CH676850A5 - - Google Patents

Description

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description

The present invention relates to new cephalosporin compounds and derivatives thereof with valuable antibiotic activity.

The cephalosporin compounds in the present description are referred to with reference to "Cepham" according to J. Amer. Chem. Soc., 1962, 84. 3400, and the term "cephem" refers to the basic cepham structure 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 against other antibiotics such as penicillin compounds , are resistant, and in the treatment of penlcillin sensitive patients. In many cases, it is desirable to use a cephalosporin antibiotic that has activity against both gram-positive and gram-negative microorganisms, and a significant amount of research has been directed to the development of various types of broad-spectrum cephalosporin antibiotics .

For example, British Patent Specification 1,399,086 describes a new class of cephalosporin antibiotics that contain a 7β- (a-etherified-oxyimino) acylamido side chain with the oxyimino group in the syn configuration. This 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 towards β-lactamases, which are produced by various gram-negative organisms.

The discovery of this class of compounds has prompted further research in the field to attempt to find compounds that have improved properties, for example over particular classes of organisms, particularly gram-negative organisms. This interest is reflected in a very large number of patent applications made with respect to cephalosporin antibiotics with special substituents both on the 7β-acylamido side chain and in the 3-position of the cephalosporin core.

For example, British Patent Specification 1,576,625 contains a general definition of Ce-phalosphorin antibiotics with a 7β- (a-etherified-oxyimino) -acetamido side chain, in which the etherifying group is an aliphatic hydrocarbon group which may have suitable substituents (including below a large number of possibilities (a carboxy or protected carboxy group and a phenyl group, substituted by up to three hydroxyl groups), the side chain being further a-substituted by a group which can be, inter alia, an amlnothiazolyl group. However, none of the compounds specifically exemplified contains a carboxy-phenylalkyl etherifying group. The group in the 3-position can also be selected from a large number of alternatives, but a hydrogen atom is not included among them.

British Patent Specification 1 604 971 describes a large variety of cephalosporin antibiotics in general, in which a 2- (2-aminothiazoI-4-yl) -2- (etherified-oxyimino) can be selected as the side chain in the 7β position. -acetamido group, in which the etherifying group can be an alkyl group (for example methyl) substituted by both phenyl and carboxy under very many possible meanings, although no specific examples of compounds having a carboxyphenylalkyl group are given and of the preferred etherifying group Group is said to be an unsubstituted methyl group. The group in the 3-position can also be selected from a large number of alternatives, and possible 3-substituents within the general definition include a hydrogen atom.

In GB patent specification 2,017,702, the oxyimino etherifying group, according to the general definition, can be, inter alia, an a-carboxyphenylmethyl radical. In the compounds specifically described by examples, the carboxyphenylmethyl group is always combined with an acetoxymethyl group in the 3-position.

GB Patent Specification 2,104,888 generally describes cephalosporin antibiotics wherein the side chain in the 7β position is a 2- (2-aminothiazol-4-yl) -2- (etherified oxyimino) acetamido group. The oxyimino etherifying group can be, inter alia, a carboxyphenylmethyl group, in which the phenyl group can be substituted by a hydroxyl group. The 3-position group is an isothlazolylthlomethyl or iminoalkylidendithiethan group.

European patent specification 197 409 describes cephalosporin antibiotics in general, in which the side chain in 7β-division is a 2- (2-aminothiazol-4-yl) -2- (etherified-oxyimino) -acetami-do group. The oxyimino etherifying group can be, inter alia, a catechol-carboxymethyl-oxyimino group. The 3-position substituent can be selected from a number of alternatives, but these do not include a hydrogen atom.

It has now been found that by selecting a (Z) -2- (2-aminothiazol-4-yl) -2- (etherified-oxyimi-no) -acetamido group in the 7ß position in combination with a hydrogen atom In 3- Position and by selection of an a-carboxy-substituted phenylmethoxyimino group as etherified oxyimino group cephalosporin compounds with a particularly advantageous activity profile (described in more detail below) against a wide range of commonly occurring pathogenic organisms

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and / or that they are useful as intermediates in the preparation of other active compounds.

As a result, cephalosporin compounds of the general formula (I)

IjlHR3

. = i C CDNH.

II

0CHC00R2

J

/ w • •

II I

wherein

R1 and R2, which may be the same or different, are each a hydrogen atom or a car-boxyl blocking group;

R3 represents a hydrogen atom or an amino protecting group;

R4 and RS each represent a hydroxyl or substituted hydroxyl group or R4 and R5 together with the carbon atoms to which they are attached represent a cyclic, protected diol group;

Z stands for> S or> S O (a- or ß-);

the dashed line connecting the 2, 3 and 4 positions indicates that the connection is a Ceph-2-em or Ceph-3-em connection;

and non-toxic salts and solvates (especially hydrates) thereof.

In the compounds of formula (I) wherein R1 and / or R2 are carboxyl blocking groups, the blocking group can be, for example, the residue of an ester-forming, aliphatic or araliphatic alcohol or an ester-forming phenol, silanol or stannanol (said alcohol, phenol, silanol or stannanol preferably contains 1 to 20 carbon atoms) or a symmetrical or mixed anhydride blocking group derived from a suitable acid. Particular examples of R1 or R2 include t-butyl, diphenylmethyl and p-nitrobenzyl.

Where R3 is an amino protecting group, the protecting group can be, for example, a C7-2o aralkyl group (e.g. a triphenylmethyl or 4-methoxybenzyl group), an acyl group such as an optionally substituted Ci-6-alkanoyl group (e.g. a formyl or chloroacetyl group) or an optionally substituted Ci-e-alkoxycarbonyl group (e.g. a t-butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl group), or a C7_io-aralkyloxycarbonyl group (e.g. a benzyioxycarbonyl group) or a silyl group (e.g. a trimethylsilyl group).

In general, compounds of formula (I) in which R3 is a hydrogen atom are preferred.

If R4 and R5 represent a substituted hydroxy group, it can be, for example: an acyloxy group [e.g. a formyloxy group or a group of the formula -OCOR6 (in which R6 represents a C-i-s-AI-alkyl group, e.g. a methyl group)], a carbonate group -OCO2R6 (in which R6 is as defined above), a silyloxy group [e.g. a (Ci-4-alkyl) -silyloxy group, such as a trimethylsilyloxy or t-butyldimethylsilyloxy group] or a borate [-OB (OR7) 2] or phosphate [-OP (0) (OR7) 2] group ( where R7 is Ct-4-alkyl).

Where R4 and R5 together form a cyclic, protected diol group, this may be an alkylidene dioxy group, preferably with 1 to 20 carbon atoms, e.g. a methylenedioxy, ethylidendi-oxy or isopropylidendioxy group which can carry one or more substituents, e.g. Phenyl, Ci-4 alkoxy or oxo substituents, e.g. Methoxymethylene dioxy, diphenylmethylene dioxy or carbonyldioxy groups; a cyclic borate group, e.g. -0B (0H) 0-; a cyclic phosphate group, e.g. -0P (0) (0H) 0- or -0P (0) (0R7) 0- (where R7 is as defined above), or a cyclic silyl ether group, e.g. a di- (Ci - ^ - alkyi) -silyldioxy group, such as a dimethylsilyldioxy group.

In general, such silyloxy, borate or phosphate groups are protected hydroxy groups which can be cleaved to create a compound of formula (I) with free hydroxyl groups.

In general, R4 and R5 each preferably represent an acetoxy group or in particular a hydroxy group.

In the compounds of formula (!) Z is preferably> S.

Ceph-3-em compounds according to the invention are particularly preferred.

If the compound is to be used in medicine, any ester of the carboxyl group in the molecule should be a non-toxic, metabolically labile ester function. Examples of non-toxic

//

«A _ • ■

i: i COOR1

(X)

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see, metabolically labile ester derivatives include acyloxy alkyl esters, e.g. Lower taikoyoyloxy methyl or ethyl esters such as acetoxymethyl or ethyl or pivaloyloxymethyl esters and alkoxycarbonyloxyethyl esters, e.g. Lower alkoxy-carbonyloxyethyl esters, such as the ethoxycarbonyioxyethyl ester.

Non-toxic salt derivatives which can be formed by reaction of the carboxyl group present in the compounds of formula (I) include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts); Amino acid salts (e.g. Lys'tn and arginine salts); Salts of organic bases (e.g. procaine, phenylethylbenzylamine-dlbenzyl-ethylenediamine, ethanolamine, diethanoiamine and N-methylglucosamine salts). Other non-toxic salt derivatives include acid addition salts, e.g. formed with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid and trifluoroacetic acid. The salts can also be in the form of resinates formed with, for example, a polystyrene resin or crosslinked polystyrene-divinylbenzene copolymer resin containing amino or quaternary amino groups or sulfonic acid groups, or with a resin containing carboxyl groups, e.g. a polyacrylic acid resin. Soluble base salts (e.g. alkali metal salts such as the sodium salt) of the compounds of formula (!) Can easily be used in therapeutic applications due to the rapid distribution of such salts in the body after administration. However, if insoluble salts of compounds (I) are desired in a particular application, e.g. for use in depot preparations, such salts can be formed in a conventional manner, for example with suitable organic amines.

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

-0CHC00R2

Group related to the carboxamido group. In the present description, the syn configuration is structurally referred to as:

nhr3

/ \\ S N

x0nh y n

0chc00r2

ft

I »

\ // \

R *

r5

It should be mentioned that since the compounds according to the invention are geometric isomers, some mixing with the corresponding anti-isomer can occur.

It should also be noted that the carbon atom adjacent to the oxy group in the oxime etherifying group is chiral and can therefore exist in both the R and the S configuration. The scope of the invention includes the individual R and S forms on this chiral carbon atom as well as mixtures (including diastereomeric mixtures). In general, compounds of formula (I) in which this chiral carbon atom has the S configuration and R / S mixtures in which the S isomer predominates are preferred.

The compounds according to the invention can be in tautomeric forms (e.g. with respect to

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the 2-amlnothiazolyl group) exist, and it should be noted that such tautomeric forms, e.g. the 2-iminothiazolinyl form, are included in the scope of the invention.

As indicated above, the compounds of the invention are effective against a wide range of commonly occurring pathogenic organisms and / or are useful as intermediates for the production of other active compounds. In general, if the compounds according to the invention are to be used as intermediates, the groups R 1 and R 2 will often be carboxyl-blocking groups; the group R3 will often be an amino protecting group and the groups R4 and Rs will often be protected hydroxy groups such as silyloxy, borate or phosphate groups or together will be a cyclic protected diol group. Non-toxic derivatives in which R4 and / or RS represent acyloxy groups, such as acetoxy groups, can serve both as intermediates and as active compounds.

In general, the active compounds of the invention will be ceph-3-em compounds of formula (I) wherein R1, R2 and R3 represent hydrogen atoms, Z represents> S and R4 and Rs, which may be the same or different, are hydroxy- or Ci-4-acyloxy groups, e.g. Acetoxy groups.

Important active compounds according to the invention have the formula (Ia)

fz •.

S \ H HS

II = = / \

_C CONH ^. • • N

li il, t (Ia)

N «i N •

\ // \ // \

0CHC00H 0 «H

i

C00H / \\

Yv

.a

R5

wherein R4a is a hydroxy or acetoxy group and R5a is a hydroxy or acetoxy group, and the non-toxic salts, solvates, hydrates and metabolically labile esters thereof.

A particularly preferred compound according to the invention is (6R, 7R, 2'Z, S) -7- [2- (2-aminothia-zol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl ) -methoxyimino] -acetamidol-ceph-3-em-4-carboxylic acid and the non-toxic salts, solvates, hydrates and metabolically labile esters thereof.

It was found that (6RJ7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxyimino] - acetamido] -ceph-3-em-4-carboxylic acid can be advantageously and uniformly prepared and isolated with a high degree of purity in crystalline form, and this offers another aspect of the present invention. In particular, crystalline (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxyimino] acetamido] -ceph-3-em-4-car-bonic acid hydrate produced and isolated. This new material is not only superior in its crystallinity and increased purity, but is also obtained in high yields and has an improved stability in storage, even at high temperature for extended periods. These properties of the crystalline material make it particularly useful in pharmaceutical use .

The above-mentioned crystalline, hydrated material can be characterized by the infrared spectrum and / or by its X-ray powder diffraction pattern.

IR spectrum (Nujol)

vmax3700-2100 (wide), 1760.1720.1660.1555.1520.1350.1300.1290.1240.1215.1170.1155.1120.1030, 1000, 920.860 and 755 cm-1.

X-ray diffraction patterns (given as d distances in nanometers and percent intensity, based on the intensity of the strongest peak):

1.25 (21); 0.997 (37); 0.951 (22); 0.679 (11); 0.633 (35); 0.529 (10); 0.476 (30); 0.463 (100); 0.439 (54); 0.432 (5); 0.418 (15); 0.409 (31); 0.391 (24); 0.378 (69); 0.369 (17); 0.361 (9); 0.352 (12); 0.348 (21); 0.342 (6); 0.333 (37); 0.315 (36); 0.307 (22); 0.302 (4); 0.296 (36); 0.285 (9); 0.278 (3); 0.275 (3); 0.265 (11); 0.259 (49); 0.250 (6); 0.244 (9); 0.238 (6); 0.231 (3); 0.227 (4); 0.220 (5); 0.216 (9); 0.210 (10); 0.205 (4); 0.201 (9).

The compounds according to the invention show broad-spectrum antibiotic activity against both gram-positive and gram-negative organisms, including many β-lactamases5

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of the tribes. The compounds also have high stability to β-lactamases, which are produced by a number of gram-negative and gram-positive organisms.

It has been found that the compounds according to the invention have a high activity against strains (including peniciiinase-producing strains) of gram-positive bacteria such as Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus species. This is coupled with an excellent activity against Pseudomonas species and also with a high activity against various members of the Enterobacteriaceae (e.g. strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus mirabilis and indole-positive Proteus organisms such as Proteus vulgaris, Proteus morganii and Providence species) and strains of Haemophilus influenzae and Acinetobacter calcoaceticus. This combination of high activity against gram-positive organisms with high activity against gram-negative organisms, especially towards Pseudomonas, which the compounds according to the invention possess, is unusual and particularly advantageous.

The cephalosporin derivatives described here have been found to have a desirable, long serum excretion half-life in vivo.

Compounds according to the invention can be used to treat a variety of diseases caused by pathogenic bacteria in humans and animals, such as infections of the respiratory tract and infections of the urinary tract.

The antibiotic compounds according to the invention can be formulated for administration in any suitable way in analogy to other antibiotics, and the invention therefore also includes in their field pharmaceutical compositions containing an antibiotic compound according to the invention, adapted for use in human or Veterinary medicine. Such compositions can be offered for use in the usual manner with the aid of any necessary pharmaceutical carriers or excipients.

The antibiotic compounds according to the invention can be formulated for injection and can be presented in unit dose form in ampoules or in multi-dose containers, if necessary with an added preservative. The compositions may also have such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can be in powder form for processing with a suitable carrier, e.g. sterile, pyrogen-free water, before use.

If desired, such powder formulations may contain a suitable non-toxic base to improve the water solubility of the active ingredient and / or to ensure that when the powder is treated with water the pH of the resulting aqueous formulation is physiologically acceptable. Alternatively, the base can be present in the water used to prepare the powder. The base can be, for example, an inorganic base, such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base, such as lysine or lysine acetate.

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

The compositions for veterinary medicine can be formulated, for example, as intramammal preparations in long-acting or rapidly releasing base materials.

The compositions can range from 0.1%, e.g. 0.1 to 99% of the active material, depending on the method of administration. When the compositions comprise dosage units, each unit will preferably contain 100 to 3000 mg of active ingredient, e.g. 200 to 2000 mg. The daily dose for the adult in human medicine is preferably in the range of 200 to 12,000 mg, e.g. 1000 to 9000 mg per day, depending on on the nature of the infection and the route and frequency of administration. In general, intravenous or intramuscular administration will be used, for example using 400 to 4000 mg / day of active ingredient in the treatment of adults. It should be noted that in certain circumstances, for example in the treatment of newborns, smaller dosage units and daily dosages may be desirable.

The antibiotic compounds according to the invention can be used in combination with other therapeutic agents such as antibiotics, e.g. Penicillins, cephalosporins or other β-lactam compounds can be administered.

The compounds of the invention can be prepared by a number of methods which are discussed below.

Accordingly, according to a further feature of the invention, the preparation of an antibiotic compound of the general formula (1), as defined above, or a salt or solvate thereof is achieved by acylating a compound of the formula (II)

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CH 676 850 A5

H

H2N-

//

H Z

H/ \

"î: f

_N / •

\ .7 \

H

! , C00R1

(II)

wherein R1, Z and the dashed line are as defined for general formula (I), or a salt, e.g. an acid addition salt (formed with, for example, 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-suifonic acid), or a 7-N-silyl derivative thereof with a corresponding one acylating agents;

whereupon an A2 isomer is optionally converted into the desired A3 isomer and / or a non-toxic salt or solvate of the compound obtained is formed.

In the acylation process, the starting material of formula (II) is preferably a compound in which Z is> S and the broken line means a ceph-3-em compound.

Acylating agents which 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 obtained by reaction of an acid (III)

f

NHR3 I

A \

f • (III)

£ »COOH I

\

0 (j: HC00R2

A

\ // \

R1 *

R

5

or a salt thereof with a halogenating agent, e.g. Phosphorus oxychloride, thionyl chloride or oxalyl chloride can be prepared.

Acylations using acid halides can be effected in aqueous or non-aqueous reaction media, advantageously at temperatures from -50 to + 50 ° C, preferably -40 to + 30 ° C, if desired in the presence of an acid-binding agent. Suitable reaction media include aqueous ketones, such as aqueous acetone, aqueous alcohols, such as aqueous ethanol, esters, such as ethyl acetate, halogenated hydrocarbons, such as methylene chloride, amides, such as dimethylacetamide, nitrites, 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 low 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) which bind the hydrogen halide released in the acylation reaction.

Acids of formula (III) themselves can be used as acylating agents in the preparation of the compounds of formula (I). Acylations using the acids (III) are desirably carried out in the presence of a condensing agent, e.g. a carbodiimide such as N, N'-dicyclohexylcarbodiimide or N-ethyl-N'-y-methylaminopropylcarbodiimide; a carbonyl compound such as carbonyldiimidazole; or an isoxazolium salt such as N-ethyl-5-phenylisoxazolium perchlorate; or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

The acylation can also be carried out with other amide-forming derivatives of acids of the formula (III), such as e.g. an activated ester, a symmetrical anhydride or a mixed anhydride (e.g. formed with pivalic acid or with halogen formate such as lower alkyl haloformate). Ge7

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mixed anhydrides can also be formed with phosphoric acids (e.g. phosphoric or phosphorous acids), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. toluene-p-sulfonic acid). An activated ester can conveniently be formed in situ using, for example, 1-hydroxybenzotriazole in the presence of a condensing agent as mentioned above. Alternatively, the activated ester can be pre-formed.

Acylation reactions, including free acids or their amide-forming derivatives mentioned above, are conveniently carried out in an anhydrous reaction medium, e.g. Methylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylacetamide or dimethyl sulfoxide.

An alternative method of activation consists, for example, in reacting an acid of the formula (III) with a solution or suspension, which by adding a carbonyl halide, in particular oxalyl chloride or phosgene, or a phosphoryl halide, such as phosphorus oxychloride, to a solvent, such as a halogenated hydrocarbon, e.g. Methylene chloride containing a low acyl tertiary amide such as N, N-dimethylformamide was pre-formed. The activated form of the acid of formula (III) can then be treated with a 7-amino compound of formula (II) in a suitable solvent or mixture of solvents such as halogenated hydrocarbons e.g. Dichloromethane; Alcohols such as alkanol e.g. Ethanol or industrial methylated spirit; Esters, e.g. Ethyl acetate; Ethers, e.g. Tetrahydrofuran or dioxane; Ketones, e.g. Acetone; Amides, e.g. Dimethylacetamide; Acetonitrile; Water and mixtures thereof can be implemented.

The acylation reaction can conveniently be carried out at temperatures from -50 to 50 ° C, preferably -40 to + 30 ° C, if desired in the presence of an acid binding agent, e.g. as described above (e.g. dimethylaniline, triethylamine or sodium bicarbonate).

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

The acids of formula (III) and the acylating agents corresponding to them can, if desired and where appropriate, be prepared and used in the form of their acid addition salts. For example, acid chlorides can suitably be used as their hydrochloride salts and acid bromides as their hydrobromide salts.

For use as starting materials for the preparation of the compounds of the general formula (I) according to the invention, the compounds of the general formula (III) and the amide-forming derivatives thereof, such as 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 containing at least 90% of the syn isomer used.

Acids of the formula (III) and their derivatives can be prepared by etherification of a compound of the formula (IV)

NHR *

l

/ \

î ï 8

• = .— c.c00r8

n

0H

(17)

wherein R3 is as defined above and R8 represents a hydrogen atom or a carboxyl blocking group, or a salt thereof by selective reaction with a compound of the general formula (V)

t.chc00r2

l

/ \\

(V)

\ // "\

r '

r5

wherein T represents a chlorine, bromine or iodine atom, a sulfate group or a sulfonate group such as tosylate, and then removal of any carboxyl-blocking groups R8. The etherification reaction is conveniently carried out in the presence of a base, e.g. Potassium carbonate or

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Sodium hydride, and is preferably in an organic solvent, e.g. Dimethyl sulfoxide, a cyclic ether, such as tetrahydrofuran or dioxane, or an N, N-disubst. Amide, such as dimethylformamide.

The isomers can be separated either before or after such etherification. Under the conditions described above, the configuration of the oxyimino group is essentially unchanged by the etherification reaction.

When the compound of formula (IV) is used in the form of a free acid or salt with a base, the etherification reaction is generally carried out in the presence of a strong base, e.g. Kai-um-t-butoxide, performed, with enough base added to form a dianion. Furthermore, the reaction should be carried out in the presence of a base when an acid addition salt of a compound of formula (IV) is used, the amount of base being sufficient to rapidly neutralize the acid in question.

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

nhr3

f

^ tj (VI)

• => _ c0.c00r8 (in which R3 and R8 are as defined above) with a compound of the formula (VII)

h2n.o.çhooor2

r

/ (VII)

• •

\ // V

I.

R5

Rk

(wherein R2, R4 and R5 are as defined above), followed by the removal of any car-boxyl blocking groups R8 and, if necessary, separation of the syn and anti isomers.

The reaction is conveniently carried out in a solvent such as dimethylformamide, dimethylacetamide, dimethyl sulfoxide, tetrahydrofuran or methanol, all optionally in the presence of water, at a temperature of from -20 to + 50 ° C., preferably 0 to 30 ° C.

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

Intermediate compounds of formula (VII) can be obtained by treating compounds of formula (VIII)

y.0.chc00r2

I.

/ \ (VIII)

• •

II I • •

\ // v

Rk r5

(wherein Y represents an imido group, e.g., a phthalimido, succinimido, or maleimido group) with a hydrazine reagent, such as hydrazine hydrate, or an alkylhydrazine, such as methylhydrazine. The reaction is generally carried out in an inert solvent, e.g. a halogenated hydrocarbon such as methylene chloride at low temperature, e.g. -70 to + 30 ° C, carried out.

Intermediate compounds of formula (VIII) can be obtained by alkylation with compounds of formula (IX)

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(IX)

(in which shark represents a halogen atom such as a chlorine or bromine atom) of a suitable N-hydroxyimide (e.g. N-hydroxyphthalimide, N-hydroxysuccinimide or N-hydroxymaleimide) in the presence of a base such as triethylamine in a solvent such as acetonitrile eg -10 to + 30 ° C can be produced.

Intermediate compounds of formula (IX) are either known or can be prepared using methods analogous to those used to prepare the known compounds.

Compounds of formula (II) used as starting materials in the acylation process are known from the literature, e.g. British patent application 2 159 817, known or can be prepared according to information from the literature.

An A ^ cephalosporin ester derivative obtained according to the above method of the invention can be converted into the corresponding desired A3 derivative by, for example, treating the A2 ester with a base such as pyridine or triethylamine.

A ceph-2-em reaction product can also be oxidized to give the corresponding ceph-3-em-1-oxide, e.g. by reaction with a peracid, e.g. Peracetic acid or m-chloro-perbenzoic acid; the resulting sulfoxide can then be reduced as described below to give the corresponding desired ceph-3-em sulfide.

If a compound is obtained in which Z is> S - »O, it can be converted into the corresponding sulfide, for example by reducing the corresponding acyloxysulfonium or Al-koxysulfoniumaslzes, which in situ by reaction with, for example, acetyl chloride in the case of an acetoxy sulfonium salt was produced, the reduction by, for example, sodium dithionite or by iodide ions, such as in a solution of potassium iodide in a solvent, for example Acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature of from -20 to + 50 ° C.

In the oxidation and reduction processes described above, the groups R4 and R5 in the starting materials are expediently other than hydroxyl groups.

Metabolically labile ester derivatives of the carboxyl groups in the compounds of formula (I) can be conveniently prepared by reacting a compound of formula (I) or a salt or protected derivative thereof with the appropriate esterifying agent, such as an acyloxyalkyl halide or alkoxy-carbonyloxyalkyl halide (e.g. iodide) in an inert organic solvent such as dimethylformamide or acetone and then, if necessary, removing any protecting groups.

Base salts of the compounds of formula (I) can be prepared by reacting an acid of formula (I) with a suitable base. For example, sodium or potassium salts can be produced using the corresponding acetate salt, 2-ethylhexanoate salt or hydrogen carbonate salt. Acid addition salts can be prepared by reacting a compound of formula (I) or a metabolically labile ester derivative thereof with the appropriate acid.

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

It should be noted that with some of the above conversions, it may be necessary to protect any sensitive groups in the molecule of the compound in question to avoid undesirable side reactions. Examples of suitable protective groups are given in “Protectîve Groups in Organic Synthesis” by Theodora W. Green (John Wiley and Sons, 1981).

For example, during any of the above sequences of reactions, it may be necessary to protect the NH2 group of the aminothiazolyl portion, for example by tritylation, acylation (e.g. chloroacetylation or formylation), protonation, or other common method. The protecting groups can then be removed in any suitable manner which does not cause the desired compound to be broken down, e.g. in the case of a trityl group, by using an optionally halogenated carboxylic acid, e.g. Acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid, or by 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.

Hal-ÇHCOOR2

A

• m

Il I

V'V

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Likewise, it may be necessary to protect the hydroxy group of the catechol moiety during any of the above reaction sequences. Hydroxy protecting groups which can be removed under mild conditions will generally be suitable, e.g. Acetyl or silyl groups. Such groups can be introduced in the usual way and, if desired, removed in such a way that decomposition of the product does not occur. For example, in the case of an acetyl group, the group can be solvolyzed with an aqueous solvent such as aqueous methanol or aqueous ethanol in the presence of a base, e.g. Sodium bicarbonate, ammonium hydroxide, ammonium carbonate or ammonium carbamate can be removed. A trimethylsilyl group can be split off, for example by treatment with a dilute, aqueous acid.

Carboxyl-blocking groups which are used in the preparation of the compounds of the formula (I) or in the preparation of necessary starting materials will desirably be groups which can easily be split off in a suitable stage in the reaction sequence, expediently in 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. ace-toxymethyl or ethyl or pivaloyloxymethyl) and to retain them in the end product in order to provide a suitable one To give ester derivative of a compound of formula (I).

Suitable carboxyl blocking groups are well known in the art, and a list of representative blocked carboxyl groups is given in British Patent 1,399,086. Preferred blocked carboxyl groups include: aryl-lower alkoxycarbonyl groups such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; Lower alkoxycar bonyl groups such as t-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking group can then be removed by any of the appropriate methods given in the literature; for example, acid-catalyzed hydrolysis or reduction can be used in many cases, such as enzymatically catalyzed hydrolysis.

If a particular enantiomer of a compound of formula (I) is required, starting materials with the desired stereochemical configuration should be used in the above procedures. Such interconnects can be obtained using conventional splitting procedures. For example, enantiomeric intermediates of formula (VIII), wherein R2 is a hydrogen atom, wherein the chiral carbon atom is in the (R) or (S) configuration, can be obtained by reacting a mixture of the enantiomers with a cleaving agent such as a chiral organic base [e.g. R - (+) - a-methylbenzylamine] can be obtained in a solvent such as acetone or acetonitrile to form the corresponding diastereomeric salts. The salts can then be separated by known methods and the desired chiral intermediate of formula (VIII) by treatment with an aqueous acid, e.g. aqueous hydrochloric acid, for example at room temperature, are regenerated.

The crystalline (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazoI-4-yI) -2 - [(carboxy) - (3,4-dihydroxyphenyI) -me-thoxyimino] -acetamido ] -ceph-3-em-4-carboxylic acid as its hydrate can conveniently be prepared from an aqueous solution of a salt of the above cephalosporin or a solvate thereof.

According to a further embodiment of the invention, a process for the preparation of crystalline, hydrated (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4-yl) -2 - [(carboxy) - (3,4-dihydroxy-phenyl) -methoxyimino] -acetamido] -ceph-3-em-4-carboxylic acid created by crystallizing this acid from an aqueous solution, preferably an aqueous solution of an acid addition salt or base salt thereof or a solvate of these salts to form this crystalline, hydrated product. The product is usually isolated and dried after crystallization.

Suitable base salts include, for example, inorganic base salts such as alkali metal salts and alkaline earth metal salts, as well as organic base salts as described above. A particularly suitable base salt is the sodium salt.

The starting acid addition salts can be formed with an organic or inorganic acid. Organic acids that can be used include carboxylic and sulfonic acids, e.g. Formic acid, trifluoroacetic acid and methanesulfonic acid. Inorganic acids that can be used include mineral acids, e.g. Hydrochloric acid, hydrobromic acid or sulfuric acid.

According to a further aspect of the invention, the desired material can be obtained from a solution of an acid or base salt of (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazoI-4-yl) -2 - [( carboxy) - (3,4-dihydroxy-phenyl) -methoxyimino] -acetamidoj-ceph-3-em-4-carboxylic acid or a solvate thereof can be crystallized in an aqueous medium by adjusting the pH to 1.0 to 4.0 becomes.

For example, a hydrate can be crystallized from an aqueous solution of a base salt with the addition of an organic or inorganic acid at a pH in the above ranges. Suitable acids which can be used in the crystallization include, for example, hydrochloric acid and sulfuric acid. Alternatively, the desired hydrate can be crystallized from an aqueous solution of an acid addition salt by adding an organic or inorganic base at a suitable pH in the above ranges. Bases that can be used include, for example, alkali or alkaline earth metal hydroxides, carbonates, bicarbonates or acetates such as sodium hydroxide, sodium carbonate, sodium bicarbonate or sodium acetate.

The aqueous medium can be a water-miscible organic solvent, such as an Alko11

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fetch e.g. Ethanol or isopropanol, an ether, e.g. Tetrahydrofuran or dîoxan, an amide, e.g. N, N-dimethylformamide or N, N-dimethyl acetamide, a ketone, e.g. Acetone, or a nitrii, e.g. Acetonitrile.

Crystallization is desirably carried out at ambient temperature, e.g. from 0 to 30 ° G, preferably from 15 to 259C. The crystalline product can be obtained by filtration and washed and dried in a customary manner, for example by air drying or by careful drying under reduced pressure.

The following examples illustrate the invention. All temperatures are given in ° C. Nujol and Sorbsil are trademarks. Sorbsil U30 is a silica gel produced by Joseph Crosfield and Son, Warrington, Gheshire, England. Unless otherwise stated, the NMR spectra were recorded in DMSO-dß, X-ray diffraction measurements were carried out on a Siemens D-500 diffractometer using the CuKa radiation. X-ray intensities were measured at 0.02 ° increment of 20 for 5 second intervals using a scintillation counter between the values of 2 ° and 90 °. The results were saved on a computer for processing.

Interconnection 1

2-f3.4-DioxvcarbonvlDhenvfl-2-fohthalimidooxvVessiasäure

A solution of 14.6 g of N-hydroxyphthalimide and 25 ml of triethylamine in 50 ml of acetonitrile was added to a stirred suspension of 20.5 g of 2- (3,4-dioxycarbonyiphenyl) -2-chloroacetic acid in acetonitrile at -2 ° for 20 min given. After another hour at about 0 °, a solution of 7.5 ml of concentrated hydrochloric acid in 100 ml of water was quickly added. 100 ml of water was slowly added and the original, released oil crystallized, supported by seeding. The mixture was filtered and the filter cake was washed with water and ethyl acetate / petroleum ether (bp 40-60 °) (1/2) and dried to give 30 g of the title compound, m.p. 183 to 185 °;

5 5.84 (s, OCH), 7.53 (s, catechol 5-H and 6-H), 7.69 (s, catechol 2-H) and 7.85 (s, phthalimido protons) .

Interconnection 2

fai (RH + Va-Methvlbenzvlaminsalz of fSi-2 - ('3.4-DioxvcarbonvlDhenvn-2-Cphthalimidooxvi-Essiasäure

A solution of 16.3 ml of R - (+) - a-methylbenzylamine in 100 ml of acetone was quickly added to a magnetically stirred solution of 45 g of intermediate 1 in 1.25 l of acetone at 21 ° under nitrogen. After 30 min the mixture was filtered and the precipitate was washed thoroughly with acetone to give 16.57 g of the title compound;

[<x] 2i = + 242 ° (c 1.07, EtOH);

§1.46 (d, J = 7Hz, CHaCH. 5.48 (s, OCH), 7.3 to 7.6 (m, aromatic protons) and 7.80 (s, phthalimido protons).

(bi DiDhenvlmethvl-fSï-2-f3.4-dioxvcarbonvlphenvlV2-fohthalimidooxvi-acetate

10 ml of 2M hydrochloric acid was added under nitrogen at 21 ° to a stirred suspension of 5.0 g of intermediate 2 (a) in 30 ml of water. After 2 minutes, a solution of diphenyldiazomethane containing one equivalent in 11 ml of methylene chloride was added. After stirring vigorously for 35 minutes, the organic layer was separated and added dropwise to 150 ml of stirred ethanol. The mixture was stirred at 21 ° for 10 min and then left at 4 ° for 1 h. The crystals were collected by filtration, washed with ethanol and dried and gave 3.59 g of the title compound, mp. 135 to 135.5 °;

M | 1 = + 112.6 ° (c 1.18, ethyl acetate).

Interconnection 3

(SW3.4-DihvdroxvDhenvlWdiDhenvlmethoxvcarbonvn-methoxvamin

5.71 g of intermediate 2 (b) was stirred in 390 ml of methanol with 5.5 ml of M hydrochloric acid at about 40® for 4.5 hours. The solution was concentrated and mixed with methylene chloride. After washing twice with water, the solution was dried over magnesium sulfate and evaporated to a foam. A solution of this foam in 176 ml of methylene chloride was cooled to -50 ° with stirring and nitrogen and 1.5 ml of hydrazine hydrate were added. The mixture was slowly allowed to warm to 21 ° and stirred. After 5.75 h the mixture was filtered and the filter cake was extracted with methylene chloride12

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leached. The combined filtrates were diluted with ethyl acetate and washed with citric acid solution and brine. After drying over magnesium sulfate and evaporation, 4.35 g of the title compound were obtained as a foam;

[oc] 21 = + 17.8 ° (c 1.03, methanol);

8 5.02 (s, OCHCO), 6.68 and 6.81 (m, thiazole H, OCH and catechol protons), 7.1 to 7.4 (m, aromatic protons), 9.04 (s, OH).

Interconnection 4

fZ.SÌ-2- (2-aminothiazol-4-vn-2-IY3.4-dihvdroxvDhenvlWdÌDhenvlmethoxvcarbonvlì-methoxviminol-Essiasäure

1.91 g of 2- (2-aminothiazol-4-yl) glyoxylic acid were added over 3 minutes to a solution of 4.20 g of intermediate compound 3 in 22 ml of N, N-dimethylformarnide at 3 ° with stirring. After a further 30 minutes while cooling with ice-water, the solution was allowed to warm to 21 ° over 1.5 hours and then added dropwise to 110 g of the ice-water mixture with stirring over 20 minutes. The precipitate was collected by filtration, washed with water and dried. It was resuspended in 45 ml of methylene chloride and stirred 15 min before filtering. The filter cake was washed with methylene chloride and dried to give 3.76 g of the title compound;

[a] 2i = + 25.4 ° (c 1.02, methanol);

5 5.59 (s, OCHCO), 6.6 to 6.9 (m, thiazole H, OCH and catechol protons), 7.0 to 7.5 (m, NH2 and phenyl protons) and 9.06 and 9.13 (2s, OH).

Interconnection 5

(Z.Si-2- (2-Formamidothiazol-4-vh-2-IY3.4-dihvdroxvDhenvlHdiDhenvlmethoxvcarbonvh-methoxvimino1-essiaic acid

6.96 g of 2- (2-formamidothiazol-4-yl) glyoxylic acid were added to a stirred solution of 12.73 g of [(3,4-dihydroxyphenyl) - (diphenylmethoxycarbonyl)] methoxyamine in 100 ml of N, N-dimethylformamide given at ambient temperature. After 1.5 h, a further 40 ml of N, N-dimethylformamide were added, then at 2.5 h the resulting solution was poured into 700 ml of water. The products were extracted into 3 x 250 ml of ethyl acetate. The combined extracts were washed with 2 x 250 ml of water, dried over magnesium sulfate and then evaporated to a solid. This was treated with 20 ml of ethyl acetate and then with 200 ml of dichloromethane to give a suspension. After cooling, the solid was collected by filtration, washed with dichloromethane and dried to give 11.38 g of the title compound, mp 125-127 ° C;

[<x] d = + 22.2 ° (c 0.99, methanol).

example 1

Diphenvlmethvl- (6R.7R.2'Z.SV7-r2- (2-aminothiazole-4-vfl-2-lT3.4-dihvdvroxvphenvh- (diphenvlmethoxvcarbonvD-methoxviminol-acetamidol-ceph-3-em-4-carboxvlat

The tosylate salt of diphenylmethyl (6R, 7R) -7-amino-ceph-3-em-4-carboxylate (1.24 g) was converted to the free amine by partitioning between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was washed with water and dried with magnesium sulfate. Evaporation gave a foam which was mixed with 1.0 g of intermediate 4 in 25 ml of THF with stirring and 830 mg of N.N'-dicyclohexylcarbodiimide and 290 mg of hydroxybenzotriazole hydrate were added. After stirring at 21 ° for 16 hours, the mixture was filtered and the filter cake leached with ethyl acetate. The combined organic solutions were evaporated to a foam, which was redissolved in ethyl acetate and filtered through a column of 100 g Sorbsil U30 in ethyl acetate. Evaporation of the appropriate eluate gave the crude product which was redissolved in chloroform and loaded onto a column of Sorbsil U30 (100 g) made up in chloroform. The column was eluted with chloroform and then 1%, 2% and 3% methanol in chloroform. Evaporation of the corresponding eluate gave 800 mg of the title compound as a foam;

[cc] 21 = + 36.25 ° (c 1.17, DMSO);

Xinfl (EtOH) 230.8 (E ^ 303), 290 (E1% m 117) and 300.4 nm (E ^ 84).

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Example 2

(6R.7R.2'Z.SY-7-r2-f2-Aminothiazol-4-vn-2-iïcarboxvH3.4-dihvdroxvphenvn-methoxviminol-acetami-do1-Géph-3-em-4-carboxylic acid.Trifluoroessiasate acid salt

740 mg of the compound from Example 1 was stirred with 1.5 ml of anisole and 7.5 ml of trifluoroacetic acid were added. After 1 min, 50 ml of diisopropyl ether were added. The precipitate was collected by filtration, washed with diisopropyl ether and dried in vacuo to give 450 mg of the title compound, - [«II1- + 102.8 ° (c 0.88, DMSO);

W (pHB buffer) 236.8 nm (El% m 335), Xinfl 250.0 (El% m 257), 277.4 (El% m 173} and 296.0 nm (E1% m

139).

Example 3

DiPhenvlm6thvl-f6R.7R.2, Z.SV7-r2- (2-formamidothiazol-4-vn-2-rf3.4-dihvdroxvphenvlV fdiphenvImethoxvcarbonvn-methoxvimino1-acetamidoi-ceph-3-em-4-carboxvlat

1.2 g of intermediate 5 was suspended in 20 ml of methylene chloride with stirring and nitrogen, and 4 ml of N, N-dimethylacetamide was added. The solution was cooled to -25 ° and 0.28 ml of phosphorus oxychloride was added. After stirring for one hour at -25 to -20 °, a solution of diphenylmethyl-6R, 7R) -7-amino-ceph-3-em-4-carboxylate [formed from 1.35 g of its tosylate salt by the action of sodium bicarbonate solution] in 20 ml of methylene chloride, containing 2 ml of N, N «dimethylaniline, was added. The reaction solution was then at -10 ° and was then surrounded with ice-water and stirred for 1.75 h. The reaction mixture was then washed successively with sodium bicarbonate solution, dilute hydrochloric acid and water three times, the aqueous layers each being back extracted with methylene chloride. The combined organic layers were dried with magnesium sulfate and concentrated. The crude product in methylene chloride was placed on a column of 50 g of Sorbsil U30, provided with 40% ethyl acetate in petroleum ether (bp 40-60 °), containing 2% acetic acid. Evaporation of the appropriate eluate gave 1.56 g of the title compound;

[«] 21+ 36.2 ° (S 1.05, DMSO);

W (EtOH) 269.2 nm (E1% m 184) Xinfi 232.0 (E ^ 285), 260.4 (E1% m 179) and 266.8 nm (E ^ 183). Example 4

Diphenvimethvl-f6R.7R.2'Z.Si-7-r2- (2-aminothiazol-4-vn-2-IY3.4-dihvdroxvphenvfl-fdiphenvlmethoxvcarbonvfl-methoxvimino1-acetamido1-ceph-3-em-4-carboxvlat

1.5 g of the compound from Example 3 were stirred with 15 ml of methanol at 21 ° and 1 ml of 60% perchloric acid was added. After 2.5 hours the solution was partitioned between water and ethyl acetate and excess sodium bicarbonate solution was carefully added. The aqueous layer was extracted with more ethyl acetate and the combined organic layers were washed twice with brine, dried with magnesium sulfate and evaporated; 1.34 g of the title compound were obtained; [<x] 21 = + 36.5 ° (c 0.96, DMSO);

Vmax (Nujol) 3600 to 3100 (wide), 1785, 1730 and 1680 cm ~ i Example 5

(6R, 7R, 2'Z.SV7-r2-f2-Amînothiazol-4-vn-2-iïcarboxvW3.4-dihvdroxvphenvlVmethoxvîminol-acetarni-dol-ceph-3-em-4-carboxylic acid. Sodium salt

11 g of the compound from Example 2 were dissolved in 110 ml of ethanol with stirring at 21 ° and 4.8 ml of saturated sodium acetate solution were added. After 10 min the mixture was filtered and the filter cake washed a good four times with ethanol and four times with ether and dried in vacuo; 5.45 g of the title compound were obtained. Another 2.73 g yield was obtained by adding more saturated sodium acetate solution (2 ml) to the mother liquors;

[a] 21 = + 185.0 ° (c 0.78, DMSO);

W (pH6 buffer) 234.4 (E1% m 386); Xînfi 250.4 (E ^ 276), 276.8 (El% m 184) and 294.4 nm (E]% m 148).

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CH676 850A5

Example 6

(6R.7R.2'Z.Sì-7-r2- (2-aminothiazol-4-vlì-2-r (carboxvW3.4-dihvdroxvDhenvn-methoxviminol-acetami-do1-ceph-3-em-4-carboxylic acid

1.0 g of the compound of Example 5 was mixed with 4 ml of water and 41 mg of sodium acetate was added when a solution formed. This solution was filtered and crystallization initiated by scratching. The mixture was stored at 21 ° C for 14.5 h. Then the crystals were collected by filtration, washed with water and dried in vacuo at 21 °; 250 mg of the title compound were obtained. Addition of 0.9 ml of 2N hydrochloric acid gave 360 mg of further crystalline product;

[ot] 2l + 136.27 ° (ç 0.54, DMSO);

Xmax234.4nm (E ^ 408), Jtjnfi249.6 (E [%. 295), 277.8 (E ^ 192) and 295, O nm (E1% m 156).

Example 7

(6R.7R.2'Z.SV7-r2- (2-aminothiazol-4-vlV2-r (carboxv '> (3.4-dihvdroxvphenvl') - methoxviminol-acetami-dol-ceph-3-em-4-carboxylic acid. Hydrochloric acid salt

27.4 g of the compound from Example 4, 110 ml of formic acid were dissolved with stirring at 20 ° and 8.2 ml of conc. Hydrochloric acid, 3 equivalents, was added. The mixture was stirred for a further 15 minutes and then added dropwise to 1.1 liters of diisopropyl ether with stirring at 20 ° over 6 minutes. The precipitate was collected by filtration, washed with 500 ml of diisopropyl ether and dried in vacuo; 18.02 g of the title compound were obtained;

vmax (Nujol) 3600-2800 (wide) and 1780 cm-1;

8 3.3-3.7 (m, H-2), 5.05 (d, H-6), 5.4 (s, ÇHON), 5.8 (m, H-7), 6.46 (m, H-3) and 9.6 (d, NHCO).

Example 8

(6R.7R.2'Z.Si-7-r2- (2-aminothiazole-4-vn-2-lYcarboxvH3.4-dihvdroxvphenvD-methoxvimino1-acetami-do1-ceph-3-em-4-carboxylic acid

2.65 g of the compound of Example 7 was added to 10.6 ml of distilled water at 20 ° with stirring and the mixture was stirred for 30 minutes during which time crystallization occurred. The stirred suspension was vigorously cooled in ice-water for 15 min and then the crystals were collected by filtration, washed with 10 ml of vigorously cooled, distilled water and dried in an air oven at 30 ° C .; 2.09 g of the title compound were obtained; Water content 12% (Karl Fischer);

IR spectrum (Nujol)

vmax 3700-2100 (wide), 1760, 1720, 1660, 1555, 1520, 1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 860 and 755 cnr »;

X-ray diffraction pattern (given as d-distances in angstrom units and percent intensities I)

12.5 (21); 9.97 (37); 9.51 (22); 6.79 (11); 6.33 (35); 5.29 (10); 4.76 (30); 4.63 (100); 4.39 (54); 4.32 (5); 4.18 (15); 4.09 (31); 3.91 (24); 3.78 (69); 3.69 (17); 3.61 (9); 3.52 (12); 3.48 (21); 3.42 (6); 3.33 (37); 3.15 (36); 3.07 (22); 3.02 (4); 2.96 (36); 2.85 (9); 2.78 (3); 2.75 (3); 2.65 (11); 2.59 (49); 2.50 (6); 2.44 (9); 2.38 (6); 2.31 (3); 2.27 (4); 2.20 (5); 2.16 (9); 2.10 (10); 2.05 (4); 2.01 (9).

Example 9

tert-Butvl-f6R.7R.2'Z.SV7-r2- (2-formamidothiazol-4-vli-2-ïï3.4-dvdroxvphenvh- (diphenvlmethoxvcarbonvn-methoxvimino1-acetamidol-ceph-3-em-4-carboxvlat

1.53 g of intermediate 5 were dissolved in 15 ml of methylene chloride and 2.9 ml of N, N-dime-thylacetamide with stirring, and the solution was cooled to -35 ° and 0.41 ml of phosphorus oxychloride was added. The mixture was stirred at -25 to -20 ° for 1 hour and then a solution of tert-butyl- (6R, 7R) -7-amino-ceph-3-em-4-carboxylate [originating from 1.0 g its tosylate salt by the action of aqueous sodium bicarbonate solution, as described in Example 1 for the diphenyl methyl ester] in 15 ml of methylene chloride containing 2.9 ml of N, N-dimethylaniline. The reaction mixture was kept at about 0 ° for 16 h and then washed successively with water, dilute hydrochloric acid (twice) and water; the aqueous layer was back extracted with methylene chloride each time. The combined organic layers were concentrated to a foam, which was redissolved in 15 ml of methylene chloride and passed through a column of 5 g of Sorbsil U30 silica gel eluting with 30 ml of methylene chloride. The eluate was concentrated to a small volume and treated with 15 ml of diisopropyl ether to precipitate the title compound as a white solid (1.2 g);

8 (CDCI3) 1.57 (s, (CH3) 3), 5.74 (s, OCHCO), 6.15 (m, H-7), 6.49 (d, H-3), 8.4 -8.7 (m, NHCO and -OH).

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Example 10

tert.-Butvl-f6R.7R.2, Z.SÌ-7-r2 - ('2-aminothiazol-4-vh-2-ff3.4-dihvdroxvphenvl) -fdipherivlmethoxvcarbonvn-methoxvimino1-acetamido1-ceph-3-em- 4-carboxvlat

6.29 g of the compound from Example 9 were stirred in 64 ml of methanol and 16 ml of 1,4-dioxane at 20 ° and 5.63 ml of 60% perchloric acid were added. After 3.5 h the solution was added to a rapidly stirred sodium bicarbonate solution (240 ml). The mixture was stirred for an additional hour and then cooled heavily. The product was collected by filtration, washed with water and dried. It was then dissolved in a mixture of ethyl acetate and methylene chloride (1/1) and the solution applied to a column of Sorbsil U30 silica gel (65 g) which was eluted with additional solvent. Evaporation of the appropriate fraction of the eluate gave 4.0 g of the title compound;

8 1.5 (s, (CH3) 3), 5.06 (d, H-6), 5.61 (s, CHON), 5.8 (m, H-7), 6.41 (m, H-3), 9.0 (broad, -OH), 9.5 (d, NHCO).

Example 11

(6R.7R.2'Z.SV7-f2-f2-aminothiazole-4-vlV2-iïcarboxvH3.4-dihvdroxvphenvh-methoxviminol-acetami-doT-ceph-3-em-4-carboxylic acid. Hydrochloric acid salt

1.5 g of the compound from Example 10 were dissolved in 6 ml of formic acid with stirring at 20 °. 0.35 ml (2.1 equivalents) conc. Hydrochloric acid was added. The mixture was stirred for 2 hours, then clarified by filtration and finally evaporated under reduced pressure. To the residue was added 6 ml of ethyl acetate and the mixture was evaporated again to give a foam which was triturated with 6 ml of ethyl acetate. The resulting suspension was stirred for 30 minutes at ambient temperature. The solid was collected by filtration, washed twice with ethyl acetate and dried in vacuo; 1.33 g of the title compound were obtained, which was identical to the product from Example 7.

Pharmaceutical example

Dry powder for injection per vial

(6R, 7R, 2'Z, S) -7- [2- (2-aminothiazole-4-500 mg yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxyimino] acetamido ] -ceph-3-em-4-carboxylic acid

Sodium carbonate (anhydrous) 99 mg

The two sterile components are mixed aseptically and filled into sterile vials. The top air space of the vial is flushed with sterile nitrogen. The vials are sealed using rubber stoppers and metal capsules (applied by crimping). The product can be prepared by dissolving in water for injections or other suitable sterile vehicle just prior to administration.

Claims (13)

Claims 1. Cephalosporin compounds of the formula (I): 16 5 10th 15 20th 25th 30th 35 40 45 50 55 60 65 CH 676 850 A5 nhr 3rd CD V V R5 wherein R1 and R2, which may be the same or different, each represent a hydrogen atom or a carboxyl blocking group; R3 represents a hydrogen atom or an amino protecting group; R4 and R5 each represent a hydroxyl or substituted, hydroxyl group or R4 and R5 together with the carbon atoms to which they are attached represent a cyclic, protected diol group; Z stands for -S- or -SO- (a- or ß-) and the dashed line connecting the 2, 3 and 4 divisions indicates that the connection is a Ceph-2-em or Ceph- 3-em compound; and salts and solvates thereof. 2. Compounds according to claim 1 of the formula (Ia): nh2 (la) wherein R4a is a hydroxy or acetoxy group and R5a represents a hydroxy or acetoxy group, and the non-toxic salts, solvates, e.g. hydrates, and metabolically labile esters thereof. 3. Compounds of formula (Ia) according to claim 2, wherein the oxime etherifying group has the S configuration. 4. (6R, 7R) 2'Z, S) -7- [2- (2-aminothiazol-4-y () - 2 - [(carboxy) - (3) 4-dihydroxyphenyl) methoxyimino3-acetamido] - ceph-3-em-4-carboxylic acid and the non-toxic salts, solvates, for example hydrates and metabolically labile esters thereof according to claim 2. 5. A compound according to claim 4 in crystalline, hydrated form. 6. The crystalline, hydrated compound according to claim 5, characterized by an infrared spectrum containing absorption bands at 3700-2100 (broad), 1760.1720, 1660, 15555, 1520, 1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 860 and 755 cm "i. 17th 5 10th 15 20th 25th 30th 35 40 45 50 55 CH 676 850 A5 7. The crystalline, hydrated compound according to claim 5, characterized by the following X-ray diffraction pattern, in which the d distances are given in nanometers and the relative intensity in percent, based on the intensity of the strongest peak, is in brackets: 1.25 (21); 0.997 (37); 0.951 (22); 0.679 (11); 0.633 (35); 0.529 (10); 0.476 (30); 0.463 (100); 0.439 (54); 0.432 (5); 0.418 (15); 0.409 (31); 0.391 (24); 0.378 (69); 0.369 (17); 0.361 (9); 0.352 (12); 0.348 (21); 0.342 (6); 0.333 (37); 0.315 (36); 0.307 (22); 0.302 (4); 0.296 (36); 0.285 (9); 0.278 (3); 0.275 (3); 0.265 (11); 0.259 (49); 0.250 (6); 0.244 (9); 0.238 (6); 0.231 (3); 0.227 (4); 0.220 (5); 0.216 (9); 0.210 (10); 0.205 (4); 0.201 (9). 8. A process for the preparation of compounds of the formula (I) as defined in claim 1, or salts or solvates thereof, characterized in that a compound of the formula (II) wherein R1, Z and the dashed line are as defined in claim 1, or a salt or a 7-N-silyl derivative thereof is acylated with a corresponding acylating agent; whereupon an isomer is optionally converted into the desired A3 isomer and / or a non-toxic salt or solvate of the compound obtained is formed. 9. The method according to claim 8 for the preparation of the crystalline hydrate according to claim 5, characterized in that an aqueous solution of (6R, 7R, 2'Z, S) -7- [2- (2-aminothiazol-4 "yl) -2 - [(carboxy) - (3,4-dihydroxyphenyl) methoxyimino] acetamido] ceph-3-em-4-carboxylic acid or an acid addition salt or base salt thereof or a solvate of this salt is formed and the hydrate is crystallized therefrom. 10. The method according to claim 9, characterized in that an aqueous solution of an acid addition or base salt of (6R, 7R, 2'Z, S) -7- [2- (2 ~ aminothiazol-4-yl) -2 - [(carboxy) (3,4-dihy-droxyphenyI) -methoxyimino] -acetamido] -ceph-3-em-4-carboxylic acid or a solvate thereof and the pH of this solution is adjusted to between 1.0 and 4.0 becomes. 11. A pharmaceutical composition comprising as active ingredient a compound of formula (Ia), a non-toxic salt or solvate or a metabolically labile ester thereof as defined in claim 2. 12. A pharmaceutical composition according to claim 11, wherein the active ingredient is a compound according to claim 4. 13. A pharmaceutical composition according to claim 12, wherein the active ingredient is the crystalline, hydrated compound according to claim 5. H2N. H HZ = = / \ »• • 0 H COOR1 18th