CH645906A5 - CEPHALOSPORINANTIBIOTICS. - Google Patents

Description

The invention relates to cephalosporin compounds with valuable antibiotic properties.

The above cephalosporin compounds are described with reference to "Cepham" according to J. Amer. Chem. Soc., 1962, 84, 3400, the term “cephem” referring to the basic structure of cepham with a double bond.

Cephalosporin antibiotics are widely used in the treatment of diseases caused by pathogenic bacteria in humans and animals, and are particularly useful in the treatment of diseases caused by bacteria resistant to other antibiotics such as penicillin compounds, as well as in the Treatment of penicillin sensitive patients. In numerous cases, it has been desired to use a cephalosporin antibiotic that has activity against both Gram-positive and Gram-negative microorganisms, and extensive research has been directed to the development of various types of broad-spectrum cephalosporin antibiotics.

So z. B. in GB-PS 1399 086 describes a new class of cephalosporin antibiotics which contain a 7β- (a-etherified oxyimino) acylamido group, the oxyimino group having a syn configuration. This class of antibiotic compounds is characterized by a high antibacterial activity against a range of Gram-positive and Gram-negative organisms in connection with a particularly high stability towards ß-lactamases, which are formed by numerous Gram-negative organisms.

The discovery of this class of compounds stimulated further research in the same field in order to find compounds with improved properties, for example compared to special classes of organisms, in particular Gram-negative organisms.

GB-PS 1496757 describes cephalosporin antibiotics which are a 7β-acylamido group of the formula

5 n

R.C.CO.NH- - (A)

il "A v J

N f

0. (CH „) C (C, H_) COOH 2. m. 2 n io l "

R

(where Rc represents a thienyl or furyl group; RA and RB can vary widely and include, for example, hydrogen atoms and m and n are each 0 or 1 15 such that the sum of m and n is O or 1) , wherein the compounds are syn isomers or mixtures of syn and anti isomers with at least 90% of the syn isomer. The 3-position of the cephalosporin molecule can be unsubstituted or contain a wide range of possible substituents 20 including, for example, the pyridinium methyl group. These compounds showed that they have particularly good activity against Gram-negative organisms. The patent also describes ester derivatives of the above compounds which are formed by esterification of one or both of the 25 carboxyl groups which are present in the 4-position or in the above 7-side chain.

Other compounds with a similar structure have been developed from these compounds in further attempts to obtain antibiotics with an improved broad antibiotic activity spectrum and / or high activity against Gram-negative organisms. Such developments included changes not only in the 7β-acylamido group of formula (A), but also the introduction of special groups in the 3-position of the cephalosporin molecule. 35 So B. described in GB-PS 836 813 cephalosporin compounds, in which the 7β-acylamido side chain is a 2- (2-aminothiazol-4-yl) -2- (hydroxyimino or blocked hydroxyimino) acetamido group. The blocked hydroxy imino group can. B. be a methoxyimino group. In the 40-type compounds, the 3-position of the cephalosporin molecule is substituted by a methyl group, which in turn may be replaced by any of a large number of residues of the nucleophilic compounds described therein, e.g. can be substituted by the pyridinium group. In the above 45 patent, such compounds, which are only mentioned as intermediates for the preparation of the antibiotics described in this patent, are not ascribed any antibiotic activity.

BE-PS 853545 describes cephalosporin antibiotics, 50 in which the 7β-acylamido side chain is predominantly a 2- (2-aminothiazol-4-yl) -2- (syn) -methoxyimino-acetamido group and the substituent is broadly defined in the 3-position is analogous to the aforementioned BE-PS 836 813. The compounds specifically illustrated in the patent comprise 55 a compound in which the 3-position is substituted by a pyridinium methyl group.

The South African patent specification 78/1870 describes cephalosporin antibiotics in which the 7β-acylamido side chain u. a. is a 2- (2-aminothiazol-4-yl) -2- (optionally substituted-60 substituted alkoxyimino) acetamido group and the 3-position is e.g. B. may be substituted by the group -CH2Y, wherein Y represents the residue of a nucleophile, the patent description contains u. a. numerous other examples, references to compounds in which the above-given alkoxyimino group, if substituted, is a carboxyalkoxyimino or alkoxycarbonylalkoxyimino e.g. is a carboxy-methoxy, ethoxycarbonylmethoxy or t-butoxycarbonyl-methoxyimino group. With regard to the 3 position is on

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the pyridinium methyl substituent in numerous other ways. The South African patent description 78/2168 discloses in very general form cephalo-sporin-l-oxide of the sulfides described in the above-mentioned patent description.

South African patent specification 78/1630 describes 3-acetoxymethyl-cephalosporin antibiotics in which the group Rc in the above formula (A) can be replaced by a 2-aminothiazol-4-yl group and the oxyimino group an alkyl group substituted by a carboxy group ( or a salt or C 1-4 alkyl ester thereof), a nitrile group or a carbamoyl group. The patent specification describes the preparation of these compounds by acylation of a 7-aminocephalosporin compound with a suitable carboxylic acid (or a functional derivative thereof). In the latter materials, any carboxy substituent of the alkoxyimino group and the like may be used. a. be protected by a group that is easily removed by acid hydrolysis or by hydrogenolysis.

It has now been found that through a suitable selection of a small number of special groups in the 7-β position in combination with a pyridinium methyl group in the 3-position, cephalosporin compounds with particularly advantageous activity (as will be described in more detail below) over a wide range can be achieved on pathogenic organisms commonly encountered.

The present invention provides cephalosporin antibiotics of the general formula:

nh

/ w h h (i)

SN; ;

^ • - c.co.nh. j ^ r.—o.

o. ch ^ coor wherein R is a hydrogen atom or a C ^ alkyl group, preferably a straight chain alkyl group, i. H. means a methyl, ethyl, n-propyl or n-butyl group and in particular a methyl or ethyl group, and their non-toxic salts, their non-toxic metabolically labile esters and their solvates.

The compounds according to the invention are syn isomers. The syn isomeric form is determined by the configuration of the group

O. CH2COOR

defined with regard to the carboxamido group.

In the present case, the syn configuration is structurally as

S N

C.CO.NH

II

'N

^ 0. CH2C00R

designated.

It goes without saying that since the compounds according to the invention are capable of geometric isomerism, a mixture with the corresponding anti-isomers can occur.

The invention also includes solvates, including the hydrates, of the compounds of formula (I). It also includes salts of esters of the compounds of formula (I).

The compounds according to the invention can occur in tautomeric forms (for example with regard to the 2-aminothiazolyl group) and it is understood that such tautomeric forms, for. B. the 2-iminothiazolinyl form fall within the scope of the invention. Furthermore, the compounds of formula (I) shown above can also be present in alternative zwitterionic compounds. Means e.g. if the group R is not a Ci_4-alkyl group, the 4-carboxyl group may be protonated and the carboxyl group in the 7-side chain deprotonated. Such alternative forms are within the scope of the invention.

The compounds according to the invention show a broad spectrum of antibiotic activity. The activity towards grief-negative organisms is unusually high. This high activity extends to numerous β-lactamase-forming gram-negative strains. The compounds also have high stability to β-lactamases, which are formed by a range of Gram-positive and Gram-negative organisms.

It was found that the compounds according to the invention have good activity against a wide range of organisms, including numerous individuals of Enterobacte-riaceae, such as strains of Escherichia coli, Klebsiella pneumoniae, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae, Serratia marcescens, providence species , Proteus mirabilis and in particular indole-positive Proteus organisms such as Proteus vulgaris and Proteus morganii. They also have good activity against Haemophilus influenzae and Pseudomonas aeruginosa. The compounds according to the invention in which R denotes a CM alkyl group also show good activity against Staphylococcus organisms such as Staphylo coccus aureus strains.

Non-toxic salts with bases can be formed from the compounds of formula (I) by reacting the carboxyl function in the 4-position and / or that which is in the 7-side chain in the case when R is a hydrogen atom. It is understood that when R represents a C1-4 alkyl group and the compound of formula (I) is in the form of a base salt, this compound of formula (I) is in association with a suitable anion. These salts include salts of inorganic bases such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth salts (e.g. calcium salts); Amino acid salts (e.g. lysine and arginine salts); Salts of organic bases (e.g. procaine, phenethylbenzylamine, dibenzylethylene diamine, ethanolamine, diethanolamine and N-methylglucosamine salts). Other non-toxic salts include acid addition salts, e.g. B. those formed with hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, phosphoric acid, formic acid and trifluoroacetic acid; the salts may also be in the form of resinates, e.g. B. with a polystyrene resin or a cross-linked polystyrene di-vinylbenzene copolymer resin containing amino or quaternary amino groups or sulfonic acid groups, or with a resin containing carboxyl groups, such as. e.g. B. a polyacrylic acid resin. Soluble base salts (e.g. alkali metal salts such as the sodium salt) of the compounds of formula (I) can be used in therapeutic applications due to the rapid distribution of such salts in the body after administration. However, if insoluble salts of the compounds (I) in a special application e.g. B. are desired for use in depot preparations, such salts can be formed in a conventional manner, for example with suitable organic amines.

These and other salts, such as the salts with toluene-p-sulfonic acid and methanesulfonic acid, can be used as intermediates in the preparation and / or purification of the parent compounds of the formula (I) z. B. used in the methods described below.

Non-toxic metabolically labile esters can be obtained from compounds of the formula (I) by esterification of the carboxyl function in the 4-position and / or that which is present in the 7-side chain, in the case where R denotes a hydrogen atom,

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

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be formed. These esters include acyloxyalkyl esters, e.g. B. low alkanoyloxymethyl or ethyl such as acetoxy methyl or ethyl or pivaloyloxymethyl.

Preferred compounds according to the invention comprise (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxy-imino) -acetamido] -3- (l-pyridiniummethyl) -ceph- 3-em-4-carboxylate, (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxycarbonylmethoxyimino) acetamido] -3- (l-pyridiniummethyl ) -ceph-3-em-4-carboxylate and (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxycarbonylmethoxyimino) acetamido] -3- (l -pyridiniummethyl) -ceph-3-em-4-carboxylate and their non-toxic salts and non-toxic metabolically labile esters.

The compounds of formula (I) can be used to treat a variety of diseases caused by pathogenic bacteria in humans and animals, such as respiratory and urinary tract infections.

According to the invention there is further provided a process for the preparation of an antibiotic compound of the general formula (I) as defined above and / or a non-toxic salt thereof, which comprises (A) the acylation of a compound of the formula:

(II)

wherein R3 and B are as defined above, R4 and R4a can independently represent hydrogen or a carboxyl blocking group and X represents an exchangeable residue of a nucleophile, e.g. an acetoxy or dichloroacetoxy; group or a halogen atom such as chlorine, bromine or iodine, or a salt thereof with pyridine; or

(C) when a compound of formula (I) wherein R represents a CM alkyl group is desired, reacting a compound of formula

10th

15

4th

(V)

.c.co.nh

ü

N

\

0. clu1

®n

cocr whereinB) S or) S- »0 (a- or ß-), or a salt, e.g. B. an acid addition salt (for example formed 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 p-toluenesulfonic acid), or an N-silyl derivative thereof or a corresponding compound having a group of the formula COOR1 in the 4-position, wherein R1 represents a hydrogen atom or a carboxyl blocking group, e.g. B. means the remainder of an ester-forming aliphatic or aliphatic alcohol or an ester-forming phenol, silanol or stannanol (this alcohol, this phenol, silanol or stannanol preferably containing 1 to 20 carbon atoms) and an associated anion Ye, such as a halide, e.g. Chloride or bromide or trifluoroacetate anion, with an acid of

35

Formula:

, 3rd

A

S

Vz

(in)

- C.COOH

II

N

2nd

o.CH2C00R

wherein R2 is a carboxyl blocking group, e.g. B. as described above for R1, and R3 represents an amino or protected amino group, or with a corresponding acylating agent;

(B) the reaction of a compound of the formula:

(IV)

R "s n

\ = Z_

c.co.nh so, ch2coor coor ch2x 4a wherein R3 is as defined above, R5 represents a carboxyl blocking group and Q represents a carboxyl group or a 20, functional equivalent thereof, with an alkylating agent which serves the group Convert Q to a COOR group, wherein R represents a CM alkyl group; and then when the acylation (A) or the reaction (B) is carried out with a starting product of the formula (II) or (IV) in which B 25 stands for) S - = ► O, the sulfoxide obtained is used for corresponding thio compound is reduced, on the compound obtained by the acylation (A) or the reaction (B) or (C), any carboxyl-blocking groups and / or amino protecting groups are split off, after the acylation (A) and the reaction (B ) the latter process step and the reduction of the sulfoxide group can also be carried out in the reverse order, and if desired converting a carboxyl group into a non-toxic salt in the compound obtained.

It is to be understood that the compound of formula (V) above can be used in appropriate cases together with one or more ions with an appropriate charge to ensure that the molecule as a whole has a balanced charge.

40 In the method (A) described above, the starting material of the formula (II) is preferably a compound in which (B)) is S.

The reaction should be carried out in the presence of a base when an acid addition salt of a compound of formula (II) is used.

It is understood that in processes (A) and (B) above, the carboxyl blocking groups R2 and R4 can represent Ci_4-alkyl groups, in which case the appropriate group can be retained in the final product if a 50th Compound of formula (I) in which R represents a CH alkyl group is desired.

Acylating agents that can be used in the preparation of the compounds of formula (I) include acid halides, especially acid chlorides or bromides. Such acylating agents can be prepared by combining an acid (III) or a salt thereof with a halogenating agent e.g. B. phosphorus pentachloride, thionyl chloride or oxalyl chloride.

Acylations using acid halides can be carried out in aqueous and non-aqueous reaction media, suitably at temperatures from -50 to + 50 ° C, preferably from -20 to + 30 ° C, if desired in the presence of an acid-binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as 65 ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylformamide or dimethylacetamide, nitriles such as acetonitrile or mixtures of two or more such solvents. Suitable acid binding agents

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include tertiary amines (e.g. triethylamine or dimethyl aniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes such as low 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which bind the hydrogen halide released in the acylation reaction.

The acids of formula (III) in turn can be used as acylating agents in the preparation of the compounds of formula (I). Acylations using acids (III) are desirably carried out in the presence of a condensing agent, for example a carbodiimide such as N, N-di-cyclohexylcarbodiimide or N-ethyl-N'-dimethylaminopropyl-carbodiimide; a carbonyl compound such as carbonyldiimide azole; or an isoxazolium salt such as N-ethyl-5-phenyl-isoxazolium perchlorate.

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

The acylation reactions with free acids or their amide-forming derivatives mentioned above are desirably carried out in an anhydrous reaction medium e.g. with methylene chloride, tetrahydrofuran, dimethylformamide, dimethylacetamide or acetonitrile.

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

If desired, the acids of formula (II) and the acylating agents corresponding to them can be prepared and used in the form of their acid addition salts. For example, Acid chlorides are suitably used in the form of their hydrochloride salts and acid bromides in the form of their hydrobromide salts.

Pyridine can act as a nucleophile to exchange numerous X substituents from the cephalosporin of formula (IV). The ease of exchange is related to the pKa of the acid HX from which the substituent is derived. Thus, atoms or groups X derived from strong acids generally tend to be exchanged more easily than atoms or groups derived from weaker acids.

The exchange of X for pyridine can conveniently be carried out by keeping the reactants in solution or suspension. The reaction is preferably carried out using 1 to 10 molar equivalents of pyridine.

Nucleophilic exchange reactions can expediently be carried out on those compounds of the formula (IV) in which the substituent X is a halogen atom or an acyloxy group, for. B. as discussed below.

Acyloxy groups

Compounds of formula (IV) wherein X represents an acetoxy group are suitable starting materials for use in the nucleophilic exchange reaction with pyridine. Alternative starting materials in this class include compounds of formula (IV) wherein X is the residue of a substituted acetic acid, e.g. B. chloroacetic acid, trichloroacetic acid and tri-fluoroacetic acid.

Exchange reactions on the compounds (IV) with X substituents of this class, in particular in the case where X is a

Acetoxy group means can be facilitated by the presence of iodide or thiocyanate ions in the reaction medium. Reactions of this type are described in more detail in GB-PS 1132621 and 1171603.

5 The substituent X can also be derived from formic acid, a halogen formic acid, such as chloroformic acid or a carbamic acid.

When a compound of formula (IV) is used in which X represents an acetoxy or substituted acetyoxy group, it is generally desirable that the group R4a in formula (IV) should be a hydrogen atom and B) S should be. In this case, the reaction is advantageously carried out in an aqueous medium, preferably at a pH of 5 to 8, in particular 5.5 to 7.

The process described above using compounds of formula (IV), wherein X is the residue of a substituted acetic acid, can be carried out as described in GB-PS 1241657.

If compounds of the formula (IV) are used in which X 20 denotes an acetoxy group, the reaction is expediently carried out at a temperature of 30 to 110 ° C., preferably 50 to 90 ° C.

25th

30th

40

Halogens

Compounds of formula (IV) in which X represents a chlorine, bromine or iodine atom can also be used expediently as starting materials in the nucleophilic exchange reaction with pyridine. If compounds of the formula (IV) are used in this class, R4a preferably denotes a carboxyl-blocking group. The reaction is expediently carried out in a non-aqueous medium which preferably comprises one or more organic solvents, preferably polar in nature, such as halogenated hydrocarbons e.g. B. methylene chloride or dichloroethane, ether e.g. Dioxane or tetrahydrofuran, esters e.g. Ethyl acetate, nitriles e.g. Acetonitrile, amides e.g. Formamide, dimethylformamide or dimethylacetamide and ketones e.g. Acetone. If desired, pyridine itself can also serve as a solvent. Other suitable organic solvents are described in more detail in BG-PS1326531. The reaction medium should neither be extremely acidic nor extremely basic. In the case of reactions carried out on compounds of formula (IV) in which R4 and R4a represent carboxyl-blocking groups, the 3-pyridinium methyl product can be formed as a corresponding halide salt which, if desired, can be subjected to one or more ion exchange reactions in order to Obtain salt with the desired anion.

If compounds of the formula (IV) are used in which X is a halogen atom, as described above, the reaction is conveniently carried out at a temperature of from -10 to + 60 ° C, preferably from +10 to + 30 ° C.

In process C above, alkylating agents such. B. a diazo (CM) alkane such as diazomethane, a CM alkanol and a reactive derivative thereof e.g. B. be a Cw-Alkylha-55 logenide such as methyl or ethyl iodide. If an alkyl halide is used, the reaction is preferably carried out in the presence of a base, e.g. B. a tertiary amine such as triethylamine or an inorganic base such as potassium carbonate. Q is preferably the group COOH.

If a C ^ -alkanol is used, this can with an acid (namely, where Q is COOH) of the formula (V) in the presence of coupling agents, for. B. dicyclohexylcarbodi-imide, preferably in the presence of a catalyst such as 4-dimethylaminopyridine.

The alkylation reaction is conveniently carried out in a solvent medium comprising e.g. an amide solvent such as dimethylformamide or dimethylacetamide, ketones such as acetone, esters such as ethyl acetate, halogenated hydrocarbons

50

60

65

such as methylene chloride or dichloroethane, nitriles such as acetonitrile, ethers such as dioxane, tetrahydrofuran or diethyl ether or mixtures thereof, preferably at a temperature in the range from 0 to + 50 ° C.

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

If a connection is obtained in which B) means S -> 0,

it is reduced to the corresponding sulfide, e.g. B. by reduction of the corresponding acyloxysulfonium or alkoxy sulfonium salt, prepared in situ, by reaction with z. B. acetyl chloride in the case of an acetoxysulfonium salt, the reduction e.g. with the help of sodium dithionite or iodide ion as in a solution of potassium iodide in a water-miscible solvent e.g. B. acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide is carried out.

The reaction can be carried out at a temperature of + 20 to + 50 ° C.

Metabolically labile esters of the compounds of formula (I) can be conveniently reacted with a suitable esterifying agent such as an acyloxyalkyl halide (e.g. iodide) in an inert organic solvent such as dimethylformamide or by reacting a compound of formula (I) or a salt or protected derivative thereof Acetone are prepared, followed by removal of any protecting groups if necessary.

The base salts of the compounds of formula (I) can be formed by reacting an acid of formula (I) with a suitable base. So z. B. sodium or potassium salts are formed using the respective 2-ethyl hexanoate, acetate or bicarbonate salt.

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

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

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

Acids of formula (III) can be prepared by etherifying a compound of formula

P- (VI)

/ V

S N

- C.COOIl '

If

K!

(wherein R3 is as defined above) or a salt thereof by reaction with a compound of the general formula

T. CHoCOOR2 (VII)

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(wherein R2 is as defined above and T represents a halogen atom such as chlorine, bromine or iodine; a sulfate group; or a sulfonate group such as a tosylate). The separation of the 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. B. Kalim tert-butoxide and is preferably effected in an organic solvent such as dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane or an N, N-disubstituted amide such as dimethylformamide, sufficient base being added to form a dianion. Under these conditions, the configuration of the oxyimino group remains essentially unchanged by the etherification reaction.

The acids of the general formula (III) can also be prepared by reacting a compound of the formula

R3 (VIII)

\ 'CO.COOR6

(wherein R3 is as defined above and R6 represents a hydrogen atom or a carboxyl blocking group) with a compound of the formula

H2NOCH2-COOR2 (IX)

(wherein R2 is as defined above), followed by the removal of any carboxyl blocking group R6 and, if necessary, the separation of the syn and anti isomers.

The acids of formula (III) can be converted into the corresponding acid halides and anhydrides and acid addition salts by conventional methods, e.g. B. transferred as described above.

If X represents a halogen (namely chlorine, bromine or iodine) atom in the formula (IV), the ceph-3-em starting compounds can be prepared in a conventional manner, e.g. by halogenation of a 7ß-protected amino-3-methyl-ceph-3-em-4-carboxylic acid ester-lß-oxide, removal of the 7ß-protecting group, acylation of the 7ß-amino compound obtained to form the desired 7ß-acylamido group e.g. analogous to process (A) above and subsequent reduction of the β-oxide group later in the reaction sequence. This is described in GB-PS 1326 531. The corresponding ceph-2-em compounds can be prepared by acylation of the corresponding 7β-amino compound.

When X in formula (IV) represents an acetoxy group, such starting materials can be prepared e.g. by acylation of 7-aminocephalosporanic acid e.g. B analogous to process (A) above. Compounds of the formula (IV), in which X denotes other acyloxy groups, can be prepared by acylation of the corresponding 3-hydroxymethyl compounds which, for. B. by hydrolysis of suitable 3-acetoxy-methyl compounds such. B. in GB-PS'en 1474519 and 1531212 described.

The starting materials of formula (II) can also be prepared in a conventional manner, e.g. B. by nucleophilic exchange of the corresponding 3-acetoxymethyl compound with pyridine, such as. B. in GB-PS 1028563.

Another method for the preparation of the starting materials of the formula (II) comprises the deprotection of a corresponding protected 7β-amino compound in a conventional manner e.g. using PC15.

It should be understood that some of the above conversions may require some sensitive groups in the molecule of the subject

7

5

10th

15

20th

25th

30th

35

40

45

50

55

60

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Protect connection to avoid unwanted side reactions. For example, during one of the reaction sequences mentioned above, it may be necessary to remove the NH2 group of the aminothiazolyl part e.g. protected by tritylation, acylation (e.g. chloroacetylation), protonation, or another conventional method. The protecting group can then be removed in any suitable manner which does not cause the desired compound to be broken, e.g. B. in the case of a trityl group using an optionally halogenated carboxylic acid, e.g. B. 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 with 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 required starting materials are desirably groups which can be conveniently split off during a suitable stage of the reaction sequence at the last stage. However, in some cases it may be appropriate to use non-toxic metabolically labile carboxyl blocking groups such as acyloxymethyl or ethyl groups (e.g. acetoxymethyl or ethyl or pivaloyloxymethyl groups) and to maintain these in the final product to provide a suitable ester derivative to give a compound of formula (I). Other examples of blocking groups that can be retained in the final product naturally include Ci-4 alkyl groups that esterify the free carboxyl function in the 7-side chain.

Suitable carboxyl blocking groups are well known in the art, a list of representative blocked carboxyl groups is contained in British Patent No. 1399086. Preferred blocked carboxyl groups include aryl (lower alkoxycarbonyl) groups such as benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; t-butoxycarbonyl; and 2,2,2-trichloroethoxycarbonyl. Carboxyl blocking group (s) can then be removed by any method or described in the literature. For example, acid- or base-catalyzed hydrolysis can be used in numerous cases, just as enzyme-catalyzed hydrolysis is.

Compounds which can be used as intermediates in the preparation of the compounds according to the invention include:

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (benzyloxy-carbonylmethoxyimino) -acetamido] -3- (l-pyridiniummethyl) -ceph-3-em- 4-carboxylate hydrochloride salt.

[vmax (Nujol) 1788 (β-lactam), 1750 (ester) and 1740 cm-1 (acid)] and

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (p-nitrobenzyloxycarbonylmethoxyimino) acetamido] -3- (l-pyridiniummethyl) -ceph-3- em-4-carboxylate hydrochloride salt.

[[o | d -46.1 ° (c 1.0 dimethyl sulfoxide)].

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

Manufacturing 1

(Z) -2-methoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid

A stirred solution of 7 g of sodium (Z) -2-hydroxyimino-2- (2-tritylaminothiazol-4-yl) acetate in 80 ml of dimethylformamide was treated at 0 ° C. under nitrogen with 463 mg of sodium hydride (80% dispersion ). After 2.5 hours at 0 ° C, the solution was cooled to -30 to -40 ° C and 4.74 g of methyl bromoacetate in 20 ml of dimethylformamide was added over 20 minutes. The mixture was then at -30 to -40 ° C

Treated 7.75 ml of 2N hydrochloric acid, allowed to warm to 20 ° C and partitioned between water and ethyl acetate. The organic phase was dried and evaporated to a syrup, which was dissolved in a little ethyl acetate and 5 added dropwise with petroleum ether. The resulting solid was collected and dried to give 5.3 g of the title compound t (CD13) 3.36 (thiazole), 5.30 (CH2), 6.28 (CQ2Me).

10th

Manufacturing 2

(6R, 7R) -3-acetoxymethyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -ceph-3-em-4-carboxylic acid hydrochloride salt Man cooled a stirred solution of 276 mg of t-butyl- (6R, 7R) -15 3-acetoxymethyl-7 - [(Z) -2- (t-butoxycarbonylmethoxyimino) -2- (2-tritylaminothiazol-4-yl) acetamido ] -ceph-3-em-4-carboxylate (described in Example 3 of South African patent specification 78/1630) in 0.5 ml of formic acid at 10 ° C. A 10% solution of concentrated hydrochloric acid in formic 20-sensic acid (0.9 ml) was added. The mixture was stirred at room temperature for 75 minutes and then filtered. The solid was washed with a little formic acid. The filtrate and the wash water were added to 60 ml of diisopropyl ether. The mixture was stirred at room temperature for 1 hour and then filtered. The solid was washed with diisopropyl ether and then with diethyl ether and then dried in vacuo to give 110 mg of the title compound, [a] d +49.0 (c 1.0, DMSO); Rf 0.4 (cellulose, 1-propanol-water, 7-3).

30th

example 1

40

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- (l-pyridiniummethyl) -ceph-3-em-4- carboxylate 35 A mixture of 2.01 g (6R, 7R) -3-acetoxy-methyl-7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxy-imino) - was heated acetamido] -ceph-3-em-4-carboxylic acid hydrochloride salt, 0.95 g sodium carbonate and 2.25 ml water at 50 ° C until dissolution took place. 0.75 ml of pyridine was added and the solution was heated to 80.degree. 7.5 g of sodium iodide was added and the solution was stirred at 80 ° C for 40 minutes, cooled and diluted with 100 ml of acetone. The mixture was filtered off and the solid was washed with acetone and ether to give 2.5 g of an orange product. This solid was dissolved in 10 ml of 45 water and acidified with 10 ml of glacial acetic acid. The mixture was filtered through a kieselguhr cake and the filtrate was concentrated. The residue was triturated with acetone and filtered to give 1.7 g of an orange solid. This solid was dissolved in 25 ml of water and eluted through a column of 200 g of Amberlite XAD-2 resin, using water first and then 25% ethanol in water as the elution solution. The product-containing fractions were concentrated and the residue triturated with acetone to give 0.28 g of the title compound as a monoacetone solvate, [cx]% + 20.0 ° (c 1.0, water); A.max (ethanol) 236 nm, (E} cm 299), Xinf

50

55

250nm, (Ej ™ 286) and ^ nt 291 nm (E ^ 150)

Example 2

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2-60 (ethoxycarbonylmethoxyimino) acetamido] -3- (l-pyridinium-methyl) -ceph-3-em -4-carboxylate dihydrochloride salt 690 mg of phosphorus pentachloride are dissolved in 30 ml of methylene chloride and the solution is cooled to -10 ° C. 1.55 g of (Z) -2-ethoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-65 yl) acetic acid was added and the solution was stirred at -5 ° C for 25 minutes. The solution was cooled to -10 ° C , and 0.92 ml of triethylamine and then 10 ml of water were added with stirring. The temperature was kept at 0 ° C for 5 minutes by cooling

645 906

The lower phase became 1.09 g (6R, 7R) -7-amino-3- (l-pyridiniummethyl) -ceph-3-em-4-carboxylate-dihydrochloride salt 15 ml N, N-dimethylacetamide and 15 ml of acetonitrile, containing 2.1 ml of triethylamine and pre-cooled to -20 ° C, was added. The addition was such that the temperature of the reaction mixture did not exceed -10 ° C. After 45 minutes at -5 to -10 ° C, the mixture was warmed to 21 ° C over an hour. 1 ml of methanol was added and the methylene chloride was evaporated off. The residue was partitioned between 50 ml of ethyl acetate and 50 ml of water containing salt. The ethyl acetate layer was mixed with an additional 50 ml of water and salt. The precipitated material was collected and triturated with diisopropyl ether and diethyl ether to give 1.49 g of a brown solid. 1.40 g of this solid was dissolved in 5 ml of formic acid, and 0.49 ml of 11N aqueous hydrochloric acid was added. After 1.25 hours at 21 ° C., the solution was filtered and the filter cake was leached with formic acid. The filtrate was evaporated to a gummy material which was triturated with acetone to give 970 mg of the title compound. [a] o -21.3 ° (c 1.41, dimethyl sulfoxide);). max (pH 6 buffer) 253 nm, (E £ 251) and Xinf. 282nm, (E} ^ 110).

Example 3

(6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxycarbonylmethoxyimino) -acetamido] -3- (l-pyridinium-methyl) -ceph-3-em- 4-carboxylate dihydrochloride salt 1.55 g of (Z) -2-methoxycarbonylmethoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid was added to a stirred suspension of 0.69 g of phosphorus pentachloride and 15 ml of methylene chloride at -20 ° C. The temperature was maintained at less than -5 ° C for about 20 minutes and then lowered to about -20 ° C when 0.8 ml of triethylamine was added with vigorous stirring and then 5 ml of water. After about 2 minutes the phases were allowed to separate. The organic phase was added dropwise to a stirred mixture of 1.13 g (6R, 7R) -7-amino-3- (l-pyridiniummethyl) -ceph-3-em-4-carboxylic acid dihydrochloride salt, 12 ml N, N-Dimethylacetamide and 12 ml acetonitrile containing 2.1 ml triethylamine and pre-cooled to about -25 ° C were added. After about 45 minutes the temperature was allowed to rise to about 0 ° C when 1 ml of methanol was added. The volume of the mixture obtained was reduced in vacuo and partitioned between 50 ml of ethyl acetate and 50 ml of water. The phases were separated and the aqueous phase was washed with ethyl acetate. The material which separated out was collected and triturated with diethyl ether. The solid obtained was dissolved in methanol and then precipitated in diisopropyl ether. 1.2 g of solid was added to 63 ml of stirred and ice-water-cooled formic acid, followed by the addition of 0.42 ml of IIN hydrochloric acid. After one hour the temperature had risen to 5 ° C. and the suspension obtained was filtered and the volume of the filtrate was reduced and added dropwise to 80 ml of stirred diisopropyl ether. The resulting gummy material was dissolved in methanol and added to stirred diisopropyl ether. The resulting solid was treated with acetone to give 0.87 g of the title compound, [a] d -28 ° (c 1,3, dimethyl sulfoxide); Xtaf (pH 6 buffer) 236 nm, (Ef ^ 278); Xmax 255 nm, (Ei ^ L 286) and 288 nm, (Ej ^ 177).

Pharmaceutical Formulations The antibiotic compounds according to the invention can be formulated for administration in any suitable manner in analogy to other antibiotics, and the invention therefore also includes pharmaceutical compositions which contain an antibiotic compound according to the invention adapted for use in human or veterinary medicine. Such compositions can be presented for use in a conventional manner using any required pharmaceutical carriers or excipients.

The antibiotic compounds according to the invention can be formulated for injection and presented in unit dose form in 5 ampoules or in multi-dose containers, if necessary, with the addition of a preservative. The compositions can also be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and can contain formulating agents such as suspending, stabilizing and / or dispersing agents.

Alternatively, the active ingredient in powder form for the preparation with a suitable carrier z. B Sterile pyogen-free water before use.

If desired, such powder formulations 15 can contain a suitable non-toxic base in order to improve the water solubility of the active ingredient and / or to ensure that the pH of the aqueous formulation obtained is physiologically acceptable when the powder is prepared with water. Alternatively, the base may be in the water used to prepare the powder. The base can e.g. B. 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 formulated as suppositories, e.g. Contain the usual suppository base materials such as cocoa butter or other glycerides.

Veterinary compositions may also be formulated, for example, as intramammary preparations in either long-acting or rapidly releasing bases.

The compositions can range from 0.1%, e.g. 0.1 to 99%, active ingredient depending on the method of administration.

If the compositions comprise dose units, each unit preferably contains 50 to 100 mg of active ingredient. The dose used for the treatment of the adult human is preferably in the range of 500 to 6000 mg / day depending on the route and the frequency of administration. For example, 1000 to 3000 mg / day for intravenous or intramuscular administration should normally be sufficient in the treatment of 40 adult humans. Higher daily doses may be required to treat Pseudomonas infections.

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

The following formulation illustrates how the compounds according to the invention can be prepared in pharmaceutical compositions.

Formulation - for injection formulation per ampoule

55 (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- (l-pyridinium-methyl) -ceph-3 -em-4-carboxylate 1.00 g anhydrous sodium carbonate 122 mg

60

method

The sterile cephalosporin antibiotic is mixed with sterile sodium carbonate under aseptic conditions. It is filled into the glass ampoules under aseptic conditions under a coat of sterile 65 nitrogen. The ampoules are sealed using rubber washers or stoppers held in place by aluminum outer seals to allow gas exchange

645 906 10

or to prevent microorganisms from entering. The product is prepared by dissolving it in water for injection or other suitable sterile vehicle just prior to administration.

m

Claims (10)

645 906 2. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (carboxymethoxyimino) acetamido] -3- (l-pyridiniummethyl) -ceph-3- em-4-carboxylate and its non-toxic salts as compounds according to claim 1. 2nd PATENT CLAIMS 1. Cephalosporin antibiotics of the general formula n'k. A s h c.co.nh h W (I) ffi / CH2-N "0-ch2c00r eoo (IVA) 0. ch2coor r N \ f ^ LcH2X COOR ^ 3 10th wherein R represents a hydrogen atom or a C 1-4 alkyl group, and their non-toxic salts, their non-toxic metabolically labile esters and their solvates. 3. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (ethoxycarbonylmethoxyimino) acetamido] -3- (l-pyridiniummethyl) -ceph-3- em-4-carboxylate and its non-toxic salts as compounds according to claim 1. 4. (6R, 7R) -7 - [(Z) -2- (2-aminothiazol-4-yl) -2- (methoxy-carbonylmethoxyimino) acetamido] -3- (l-pyridiniummethyl) -ceph-3- em-4-carboxylate and its non-toxic salts as compounds according to claim 1. 5. A process for the preparation of a compound of formula (I) according to claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: 15 20th 25th wherein R3 is as defined above, R4 and R4a independently represent hydrogen or a carboxyl-blocking group and X represents an exchangeable residue of a nucleophile, or a salt thereof is reacted with pyridine, any carboxyl-blocking groups R4 and R4a and / or amino splits off protective group R3 and, if desired, converts a carboxyl group of the compound obtained into a non-toxic salt. 6. A process for the preparation of a compound of formula (I) according to claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: r3 A s n \ - / (III) 60 c.cooh II N .CKjCOOR 65 in which R2 represents a carboxyl-blocking group and R3 represents an amino or protected amino group, or aeylated with one of these corresponding acylating agents, reduces the sulfoxide obtained to the corresponding thio compound, the carboxyl-blocking group R2 and one at most 645 906 existing carboxyl-blocking group R1 and / or amino protective group R3 is split off, the latter two process stages also being able to be carried out in reverse order, and if desired converting a carboxyl group of the compound obtained into a non-toxic salt. 7. A process for the preparation of a compound of the formula (I) according to claim 1, in which R is a C 1-4 alkyl group, or a non-toxic salt thereof, characterized in that a compound of the formula: r3 (V) h h i ( c.co.nh II N Eq 30th \ 0.ch2q (IIA) 35 c00v 40 or a salt or an N-silyl derivative thereof or a corresponding compound having a group of the formula -COOR1 in the 4-position, in which R1 denotes a hydrogen atom or a carboxyl-blocking group, and an associated anion Ye with an acid of the formula: 45 wherein R3 is as defined above, R5 is a carboxyl-blocking group and Q is a carboxyl group or a functional equivalent thereof, with an alkylating agent which serves to convert the group Q into a group COOR, in which R is a C ^ Alkyl group means converts the carboxyl-blocking group R5 and any amino protective group R3 that may be present and, if desired, converts a carboxyl group of the compound obtained into a non-toxic salt. 8. A process for the preparation of a compound of formula (I) according to claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: 0 * HaN—— (HB) (in) ■ VT eoo ■ CH. • 0 50 c.cooh ir N or a salt or an N-silyl derivative thereof or a corresponding compound having a group of the formula-COOR1 in the 4-position, in which R1 denotes a hydrogen atom or a carboxyl-blocking group, and an associated anion Ye with an acid of the formula: ch2coor 55 wherein R2 represents a carboxyl-blocking group and R3 represents an amino or protected amino group, or aeylated with one of these corresponding acylating agents, splits off the carboxyl-blocking group R2 and any carboxyl-blocking group R1 and / or amino-protecting group R3 and, if desired, one Converted carboxyl group of the compound obtained into a non-toxic salt. 9. A process for the preparation of a compound of formula (I) according to claim 1 or a non-toxic salt thereof, characterized in that a compound of the formula: .3 R " s n \ - / c.co Ii ■ n \ NH (IVB) 0.CH2C00R coor in which R3 is as defined above, R4 and R4a independently represent hydrogen or a carboxyl-blocking group and X represents an exchangeable radical of a nucleophile, or a salt thereof is reacted with pyridine, which reduces the sulfoxide obtained to the corresponding thio compound, possibly carboxyl-blocking Groups R4 and R4a and / or amino protective group R3 are split off, the latter two process stages also being able to be carried out in reverse order, and if desired converting a carboxyl group of the compound obtained into a non-toxic salt. 10. Pharmaceutical composition for use in human or veterinary medicine, characterized in that it contains an antibiotic compound according to one of claims 1 to 6 together with a pharmaceutical carrier or excipient.