LU87002A1 - CHEMICALS - Google Patents

Description

^ * _ 'BL- 4063 / ML

-. 1 GRAND DUCHY OF LUXEMBOURG

BrevetN ° v ...... _____ v- »* CCIJÔ · 'Minister of September 25, 1987 of the Economy and the Middle Classes _ ..., EvglTfg Intellectual Property Service

laugh o book LUXEMBOURG

3.88. , Patent Application 7. -------------------------------------: ------------ ---- (1) I. Request

The company known as: GLAXO GROUP LIMITED, Clarges House, 6-12 Clarges (2) ___ ____Street, LONDON wlY 8DH, GRANDE-BREIAGNE _ -r & pres. & Ixtée..4) ar „j ..... Ε., Χ, ... ^ ΕΕΥ1ΙΝ0ΕΕ - .. & .-. Ε .. ^ gR ^ XQBlL ·. (3) _________________46, rue du cimetière, LUXEMBOURG, agents, ___ deposit (s) this twenty-september nineteen hundred and eighty Sept_ ^ ^ at —15.00 ____ hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent of invention concerning: --------- ------ (5) __________ CRIMINAL COMPOUNDS______________ 2. the description in French ________________ language „________ of the invention in triplicate; 3 ................................... / ............. ................... drawing boards, in triplicate; 4. the receipt of taxes paid to the Luxembourg Registration Office, _2§_Rp-pi ~ prnhrp 1987; 5. the delegation of power, dated_________________________________________________________ on_________________; 6. the successor document (authorization); declare (s) assuming responsibility for this declaration, that the inventor (s) is (are): (6)

Christopher ..... Ε3Γΐ · β ····· Ν · ΕΜΑΕΕ, ·· - · 33-Ευη · - ·· θΕ · ονβ · ~ Εοη <1τ-- · Εα · 1-ί · η§ ·, —LONDON ·, —GRANDE = BRETAGNE

... Brian Edgar L00KER. 28 ...... Middleton Avenue, GREENFORD, Middlesex, GREAT BRITAIN

claim) for the above patent application the priority of one (or more) application (s) of (7) ___________________patente d * invention .__________________ filed (s) in (8) Great Britain ___________________ on (9) September 26, 1986 and on 13 March 1987_ ^ __ under N ° (10) 86 23 212__________________et. 87-05 .986 _________________________________________________________ on behalf of (11) ............. GLAXO ... GROUP ... LIME TE.D ________________________________________________________________________________________ elects (es) domicile for him (her) and, if designated , for its representative, in Luxembourg___________________ .4.6 .., ..._ x.ue .... du..xiine.ti.ë.re, LUXEMBOURG_____________________________________________________ (12) request) the grant of a patent for invention for 'object described and represented in the abovementioned appendices, with postponement of this delivery to ___________________________________________________ s.ix ______________________________ months. (13)

Le îféîXHçgK / authorized representative: --------------------------------------------- --------------------- (14) T Π. Deposit Minutes

The above patent application for jiweati ^ n has been filed with the Ministry of the Economy and the Middle Classes, InteU ^^ e! Property Service! ^ ^ * LfuÂehibourg, dated: September 25, 1987 / | Pr- Minister of Economy and Average Qasses, at 15.00— hours l | j \ £ 1 Jrp.d ^ \ V j (jf / The head of the service of intellectual property, ^ / λ / \ (fl TT ) A 68007_ 'ix \ ______ L l / / JJ EXPLANATIONS RELATING TO THE DEPOSIT FORM.

. ^ (1) if applicable "Application for certificate of addition to the main patent, to the ^ main patent application No ............ of ........ ... (2) enter the surname, first name, profession.

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^ BL-4063 / ML

! * 'i r

Claim to the priority of the invention patent application filed in GREAT BRITAIN, on 26.09.1986 and 13.03.1987 under Nos 86 23 212 and 87 05 986 * Descriptive brief filed in support of a patent application of invention for

’CHEMICALS

GLAXO GROUP LIMITED Clarges House

6-12 Clarges Street LONDON W1Y 8DH

BRITAIN

ΐ *> »f

The present invention relates to improvements in cephalosporins. More particularly, the invention relates to new compounds of the cephalosporin type and their derivatives which have an advantageous antibiotic activity.

The cephalosporin-like compounds discussed in this specification are referred to by reference to "’ cephame * "according to J. Amer. Chem. Soc., 1962, 84, 3400, the term "cephem" referring to the basic cephalic structure which has a double bond.

The use of cephalosporin-type antibiotics is widely used for the treatment of diseases caused by pathogenic bacteria in both humans and animals and is of particular interest for the treatment of diseases caused by bacteria which are resistant to other antibiotics, such as penicillin-like compounds and for the treatment of penicillin-sensitive patients. In many circumstances, it is desirable to use a cephalosporin-type antibiotic that exhibits activity against both Gram-positive and Gram-negative microorganisms and very much research has been directed towards the development of various types of antibiotics of the type of Λ »/ · ι * 2 phalosporins with broad spectrum of activity.

Thus, for example, in the description of the British patent No. 1 399 086 of the applicant, a new class of cephalosporin type antibiotics is described which contain a side chain of the genus 7ß * "(oxyimino a-etherified) acylamido , the oxyimino group having the syn configuration. This class of antibiotic compounds is characterized by a high antibacterial activity against a series of Gram-positive and Gram-negative organisms, associated with a particularly high stability towards ß-lactamases generated by various Gram- organisms. negative.

The discovery of this class of compounds has encouraged further research in the same field with the aim of discovering compounds with improved properties, for example, against particular classes of organisms, more specifically Gram-negative organisms . This interest is reflected in the very large numbers of patent applications which have been filed and which relate to antibiotics of the type, cephalosporins having particular substituents both on the 7β-acylamido side chain and in position 3 of the nucleus of the cephalospori-25 ne.

For example, the description of British Patent No. 1,576,625 contains a generic definition of cephalosporin type antibiotics which have a side chain 7β- (oxyimino α-etherified) -30 acetamido where the etherifying group is an aliphatic hydrocarbon radical which may have suitable substituents (including, among many possibilities, a protected carboxyl or carboxyl group and a phenyl group substituted by up to three hydroxyl radicals), which side chain is more

\ I

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l V * 3 α-substituted by a group which, among others, can be an aminothiazolyl radical. However, none of the compounds specifically cited in the example contains an etherifying carboxyphenylalkyl group. The radical 5 in position 3 can also be chosen from a large number of possibilities, but the hydrogen atom is not included among these.

In the specification of British Patent No. 1,604,971 a broad series of antibiotics of the cephalosporin type are described in general, where the side chain at position 7β can be, inter alia, a 2- (2-aminothiazole) radical -4-yl) -2- (etherified oxy-imino) acetamido, where the etherifying radical, among many possible meanings, may be an alkyl radical (for example methyl) substituted by both phenyl and carboxyl groups , although there is not given any specific example of compounds having a carboxyphenylalkyl radical and the preferred etherifying group is cited as the unsubstituted methyl radical. The group in position 3 can also be chosen from a large number of possibilities and the possible substituents in position 3 include a hydrogen atom in their generic definition.

25 In the specification of the United Kingdom patent

Uni No. 2,017,702, the etherifying oxyimino group may, according to the generic definition, be, inter alia, an α-carboxyphenylmethyl radical. In the compounds specifically cited in examples, the carboxy-3 radical phenylmethyl radical is always combined with an acetoxy-methyl group in position 3.

British Patent Specification No. 2,104,888 generically describes cephalosporin-type compounds, in which the 7-position lateral chain is a 2- (2-aminothiazole-fhi) radical ♦ "'· 4 4-yl) -2- (etherified oxyimino) acetamido. The ethy-rifying group of the oxyimino function can, inter alia, be a carboxyphenylmethyl radical in which the phenyl group can be substituted by a hydroxyl radical.

The group in position 3 is an isothiazolyl-thiomethyl radical or an iminoalkylidenedithiethane radical.

The specification of European patent No.

197,409 generically describes antibiotics of the cephalosporin type, in which the side chain in position 7β is a 2- (2-amino-thiazole-4-yl) -2- (etherified oxyimino) acetamido radical. The etherifying group of the oxyimino function can be, inter alia, a catechol-carboxymethyloxyimino radical. The substituent at position 3 can be selected from a number of contingencies, but these do not include the hydrogen atom.

The Applicant has now discovered that by the choice of a radical (Z) -2- (2-aminothiazole-4-yl) -2- (etherified oxyimino) acetamido in position 7β, in combination with a atom of hydrogen in position 3, and by the choice of an a-carboxylic substituted phenylmethoxyimino radical as the etherified oxyimino group, it was possible to obtain cephalosporin-type compounds having a particularly advantageous range of activities (which are will be described in more detail later in this specification) against a wide range of pathogenic organisms commonly encountered and / or useful as intermediates for the preparation of other active compounds.

Consequently, the present invention more particularly relates to compounds of the cephalosporin type corresponding to the general formula (I) 'S' • t 1 4 "5 NHR3 Λ? r p s sä 5 ί i J,: i a) N · _N / ·

0CHC00R2 0H

1 iûORL

/ \\ • ·

He I

10 \ Λ,

î5 R

R5 in which 1 2 R and R which may be the same or different, each represent a hydrogen atom or a radical blocking the carboxyl function; 2 R represents a hydrogen atom or a radical protecting the amino function; R 5 and R 4 each represent a hydroxyl or substituted hydroxyl radical, or alternatively R and R together represent a protected cyclic diol radical; Z is> S or> S * 0 (a- or β-); the dashed line crossing positions 2, 3 and 4, indicates that the compound is a substance of the ceph-2-th * 25 or ceph-3-th type; as well as the solvates (more particularly the hydrates) and the non-toxic salts of these compounds.

In the substances of formula (i) in which R and / or R represent carboxyl blocking radicals, the blocking group can be, for example, the residue of an esterogenic araliphatic or aliphatic alcohol, or a stannanol, of a si-lanol or of an esterogenic phenol (said alcohol, phenol, silanol or stannanol containing, preferably, from 1 to 35 carbon atoms), or a blocking radical of the T *, φ "type i ί * 6 symmetrical or mixed anhydride, derived from a suitable acid. As specific examples of R1 or p R, mention may be made of the t-butyl, diphenylmethyl and p-nitrobenzyl radicals.

3 5. When R represents a radical protecting the amino function, the protective group can be, for example, an aralkyl radical in Cy ”C20 (for example a triphenylmethyl or 4-methoxybenzyl radical), an acyl group, such as a C alkanoyl radical ^ -C ^ optionally-10 substituted (for example a formyl or chloroacetyl radical), or an optionally substituted -C6 alkoxycarbonyl radical (for example a t-butoxycarbonyl or 2,2,2-trichlorethoxycarbonyl radical), or an aralkoxycarbonyl group in Cy-C1Q (for example a benzyloxycarbonyl radical) or a silyl group (for example a tri-methylsilyl radical).

In general, preference is given to the compounds of formula (I) in which R represents a hydrogen atom.

When R or R represents a substituted hydroxyl group, it can be, for example, an acyloxy group / for example a formyloxy radical or a radical of the formula -OCOR ^ (in which R ^ represents a C ^ alkyl radical -Cg, for example a ^ methyl / 7 radical, a carbonate radical -OCOgR ^ (where R ^ has the meanings which have been assigned to it above), a silyloxy radical / for example a radical (C ^ alkyl - C4) silyloxy, such as a trimethylsilyloxy or t-butyldimethylsilyloxy7 radical "or a borate radical 30 / -OB (OR ^) 2_7 or phosphate / ^ 0P (0) (0R ^) 2_7 represents a C1-C alkyl radical" ).

4 5 1 ^

When R and R ^ together represent a protected cyclic diol group, it may be an alkylidenedioxy group, preferably comprising from 1 to 20 carbon atoms, for example a methylenedioxy group, Λ b "* * <7 ethylenedioxy, or isopropylidenedioxy, which may carry one or more substituents, for example phenyl, C6-C6 alkoxy or oxo, for example methoxymethylenedioxy, diphenylmethylenedioxy or carbonyldioxy; a cyclic borate group, for example -0B (OH) 0-; a cyclic phosphate group, for example -0P (0) (0H) 0-, or -0P (0) (0R7) 0- (where R7 has the meanings which were previously assigned to it) or a cyclic silyl ether group, for for example a di (C 1 -C 4 alkyl) silyldioxy radical, for example a dimethylsilyldioxy radical.

In general, such silyloxy, borate or phosphate radicals represent protected hydroxyl groups which can be cleaved so as to generate a compound of formula (I) having free hydroxyl radicals.

4 5

Overall, R and R · 'each preferably represents an acetoxy group or, more particularly, a hydroxyl group.

In the compounds of formula (I), 2 preferably represents> S.

Particularly preferred are the compounds according to the invention of the ceph-3-èrae type.

When the compound is to be used in medicine, any ester of carboxyl radicals in the molecule must be an atoxic and metabolically labile ester function. As examples of derivatives of the non-toxic and metabolically labile ester type, mention may be made of acyloxyalkyl esters, for example oxy-methyl or -ethyl lower alkanoyl esters, such as acetoxy-methyl or -ethyl or pivaloyloxymethyl esters, and alkoxycarbonyloxyethyl esters, for example lower alkoxycarbonyloxyethyl esters, such as the ethoxycarbonyl-oxyethyl ester.

\ * 4 (Ô

In addition to the ester type derivatives mentioned above, it should be understood that the present invention also extends its scope to the active compounds according to the invention in the form of other · phy-5 siologically acceptable equivalents, ie physiologically acceptable compounds which, like the metabolically labile esters, are converted in vivo to the related antibiotic compounds according to the invention.

Derivatives of the non-toxic salt type which can be formed by the reaction of the carboxyl radical present in the compounds of formula (I) include salts with organic bases, such as alkali metal salts (for example sodium salts and po-tassium) and salts with alkaline earth metals (e.g. calcium salts); salts with amino acids (e.g. lysine and arginine salts); salts with organic bases (e.g., salts of procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine and N-methylglucosamine). Other derivatives of the non-toxic salt type include ad- salts. edition of acids, for example generated with hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, formic and trifluoroacetic acids. The salts can also be in the form of resins generated, for example, with a polystyrene resin, or a resin based on a cross-linked poly-styrene-divinylbenzene copolymer, containing amino or quaternary amino radials, or sulfonic acid radicals, or with a resin containing carboxyl groups, for example a polyacrylic acid resin. Soluble base salts (for example alkali metal salts, such as sodium salts) of the compounds of the formula (i) to \ *, * 4 t ς »9 can easily be used for therapeutic purposes, due to the rapid distribution or distribution of such salts in the body after administration. However, when it is desired to have insoluble salts of the compounds (I) for a particular application, for example for depot preparations, such salts can be formed in a conventional manner, for example using suitable organic amines.

The compounds according to the invention are syn iso-10 mothers. The syn isomer form is defined by the configuration of the group -0CHC00R2 Λ

15 II I

Yv R5 with respect to the carboxamido radical. In this memo, the syn configuration is structurally represented as follows: NHR3, Λ s ï 25 l = i — C_CONH — j \ 0CHC00R 2 A \ 30 »i v v R5

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

It should also be understood that in the etherifying group of the oxime function, the carbon atom neighboring the oxy group is chiral and that it can therefore be in the R or S configuration.

The scope of the present invention obviously extends also to the individual R and S forms on this chiral carbon atom, as also to mixtures (including mixtures of diastereoisomers) of these forms. In general, preferred are the compounds of formula (I) in which this chiral carbon atom has the S configuration and the R / S mixtures in which the S isomer predominates.

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

As indicated above, the compounds according to the invention are active against a wide range of pathogenic organisms which are commonly encountered and / or constitute advantageous intermediates for the preparation of other active compounds. In general, when the compounds according to the invention are to be used as intermediates, the radicals R and R will often be groups blocking the carbo-xyl function; the R group will often be a radical protecting Λ c the amino function and the R groups and will often be protected hydroxyl radicals, such as silyloxy, borate or phosphate groups, or will together form a cyclic protected diol radical. Non-toxic 4/5 derivatives in which R and / or R- 'represent acyloxy groups, such as acetoxy radicals, can serve as intermediates or active compounds.

at 11 * 't

* J

In general, the active compounds according to the invention will be ceph-3-th compounds of the formula 1 2 3 mule (i) in which R, R and RJ represent hydrogen atoms, 2 represents> S and and which may be the same or different represent hydroxyl or acyloxy radicals C ^ ~ C ^, for example acetoxy radicals.

Important active compounds according to the invention correspond to the formula (la) 10 fz •

5 / \ l H H S

It ξ = / \ i =; - C-CONH -.- · · 15 II IJ, 1 \ // \ // \

0CHC00H 0H

i COOH

J \ (the)

It i 20 V V® I 5a R5 4a in which R represents a hydroxyl or acetoxy radical; 5a R ^ represents a hydroxyl or acetoxy radical; as well as the hydrates, solvates and non-toxic salts and metabolically labile esters of these substances.

A particularly preferred compound according to the invention is the acid (6R, 7R "2 *, Z, S) -7- / 2- (2-aminothiazo-le -4-yl) -2- / Jcarboxy) -3 , 4-dihydroxyphenyl) methoxy-imino7acetamido7ceph-3-th-4-carboxylic acid, as well as the hydrates, solvates and non-toxic salts and metabolically labile esters of this compound.

'i * * 12

The applicant has discovered that the acid (6R, 7R> 2 'Z, S) -7- / 2- (2-aminothiazole-4-yl) -2- / Jcarboxy) (3,4-di-hydroxyphenyl) methoxyimino7 acetamido / ceph-3-th-4-carboxylic can advantageously and uniformly prepare and isolate with a high degree of purity in crystalline form and this characteristic constitutes another aspect of the present invention. More specifically, the Applicant has prepared and isolated the acid (6R, 7R "2'Z, S) -7- / 2- (2-aminothiazole-4-yl) -10 2- / J c ar boxy) (3,4-dihydr oxyphenyl) methoxyimino7 - acetamido7ceph-3-th-4-carboxylic crystalline and hydrated. This new compound is superior not only in its crystallinity and increased purity, but is also obtained in high yields and has superior stability during storage, even at elevated temperature for extended periods of time. These properties of the crystalline material make it of particular interest for use in the pharmaceutical field.

The hydrated crystalline substance mentioned above can be characterized by its infrared spectrum and / or its powder X-ray diffraction grating. IR spectrum (Nujol) ^ max 3700-2100 (large), 1760, 1720, 1660, 1555,, 1520, 25 1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 860 and 755 cm “1.

X-ray diffraction grating (given as spacings d in angstrom units and intensities I in percentages).

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); 35 2.31 (3); 2.27 (4); 2.20 (5); 2.16 (9); 2.10 (10); 2.05 (4); 2.01 (9).

”I * t * i * 13

The compounds according to the present invention exhibit broad spectrum antibiotic activity towards both gram-positive and gram-negative organisms, including strains producing β-5 lactamases. The compounds also have high stability towards ß-lactamases produced by a variety of gram-negative and gram-positive organisms.

Compounds according to the present invention have been found to exhibit high activity against strains of gram-positive bacteria (including penicillinase producing strains) such as Stanhylococcus aureus, Staphvlococcus epidermidis and Streptococcus species. This activity is associated with excellent activity against the species Pseudomonas and also with high activity against various members of enterobacteriaceae (eg strains of Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, Proteus 20 mirabilis and Proteus indole-positive 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 and high activity against gram-negative organisms, more particularly against Pseudomonas, which the compounds according to the present invention possess, is unusual and particularly advantageous.

As noted, the cephalosporin type derivatives described herein have, in vivo, a desirable long serum elimination half-life.

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

The antibiotic compounds according to the invention can be presented for administration in any convenient manner, by analogy to what happens in the case of other antibiotics, and therefore the scope of the present invention also extends. to 10 pharmaceutical compositions which comprise an antibiotic compound according to the invention, suitable for use in human medicine or in veterinary medicine. The compositions in question can be presented in a conventional manner using any necessary excipients or pharmaceutical vehicles.

The antibiotic compounds according to the invention can be put into formulas which are suitable for injection and can be in the form of unit doses, in ampoules, or in containers which contain multiple doses, if necessary with added preservative. . The compositions may also adopt forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain composing agents, such as suspending, stabilizing and / or dispersing agents. As an alternative, the active ingredient can also be in the form of a powder from which the active medicament is reconstituted using an appropriate vehicle, for example sterile apyrogenic water, before use.

If desired, such powder compositions may contain a suitable non-toxic base in order to increase the water solubility of the active ingredient and / or to ensure that when the drug is reconstituted with of water, the pH of the resulting aqueous solution is physiologically acceptable. As an alternative, the base may be present in the water used to reconstitute the drug.

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

Compositions for use in veterinary medicine may, for example, be formulated as intramammary preparations in bases of slow or rapid release of the drug substance.

The compositions may contain from 0.1% t ^ for example from 0.1 to 99% of the active material, depending on the mode of administration. When the compositions are in the form of unit doses, each unit dose preferably contains from 100 to 3000 mg of the active ingredient, for example 200 to 2000 mg of this ingredient. The daily dose for the treatment of the adult human being varies, preferably, from 200 to 12,000 mg, for example from 1000 to 9000 mg, per day, depending, inter alia, on the nature of the infection and the mode and the frequency of administration. In general, administration is administered intravenously or intramuscularly, for example using 400 to 4000 mg per day of the active ingredient for the treatment of adult humans. It should be understood that in certain circumstances, for example for the treatment of newborns, doses' i t,

, P

t 16 units and lower daily doses may be desirable.

The antibiotic compounds according to the present invention can be administered in combination with 5 other therapeutic agents, such as antibiotics, for example penicillins, cephalosporins or other β-lactamic compounds.

The compounds according to the invention can be prepared according to a number of methods described below.

Thus, according to one of the embodiments of the present invention, the latter relates to the preparation of an antibiotic compound of the general formula (i) as defined above or of a hydrate, solvate or non-toxic salt of this compound, by acylation of a compound of formula (II)

H HZ

20 H2N- · -f \ (II) 'I I · • -N /.

// V '/ \

0. H

CQOR1 25

AT

(in which R, 2 and the dashed line are as defined in connection with the general formula (i)) or a salt, for example an acid addition salt (generated, for example, with a mineral acid, such as hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid or with an organic acid, such as methanesulfonic acid or toluene-p-sulfonic acid), or a 7-N derivative -silylated of such a compound, with an acid of the formula (III) '* i * 17 NHR3 5 A (III) ^ N v'

ι ~ · _C.COOH

II

NOT

\ o ^ hcoor2

10 A

î! \ /AT "

'5 R

R5 (in which R ^, R ^, R ^ and R ^ have the meanings which have been previously assigned to them) or a salt of this acid, or with an acylating agent which corresponds thereto; This acylation being followed, if this proves necessary and / or desirable in each circumstance, by any of the following reactions, in any suitable order: i) conversion of a tr isomer to a isr isomer, Ii) reduction of a compound in which Z is> S · * 0 to form a compound in which Z is> S, iii) conversion of a carboxyl radical into an atoxic and metabolically labile ester function, iv) formation of a solvate or an atoxic salt, v) elimination of any radicals blocking the carboxyl function and / or N-protectors, and vi) elimination of any radicals blocking the hydroxyl function.

The reactions i) to vi) can be carried out in a conventional manner.

"Λ, * 4 φ * 18

When carrying out the acylation process, the starting material of formula (II) is preferably a compound in which Z is> S and the dashed line represents a compound of ty-5 pe ceph -3-th.

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

Acylations using acid halides can be carried out in aqueous and non-aqueous reaction media, conveniently at temperatures ranging from -50 to + 50 ° C, preferably from -40 to + 30 ° C, if it is desired in the presence of an acid fixing agent. Suitable reaction media include aqueous ketones, such as aqueous acetone, aqueous alcohols, such as aqueous ethanol, esters, such as ethyl acetate, halogenated hydrocarbons, such as chloride methylene, amides, such as dimethylacetamide, nitriles, such as acetonitrile, or mixtures of two or more of two such solvents. Suitable acid scavengers include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium bicarbonate) and oxiranes, such as 1,2-alkylene oxides lower (eg ethylene oxide or propylene oxide) which fix the hydrohalic acid released during the acylation reaction.

Acids of the formula (III) * i, 9 i 19 themselves can be used as acylating agents for the preparation of compounds of formula (i). Acylations using acids (III) are advantageously carried out in the presence of a condensing agent, for example a carbodiimide, such as N, N * -dicyclohexylcarbo-diimide or N-ethyl-N'-y-dimethylaminopropylcarbodi - “imide; a carbonyl compound, such as carbonyldiimidazole; or an isoxazolium salt, such as N-ethyl-5-phenylisoxazolium perchlorate; or N-ethoxycarbonyl-10 2-ethoxy-1,2-dihydroquinoline.

Acylation can also be carried out with other amidogenic acid derivatives of formula (III), such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (formed, for example, with pivalic acid or with a haloformate, such as a lower alkyl haloformate).

Mixed anhydrides can also be formed with phosphorus acids (e.g. phosphoric acid or phosphorous acid) * sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. toluene-p-sulfonic). One can conveniently form an activated ester in situ using, for example, 1-hydroxybenzotriazole, in the presence of a condensing agent, as previously indicated. Alternatively, the activated ester can also be preformed.

The acylation reactions involving the free acids or their amidogenic derivatives mentioned above, are advantageously carried out in an anhydrous reaction medium, for example methylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile, dimethylacetamide or dimethyl sulfoxide. .

Another acylation process consists, for example, in reacting an acid of formula (III) with a preformed solution or suspension by adding a carbonyl halide, more particularly * * 4 4, * 20 chloride of oxalyl or phosgene, or a phosphoryl halide, such as phosphorus oxychloride, in a solvent, such as a halogenated hydrocarbon, for example methylene chloride, containing a lower acyl amide tertiary, such as N, N-dimethylformamide. The activated form of the acid of formula (III) can then be reacted with a 7-amino type compound of formula (II) in a solvent or a mixture of solvents, for example halogenated hydrocarbons, by example dichloromethane; alcohols, such as an alkanol, for example ethanol or denatured industrial alcohol with methanol; esters, for example ethyl acetate; ethers, for example tetrahydrofuran or dioxane; born keto-15s, for example acetone; amides, for example dimethylacetamide; acetonitrile; water and their mixtures.

The acylation reaction can conveniently take place at temperatures which vary from -50 to 50 ° C, preferably from -40 ° to + 30 ° C, if desired, in the presence of an acid-fixing agent, for example, such as that described above (for example dimethyl-aniline, triethylamine or sodium bicarbonate).

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

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

35 For use as starting materials for

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AT

mW

In the preparation of compounds of general formula (i) according to the present invention, the compounds of general formula (III) and their amido-gene derivatives, such as acid halides and the corresponding anhydrides, are used. preferably in their syn isomer form or in the form of mixtures of the svn isomers and the corresponding anti isomers which contain at least 90% of the syn isomer.

The acids of formula (III) 10 and their derivatives can be prepared by the etherification of a compound of formula (IV) - NHR3

AT

S N

15 i — i — ÇJ.C00R8 (IV)

NOT

\

OH

3 \ (in which R has the meanings which

O

have been previously assigned and R represents a hydrogen atom or a radical blocking the carboxyl function) or a salt of such a compound, according to a selective reaction on a compound of the general formula (V) T. CHCOOR2 25 i / \\ • · (v)

II I

\ //% u

î5 R

R5 30 (in which T represents a chlorine, bromine or iodine atom; a sulphate radical; or a sulphonate radical, such as tosylate), followed by elimination

Q

of the group blocking the carboxyl function R.

The etherification reaction is carried out in the same way as V 4 * * 4 β-Φ 22 in the presence of a base, for example potassium carbonate or sodium hydride and it is preferably carried out in an organic solvent. , for example dimethyl sulfoxide, a cyclic ether, such as tetrahydrofuran or dioxane, or a Ν, Ν-disubstituted amide, such as dimethylformamide.

The separation of the isomers can be carried out either before or after such etherification. Under the conditions described above, the configuration of the oxyimino group remains substantially unchanged by the etherification reaction.

When the compound of formula (IV) is used in the form of a free acid or a salt with a base, the etherification reaction is generally carried out in the presence of a strong base, by for example potassium t-butoxide, a sufficient amount of base being added to form a dianion. Furthermore, the reaction must be carried out in the presence of a base if 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 the reaction of a compound of formula (VI) 25, NHR3! Λ (VI)

? I

• IZH · _CO. COOR 8 30

7 P

(in which R and R have the meanings which have been previously assigned to them), on a compound of the formula (VII) .- 4, * ι t 23 H2N.0. (jHC00R2 / \ (VII)

5 II I

Vv R5 ο λ 5 (in which R, R and R have the meanings previously attributed to them), followed by the elimination of any group blocking the carboxyl function R 8, and, if this is the case proves necessary, the 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 of these compounds possibly being used in the presence of water, at a temperature of -20 ° to + 50 ° C, preferably 0 ° C to 30 ° C.

The acids of formula (III) can be converted to the corresponding acid anhydrides and halides and the acid addition salts by means of conventional methods, for example as previously described. * 25 The intermediates of formula (VII) can be prepared by treating compounds of formula (VIII) Y.0.CHC00R2 Λ

It YV (VIII) R5 24 * Λ / (in which Y represents an imido group, for example a phthalimido, succinimido or maleimido radical) by a reagent of the hydrazine type, such as hydrated hydrazine, or an alkyl hydrazine, such as methyl 5 hydrazine. The reaction will generally be carried out in an inert solvent, for example a halogenated hydrocarbon, such as methylene chloride, at low temperature, for example from -70 ° C to + 30 ° C.

Intermediates of formula (VIII) can be prepared by alkylation with compounds of formula (IX)

Hal-CHCOOR2 Λ 19 iî î * # ·

V V

R5 (in which Hal represents a halogen atom, such as a chlorine or bromine atom) of an appropriate N-hydrbxyimide, (for example N-hydroxyphthalimide, N-hydroxysuccinimide or N-hydroxymaleimide), presence of a base, such as triethylamine, in a solvent, such as acetonitrile, at a temperature which varies, for example, from -10 ° to + 30 ° C.

The intermediates of formula (IX) are either known compounds or can be prepared according to methods analogous to those used for the preparation of known compounds.

The compounds of formula (II) used as starting materials in the acylation process are known from the literature, for example British patent application No. 2 159 817 "or can be prepared according to information that can be found in the appropriate technical literature.

* 4 * i 25 t <

It is possible to convert a derivative of the Δ2-cephalosporinic ester type obtained by implementing the process according to the present invention, into the derivative t? desired corresponding, for example, by treating the ester Δ2 with a base, such as pyridine or triethylamine.

It is also possible to oxidize a reaction product of the ceph-2-th type so as to obtain the corresponding 1-oxide of ceph-3-th, for example, by reaction on a peracid, for example peracetic acid or the acid m-chloroperbenzoic; the sulfoxide thus obtained can then be reduced in the manner described in the remainder of this specification, so as to collect the corresponding desired ceph-3-th sulfide.

15 When a compound is obtained in which Z

is> S · »0, the latter can be converted into the corresponding sulfide, for example by reduction of the corresponding acyloxysulfonium or alkoxysulfonium salt, prepared in situ, by reaction on, for example, acetyl chloride, in the case of an acetoxy sulfonium salt, the reduction being carried out, for example, using sodium dithionite or by an iodide ion, as in a solution of potassium iodide in a solvent, for example acetic acid, acetone, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction in question can be carried out at a temperature which varies from -20 ° to + 50 ° C.

In the aforementioned oxidation and reduction processes, the groups and in the starting materials are advantageously other than hydroxyl radicals.

Metabolically labile ester derivatives of the carboxyl radicals in the compounds of formula (I) can be prepared by reacting a compound * with J * a.

426 of formula (i) or a protected salt or derivative thereof, on a suitable esterifying agent, such as an acyloxyalkyl halide or an alkoxycarbonyloxyalkyl halide (e.g. iodide), conveniently in a solvent inert organic, such as dimethylformamide or acetone, this reaction being followed, when necessary, by the removal of any protective radicals.

Salts with bases of the compounds of formula (i) can be formed by reacting an acid of formula (i) on a suitable base. Thus, for example, the sodium or potassium salts can be prepared using the salt of the respective acetate, 2-ethylhexanoate or hydrogen carbonate type. Acid addition salts can be prepared by reacting a compound of formula (I) or a derivative of the metabolically labile ester type of this compound on the appropriate acid.

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

It should be understood that in some of the above-mentioned transformations, it may be necessary to protect any sensitive radicals in the molecule of the compound in question in order to avoid undesirable side reactions. Examples of suitable protective radicals are given in the work "Protective Groups in Organic Synthesis" by Theodora ¥. Greene (John Wiley and Sons, 1981).

For example, during any of the reaction sequences mentioned above, it may be necessary to protect the NIL radical, from the aminothiazolyl group, for example by tritylation, acyla-> ► 9 Λ ti * 27 tion (by example chloracetylation or formylation), protonation or any other conventional process. The protective radical can then be removed in any convenient manner which does not cause decomposition or degradation of the desired compound, for example in the case of a trityl radical, using an optionally halogenated carboxylic acid, for example Acetic acid, formic acid, chloroacetic acid or trifluoroacetic acid, or by using a mineral acid, for example hydrochloric acid, or mixtures of such acids, preferably in the presence of a protic solvent, such as water, or, in the case of the chloracetyl radical, by treatment with thiourea.

Similarly, the hydroxyl radicals of the catechol group can request protection during any of the above-mentioned reaction sequences. Radicals protecting the hydroxyl function, which can be removed under moderate conditions, will generally be suitable, for example acetyl or silyl radicals. Such radi-. waters can be introduced in a conventional manner and, if desired, removed so that degradation or decomposition of the product does not occur. For example, in the case of the acetyl radical, this group can be removed by solvolysis with an aqueous solvent, such as aqueous methanol or aqueous ethanol, in the presence of a base, for example sodium bicarbonate, ammonium hydroxide, ammonium carbonate or ammonium carbamate. A trimethylsilyl radical can be split, for example, by treatment with a dilute aqueous acid.

The radicals blocking the carboxyl function, used for the preparation of the compounds of formula 35 (I), or for the preparation of the starting materials ne- V * t 9 t

AT

4 »28 are radicals which can advantageously be easily separated during an appropriate stage of the continuation of the reactions, conveniently during the last stage. It may however be convenient, in certain circumstances, to use non-toxic and metaboli-labile carboxyl blocking radicals, such as acyloxy-methyl or -ethyl (for example acetoxy-methyl or -ethyl or pivaloyloxymethyl) radicals. keep these radicals in the final product, so as to obtain a suitable ester type derivative of a compound of formula (I).

Suitable carboxyl blocking radicals are well known to those skilled in the art and a list of representative blocked carboxyl groups is given in British Patent No.

1,399,086. Preferred blocked carboxyl radicals include aryl-lower alkoxy-carbonyl radicals such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxy-carbonyl and diphenylmethoxycarbonyl; lower alkoxy-carbonyl radicals, such as p-butoxycarbonyl; and lower haloalkoxycarbonyl radicals, such as 2,2,2-trichlorethoxycarbonyl. The carboxyl blocking group can be removed by any of the suitable methods described in the technical literature; thus, for example, an acid catalyzed reduction or hydrolysis can be applied in many cases, such as enzymatically catalyzed hydrolysis.

When a particular enantiomorph of a compound of the formula (I) is desirable, starting materials which have the desired stereochemical configuration should be used in the above-mentioned methods. Such intermediaries can be obtained by implementing conventional resolution methods. So, for example, intermediaries enantio- »> ÿ 4 4

AT

29 Λ morphs of formula (VIII) in which represents a hydrogen atom in which the chiral carbon atom is in configuration (R) or (S), can be obtained by the reaction of a mixture of enantiomorphs 5 on a resolving agent, such as a chiral organic base / for example R - (+) - a-methylbenzylamine7, in a solvent, such as acetone or acetonitrile, so as to generate the corresponding diastereoisomeric salts. The salts can then be separated by known processes and the desired chiral intermediate of formula (VIII) can be regenerated by treatment with an aqueous acid, for example aqueous hydrochloric acid, for example, at room temperature .

The acid (6R, 7R "2'Z, 15 S) -7- / 2- (2-amino thiazole-4-yl) -2- / Jcarboxy) (3,4-di-hydroxyphenyl) can be conveniently prepared. methoxyimino7 acetamido / ceph-3-th-4-carboxylic crystalline, in the form of its hydrate, from an aqueous solution of a salt of the above-mentioned cephalosporin, or a solvate of this compound.

Consequently, in accordance with an embodiment according to the invention, the latter relates to a process for the preparation of (6R, 7R, 2 'Z, S) -7- / 2- (2-aminothiazole-) acid. 4-yl) -2-i / tcarboxy) (3,4-dihydroxyphenyl) methoxyimino7 acetamidp7 ceph-3-th-4-carboxylic hydrate and crystalline, by the crystallization of said acid from an aqueous solution, preferably a aqueous solution of an acid addition salt or a salt with a base of the acid in question, or of a solvate of the aforementioned salts, so as to produce the crystalline hydrated product. Normally, crystallization is followed by isolation and drying of the product.

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

Starting acid addition salts can be formed with an organic or inorganic acid. As organic acids which can be used, mention may be made of carboxylic and sulfonic acids, for example formic, trifluoroacetic and methanesulfonic acids. As inorganic acids which can be used, there may be mentioned mineral acids, for example hydrochloric, hydrobromic or sulfuric acids.

According to another of the characteristics of the present invention, the desired substance can be crystallized from a solution of an acid or base salt of the acid (6R, 7R, 2'Z, S) -7 “2l2“ (2 ~ aminothiazole- 4-yl) -2- / Jcarboxy) (3,4-dihydroxyphenyl) methoxyimino7-acetamido7céph-3-th-4-carboxylic acid, or a solvate of this compound, in an aqueous medium , by adjusting the pH to a value varying from 1.0 to 4.0.

For example, a hydrate can be crystallized from an aqueous solution of a salt of a base by the addition of an organic or inorganic acid, at a pH which is within the above-mentioned ranges of suitable acids that can be used during 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 base or an inorganic base at an appropriate pH, within the above-mentioned limits. Bases which can be used include, for example, acetates, bicarbonates, carbonates or hydroxides of alkali metals or alkaline earth metals, for example sodium hydroxide, sodium carbonate, bi-

β I

4 4 4 31 sodium carbonate or sodium acetate.

The aqueous medium may contain a water-miscible organic solvent, such as an alcohol, for example ethanol or isopropanol, an ether, for example tetrahydrofuran or dioxane, an amide, for example N, N-dimethylformamide or N, N-dimethylacetamide, a ketone, for example acetone, or a nitrile, for example acetonitrile.

The crystallization is advantageously carried out at room temperature, for example at a temperature of 0 ° to 30 ° C, preferably 15 to 25 ° C. The crystalline product can be recovered by filtration and washed and dried in the conventional manner, for example by air drying or by careful drying under reduced pressure.

The following examples illustrate the present invention. All temperatures are given in degrees Celsius. '’Nu ^ ol *’ and' ’Sorbsil '* are trademarks. ’Sorbsil U30 is silica gel 20 made by Joseph Crosfield and Son of Warrington, Cheshire, England. Unless otherwise specified, the nuclear magnetic resonance (NMR) spectra were recorded in EMSO-d ^ (DMSO = dimethyl sulfoxide). X-ray diffraction measurements were made on a Siemens D-500 diffractometer, using CuKa radiation. X-ray intensities were measured in increments of 0.02 ° from 29 for 5 second intervals, using a scintillation counter, between values from 2 ° to 90 °. The results were stored on a computer for processing.

Intermediate 1

Acid 2- (3 "4-dioxvcarbonvlphénvl) -2- (phtalimidooxv) 35 acetic t), ψ l t * · 32

A solution of N-hydroxyphthalimide (14.6 g) and triethylamine (25 ml) in acetonitrile (50 ml) was added to a stirred suspension of 2- (3,4-dioxycarbonylphenyl) acid - 2-chloroacetic (20.5 g) in -2% acetonitrile for 20 minutes. After an additional hour at approximately 0 °, a solution of concentrated hydrochloric acid (7.5 ml) in water (100 ml) was quickly added. Water (100 ml) was slowly added and crystallized the initial oil released, crystallization being facilitated by sowing.

The mixture was filtered and the filter cake was washed with water and a mixture of ethyl acetate and petroleum ether (mp 40-60 °) (12) and dried. so as to collect the compound indicated in the title (30 g) "having a melting point of 183 to 185 °; 6 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).

¥ 20 Intermediate 2 (a) Acid salt (S) -2- (3 "4-dioxycarbonylphenyl) -2- (• phthalimidooxy) acetic with (R) - (+) - g-methylbenzyl-amine

A solution of R - (+) - a-25 methylbenzylamine (16.3 ml) in acetone (100 ml) was quickly added to a magnetically stirred solution of Intermediate 1 (45 g) in acetone (1.25 liter) to 21®, under a nitrogen atmosphere. After 30 minutes, the mixture was filtered and the precipitate was washed vigorously with acetone so as to obtain the title compound (16.57 g); + 242 ° (ç 1.07, EtOH); δ 1.46 (d, J 7Hz, CH3ÇH), 5.48 (s, OCH), 7.3 to 7.6 (m, aromatic protons) and 7.80 (s, phthalimido protons).

(b) (S) -2- (3.4-Dioxycarbonvlphenyl) -2- (phthalimidooxy) 35 diphenylmethyl acetate

"I

"/ 33

2M hydrochloric acid (10 ml) was added to a stirred suspension of Intermediate 2 (a) (5.0 g) in water (30 ml), under nitrogen, at 21 ° . After 2 minutes, a solution of 5-diphenyl diazomethane containing an equivalent in methylene chloride (11 ml) was added * After vigorous stirring for 35 minutes, the organic layer was separated and added dropwise. drop, with stirred ethanol (150 ml). The mixture was stirred at 21 ° for 10 minutes and then kept at 4 ° for 1 hour. The crystals were collected by filtration, washed with ethanol and dried to obtain the title compound (3.59 g) "P.F.

135-135.5 °; Z_7 | 1+ 112.6 ° (c, 1.18 "ethyl acetate).

Intermediate 3 (S) - (5,4-Dihvdroxyphénvl) (diphenvlmethoxvcarbonvl) -methoxvamine 20 Intermediate 2 (b) (5.71 g) was stirred in methanol (390 ml) with hydrochloric acid M ( 5.5 ml) at around 40 ° for 4.5 hours. The solution was concentrated and mixed with 1-methylene chloride. After a double wash with water, the solution was dried over magnesium sulfate and evaporated until a foam was obtained. A solution of this foam in methylene chloride (176 ml) was cooled to -50 ° with stirring under a nitrogen atmosphere and hydrated hydrazine (1.5 ml) was added. The mixture was allowed to warm to 21 ° and stirred. After 5.75 hours, the mixture was filtered and the filter cake was leached with methylene chloride. The combined filtrates were diluted with ethyl acetate and washed with citric acid solution and brine. After drying on

. I

34 magnesium sulphate, evaporation made it possible to obtain the compound indicated in the title (4.35 g) in the form of a foam; t + J + 17.8 ° (c 1.03, methanol); 5 ô 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) .

Intermediate 4 10 Acid (Z, S) -2- (2-aminothiazole-4-vl) -2- / 5,4-dihvdroxv-phenyl) (diphenylmethoxycarbonvl) methoxvimino7 acic acid 2- (2 -aminothiazole-4-yl) glyoxylic (1.91 g) within 3 minutes to a solution of Intermediate 3 (4.20 g) in N, N-15 dimethylformamide (22 ml) at 3 ° , with stirring. After an additional 30 minutes under ice cooling, the solution was allowed to return to 21 ° over 1.5 hours and then added dropwise to a mixture of ice and water ( 110 g) with 20 shakes, within 20 minutes. The precipitate was collected by filtration, washed with water and dried. It was resuspended in methylene chloride (45 ml) and stirred for 15 minutes before proceeding to filtration. The filter cake was washed with methylene chloride and dried to obtain the title compound (3.76 g); Z6L7j) 1+ 24.4 ° (£ 1> 02, methanol); at 5.59 (s, OCHCO), 6.6 at 6.9 (m, thiazole H, OCH, and 30 catechol protons), 7.0 at 7.5 (m, NH2 and phenyl protons) and 9 , 06 and 9.13 (2s, OH).

Intermediate 5

Acid (Z, S) -2- (2-Formamidothiazole-4-yl) -2- / T3.4-di- hydroxyphenyl) (diphenylmethoxycarbonvl) acetic methoxyimino7 ">, f" - * 4 35

2- (2-Formamidothiazole-4-yl) glyoxylic acid (6.96 g) was added to a stirred solution of / T 3,4-dihydroxyphenyl) (diphenylmethoxycarbonylj / -methoxyamine (12.73 g) in N, N-dimethylformamide 5 (100 ml) at room temperature. After 1.5 hours, an additional amount of N, N-dimethylformamide (40 ml) was added, then, within 2 hours, The solution thus obtained was poured into water for 5 hours (700 ml). The products were extracted with ethyl acetate (3 × 250 ml). The combined extracts were washed with water (2 x 250 ml), dried over magnesium sulphate, then evaporated to obtain a solid, which solid was treated with ethyl acetate (20 ml) and then with dichloromethane (200 ml) to obtain a solution. After cooling, the solid was collected by filtration, washed with dichloromethane and dried to obtain the title compound (11.38 g) PF 125-127 °; Ζά_7β1 + 22.2® (c 0.99, methanol).

20

Example 1 (6R, 7R. 2 "Z, S) -7- / 2- (2-Aminothiazole-4-yl) -2- / 5" 4-di-hydroxyphenyl) (diphenylmethoxycarbonyl) methoxy imino7-acetamido7ceph-3 -th ~ 4-diphenyl methyl carboxylate 25 The tosylate salt of (6R, 7R) -7- aminceph-3-th-4-carboxylate of diphenylmethyl (1.24 g) was converted into the free amine methylene chloride and an aqueous solution of sodium bicarbonate. The organic layer was washed with water and dried over magnesium sulfate. Evaporation gave a foam which was mixed with Intermediate 4 (1.0 g) in THF (25 ml), with stirring and then N, N'-dicyclohexyl-carbodiimide (830) was added. mg) and hydroxybenzotriazole hy-35 drate (290 mg). After stirring at 21 ° for 16 hours, 4 1 36! >? the mixture was filtered and the filter cake was leached with ethyl acetate. The combined organic solutions were evaporated, so as to obtain a foam which was redissolved in ethyl acetate and filtered through a column of Sorbsil U30 (100 g) in ethyl acetate . Evaporation of the appropriate eluate gave the crude product which was redissolved in chloroform and loaded into a column of Sorbsil U30 (100 g) in chloroform. The column was eluted with chloroform and then with 1% t 2% and 3% methanol in chloroform. Evaporation of the appropriate eluate provided the title compound (800 mg) in the form of a foam; ßj ^ * 36.25 ° (o 1.17, DMSO); 15 λ infl (BtOH) 230.8 (E ^ B 303), 290 (ï ^ 117 and 300.4 n »(E1 ^ m 84).

Example 2

Acid (6R.7R.2'ZS) -7- / 2- (2-aminothiazole-4-vl) -2-20 / Tcarboxv) (5.4-dihvdr oxyphenvl) methoxyimino7 acetamido7 ° - ceph-5-th-4- carboxyliquetsel with trifluoracetic acid

The compound of Example 1 (740 mg) was stirred with anisole (1.5 ml) and trifluoroacetic acid (7.5 ml) was added. Di-isopropyl ether (50 ml) was added after one minute. The precipitate was collected by filtration, washed with di-isopropyl ether and dried in vacuo to collect the title compound (450 mg); 30 / 7_7n1 + 102.8 ° (c 0.88, DMSO); Âmax (buffer at pH6) 236.8 nm (E ^ 335), λ infl 250.0 (E1om 257) ’277.4 (Elcm 173) and 295.0 nm (EÎom 139> · / l •” 4 37

Example 5 (6R, 7R "2 * Z, S) -7- / 2- (2-Formamidothiazole-4-vl) -2- / T 5" 4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxvlminoT-ac etamido7ceph-3-th -4-c diphenylmethyl arboxylate 5 Intermediate 5 (1.2 g) was suspended in methylene chloride (20 ml) with stirring and under a nitrogen atmosphere and N, N- was added dimethylacetamide (4 ml). The solution was cooled to -25 ° and phos-10 phore oxychloride (0.28 ml) was added thereto. After stirring for one hour at a temperature varying from -25e to -20e, a solution of diphenylmethyl (6R, 7R) -7-aminceph-3-th-4-carboxylate (derived from its tosylate salt ( 1.35 g) by the action of a solution of sodium bicarbonate) in methyl chloride (20 ml) containing N, N-dimethylaniline (2 ml). The reaction solution was then at -10 ° and was then surrounded by ice water and stirred thus for 1.75 hours. The reaction mixture was then washed successively with sodium bicarbonate solution, dilute hydrochloric acid and water three times, each time re-extracting the aqueous layers with methylene chloride. The combined organic layers were dried over magnesium sulfate and concentrated. The crude product was loaded into methylene chloride in a column of Sorbsil U30 (50 g) in 40% ethyl acetate in petroleum ether (PE 40 at 60 °) containing 2% acid acetic. Evaporation of the appropriate eluate provided the title compound (11.56 g); 36.2 ° (£ 1.05 »DMSO);

Xmax (EtOH) 269.2 nm (E ^ m 184) λ infl 232.0 (E ^ m 285), 260.4 (E, Jm 179), and 266.8 nm (E ^ m 183).

38

X

• 9 (fr

Example 4 (6R "7R.2'ZS) -7- / 2- (2-Aminothiazole-4-yl) -2- / T3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimlno7-acetamido7ceph-3-th-4-carboxylate The compound of Example 3 (1.5 g) was stirred with methanol (15 ml) at 21 ° and 60% perchloric acid (1 ml) was stirred. After 2.5 hours, the solution was partitioned between water and ethyl acetate and an excess of sodium bicarbonate solution was carefully added. The aqueous layer was extracted with additional ethyl acetate and the combined organic layers were washed twice with one. brine, dried over magnesium sulfate and evaporated to collect the title compound (1.34 g); Z “-7 | 1+ 36.5 ° (ç 0.96, DMSO); max ^^ ol) 3600 to 3100 (wide), 1785,1730 and 1680cm "“ 1.

Example 5 20 (6R, 7R.2 * Z.S) -7- / 2- (2-aminothiazole) -2- / Tcarboxv) - (3.4-dihydroxyphenvl) methoxyimino7acetamido7ceph-3-th-4-carboxylic acid, sodium salt

The compound of Example 2 (11 g) was dissolved in ethanol (110 ml), with stirring, at 21 °, and a saturated sodium acetate solution (4.8 ml) was added . After 10 minutes, the mixture was filtered and the filter cake was washed well with ethanol four times, with ether four times and dried in vacuo to keep the compound indicated in the title (5.45 g). An additional crop of product (2.73 g) was obtained by adding an additional amount of saturated sodium acetate solution (2 ml) to the mother liquors; Z <x_7d1 + 185.0 ° (ç 0.78, DMSO); 35 Xmax (buffer at ph6) 234.4 (E ^ m 386); \ infl 250.4

t I

• ·

4 • A

39 (B1om 276): 276> a (B1om 184) and 294.4 (E1cm 148) Example 6

Acid (6R.7R.2'Z.S) -7- / 2- (2-aminothiazole-4-yl) -2-5 / Tcarboxy) (g 14-dihydroxyphenyl) methoxvimino7 acetamido7-ceph-3 ~ th-4-carboxylic

The compound of Example 5 (1.0 g) was mixed with water (4 ml) and sodium acetate (41 mg) was added so that a solution was formed. This solution was filtered and scraping initiated crystallization. The mixture was kept at 21 ° for 14.5 hours and the crystals were then collected by filtration, washed with water and dried in vacuo at 21 ° so as to obtain the title compound ( 250 mg). Addition of 2N hydrochloric acid (0.9 ml) gave an additional amount of crystalline product (360 mg); Z ° L7§1 + 136.27 ° (c 0.54, DMSO);

Xmax 234.4 nm (e} * ~ 408), Xinfl 249.6 (E ^ m 295), 277.8 2 ° (¾ 192) and 295.0 nm (E ^ m 156).

Example 7

Acid (6R, 7R, 2'Z, S) -7- / 2- (2-aminothiazole-4-yl) -2- / Tcarboxy) (3.4-dihydroxyphenyl) methoxyimino7acetamido7-25 ceph-3-th-4-carboxylic acid , salt with chlorhvdri- 2ue acid

The compound of Example 4 (27.4 g) was dissolved in formic acid (110 ml), with stirring, at 20 ° C and 3 equivalents of concentrated hydrochloric acid were added (8 , 2 ml). The mixture was stirred for an additional fifteen minutes and then added dropwise over six minutes to diisopropyl ether (1.1 liters), with stirring and at 20 °. The precipitate was collected by filtration, washed with diisopropyl ether (500 ml) and dried in vacuo to give the title compound (18 , 02 g); ç max (Nujol) 3600-2800 (wide) and 1780 cm-1; δ 3.3-3.7 (m, H-2), 5.05 (d, H-6), 5.4 (s, CHON), 5.8 5 (m, H-7), 6, 46 (m, H-3) and 9.6 (d, NHCO).

Example 8

Acid (6R, 7R.2'ZS) -7- / 2- (2-aminothiazole-4-vl) -2- / Tcarboxy) (3,4-dihvdroxyphenvl) methoxvimino7acetamido7-10 ceph-5-th-4-carboxylic "

The compound of Example 7 (2.65 g) was added, with stirring, to distilled water (10.6 ml) at 20 ° and the mixture was stirred for thirty minutes, during which time crystallization occurs. The stirred suspension was vigorously cooled in a mixture of ice and water for fifteen minutes and the crystals were then collected by filtration, washed with cooled distilled water (10 ml), dried in an air circulating oven at 30 ° C so as to obtain the title compound (2.09 g); water content 12% (Karl Fischer); IR spectrum (Nujol) ^ max 3700-2100 (wide), 1760, 1720, 1660, 1555, 1520, 25 1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 860 and 755 cm “1; X-ray diffraction grating (given in the form of spacings in angstrSm units and intensities in percentages I).

12.5 (21); 9.97 (37); 9.51 (22); 6.79 (11); 6.33 (35); 5.29 (10); 4.76 (30); 4j63 (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).

i "• ·

AT

t 41

Example 9 (6R ♦ 7R "21Z, 5) -7- / 2- (2-Formamidothiazole-4-vl) -2- / T5.4-dihvdroxvphénvl) (diphenvlmethoxvcarbonvl) methoxvimino7-a c and friend do7 c eph-5 -ème-4-carboxyl ate tert-butvle.

Intermediate 5 (1.53 g) was dissolved, with stirring, in methylene chloride (15 ml) and N, JN-dimethylacetamide (2.9 ml) and the solution was cooled to - 35 ° C and phosphorus oxychloride (0.41 ml) was added. The mixture was stirred at -25 ° to -20 ° for one hour and then a solution of tert-butyl aminceph-3-th-4-carboxylate (6R, 7R) -7 was added / from its tosylate salt (1.0 g) under the action of an aqueous solution of sodium bicarbonate, as described in Example 1 in connection with the diphenylmethyl ester7 in methylene chloride ( 15 ml) containing N, N-dimethylaniline (2.9 ml). The reaction mixture was kept at about 0 ° for 16 hours, then washed with water, dilute hydrochloric acid (twice) and water; each time, the aqueous layer was reextracted with methylene chloride. The combined organic layers were concentrated until a foam was obtained which was redissolved in methylene chloride (15 ml) and the solution was lowered into a column of "Sorbsil" silica Ü30 (5g ) by eluting with methylene chloride (30 ml). The eluate was concentrated to a small volume and treated with diisopropyl ether (15 ml) so as to precipitate the title compound as a white solid ( 1 »2 g); δ (CDC15) 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).

. * »* * * L 42

Example 10 (6R, 7R, 2'Z, S) -7- / 2- (2-Aminothiazole-4-yl) -2- / T 3.4-dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimino7-acetamido7ceph-3-th-4- tert-butyl carboxylate 5 The compound of Example 9 (6.29 g) was stirred in methanol (64 ml) and in 1,4-dioxane (16 ml) at 20 ° and l was added. perchloric acid 60% (5.63 ml). After 3.5 hours, the solution was added to a rapidly stirred solution of sodium bicarbonate (240 ml). The mixture was stirred for an additional hour and then refrigerated. 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 was introduced into a column of "Sorbsil" U30 silica (65 g) which was then eluted with an additional amount of solvent. Evaporation of the appropriate fraction of eluate afforded the title compound (4.0 g); 20 δ 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, NHC0).

Example

Acid (6R.7R.2'ZiS) -7- / 2- (2-aminothiazole-4-vl) -2-2 5 / "carboxy) (5.4-dihvdroxvphénvl) methoxvimino7acétamido7-ceph-5-th-4-carboxylic acid salt with hydrochloric acid.

The compound of Example 10 (1.5 g) was dissolved in formic acid (6 ml), with stirring, at 20 ° 30 and concentrated hydrochloric acid (0.35 ml, 2 , 1 equivalent). The mixture was stirred for 2 hours, then clarified by filtration and then evaporated under reduced pressure. Ethyl acetate (6 ml) was added to the residue and the mixture was re-evaporated to give a foam which was then dried.

AT

43 triturated with ethyl acetate (6 ml). The suspension thus obtained was stirred for 30 minutes at room temperature. The solid was collected by filtration, washed twice with ethyl acetate and dried in vacuo to give the title compound (1.33 g ) identical to the product of Example 7.

Pharmaceutical example 10 Dry powder for injection

Per vial

Acid (6R, 7R, 2'2, S) -7- / 2- (2-amino-thiazole-4-yl7 ”2- / Tcarboxy) (3,4- 500 mg dihydroxyphenyl) methoxyimino7- acetamido7 ceph-3 -eme-4-carboxylic.

Anhydrous sodium carbonate 99 mg.

20 Mix the two sterile components aseptically and place them in sterile vials. Purge the upper space of the flask with sterile nitrogen; close the vials using rubber stoppers and metal caps (applied by crimping). The product can be made up by dissolving in water for injections or in any other suitable sterile vehicle, shortly before its administration.

Claims (13)

1. Compounds of the formula (i) tjIHR3 5 Λ? rs = a -CONH- N · _N / · \ 2 / \ // \ 0CHC00R2 0 · H i COOR1 (I) 10. w \\ I * \ / A „UR R5 15 in which 1 2 R and R which can be identical or different, each represents a hydrogen atom or a radical blocking the carboxyl function; 3 R represents a hydrogen atom or a radical protecting the amino function; 45 and R 5 each represent a hydroxyl or substituted hydroxyl radical, or else R and R together represent a protected cyclic diol radical; Z is-S- or -SO- (a- or ß-); the line in broken lines crossing positions 2, 3 and 4 indicates that the compound is a substance of the ceph-2-th or ceph-3-th type; as well as solvates (including hydrates) and non-toxic salts of these compounds. 2. Compounds according to claim 1, of the formula (la) i "l" P "45 [jlH2 S7 \ HHS Il Ξ = / \ • = # - ii-C0NH î l! N \ / ~ ^ \ / \ OCHCOOH O · H 5. toOH / w î <Ia> WI 5a R5 10 4a in which R represents a hydroxyl or acetoxy radical; 5a, R represents a hydroxyl or acetoxy radical; as well as the metabolically labile esters, the solvates ( including hydrates) and the non-toxic salts of these compounds. 3. Compounds of the formula (la) according to claim 2, wherein the etherifying group of the oxime function has the S configuration. 4. Acid (6R, 7R »2'Z, S) -7- / 2- (2-aminothiazole- 4-yl) -2- / Jcarboxy) (3,4-dihydroxyphenyl) methoxyimino7-acetamido7ceph-3-th- 4-carboxylic and metabolically labile esters, solvates (including hydrates) and non-toxic salts of this compound. 5 M • · —JC. COOH (III) N OIJHCOOR2 / \ 10. ii I Vv R5 15 (in which R ^, R ^, R ^ and R ** have the meanings which were assigned to them in claim 1), or a salt of a such compound, or with an acylating agent which corresponds to it; then, if necessary and / or desirable under each circumstance, any of the following reactions can be carried out in any suitable order: O 7 i) conversion of an isomer Δ to the desired Q isomer! Ii) reduction of a compound in which Z is -S0- to form a compound in which Z is -S-, iii) conversion of a carboxyl group to a metabolically labile and non-toxic ester function, iv) formation of a solvate or non-toxic salt, 30 v) elimination of any radicals blocking the carboxyl and / or N-protective function, and vi) elimination of any radicals blocking the hydroxyl function. 5. Compound according to claim 4, in hydrated crystalline form. 6. A hydrated crystalline compound according to claim 5, characterized by an infrared spectrum containing absorption bands at 3700-2100 (wide), 1760, 1720, 1660, 1555, 1520, 1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1030, 1000, 920, 860 and 755cm “1. 7. A hydrated crystalline compound according to claim 5, characterized by an X-ray diffraction grating (expressed in the form of spaces d in / 'I "• * Λ t Λ + 46 angstrom units and in intensities in percentages) which follows : 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 5 (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). 8. Process for the preparation of compounds of formula (i) as defined in claim 1, or of salts or of solvates of these compounds, characterized in that a compound of the formula (II) is acylated 15 H HZ Ξ = 1 \ h2n -.-. • _N / · (II) // \ // \ 0. H C00R1 -j (in which R, Z and the dashed line have the meanings assigned to them in claim 1) or a salt or 7-N-silyl derivative of such a compound, with a compound of formula (III) [* '»* * t- 4 47 NHR3 / \\ 9. A process for the preparation of the hydrate crystal-35 lin according to claim 5, characterized in that * mth '48 an aqueous solution of the acid is formed (6R, 7R, 2'Z, S) -7 - / 2- (2-aminothiazole-4-yl) -2- / jCcarboxy) (3,4-di-hydroxyphenyl) methoxyimino / acetamido / -ceph-3-th-4-carboxylic acid, or a salt thereof addition of acid or a salt with a base of the acid in question, or of a solvate of the salt concerned and the hydrate j in question is crystallized therefrom. 10. Process for the preparation of the crystalline hydrate according to claim 5, characterized in that an aqueous solution of an acid addition salt or of a salt with an acid base is formed ( 6R, 7R "2'Z, S) -7- / 2- (2-aminothiazole-4-yl) -2- / Tcarboxy) - 3,4-dihydroxyphenyl) methoxyimino7-acetamido7-ceph-3-th-4 -carboxylic or a solvate of this compound and the pH of said solution is adjusted to a value which varies from 1.0 to 4.0. 11. Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound of formula (la) as defined in claim 2. 12. Pharmaceutical composition according to claim 11, characterized in that the active ingredient is a compound as defined in claim 4. 13. Pharmaceutical composition according to claim 12, characterized in that the active ingredient is the hydrated crystalline compound of claim 5.