus mirabilis and especially positive Proteus organisms such as Proteus vulgaris and Proteus morganii). as well as against strains of Haemophilus influenzae and good activity against strains of Pseudomonas organisms e.g. "strains of Pseudomonas aeruginosa. This activity against strains of indole-positive Proteus and Pseudomonas organisms is unusual considering the antibacterial activity of known 3-methylcephalosporin antibiotics.

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In addition to their high antibiotic activity, the 3-methyl compounds according to the invention have the further advantage that they are more complicated compared to analog connections Having 3-substituents, relatively easily and economically on an industrial scale from readily available starting materials, i. Penicillin G or penicillin V can be produced.

Non-toxic salt derivatives obtained by reacting one or both of the compounds of the general formula (I) Carboxyl groups can be formed include salts with inorganic bases such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g., calium salts); Amino acid salts (e.g. lysine and arginine salts); Salts with organic Bases (e.g. procaine, phenylethylbenzylamine, dibenzylethylenediamine, Ethanolamine, diethanolamine and N-methylglucosamine salts) Other non-toxic salt derivatives include acid addition salts, which are, for example, with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, Phosphoric acid, formic acid and trifluoroacetic acid are formed. The salts can also be in the form of resinates, those containing, for example, a polystyrene resin or a crosslinked polystyrene-divinylbenzene copolymer resin Amino or quaternary amino groups, sulfonic acid groups or with a carboxyl group-containing resin, e.g. a polyacrylic acid resin, are formed. Soluble salts with bases (e.g. alkali metal salts such as the sodium salt) of the compounds of the formula (I) can be used in therapeutic applications due to the rapid distribution of these salts in the body after administration will. However, they are insoluble salts of the compounds (I) in a special application, e.g. for use in depot preparations if desired, such salts can be formed in a conventional manner, for example with suitable organic amines will.

These and other salt derivatives, such as the salts with toluene-p-sulfone-

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and methanesulfonic acid can be used as intermediates in the manufacture and / or purification of the present compounds of formula (I), for example in the processes described below be used.

Non-toxic metabolically labile ester derivatives produced by esterification can be formed by one or both carboxyl groups in the parent compound of formula (I) include acyloxyalkyl esters e.g. low alkanoyloxymethyl or ethyl esters, such as the acetoxymethyl or ethyl or pivaloyloxymethyl esters. Additionally In addition to the above ester derivatives, the invention encompasses compounds of the formula (I) in the form of other physiologically acceptable ones Equivalents, i.e. physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo into the antibiotic Parent compound of the formula (I) are converted.

Preferred compounds of the invention include the following compounds of formula (I) and their non-toxic salts and namely, non-toxic metabolically labile esters

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3-methylceph-3-em-4- carboxylic acid

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (i-carboxycyclobut-1-oxyimino) acetamido] -3-methylceph-3-em-4- carboxylic acid and

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclopent-1-yloxyimino) -acetamido] -3-methylceph-3-em - ^ - carboxylic acid.

Further examples of compounds of the formula (I) according to the invention include those in which the groups I ^ and R are in have the meanings given in the following table.

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Tabel

a) alkyl groups

CH,

C ₂ H ₅

C ₂ H ₅

b) cycloalkylidene groups

Cyclopropylidene
Cyclohexylidene

The compounds of formula (I) can be used to treat numerous diseases caused by pathogenic bacteria Both humans and animals are caused as well as infections of the respiratory system and the urinary system.

According to a further embodiment of the invention, a method for the preparation of an antibiotic compound of the general formula (I) as defined above or a non-toxic one Salt or a non-toxic metabolically labile ester the same which comprises: acylating a compound of the formula.

(Hi

COOR

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ORIGINAL INSPECTED

[where B> S or> S- ^ O (α- or β-); R is a hydrogen atom or a carboxyl blocking group, e.g. the rest an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol (this alcohol, phenol, silanol or stannanol preferably containing 1 to 20 carbon atoms) and the dashed line indicates the line connecting the 2, J and 4 positions, that the compound is a Ceph-2-em or Ceph-3-em compound] or a salt, e.g. an acid addition salt (formed for example with a mineral acid such as hydrochloric acid, hydrobromic acid, Sulfuric acid, nitric acid or phosphoric acid or an organic acid such as methanesulfonic acid or toluene-p-sulfonic acid) or an N-sllyl derivative thereof with an acid the formula

C. COOH R ^a II
N ¹ 2
.C.COOR 0 ■ b R.

(wherein R ^a and R are as defined above; R is a carboxyl blocking group, for example as described for R; and R ^ is an amino or protected amino group) or with an acylating agent corresponding thereto, followed optionally by one or more of the following reactions in any suitable Sequence to be carried out:

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1) the conversion of a Λ -isomer into the desired ^ -isomer
ii) the reduction of a compound in which B> S - ^ - 0 means ^

to form a compound in which B ^ S is iii) the conversion of a carboxyl group to a non-toxic one

Salt or a metabolically labile ester function and iv) the removal of any carboxyl blocking and / or N-protecting groups.

In the process described above is the starting material of the formula (II) preferably a compound in which B 1 denotes S and the dashed line denotes a Ceph-J-em compound represents.

Acylating agents useful in preparing the compounds of formula (I) include acid halides, especially acid chlorides or bromides. Such acylating agents can be prepared by adding an acid (CU) or a salt thereof with a halogenating agent, e.g. Phosphorus pentachloride, thionyl chloride or oxalyl chloride reacts.

Halides acylations can be used preferably -20 to + J5G ° C, an acid binding agent are carried out optionally in the presence in aqueous and nonaqueous reaction media suitably carried out at temperatures of -50 to +50 ⁰ C. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile or mixtures of two or more such solvents. Suitable acid binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide), which bind hydrogen halide released in the acylation reaction.

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Acids of the formula (III) can in turn be used as acylating agents in the preparation of compounds of the formula (I) will. The acylations using acids of formula (III) are desirably carried out in the presence of a condensing agent for example a carbodiimide, such as Ν, Ν'-dicyclohexylcarbodiimide or N-ethyl-N '- ^ dimethylaminopropylcarbodiimide; one Carbonyl compound such as carbonyldiimidazole; or an isoxazolium salt carried out as N-Xthyl-5-phenylisoxazolium perchlorate.

The acylation can also be carried out with other amide-forming derivatives of acids of formula (III) such as an acylated ester, a symmetrical anhydride or a mixed anhydride (e.g. formed with pivalic acid or with a haloformate such as a lower alkyl haloformate). Mixed anhydrides can also with phosphoric acids or phosphorus-containing acids (e.g. phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. toluene-p-sulfonic acid) are formed. An activated ester can suitably be prepared in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensing agent as indicated above. Alternatively, the activated ester be formed in advance.

The free. Acid: or the amide-forming thereof mentioned above Acylation reactions comprising derivatives are desirably carried out in an aqueous reaction medium such as methylene chloride, tetrahydrofuran, dimethylformamide or acetonitrile.

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

The acids of the formula (III) and the acylating agents corresponding to them can, if desired, in the form of their acid addition

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Salts are made and used. For example, acid chlorides can conveniently be in the form of their hydrochloride salts and acid bromides can be used in the form of their hydrobromide salts.

The reaction product can from the reaction mixture, for example may contain unchanged cephalosporin starting material and other substances, by numerous processes including recrystallization ^ ionophoresis, column chromatography and the use of ion exchangers (e.g. by chromatography on ion exchange resins) or separated from macroreticular resins.

The Δ- cephalosporin ester derivatives obtained by the process according to the invention can be converted into the corresponding Δ - ^ - derivatives, for example by treating the A -ester with a base such as pyridine or triethylamine.

A Ceph-2-em reaction product can also be used to achieve the corresponding Ceph-3-em-i-oxAäs, for example, by reaction with a peracid e.g. peracetic acid or m-chlorobenzoic acid will; the sulfoxide obtained can, if desired, then as described below, to obtain the corresponding Ceph-3-em-sulfide.

If a compound is obtained in which B \ S— ^ O, this can be converted into the corresponding sulfide, for example by reducing the corresponding acyloxysulfonium or alkoxysulfonium salt, prepared in situ by reaction with, for example, acetyl chloride in the case of an acetoxysulfonium salt, the Reduction is carried out, for example, with sodium dithionite or with an iodide ion such as in a solution of potassium iodide in a water-miscible solvent, for example acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction may be carried out at a temperature of -20 to +50 ⁰ C.

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Metabolically labile ester derivatives of the compounds of the formula (I) can by reacting a compound of the formula (I) or a salt or a protected derivative thereof with the suitable esterifying agent such as an acyloxyalkyl halide (e.g. iodide) suitably in an inert organic solvent such as dimethylformamide or acetone, which if necessary the removal of any protecting groups follows.

The salts with bases of the compounds of the formula (I) can be prepared by reacting an acid of the formula (I) with the suitable base getting produced. For example, sodium and potassium salts can be produced using the respective 2-ethylhexanoate or hydrogen carbonate salt can be made. Acid addition salts can by reaction a compound of formula (I) or a metabolically labile ester derivative thereof with the appropriate acid will.

If a compound of the formula (I) is obtained as a mixture of isomers, the syn isomer can, for example, by conventional methods how to obtain crystallization or chromatography.

For use as starting material in the preparation of the compounds of the general formula (I) according to the invention, the compounds of the general formula (III) and their corresponding acid halides and anhydrides are preferably used in their syn-isomeric form or in the form of mixtures of the syn- Isomers and the corresponding anti isomers, which contain at least 90% of the syn isomer, are used.

Acids of the formula (III) / provided that R and R together no cyclopropylidene group with the carbon atom to which they are attached form) can through etherification of a connection

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the formula

- / _ G.COOR

(IV)

(wherein Br is as defined above and R is a carboxyl blocking group) by reaction with a compound of the general formula

R ^a TCCOOR ²

(wherein R ^a and R are as defined above and T is halogen such as chlorine, bromine or iodine, sulfate or sulfonate such as tosylate), followed by removal of the carboxyl blocking group B are prepared. The separation of isomers can be carried out either before or after the etherification. The etherification reaction is generally carried out in the presence of a base, e.g. potassium carbonate or sodium hydride, and is preferably carried out in an organic solvent, e.g. dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane, or a Ν, Ν-disubstituted amide such as dimethylformamide. Under these conditions the configuration of the oxyimino groups remains essentially unchanged by the etherification reaction. The reaction should be carried out in the presence of a base, if an acid addition salt of a compound of the

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Formula (IV) is used. The base should be in sufficient quantity can be used to quickly neutralize the acid in question.

Acids of the general formula (III) can also be obtained by reacting a compound of the formula

R ³

\ -

(wherein Br and R are as defined above) with a compound of the formula

.OCCOOR ² (VII)

from P
(wherein R and R and R are as defined above) on what

Jl

the removal of the carboxyl blocking group R and if necessary the separation of the syn and anti isomers can then be prepared.

The last-mentioned reaction is particularly applicable to the preparation of acids of formula (III) in which R ^a and R together with the carbon atom to which they are attached form a cyclopropylidene group. In this case, the relevant compounds of the formula (VII) can be prepared in a conventional manner, for example according to the synthesis described in BE-PS 866 422 for the preparation of f-butyl-1-amino-oxycyclopropanecarboxylate. 8098 4 9/0 7D7

The acids of the formula (III) can be converted into the corresponding acid halides and anhydrides and acid addition salts are converted by conventional methods.

It will be understood that in some of the above conversions it may be necessary to protect any sensitive groups in the molecule of the compound in question in order to avoid undesirable side reactions. For example, during one of the reaction sequences referred to above, it may be necessary to protect the NHp group of the aminothiazolyl moiety, for example by tritylation, acylation (e.g. chloroacetylation), protonation, or by some other conventional method. The protecting group may thereafter by any suitable route of _t no disruption of the desired compound caused, for example, in IaH. a trityl group using an optionally halogenated carboxylic acid, e.g. acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid, or using a mineral acid e.g. hydrochloric acid or mixtures of such acids, preferably in the presence of a protic solvent such as water or, in the case of a chloroacetyl group, by treatment with thiourea.

Carboxyl blocking groups used in the preparation of the compounds of formula (I) or in the preparation of necessary starting materials are desirably groups which can be cleaved off rapidly during a suitable step in the reaction sequence, conveniently during the last step. However, in some cases it may be appropriate to use non-toxic metabolically labile carboxyl blocking groups such as acyloxymethyl or ethyl (e.g. acetoxymethyl or ethyl and pivaloyloxymethyl) and keep these in the final product in order to obtain a suitable ester derivative of a compound of formula (I).

Suitable carboxyl blocking groups are from the prior art

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nik well known, a list of representative blocked carboxyl groups being given in GB-PS 1,399,086. Preferred blocked carboxyl groups include aryl-lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups such as
t-Butoxycarbonylj and lower-haloalkoxycarbonyl groups such as
2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group (s)
can then be removed by any suitable method described in the literature; for example, in numerous cases acid- or base-catalyzed hydrolysis as well as enzymatically-catalyzed hydrolysis can be used.

The antibiotic compounds according to the invention can be administered in any suitable manner in an analogous manner
to be formulated to other antibiotics and the invention therefore includes pharmaceutical compositions containing an antibiotic compound of the invention suitable for use in the
Human or veterinary medicine is suitable. Such
Compositions can be for use in conventional
Way with the help of any required pharmaceutical
Carriers or excipients are presented. '

The antibiotic compounds of the present invention can be formulated for injection and can be presented in unit dosage form in ampoules or in multiple dose containers with an added preservative or preservative if necessary. The compositions can also take further forms
accept as suspensions, solutions or emulsions in oily
or aqueous carriers and can contain formulation agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for reconstitution with a suitable carrier, for example sterile pyrogen-free water.

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If desired, such powder formulations can be a suitable one contain non-toxic base to improve the water solubility of the active ingredient and / or to ensure that, if the powder is repulped with water, the pH of the obtained aqueous formulation is physiologically acceptable. Alternatively, the base can be in water, with which the powder can be restored is processed. The base can, for example, be an inorganic base such as sodium carbonate, sodium bicarbonate or sodium acetate or an organic base such as lysine or lysine acetate.

The antibiotic compounds can also be used as suppositories that contain, for example, conventional suppository bases such as cocoa butter or other glycerides.

Veterinary compositions can be used, for example, as preparations formulated for administration to the udder or teats in either long-acting or rapid-release bases will.

The compositions may contain from 0.1 % upwards, for example 0.1 to 99%, of active material depending on the method of administration. If the compositions comprise dosage units, each unit preferably contains 50 to 1,500 mg of active ingredient. The dose used in the treatment of the adult is preferably in the range of 500 to 6,000 mg per day depending on the route of administration and the frequency of administration. Normally, for example, in the treatment of adults, 1,000 to 3,000 mg per day are sufficient for intravenous or intramuscular administration. When treating Pseudoraonas infections, higher daily doses may be required.

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

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The following examples illustrate the invention. The designation "Petroleum ether" means petroleum ether with a boiling point of 40 to 60 ° C., unless otherwise stated.

Manufacturing 1 Ethyl (Z) -2- (2-aminothiazol-4-yl) -2- (hydroxyimino) acetate

Was added to a stirred and ice-cooled solution of 292 g of ethyl acetoacetate in 296 ml of glacial acetic acid, a solution of 180 g ITatriumnitrit in 400 ml of water at such a rate that the reaction temperature was kept below door 10 ⁰ C. Stirring and cooling were continued for about 30 minutes, after which a solution of 160 g of potassium chloride in 800 ml of water was added. The resulting mixture was stirred for 1 hour. The lower oily phase was separated off and the aqueous phase was extracted with diethyl ether. The extract was combined with the oil, washed successively with water and saturated brine, dried and evaporated. The remaining oil, which solidified on standing, was washed with petroleum ether and dried in vacuo over potassium hydroxide, 309 g of ethyl (Z) -2- (hydroxyimino) -3-oxobutyrate being obtained.

A stirred and ice-cooled solution of 150 g of ethyl (Z ) -2- (hydroxyimino) -3-oxobutyrate in 400 ml of methylene chloride was treated dropwise with 140 g of sulfuryl chloride. The solution obtained was kept at room temperature for 3 days and then evaporated. The residue was dissolved in diethyl ether, washed with water until the wash waters were almost neutral, dried and evaporated. 177 g of the remaining oil were dissolved in 500 ml of ethanol and 77 ml of dimethylaniline and 42 g of thiourea were added with stirring. After 2 hours the product was collected by filtration, washed with ethanol and dried to give 73 g of the title compound , Έ = 188 ⁰ O (dec.)

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Manufacturing 2 Ethyl- (Z) -2 ~ hydroxyimiPO-2- (2 - tritylaminothiazol-4-yl) ~ acetate -

hydrochloride

Was added portionwise 16.75 g of trityl chloride in the course of 2 hours to a stirred and cooled (-30 ⁰ C) solution of 12.91 g of the product of Preparation 1 in 28 ml of _{dimethylformamide;} containing 8.4 ml of iriethylamine _; to. The mixture was allowed during the course of 1 hour at 15 ⁰ C to warm, stirring was continued for 2 hours and then partitioned between 500 ml water and 500 ml ethyl acetate. The organic phase was separated off, washed twice with 500 ml of water and then shaken with 500 ml of 1N HCl. The precipitate was collected, washed sequentially with 100 ml of water, 200 ml of ethyl acetate and 200 ml of ether and dried in vacuo to give the title compound as 16.4 g of white pesticide. F = 184 to 186 ⁰ C (dec.).

Manufacturing 5

Ethyl (Z) -2- (2-t-butoxycarbonylprop-2-oxyimino) -2- (2-trityl-aminothiazol-4-yl) acetate

34.6 g of potassium carbonate and 24.5 g of t-33utyl-2-bromo-2-methylpropionate in 25 ml of dimethyl sulfoxide were added to a stirred solution, kept under nitrogen, of 49.4 g of the product of preparation 2 in 200 ml of dimethyl sulfoxide and the mixture was stirred the mixture for 6 hours at room temperature. The mixture was poured into 21 water, stirred for 10 minutes and filtered. The solid was washed with water and dissolved in 600 ml of ethyl acetate. The solution was washed successively with water, 2N hydrochloric acid, water and saturated saline, dried and evaporated. The residue was recrystallized from petroleum ether (boiling point 60 to 80 ⁰ C) to give 34 g of the title compound. F = 123.5 to 125 ⁰ C.

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Manufacturing 4

(Z) -2- (2-t-Butoxycarbonylprop-2-oxyimino) -2- (2-tritylamino-thiazol-4-yl-acetic acid

2 g of the product from Preparation 3 were dissolved in 20 ml of methanol and 3.3 ml of ZN sodium hydroxide were added. The mixture was refluxed for 1.5 hours and then concentrated. The residue was taken up in a mixture of 50 ml of water, 7 ml of 2F hydrochloric acid and 50 ml of ethyl acetate. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate. The organic solutions were combined, washed successively with water and saturated brine, dried and evaporated. The residue was recrystallized from a mixture of carbon tetrachloride and petroleum ether to give 1 g of the title compound. F = 152-156 ⁰ C (dec.).

Manufacturing 5 Ethyl- (Z) -2- (2-tritylaminothiazol-4-yl) -2- (1-t-butoxy-carbonyl-

cyclobut-1-oxyimino) acetate

55.8 g of the product from preparation 2 were stirred under nitrogen in 400 ml of dimethyl sulfoxide with 31.2 g of finely ground potassium carbonate at room temperature. After 30 minutes, 29.2 g of t-butyl i-bromocyclobutane carboxylate were added. After 8 hours a further 31.2 g of potassium carbonate were added. Further potassium carbonate was added 6x in 16 g portions over the next 3 days and a further 3.45 g of t-butyl i-bromocyclobutane carboxylate were added after 3 days. After a total of 4 days, the mixture was poured into about 3 liters of ice water and the solid was collected by filtration and washed well with water and petroleum ether. The solid was dissolved in ethyl acetate and the solution washed 2x with brine, dried with magnesium sulfate and evaporated to a foam. This foam was dissolved in Ätnylaeetat-petroleum ether (1: 2) and filtered through 500 g of silica gel. Evaporation gave 60 g of vanity compound as a foam V _fflax (CHBr ₃ ) 3400 (HH

»Na 1 730 cm- ¹ (E _s ter?. ° ^{9849/0? Ö7}

Manufacturing 6

(Z) -2- (1 ~ t-ButoxycarT3onylcycloT3ut-1-oxyiniino) -2- (2-trityl-aminothiazol ^ 4-yl) -acetic acid

A mixture of 3.2 g of the product from Preparation 5 was cooked and 1.65 g of potassium carbonate in 180 ml of methanol and 20 ml of water under reflux for 9 hours and the mixture cooled to room temperature al ». The mixture was concentrated and the residue partitioned between ethyl acetate and water, to which 12.2 ml of 2N HCl were added. The organic phase was separated off and the aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated saline, dried and evaporated to give 2.3 g of the title compound. ^ Ä) 265 nm (2 ^

Manufacturing 7 Ethyl- (Z) -2- (1 -t-butoxycarbonylcyclopent-i-yloxyimino) -2- (2-tri-

tyl-aminothiazol-4-yl) acetate

10 g of product from preparation 2 were stirred with 7 g of t-butyl 2-bromocyclopentane carboxylate in 40 ml of dimethyl sulfoxide _? containing 10 g of potassium carbonate, 21 hours under nitrogen at 21 ^° C. The mixture was poured into 500 ml of ice water and the gray solid was collected by filtration, washed with water and air-dried. Recrystallization of the solid from 500 ml of methanol gave 11.7 g of the title compound. F = 179 to 180 ° C; ^V max ( ^CEBr 3) 3410 (NH), 1735 (ester), 1275 (ester) and 755 cm " ¹ (phenyl).

Manufacturing 8

(Z) -2- (i-t-Butoxycarbonyl-cycloT3ent-1-yloxyimino) -2- (2-tritylaminothiazol-4-yl) -acetic acid

625 mg of product from preparation 7 were boiled with 0.5 ml of 2ΪΤ sodium hydroxide solution and 1 ml of water in 12 ml of methanol for 7 hours

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at reflux. The mixture was allowed to cool overnight. After diluting with water, orthophosphoric acid was added to adjust the solution to pH 2. The precipitate was extracted with ether and the combined extracts washed with brine. After drying with magnesium sulfate, the solvent was evaporated to give 493 mg of gummy material. Crystallization from diisopropyl ether gave 356 mg of the title compound. Έ = 171 to 173 ° C; ^ _mov (CHBr,) 2,500 to 3,500 (OH and HH), 1,755 (ester), 1,692 (acid) and 755 and 770 cm " ¹ (phenyl).

example 1

a) DJT) henylmethyl- (6R, 7R) -r (Z) -2- (2-t-butoxycarbonylproO-2-oxy imino) -2- (2-tritylaminothiazol-4-yl) -acetamidol-3-methylceph-3- em-4-carboxylate

A stirred solution of 2.86 g of the product from Preparation 4 and 2.09 g of diphenylmethyl (6R, 7R) -7-amino-3-methyl-ceph-3-em-4-carboxylate in 50 ml of dimethylformamide was cooled to ⁰ ° C. and treated with 745 mg of hydroxybenzotriazole and 1.14 g of dicyclohexylcarbodiimide. The mixture was warmed to room temperature and stirred overnight. The mixture was filtered and the white plague washed with a little ethyl acetate. The piltrate and wash waters were diluted with 100 ml of water and extracted with ethyl acetate. The organic extracts were combined, washed successively with 2N hydrochloric acid, water, sodium bicarbonate solution and saturated brine, dried and evaporated. The residue was eluted through a silica column with ethyl acetate. The eluate containing the product was collected and concentrated to give 3.6 g of the title compound; X _mQV (ethanol) 238 nm (E ^

Λοϊ On max icm

²⁶³ ' ^{5 nm (E} 1cm ^186); ^ D ^{+ 6} » ^{5 (} £ ¹ » ° »

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b) (6R, 7R) -7-r (Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido "| -3-methylceph-3 ~ em -4-carboxylic acid

20 ml of trifluoroacetic acid were added to a solution of 2.8 g of the product from stage a) in 20 ml of anisole at ⁰ ° C. The mixture was stirred at room temperature for 2 hours and concentrated. The residue was dissolved in ether and evaporated again. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The pH of the aqueous extracts was adjusted to 6 and the solution was washed with ethyl acetate. The aqueous phase was acidified to pH 1.5 under ethyl acetate and extracted with ethyl acetate. The combined organic extracts were washed with saturated brine, dried and evaporated. The residue was dissolved in 40 ml of warm 75% aqueous formic acid and left to stand for 1 hour. The mixture was diluted with water and filtered. The piltrate was concentrated. The residue was taken up in water, filtered again and lyophilized to give 900 mg of the title compound, Ä * _nf (pH 6 buffer) 236 nm (E] J _n 287), 261 nm (E] J _n 254), 296 nm (E] J _n 115); % _mgx (Nujol) 1530, 1665 (CONH), 1720 (CO ₂ H), 1765 cnT ¹ (β-lactam).

Example 2

a) Dipheny! methyl- (6R, 7R) -7-F (Z) -2- (1-t-butoxycarbonylcyclobut-i oxyimino) -2- (2-tritylaminothiazol-4-yl) -acetamido1-3-methylceph- 3- em-4-carboxylate

A stirred solution of 2.2 g of the product of Preparation 6 and 2.2 g of diphenylmethyl (6R, 7R) was cooled -7-amino-3-metbylceph-3-em-4-carboxylate in 45 ml of dimethylformamide to ⁰ ° C and added 655 mg of 1-hydroxybenzotriazole followed by 982 mg of dicyclohexylcarbodiimide. The mixture was warmed to room temperature and stirred overnight. The mixture was filtered off. That

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The filtrate was diluted with 300 ml of water and extracted with ethyl acetate. The organic ones were united. Extracts, washed successively with 2ΪΤ hydrochloric acid, sodium bicarbonate solution and saturated hydrochloric acid, dried and evaporated. The residue was eluted through a silica column with ether-petroleum ether (3: 1). The appropriate fractions were concentrated to give 2.1 g of the title compound, %. ~ (Ethanol) 244 nm (e] '° 238), 302 nm

1 <4> -s lux ι cm u

(E ^ _m 67); ymax (CHBr ₃ ) 1520, 1682 (CONH), 1722 (CO ₂ R), 1788 cm " ¹ (β-lactam).

b) (6R, 7R) -7-Γ (Z) -2- (2-aminothiazole-4-vl) -2- (1-carboxycyclobut-1-oxyimino) -acetamido1-3-methylceph-3-em-4 -carboxylic acid

8 ml of trifluoroacetic acid were added to a solution of 1.9 g of product from stage a) in 2 ml of anisole at ⁰ ° C. The mixture was stirred for 5 minutes and 32 ml of trifluoroacetic acid were added. The mixture was stirred at room temperature for 30 minutes and concentrated. The residue was dissolved in ethyl acetate and evaporated again. The residue was dissolved in ethyl acetate and extracted with saturated sodium bicarbonate solution. The aqueous extracts were washed at pH 7 to 7-5 with ethyl acetate, acidified to pH 1.5 under ethyl acetate and extracted with ethyl acetate. The combined organic extracts were dried and evaporated. The residue was dissolved in 30 ml of formic acid. 9 ml of water were added and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 200 ml of water and filtered. The piltrate was concentrated. The residue was taken up in water, filtered again and lyophilized to give 730 mg of the title compound,% ___ (pH 6 buffer) 241 nm

1 oL Λ 1 oL max λ, j

(E ^ 272), / V. _f 252 nm (EJ ^ 269), 291 nm (eJ £

[α] ²⁰ + 62.5 ° (ο 1.0, DMSO).

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Example 3

a) Diphenylmethyl- (6R, 7R) -7-Γ (Z) -2- (1 -tt> utoxycarbonylcyclopept-1-yloxyimino) -2 ~ (2-tritylaiiiinothiazol-4-yl) -acetamido1-3-methylceph- 3-em-4-earboxylate

1 g of the product from preparation 8 was dissolved in 25 ml of tetrahydrofuran and 760 mg of diphenylraethyl (6R, 7R) -7-amino-3-methylceph-3-em-4-carboxylate and 380 mg of 1-hydroxybenzotriazole hydrate were added with stirring. After formation of a clear solution 520 was mg of dicyclohexylcarbodiimide, and the mixture stirring for 24 hours, "at 21 ⁰ C. The solution was filtered and concentrated, the Piltrat. This solution was passed through a short column of 30 g of neutral alumina eluting with Ithylacetat-petroleum ether . (1: 3) (60 to 80 ⁰ C) percolated The product was purified on a silica column (silica gel 60 g, having a particle size of 15 / aM; 50 g) is applied This column was eluted with ethyl acetate-petroleum ether (60 to 80 ^0. C) (1: 3) eluted at a pressure of 550 mbar (81b / sq..in.) And evaporation of the appropriate tractions gave 510 mg of the title compound as a foam, [a] ^ ⁹ + 25.2 ° (£ 0 , 95, CHCl ₅ )

^ m * - * - ( ^CHBr J 3405, 3275 (NH), 1790 (ß-lactam), 1727 (ester), 1683 and 1527 cm "" ¹ (amide),

b) (6R, 7R) -7-Γ (Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycylopent-1-yloxyimino) -acetamido 1-3-methylce "ph-3- em-4-carboxylic acid - trifluoroacetate salt . '"

408 mg of product from stage a) were mixed with 0.3 ml of anisole and 2 ml of trifluoroacetic acid were added. After 2 hours at 21 ^° C., the solution was concentrated and the residue was poured into 20 ml of water. The mixture was washed 3 times with Ither, the Ither each time with water. was withdrawn. The combined aqueous layers were evaporated to dryness and the residue was triturated with ether to give 88 mg of the title compound,

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⁽ *> ^H 6 lining) 239.5 nm (eJ *, 304), \ _nf 290

(Hujol) 3700-2100 (WHi, NB and OH), 1770 (β-lactam) and

* UIaX λ j

1680 cm "(amide and acid)

Pharmacological examples Example A - coarse powder for injection Formulation per ampoule

(6R, 7R) -7 - [(Z) - 2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3-methylceph-3-em-4- -carboxylic acid 500 mg Sodium Carbonate Anhydrous 113 mg

method

Mix the sterile Cephalosporin antiMotic under aseptic Conditions with sterile sodium carbonate. Aseptically fill glass vials under an atmosphere of sterile nitrogen away. The ampoules are sealed using rubber washers or stoppers that are inserted through aluminum caps are held in a suitable position, closed, preventing gas exchange or the ingress of microorganisms. The product is prepared by dissolving in water for injections or other suitable sterile vehicle just before the Administration reprocessed.

Example B - Dry powder for injection

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (1-carboxycyclobut-1-oxyimino) -acetamido] -3-methylceph-3-em- 4-carboxylic acid disodium salt in glass ampoules in such a way that each ampoule contains an amount corresponding to 500 mg of the antibiotic acid. Filling is carried out under aseptic conditions under:;

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an atmosphere of sterile nitrogen. The ampoules are made using rubber stoppers or stoppers be held in a suitable position by aluminum caps, closed, with a gas exchange or prevents the penetration of microorganisms. The product is made by dissolving in water for injections or another suitable reprocessed to sterile vehicle just prior to administration.

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Claims (9)

PATENT LAWYERS 8000 Munich 2 - BräuhausstraQe 4 - Telephone collective no. 2253 41 Telegrams Zumpat -Telex 529979 Case CE 255 GLAXO GROUP LIMITED, London W1Y 8DH Claims i_y. Cephalosporin antibiotics of the general formula ⁷ C.CO.NH ii Ra NI ₀ < ^ OCCOOH ^u Rb COOH away
wherein R and R, which can be the same or different, each from wells a C ₁ ^ alkyl group or R and R together with the carbon atom to which they are bonded, a C ^, "Forming cycloalkylidene groups and their non-toxic Salts and non-toxic metabolically labile esters. 2. Compounds according to claim 1, wherein at least one of the radicals R ^a and R is a methyl or ethyl group. S09849 / 07Q7 away 3. Compounds according to claim 1, wherein R and R together with the carbon atom to which they are attached form a C ^, _ _t - form cycloalkylidene. 4. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (2-carboxyprop-2-oxyimino) -acetamido] -3-methylceph-5-em- 4-carboxylic acid and its
non-toxic salts. 5. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (i-carboxycyclobut-1-oxyimino) -acetamido] -3-methylceph-3-em- 4-carboxylic acid and their non-toxic salts. 6. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (i-carboxycyclopent-1-yloxyimino) -acetamido] -3-methylceph-3-em- 4-carboxylic acid and their non-toxic salts. 7. Method of making an antibiotic compound of the general formula (I) according to claim 1 or a non-toxic salt or a non-toxic metabolically unstable salt Esters thereof, characterized in that a compound of the formula (II) COORl wherein 3> S or ^ S> 0, R ^{1 is} hydrogen or a Means carboxyl blocking group and represents the 2-, 3- and 4-positions connecting dashed line of the formula (II) indicates that the compound is a Ceph-2-em or Ceph-3-em compound or an acid addition salt or N-silyl derivative thereof with 909849/0707 an acid of the formula CCOOH (III) ' N ψ ^ ^{2 a} b 2 (wherein R and R are as defined in claim 1; R is a carboxyl means blocking group; and R ^ is an amino or protected one Amino group) or with one of these corresponding acylating agents acylated, after which one or more of the following reactions are optionally carried out in any suitable order: i) Conversion of a Δ -isomer into the desired .Δ -isomer ii) reduction of a compound in which B ^ S - ^ O means for Formation of a compound where B> S iii) Conversion of a carboxyl group to a non-toxic one Salt or non-toxic metabolically labile ester function and iv) removal of any carboxyl blocking and / or N-protecting groups. 8. The method according to claim 7 *, characterized in that the Starting material of formula (II) is a Ceph-3-em compound, wherein B J> S means. 9. Pharmaceutical composition for use in the Human or veterinary medicine, characterized in that they combine an antibiotic compound according to one of Claims 1 to 6 with a pharmaceutical carrier or excipient. 909849/0707 BATH