FR2604437A1 - NOVEL COMPOUNDS OF THE TYPE OF CEPHALOSPORINS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME. - Google Patents

Abstract

THE INVENTION RELATES TO COMPOUNDS OF FORMULA 1. IN THIS FORMULA R AND R, IDENTICAL OR DIFFERENT, REPRESENT H OR A GROUP BLOCKING THE CARBOXYL FUNCTION; R REPRESENTS H OR A GROUP PROTECTING THE AMINO FUNCTION; R AND R EACH REPRESENT A SUBSTITUTED HYDROXYL RADICAL OR NOT, OR R AND R TOGETHER REPRESENT A PROTECTED CYCLIC RADICAL DIOL; Z REPRESENTS -S- OR -SO- (A- OR B-) AND THE INTERRUPTED LINE INDICATES THAT THE COMPOUND IS A CEPH-2-EME OR A CEPH-3-EME. THESE COMPOUNDS ARE ANTIBIOTICS.

Description

The present invention relates to

  cephalosporin drugs. More specifically

  The invention relates to new compounds of the type

  eg cephalosporins and their derivatives which possess an interesting antibiotic activity. The cephalosporin-like compounds referred to herein are referred to by reference to "cepham" according to J. Amer Chem., Soc., 1962, 84, 3400, the term "cephem" referring to the base cephalic structure that has a double bond.

  The use of cephalic antibiotics

  losporins is widespread for the treatment of diseases caused by pathogenic bacteria in both humans and animals, and

  are particularly interesting for the treatment of

  diseases caused by bacteria that

  other antibiotics, such as

  penicillins and for the treatment of

  sensitive to penicillins. In many

  circumstances, it is desirable to use an anti-

  cephalosporin biotic that exhibits activity against both Gram-positive organisms

  and Gram-negative and very

  many researches have been directed towards the

  various types of antibiotics such as

  phalosporins with broad spectrum of activity.

  For example, in the description of the patent

  British Patent No. 1,399,086 of the Applicant describes a new class of cephalosporin antibiotics which contain a side chain of the genus 7 (oxyimino a-etherified) acylamido, the oxyimino group having the syn configuration. This class

  antibiotic compounds is characterized by an

  antibacterial activity against a series of organisms

  Gram-positive and gram-negative

  particularly high stability with regard to

  lactamases generated by various Gram-

negative.

  The discovery of this class of compounds has

  carried out further research in the same field in order to discover compounds with improved properties, for example, against classes

  particular organisms, especially

  Gram-negative mechanisms. This interest is reflected in the very large numbers of patent applications that have been filed concerning cephalosporin antibiotics with substituents

  particulars both on the side chain 79-

  acylamido and at the 3-position of the cephalosporin nucleus

born.

  For example, the description of the British patent

  that No. 1,576,625 contains a generic definition

  antibiotics of the cephalosporin type which possess

  tooth a side chain 7? - (oxyimino a-etherified) -

  acetamido, where the etherifying group is a hydro-

  aliphatic carbon which may have substituents

  appropriate (including among a large number of

  a carboxyl or carboxyl protected group and a phenyl group substituted with up to three hydroxyl groups), which side chain is further substituted with a group which, inter alia, may be an aminothiazolyl group. However, none of the specifically exemplified compounds contain an etherifying carboxyphenylalkyl group. The radical at position 3 can also be chosen from a large number of possibilities, but the hydrogen atom is not

not included among them.

  In the specification of British Patent No. 1,604,971, a broad series of cephalosporin antibiotics is generally described.

  the side chain in position 7? can be, between

  very, a 2- (2-aminothiazol-4-yl) -2- (oxy)

  imino etherified) acetamido, where the etherifying radical, among many possible meanings, can

  be an alkyl radical (for example methyl) substituted

  both phenyl and carboxyl groups, although no specific example is given 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

  eventualities and substituents in the 3 possible position

  include a hydrogen atom in their definition

generic

  In the specification of the United Kingdom patent

  No. 2,017,702, the oxyimino etherifying group may, according to the generic definition, be, inter alia, an acarboxyphenylmethyl radical. In compounds

  specifically mentioned as examples, the carboxyl radical

  phenylmethyl is always combined with an acetoxy-

methyl in position 3.

  United Kingdom Patent Specification No. 2,104,888 discloses generically

  cephalosporins, in which the chain la-

  7P is a 2- (2-aminothiazole) radical.

  4-yl) -2- (oxyimino etherified) acetamido. The ethical group

  oxyimino function may, inter alia, be a carboxyphenylmethyl radical in which the group

  phenyl may be substituted with a hydroxyl radical.

  The group at position 3 is an isothiazolyl radical

  thiomethyl or an iminoalkylidenedithiethane radical.

  The specification of European Patent No. 197 409 generically describes cephalosporin antibiotics, in which the chalne

  in position 7? is a 2- (2-amino) radical

  thiazol-4-yl) -2- (oxyimino etherified) acetamido. The

  group etherifying the oxyimino function can be, in

  others, a catechol-carboxymethyloxyimino radical.

  The substituent in position 3 can be selected from a number of eventualities but these do not

  do not include the hydrogen atom.

  The Applicant has now discovered that by

  the choice of a radical (Z) -2- (2-aminothiazol-4-yl) -

  (etherified oxyimino) acetamido at position 7P, in

  pairing with a hydrogen atom in position 3, and by

  the choice of a substituted phenylmethoxyimino radical

  As α-carboxylic group as an etherified oxyimino group, cephalosporin-like compounds having a particularly advantageous range of activities (which will be described in more detail hereinafter) would be obtainable against a wide range of products. of pathogenic organisms that

  common and / or useful as information

  intermediates for the preparation of other compounds

assets.

  Therefore, the present invention more particularly relates to compounds of the cephalosporin type corresponding to the general formula (I) NHR3 / \\

H H Z

CHCONHO2 has _ H *

OCHCOOR 2 0 \ H

  R 4 R 5 in which R 1 and R 2 may be the same or different,

  each represent a hydrogen atom or a

  dical blocking the carboxyl function;

  R3 represents a hydrogen atom or a radical

  protecting the amino function; R4 and R5 each represent a hydroxyl or substituted hydroxyl radical, or R4 and R5 together represent a protected cyclic diol radical;

  Z is> S or> S 0 (a- or O-); the line in broken lines

  terminating bridge positions 2, 3 and 4, indicates that the compound is a substance of the ceph-2-th type

  or ceph-3-th; as well as the solvates (more particularly

  hydrates) and non-toxic salts of

these compounds.

  In the substances of the formula (I) in the

  which R 1 and / or R 2 represent radicals blocking the carboxyl function, the blocking group may be, for example, the remainder of an araliphatic alcohol or

  aliphatic ester, or a stannanol, of a

  lanol or an esterogenic phenol (said alcohol, phenol, silanol or stannanol containing, preferably, from 1 to 20 carbon atoms), or a blocking radical of the type

  symmetrical or mixed anhydride, derived from an acid

  venable. As specific examples of R1 or

  R 2, there may be mentioned t-butyl radicals, diphenyl-

methyl and p-nitrobenzyl.

  When R 3 represents a radical protecting the amino function, the protecting group may be, for example, a C 7 -C 20 aralkyl radical (for example a

  triphenylmethyl or 4-methoxybenzyl radical), a group

  acyl, such as an optionally substituted C1-C6 alkanoyl radical

  is substituted (for example a formyl or chloroacetyl radical), or a C1-C6 alkoxycarbonyl radical;

  optionally substituted (for example a radical t-

  butoxycarbonyl or 2,2,2-trichloroethoxycarbonyl), or a C 7 -C 10 aralkoxycarbonyl group (for example a benzyloxycarbonyl radical) or a silyl group (for example

  a tri-methylsilyl radical).

  In general, preference is given to the compounds of the formula (I) wherein R 3 represents a hydrogen atom. When R or R represents a substituted hydroxyl group, it may be, for example, an acyloxy group, for example a formyloxy radical or a radical of the layloxy group.

  -OCOR formula (where R represents a radical

  C1-C8 alkyl, for example a methylhex radical,

  a carbonate radical -OCO2R6 (o R6 has the meanings

  fications attributed to it above), a

  For example, a silyloxy radical

  C4) silyloxy, such as a trimethylsilyloxy or tbutyldimethylsilyloxy7 radical, or a borate radical

  ú-OB (oR7) 2 Phosphate din fiOP (0) (OR7) 2_J o R7 Represents

C1-C4 alkyl radical).

  When R and R5 together represent a group

  protected cyclic diol moiety, it may be an alkylidenedioxy group, preferably having 1 to 20 carbon atoms, for example a methylenedioxy, ethylenedioxy, or isopropylidenedioxy group, which may carry

  one or more substituents, for example substituents

  phenyl, C 1 -C 4 alkoxy or oxo, for example methoxymethylbenedioxy, diphenylmethylenedioxy or carbonyldioxy; a cyclic borate group, for example -OB (OH) O-; a cyclic phosphate group, for example

  -OP (O) (OH) O-, or -OP (O) (OR7) O- (o R7 has the

  previously assigned to it) or a cyclic silyl ether group, for example a di (C 1 -C 4 alkyl) silyldoxy radical, for example a

dimethylsilyldioxy radical.

  In general, such silyloxy radicals, borate

  or phosphate, represent hydroxyl groups

  tegates which can be cleaved to generate a compound of formula (I) having radicals

hydroxyl free.

  Overall, R4 and R5 each represent,

  preferably an acetoxy group or, more particularly,

a hydroxyl group.

  In the compounds of the formula (1), Z represents

  The compounds of formula (I) are preferably

  according to the invention of the ceph-3-th type.

  When the compound is to be used in medicine, any ester of the carboxyl radicals in the molecule must

  be an atoxic ester function and metabolically la-

  bile. By way of examples of derivatives of the ato-

  and metabolically labile, there may be mentioned acyloxyalkyl esters, for example alkanoyl lower oxymethyl or ethyl esters, such as acetoxy-methyl or ethyl esters or

  pivaloyloxymethyl, and alkoxycarbonyloxy esters

  ethyl esters, for example lower alkoxy esters

  carbonyloxyethyls, such as the ethoxycarbonyl ester

oxyéthylique.

  In addition to the above-mentioned ester derivatives

  It should be understood that the present invention also extends its scope to the following active compounds:

  the invention in the form of other physiological equivalents.

  siologically acceptable, i.e., physiologically acceptable compounds which, like metabolically labile esters, are converted in vivo

  related antibiotic compounds according to the

  vention. Non-toxic salt derivatives which can be formed by the reaction of the carboxyl radical present in the compounds of the formula (I) include

  salts with organic bases, such as metal salts,

  alkaline levels (eg sodium and

  potassium) and salts with alkaline earth metals (eg calcium salts); salts with

  amino acids (for example, lysine and

  nine); salts with organic bases (e.g.

  salts of procaine, phenylethylbenzylamine,

  2 of dibenzylethylenediamine, ethanolamine, di-

  ethanolamine and N-methylglucosamine). Other de-

  Non-toxic salt type salts include

  acid addition, eg generated with hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, formic and trifluoroacetic acids. Salts

  may also be in the form of resi-

  nates generated, for example, with a poly-

  styrene, or a resin based on a copolymer of poly-

  crosslinked styrene-divinylbenzene, containing radicals

  amino or quaternary amino groups, or sulphonic acid groups, or a group-containing resin

  carboxyl, for example a polyacrylic acid resin

  than. Soluble base salts can easily be used.

  (e.g. alkali metal salts, such as sodium salts) of the compounds of the formula (I) to -uodsaez.oo u ea.mosTil q e2uelm uTq. azeo a 'saenb -TJ, 3% moS seaJemosT sap q.uos UOT; .UAUTI.ueuATns ssod -moo salt onb 9, uuop.ue0,9, nb aJpuaJdmoo% n: II I l11 s I qU \ // \ z8OO3H3O \ NI HNO ZJti tII NS ú HN: .Tns mmoo aq.ues..zd -aa zu manzon :: s zse s uoTlezngT2uoo s' BaTom9m oz ues9Jd ael strea opTmexoqa,: o ImoTpu ne; odd. ez zed s u 4a \ // \ * e \\

z OOOH3O-

  adno.zS np UOT.BJen2TjUOO sT rad aTUTgP% se U.eS aamosT emzJo; e 'To i seaim O-OOr.SU.UOS UOTUeAuTil I.tUATns s0sodmoo se'I seaquue, & uoo senbTueSJo saTme, pappTleTl eldmexe jed' anbTsseTOla aTuem op euaeS ao Bp slis sap Jam -.zo; n% u: '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '' '? ua (I) ssodmod o sep selqnlosuT slas ap.jsodsTp elTetnos uo, tanbsJoT utepuadgoD uoT. senbTnebde.ztq. suoT! ToTIddep SUT $ sap Cl, 7 L / 097

can occur.

  It should also be understood that in the group

  By etherifying the oxime function, the carbon atom adjacent to the oxy group is chiral and can therefore be in the R or S configuration. The scope of the present invention obviously also extends to the individual R and S forms. on this chiral carbon atom, as well as mixtures (including mixtures of diastereoisomers) of these forms. In general, the compounds of formula (I) are preferred in

  which this chiral carbon atom has the confi-

  and the R / S mixtures in which the isomer

S predominates.

  The compounds of the present invention may

  exist in tautomeric forms (for example with respect to the radical 2-aminothiazolyl) and it is necessary to

  understand that the scope of the present invention is

  also tends to these tautomeric forms, for example the

2-iminothiazolinyl form.

  As indicated above, the following compounds

  The invention is active against a broad range of pathogenic organisms commonly encountered and / or are useful intermediates for the preparation of other active compounds. In general,

  when the compounds should be used according to the

  as intermediates, the radicals R1 and R2

  will often be groups blocking the carbon function

  xylE; the R3 group will often be a radical protecting

  the amino function and the R4 and R5 groups will be

  protected hydroxyl radicals, such as

  silyloxy, borate or phosphate groups, or will form

  seems a cyclic protected diol radical. Non-toxic derivatives in which R 4 and / or R 5 represent acyloxy groups, such as acetoxy radicals, may

  serve as intermediates or active compounds.

  In general, active compounds according to

  vention will be ceph-3 compounds of the

  mule (I) in which R1, R2 and R3 represent hydrogen atoms, Z represents> S and R4 and R5 which may be identical or different represent hydroxyl or acyloxy C1-C4 radicals, for example

acetoxy radicals.

  Compounds according to the invention which are

  tants correspond to formula (Ia) NH2

S N H

I I

! ..... 'ONH, *

OCHCOOH 0 TO H

  wherein R4a represents a hydroxyl or acetoxy radical; R5a represents a hydroxyl or acetoxy radical; as well as hydrates, solvates and non-toxic salts and

  metabolically labile esters of these substances.

  A compound according to the invention particularly

  preferred is (6R, 7R, 2 ', Z, S) -7-L2- (2-aminothiazo-

  le-4-yl) -2-LTcarboxy) -3,4-dihydroxyphenyl) methoxy

  imino7acetamido7ceph-3-th-4-carboxylic acid, as well as hydrates, solvates and non-toxic salts and esters

  metabolically labile of this compound.

  Applicant has discovered that the acid (6R, 7R, 2 '

  Z, S) -7- [2- (2-aminothiazol-4-yl) -2-LTcarboxy) (3,4-di-

  hydroxyphenyl) méthoxyimino7acétamido7céph-3-em-4-

  carboxylic acid can advantageously and uniformly prepare and isolate itself with a high degree of purity

  crystalline form and this characteristic constitutes

  another aspect of the present invention. In a way

  In particular, the plaintiff prepared and

  (6R, 7R, 2'Z, S) -7-L2- (2-aminothiazol-4-yl) acid -

  2-Llcarboxy) (3,4-dihydroxyphenyl) méthoxyimino7-

  crystalline acetamido-7-phen-3-th-4-carboxylic acid and

  DRATE. This new compound is superior not only

  by its crystallinity and purity, but

  also holds with high yields and has superior stability during storage,

  even at a high temperature during periods

  skirted. These properties of the crystalline material make it of particular interest for use

in the field. pharmaceutical.

  The above-mentioned crystalline hydrated substance can be characterized by its infrared spectrum and / or

  its X-ray powder diffraction grating.

  IR spectrum (Nujol) v max 3700-2100 (broad), 1760, 1720, 1660, 1555, 1520, max

  1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1030,

1000, 920, 860 and 755 cm -1.

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

in percentages).

  12.5 (21); 9.97 (37); 9151 (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).

  The compounds according to the present invention

  manifest a broad spectrum antibiotic activity

  vis-à-vis both gram-positive and gram-positive organisms

  negative, including P-producing strains

  lactamases. The compounds also have a high stability with respect to β-lactamases produced by

  a whole series of gram-negative and gram-

positive.

  It has been found that compounds according to

  this invention showed a high level of activity

  strains of Gram-positive bacteria (including

* taken penicillinase producing strains), such as Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus species. This activity is associated with excellent activity against Pseudomonas species

  and also high activity against various

  enterobacteriaceae (for example, strains

  of Escherichia coli, Klebsiella pneumoniae, Entero-

  bacter cloacae, from Serratia marcescens, from Proteus

  mirabilis and organisms of the genus Proteus indole-

  positive ones, such as Proteus vulgaris, Proteus morganii and Providence) and strains of Haemophilus influenzae and Acinetobacter calcoaceticus. This combination of high activity against organisms

  gram-positive and high activity against

  Gram-negative mechanisms, especially against

  Pseudomonas, that the compounds following the present

  vention, is unusual and particularly

advantageously.

  As we have seen, derivatives of the type of

  cephalosporins described in this specification possess

  in vivo, a desirable long half-life of

the serum.

  The compounds can be used according to the invention

  to treat a wide range of diseases

  evoked by pathogenic bacteria in humans and animals, such as

  respiratory tract and urinary tract infections.

  ners. The antibiotic compounds according to the invention can be presented for administration in any convenient manner, by analogy with other antibiotics and, therefore, the scope of the present invention also extends to pharmaceutical compositions which comprise an antibiotic compound according to the invention, adapted to

  use in human medicine or veterinary medicine.

  The compositions in question may be of

  classical way using any exci-

  pients or pharmaceutical vehicles required.

  The antibiotic compounds according to the invention

  can be put into formulas that are suitable for

  jection and may be in the form of

  units, in ampoules, or in containers in

  hold multiple doses, if necessary with

  added. The compositions may also adopt shapes such as suspensions, solutions or

  emulsions in oily or aqueous vehicles and may

  may contain compositional agents such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient can also be in the form of a powder from

  of which the active drug is reconstituted

  of a suitable vehicle, for example, apyreous water

  gene, sterile, before use.

  If desired, powder compositions

  of this kind may contain a suitable non-toxic

  to increase the solubility in water of

  the active ingredient and / or to ensure that

  constitution of the drug with water, the pH of the resulting aqueous solution is physiologically acceptable. Alternatively, the base can be present

  in the water used to reconstitute the drug.

  The base may be, for example, an inorganic base, such as sodium carbonate, sodium bicarbonate or sodium acetate, or an organic base,

  like lysine or lysine acetate.

  One can also present the composition under

  a form suitable for absorption by the gastrointestinal tract

  intestinal preparations, for example tablets, capsules or capsules, syrups or suspensions suitable for

  oral administration, and suppositions

  tories. The compositions for use in veterinary medicine may, for example, be formulated as intramammary preparations in

  bases with slow or rapid release of the substance

  dicamenteuse. The compositions can contain from 0.1%,

  for example from 0.1 to 99% of the active ingredient, 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 treatment

  of the adult human being varies preferably from 12,000 mg, for example from 1000 to 9000 mg,

  Day, depending, among other things, on the nature of the

  fection and mode and frequency of administration.

  In general, intravenous or intramuscular administration is used, 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,

  units and lower daily doses may

may be desirable.

  The antibiotic compounds of the present invention may be administered in combination with other therapeutic agents, such as antibiotics,

  such as penicillins, cephalosporins

  or other β-lactam compounds.

  The compounds can be prepared according to the invention.

  according to a number of methods described above.

below.

  Thus, according to one embodiment of the present invention, the object of the present invention is the preparation of an antibiotic compound of the general formula (I) as defined above or of a hydrate, solvate or atoxic salt thereof. compound, by the acylation of a compound of the formula (II)

H HZ

N H *

He COOR1

  (in which R1, Z and the line in broken lines

  they are as defined in relation to the general formula

  (I)) or a salt, for example an acid addition salt (generated, for example, with a mineral acid,

  such as hydrochloric acid, hydrobromic acid, sulfuric acid

  nitric or phosphoric acid or with an organic acid

  that, such as methanesulphonic acid or toluene-p-sulphonic acid), or a 7-N-silylated derivative of such a compound, with an acid of the formula (III) NHR3 I

S N ()

COOH OiHCOOR2

/

  * e o R4 I5 R5 corresponds to it; corresponds to it;

  this acylation being followed, if this proves to be

  and / or desirable under any circumstances, of any of the following reactions, in any appropriate order: i) conversion of an A2 isomer to an isomer 3, 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 to an atoxic and metabolically labile ester function, iv) formation of an atoxic solvate or salt, v) elimination of any which radicals blocking the carboxyl and / or N-protecting function, and vi) eliminating any blocking radicals

the hydroxyl function.

  Reactions i) to vi) can be realized from a

classic way.

  During the implementation of the acylation process

  the starting material of formula (II) is

  preferably, a compound in which Z is> S and the

  in broken lines represents a compound of the type

  eg ceph-3-th. Acylating agents that can be used

  for the preparation of the compounds of the formula (I)

  take acid halides, more particularly

  bromides or chlorides of acids. We can pre-

  such acylating agents by reacting a

  acid (III) or a salt thereof, on a halogenated

  genesis, for example phosphorus oxychloride,

  thionyl chloride or oxalyl chloride.

  Acylations using

  acid halides in reaction media a-

  both non-aqueous and conveniently at temperatures ranging from -50 to + 500C, preferably from -40 to + 30C, if desired in the presence of a fixing agent

  acid. Suitable reaction media include

  aqueous ketones, such as aqueous acetone, aqueous alcohols, such as aqueous ethanol, esters,

  such as ethyl acetate, halogenated hydrocarbons

  such as methylene chloride, amides, such as dimethylacetamide, nitriles, such as acetonitrile, or mixtures of two or more

  two solvents of this kind. Agents for fixing

  Suitable acids include tertiary amines (eg triethylamine or dimethylaniline), inorganic bases (eg calcium carbonate or sodium bicarbonate) and oxiranes, such as 1,2-lower alkylene oxides (eg ethylene oxide). or propylene oxide) which fix the acid

  hydrogen halide released during the acylation reaction.

  lation. It is possible to use acids of formula (III)

  themselves as acylating agents for the pre-

  paration of compounds of formula (I). Acylations

  using (III) acids are advantageously

  in the presence of a condensing agent, for example

  carbodiimide, such as N, N'-dicyclohexylcarbonyl

  diimide or N-ethyl-N'-dimethylaminopropylcarbodi

  imide; a carbonyl compound, such as carbonyldiimide

  imidazol; or an isoxazolium salt, such as perchlorate

  N-ethyl-5-phenylisoxazolium; or N-ethoxycarbonyl-

2-ethoxy-1,2-dihydroquinoline.

  Acylation with other amidogenic acid derivatives of the formula (III), such as, for example, an activated ester, a symmetrical anhydride or a mixed anhydride (formed by

  example, with pivalic acid or with halogen

  formate, such as lower alkyl haloformate).

  Mixed anhydrides can also be formed with

  phosphorus acids (eg phosphoric acid)

  phosphorous acid), sulfuric acid or aliphatic or aromatic sulphonic acids (eg

  toluene-p-sulfonic example). We can conveniently

  an activated ester in situ using, for example, 1-hydroxybenzotriazole, in the presence of a condensing agent, as previously indicated. In

  Alternatively, the activated ester can be preformed.

  Acylation reactions involving free acids or their aforementioned amidogenic derivatives,

  are advantageously achieved in a reactionary environment.

  anhydrous, for example methylene chloride, tetrahydrofuran, dimethylformamide, acetonitrile,

  dimethylacetamide or dimethylsulfoxide.

  Another acylation process consists, for example, in reacting an acid of the formula (III)

  on a preformed solution or suspension in

  as a carbonyl halide, more particularly

  oxalyl chloride or phosgene, or a halogen

  of phosphoryl, such as phosphorus oxychloride

  phore, in a solvent, such as a halohydrocarbon

  For example, methylene chloride containing tertiary tertiary amide, such as N, N-dimethylformamide. The activated form of the acid of formula (III) can then be reacted with a 7-amino compound of formula (II) in a solvent or a mixture of solvents, for example halogenated hydrocarbons, for example dichloromethane; alcohols, such as an alkanol, for example ethanol

  or industrial alcohol denatured with methanol; of its-

  ters, for example ethyl acetate; ethers, by

  for example tetrahydrofuran or dioxane; keto

  such as acetone; amides, for example

  dimethylacetamide; acetonitrile; water and their

mixtures.

  The acylation reaction can conveniently be carried out

  rolling at temperatures ranging from -50 to 50 ° C, preferably from 400 to + 30 ° C, if desired, in the presence of an acid-binding agent, for example,

  as described above (eg dimethyl

  aniline, triethylamine or sodium bicarbonate).

  If desired, the aforementioned acylation reactions can be carried out in the presence of a

  catalyst, such as 4-dimethylaminopyridine.

  The acids of the formula (III) and the agents

  corresponding acylation may, if it is

  and where appropriate, be prepared

  prepared and used in the form of their

  acid. Thus, for example, acid chlorides can be conveniently employed in the form of their hydrochloride salts, and the acid bromides,

  in the form of their hydrobromide salts.

  For use as starting materials for the preparation of compounds of the general formula (I) according to the present invention, the compounds

  of the general formula (III) and their amido derivatives

  genes, such as acid halides and the corresponding anhydrides, preferably in their isomeric form sn or in the form of mixtures of the isomers

  syn and corresponding anti isomers which contain

  at least 90% of the isomer sn.

  The acids of formula (III) and their derivatives can be prepared by the etherification of a compound of formula (IV) NHR 3 NHR 3! / ,, +

* * <. COOR.8 (IV)

  ## STR5 ## wherein R 3 has the meanings previously assigned to it and R 8 represents a hydrogen atom or a radical blocking the function.

  carboxylic acid) or a salt of such a compound, according to a reaction

  selective composition of a compound of the general formula (V)

T.CHCOOR2

At (V)

* * (

\ // \ R

  R 5 (wherein T represents a chlorine, bromine or iodine atom, a sulphate radical or a sulphonate radical, such as tosylate), followed by elimination

  of the R8 carboxyl blocking group.

  The etherification reaction is carried out conveniently

  demented in the presence of a base, for example carbo-

  potassium nitrate or sodium hydride and it is

  it is preferably carried out in an organic solvent, for example dimethylsulfoxide, a cyclic ether, such as tetrahydrofuran or dioxane, or a

  N, N-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 carried out

  usually in the presence of a strong base, for example potassium t-butoxide, a sufficient amount of base being added to form a dianion. In addition, the reaction must be carried out in the presence of a base if an acid addition salt of a compound of the formula (IV) is used, the basic amount being sufficient.

  to quickly neutralize the acid in question.

  It is also possible to prepare acids of the

  (III) by the reaction of a compound of the formula

mule (VI)

NHR 3

I (VI)

  (wherein R3 and R8 have the meanings previously assigned to them), on a compound of formula (VII)

H2N.O.îHCOOR2

r (VII)

11 I

R5

  (in which R2, R4 and R5 have the significances

  previously attributed to them), followed by

  elimination life of any blocking group

  the carboxyl function R8, and if this proves to be

  the separation of the syn and anti isomers.

  The reaction is conveniently carried out in soil

  such as dimethylformamide, dimethylacetamide and

  of, dimethylsulfoxide, tetrahydrofuran or

  methanol, all these compounds being used

  in the presence of water at a temperature of -200 to

+ 50OC, preferably 0 to 30C.

  The acids of formula (III) can be converted

  the corresponding acid anhydrides and acid halides

  and the acid addition salts by means of

  of conventional processes, for example in the

previously described.

  We can prepare the intermediaries of the

  mule (VII) by treating compounds of formula (VIII)

Y.O.CHCOOR2

I \\ $ r * I l

\ / \ R4 (VIII)

  (where Y represents an imido group, for example

  a phthalimido, succinimido or maleimido radical) with a hydrazine reagent, such as hydrazine hydrate, or an alkyl hydrazine, such as methyl hydrazine. We will generally realize the reaction in

  an inert solvent, for example a halogenated hydrocarbon

  gene, such as methylene chloride, at low temperatures

  erature, for example from -70 ° C to + 30 ° C.

  Intermediaries of the

  mule (VIII) by alkylation with compounds of formula (IX) HalCHCOOR 2 / \\

(IX)

\ // R4

  Rs (in which Hal represents a halogen atom, as

  2 a chlorine or bromine atom) of an N-hydroxyimide

  (eg N-hydroxyphthalimide, N-

  hydroxysuccinimide or N-hydroxymaleimide), in

  base, such as triethylamine, in a solvent, such as acetonitrile, at a temperature

  varies, for example, from -10 to + 30C.

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

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 may be

  prepare according to information that can be

  in the appropriate technical literature.

  A derivative of the ester type A2-

  cephalosporinic obtained by carrying out the process

  according to the present invention, in the derivative A3

  corresponding, for example, by treating the ester A2 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 ceph-3-yl-1-oxide, for example by reaction with a peracid, for example peracetic acid or m-acid. -chloroperbenzolque; the sulfoxide thus obtained can then be reduced in the manner described hereinafter in order to collect the

  corresponding ceph-3-th sulfide corresponding.

  When a compound in which Z is> S b O is obtained, the latter can be converted to the corresponding sulphide, for example by reduction of the acyloxysulfonium salt or corresponding alkoxysulphonium salt prepared in situ by reaction with for example, the

  acetyl chloride, in the case of an acetoxy

  sulfonium, the reduction being carried out, for example, using sodium dithionite or an iodide ion, such 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 abovementioned oxidation and reduction processes, the groups and R5 in the starting materials are advantageously other than hydroxyl radicals.

  Metallic ester derivatives can be prepared

  in carboxylic groups in the compounds of formula (I) by reacting a compound of formula (I) or a salt or protected derivative thereof with a suitable esterifying agent, such as a

  acyloxyalkyl halide or an alkoxy halide

  carbonyloxyalkyl (e.g., iodide), conveniently in an inert organic solvent, such as dimethylformamide or acetone, this reaction being followed, where necessary, by the removal of

* any protective radicals.

  It is possible to form salts with bases of compounds

  of formula (I) by reacting an acid of formula (I) on a suitable base. So, by

  For example, the sodium or potassium salts can be prepared.

  using the salt of the acetate type, 2-ethyl-

  hexanoate or hydrogen carbonate. We can pre-

  acid addition salts by reacting a

  compound of the formula (I) or a derivative of the ester-

  metabolically labile of this compound on the acid

  venable. When a compound of the formula is obtained

  (I) as a mixture of the isomers, it is possible to obtain

  the svn isomer, for example, by standard methods.

  as a crystallization or chromatogra-

  graphy. 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 reactions

  unwanted side effects. Examples of radi-

  Suitable protective cocks are given in the book "Protective Groups in Organic Synthesis" by Theodora

  W. Greene (John Wiley and Sons, 1981).

  For example, during any of the reaction sequences mentioned above, it may be necessary to protect the NH 2 radical from the group

  aminothiazolyl, for example by tritylating, acylating,

  (eg chloroacetylation or formylation),

  protonation or any other conventional method. The radi-

  protective pad can then be removed from any

  what a convenient way that does not cause

  sition or degradation of the desired compound, for example in the case of a trityl radical, using an optionally halogenated carboxylic acid, for example 1 '

  acetic acid, formic acid, chloroacetic acid

  or trifluoroacetic acid, or 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

  chloroacetyl radical, by treatment with thio-

  urea. Similarly, the hydroxyl radicals of the catechol group can be protected

  during any of the reaction sequences

  mentioned above. Radicals protecting the

  hydroxyl, which can be removed under conditions

  moderates, will generally be well

  example acetyl or silyl radicals. Such radi-

  may be introduced in a conventional manner and, if desired, removed in such a way that

  produce no degradation or decomposition of the product.

  For example, in the case of the acetyl radical, this group may be removed by solvolysis with an aqueous solvent, such as aqueous methanol or aqueous ethanol,

  presence of a base, for example sodium bicarbonate

  dium, ammonium hydroxide, ammonium carbonate or ammonium carbamate. A trimethylsilyl radical can be cleaved, for example, by treatment with a

dilute aqueous acid.

  The radicals blocking the carboxyl function, used

  for the preparation of the compounds of the formula

  (I), or for the preparation of the starting materials

  necessary, are radicals that can be

  easily separate in an appropriate step.

  asked for further reactions, conveniently in the last step. It may, however, be convenient in certain circumstances to use radicals

  blocking the atoxic carboxyl function and metabolizing

  ly labile, such as acyloxymethyl or ethyl (for example acetoxy-methyl or -ethyl or pivaloyloxymethyl) radicals, and to retain these radicals in the final product, so as to obtain a derivative of the type

  suitable ester of a compound of formula (I).

  Suitable carboxyl-blocking groups are well known to those skilled in the art and a list of representative blocked carboxyl groups is found in British Patent No. 1,399,086. Preferred blocked carboxyl groups include aryl-lower alkoxycarbonyl radicals.

  such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxy-

  carbonyl and diphenylmethoxycarbonyl; alkoxy lower carbonyl radicals, such as p-butoxycarbonyl; and lower haloalkoxycarbonyl radicals, such as 2,2,2-trichloroethoxycarbonyl. The group blocking the carboxyl function can be removed according to any

  which appropriate methods described in the literature

  technical classification; for example, one can apply

  in many cases a reduction or a hydro-

  acid catalysed lysis, such as catalyzed hydrolysis

enzymatic lysis.

  When a particular enantiomorph of a com-

  formula (I) is desirable, it is necessary to use

  use starting materials that have the configuration

  desired stereochemical ration in the above processes.

  mentioned. Such intermediaries can be obtained

  by implementing conventional resolution methods

  c. For example, enantiomatic intermediates

  morphs of the formula (VIII) in which R2 represents

  A hydrogen atom where the chiral carbon atom is in the (R) or (S) configuration can be obtained by the reaction of a mixture of enantiomorphs on a resolving agent, such as a chiral organic base. R - (+) - a-methylbenzylamine7, in a solvent, such as acetone or acetonitrile,

  to generate the corresponding diastereoisomeric salts

  respondents. The salts can then be separated by

  known ceded compounds and the desired chiral intermediate of the formula (VIII) can be regenerated by treatment with an aqueous acid, for example hydrochloric acid.

  aqueous, for example, at room temperature.

  The acid (6R, 7R, 2'Z,

  S) -7-L2- (2-aminothiazol-4-yl) -2-carboxy) (3,4-di-

  hydroxyphenyl) méthoxyimino7acétamido7céph-3-em-4-

  crystalline carboxylic acid, in the form of its hydrate,

  from an aqueous solution of a cephalometric salt

  aforementioned sporine, or a solvate thereof.

  Therefore, according to an embodiment according to the invention, the latter relates to a process for the preparation of the acid (6R, 7R,

  2'Z, S) -7-2- (2-aminothiazol-4-yl) -2-ztcarboxy) (3,4-

  dihydroxyphenyl) méthoxyiminoacétamido7céph-3-em-4-

  carboxylic acid hydrate and crystalline, by crystallization

  sation of said acid from an aqueous solution, preferably an aqueous solution of an addition salt

  acid or a salt with a base of the acid in ques-

  tion, or a solvate of the aforementioned salts, so as to

  generate the crystalline hydrated product. We make normal

  follow the crystallization of isolation and

drying the product.

  Suitable basic salts are:

  for example, salts with inorganic bases, such as alkali metal salts and alkaline earth metal salts and salts with organic bases, as described above. A salt with a base

  particularly suitable is the sodium salt.

  Starting acid addition salts can be formed with an organic or inorganic acid. As organic acids that may be used, there may be mentioned carboxylic and sulfonic acids, for example formic acid, trifluoroacetic acid and methanesulfonic acid. As inorganic acids that may be used, there may be mentioned mineral acids, for example hydrochloric, hydrobromic or sulfuric acids. According to another of the features of the present invention, the desired substance can be crystallized from a solution of an acid salt or

  (6R, 7R, 2'Z, S) -7-L2- (2-aminothiazole) acid base

  4-yl) -2-carboxy) (3,4-dihydroxyphenyl) methoxyimino

  acetamido-7-en-3-yl-4-carboxylic acid, or a solvate thereof, in an aqueous medium, by adjusting the

  pH at a value ranging 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 to a pH that is within the aforementioned ranges. Acids

  which can be used during the

  include, for example, chlorinated

  water and sulfuric acid. Alternatively, we can

  crystallize the desired hydrate from a solution

  addition of an acid addition salt, by adding

  an organic base or an inorganic base at an acceptable pH

  property, within the limits mentioned above. The bases that

  can be used include, for example,

  alkali metal or alkaline earth metal tates, bicarbonates, carbonates or hydroxides, for example

  sodium hydroxide, sodium carbonate, bi-sodium

  sodium carbonate or sodium acetate.

  The aqueous medium may contain an organic solvent

  water-miscible 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

example acetonitrile.

  The crystallization is advantageously carried out

  at room temperature, for example at a temperature of

  from 0 ° to 30 ° C, preferably from 15 ° to 25 ° C. The crystalline product can be recovered by filtration and washed and dried in a 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. '' Nujol '' and '' Sorbsil '' are trademarks of

  manufactures. Sorbsil U30 is silica gel manufactured by Joseph Crosfield and Son of Warrington, Cheshire, England. Unless otherwise specified

  contrary, the nuclear magnetic resonance spectra

  re (NMR4) were recorded in DMSO-db (DMSO = dimethyl sulfoxide). X-ray diffraction measurements were made on a Siemens D-500 diffractometer, using CuKa radiation. Intensities

  X-rays were meaured by increasing fractions

  0.02 to 20 for 5-second intervals, using a scintillation counter, between values of 2 to 90 Å. The results have been memorized

  in a computer for processing.

  Intermediate 1 2- (3,4-dioxycarbonyl) phenyl-2- (phthalimidooxy) acetic acid A solution of N-hydroxyphthalimide was added

  (14.6 g) and triethylamine (25 ml) in acetoin

  nitrile (50 ml) to a stirred suspension of 2- (3,4-

  dioxycarbonylphenyl) -2-chloroacetic acid (20.5 g) in acetonitrile at 20 minutes. After an additional hour at about 0, a solution of concentrated hydrochloric acid (7.5 ml) in water (100 ml) was rapidly added. Water (100 ml) was slowly added and crystallized the liberated initial oil,

  the crystallization being facilitated by seeding.

  The mixture was filtered and the filter cake washed.

  with water and a mixture of ethyl acetate and petroleum ether (mp 40-60) (1: 2) and dried to recover the title compound ( g), having a melting point of 183 to; Δ 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).

Intermediate 2

  (a) Salt of the tacid (S) -2- (3,4-dioxvcarbonylphenyl) -2-

  (Phthalimidooxy) acetic acid with (R) - (+) - α-methylbenzyl

amine

  A solution of R - (+) - = -

  methylbenzylamine (16.3 ml) in acetone (100 ml) to a magnetically stirred solution of Intermediate I (45 g) in acetone (1.25 liter) at 210 under a nitrogen atmosphere. After 30 minutes, the mixture was filtered and the precipitate vigorously washed with acetone to give the title compound (16.57 g); 71+ 242 (c 1.07, EtOH); 1.46 (d, J 7Hz, CH 3 CH), 5.48 (s, OCH), 7.3-7.6 (m,

  aromatic protons) and 7.80 (s, phthalimido protons).

  (b) (S) -2- (3,4-Dioxcarbonyldienyl) -2- (phthalimidooxy) diphenylmethyl acetate 2M hydrochloric acid (10 ml) was added to a stirred suspension of Intermediate 2 (a) (5). , 0 g)

  in water (30 ml) under nitrogen atmosphere at 210.

  After 2 minutes, a solution of diphenyl-

  diazomethane containing an equivalent in methylene chloride (11 ml). After vigorous stirring for 35 minutes, the organic layer was separated and added dropwise to stirred ethanol (150 ml). The mixture was stirred at 210 for 10 minutes.

  minutes and then kept at 4 for 1 hour.

  re. The crystals were collected by filtration,

  washed with ethanol and dried to obtain

  denote the title compound (3.59 g), m.p.

at 135.50;

  721 + 112.60 (c, 1.18, ethyl acetate).

Intermediate 3

  (S) - (3,4-dihydroxyphenyl) (dinhénvlméthoxvcarbonyl) -

  Methoxyamine Intermediate 2 (b) (5.71 g) in methanol (390 ml) was acidized with M hydrochloric acid (5.5 ml) at about 40 ° for 4.5 hours. We concentrated

  the solution and mixed with methylene chloride.

  born. After double washing with water, the solution was dried

  The solution was magnesium sulfate and evaporated to a foam. A solution of this foam in methylene chloride (176 ml) was cooled to -50 ° with stirring under a nitrogen atmosphere and hydrazine hydrate (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 over magnesium sulphate, evaporation made it possible to obtain

  the title compound (4.35 g) under the formula

  me of a foam; δ_72'1 + 17.8 (c 1.03, methanol); 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

  (ZS) -2- (2-Aminothiazol-4-yl) -2- [3,4-dihydroxy] acid

  phenyl) (diphenylmethoxycarbonyl) methoxyiminoacetic acid 2- (2-aminothiazol-4-yl) glyoxylic acid (1.91 g) was added over a period of 3 minutes to a

  solution of Intermediate 3 (4.20 g) in N, N-

  dimethylformamide (22 ml) at 3, with stirring. After

  additional minutes under cooling -

  ice, the solution was allowed to return to 21 in the

  1.5 hours and then added dropwise to a mixture of ice and water (110 g) with stirring over a period of 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 filtration. The filter cake was washed with methylene chloride and dried to give the title compound (3.76 g); _7'21 + 24.40 (c 1.02, methanol); 6.59 (s, OCHCO), 6.6 to 6.9 (m, thiazole H, OCH, and

  protons catechol), 7.0 to 7.5 (m, NH2 and protons

nyl) and 9.06 and 9.13 (2s, OH).

Intermediate 5

  (ZS) -2- (2-Formamidothiazol-4-yl) -2- / T3,4-diol

  hydroxyphenyl) (diohenylmethoxycarbonyl) methoxyiminoacetic acid

  2- (2-Formamidothiazole) was added

  4-yl) glyoxylic acid (6.96 g) to a stirred solution of

  LT3,4-dihydroxyphenyl) (diphenylmethoxycarbonyl) -7-

  methoxyamine (12.73 g) in N, N-dimethylformamide (100 ml) at room temperature. After 1.5 hours,

  an additional amount of N, N-dimethyl-

  formamide (40 ml) and then, over a period of 2.5 hours, the solution thus obtained was poured into water (700 ml). The products were extracted with ethyl acetate (3 x 250 ml). The combined extracts were washed with water (2 x 250 ml), dried over magnesium sulphate and then evaporated to give a solid. This solid was treated with ethyl acetate (20 ml), followed by

  dichloromethane (200 ml) to obtain a solution of

  tion. After cooling, the solid was collected by filtration, washed with dichloromethane and dried to give the title compound (11.38 g) m.p. 125-127;

Z 7 21+ 22.20 (c 0.99, methanol).

Example 1

  (6R 7 R 2 'ZS) -7- / - (2-Aminothiazol-4-yl) -2 - /, 4-di-

  hydroxyphenyl) (di (phenylmethoxycarbonyl) methoxyimino)

  Diethylphenyl acetamido-3-e-4-carboxylate

  The tosylate salt of (6R, 7R) -7-

  diphenylmethyl aminocéph-3-th-4-carboxylate (1.24

  (g) in the free amine, by distribution between chlorine

  methylene and an aqueous solution of sodium bicarbonate. The organic layer was washed with water and

  it was dried over magnesium sulfate. The evaporation

  gave a foam which was mixed with the Inter-

  Medium 4 (1.0 g) in THF (25 ml), under stirring.

  and then added N, N'-dicyclohexyl-

  carbodiimide (830 mg) and hydroxybenzotriazole hy-

  drate (290 mg). After stirring at 21 for 16 hours, the mixture was filtered and the cake was leached.

  filtration with ethyl acetate. The solvents were evaporated

  The organic components were combined to give 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%, 2% and 3% methanol in chloroform. evaporation

  of the appropriate eluate gave the compound

  titled in the title (800 mg) as a foam; J.74D1 + 36.250 (c 1.17, DMSO); X infl (EtOH) 230.8 (Elm 303), 290 (Em 117 and 300.4 1% 1cm lem

nm (Elcm 84).

Example 2

  (6R7R, 2 'Z. S) -7- / - (2-aminothiazol-4-yl) -2- (2-aminothiazol-4-yl) acid

  (carboxy) (3,4-dihydroxy-phenyl) methoxyiminoacetamido)

  CeDh-3-th-4-carboxy, salt with trifluoride

  The compound of Example 1 (740 mg) was stirred with anisole (1.5 ml) and acid was added.

  trifluoroacetic acid (7.5 ml). Added diethyl ether

  isopropyl (50 ml) after one minute. We collected

  precipitated by filtration, washed with diethyl ether,

  isopropyl and dried under vacuum to give the title compound (450 mg);

1102.8 (0.88, DMSO);

  Xmax (pH6 buffer) 236.8 nm (Elcm 335), X infl 250.0

  (E1% m 257), 277.4 (Em 173) and 296.0 nm (E21m 139).

Example 3

  (6R.7R, 2 'Z.S) -7 - / - - (2-Formamidothiazol-4-yl) -2- / T 3.4-

  dihydroxyphenyl) (di-phenylmethoxycarbonyl) methoxyimino7-

  Diphenylmethyl acetamido-3-e-4-carboxymate Intermediate 5 (1.2 g) was suspended.

  in methylene chloride (20 ml) under stirring.

  under a nitrogen atmosphere and N, N-

  dimethylacetamide (4 ml). The solution was cooled

  Up to -250 and added phosphorus oxychloride

  phore (0.28 ml). After stirring for one hour at a temperature ranging from -25 to -20 °, a solution of diphenylmethyl (6R, 7R) -7-aminocaep-3-yl-4-carboxylate (derived from its tosylate salt (1 35) by the action of sodium bicarbonate solution) in methyl chloride (20 ml) containing N, N-dimethylaniline (2 ml). The reaction solution was then at -10 'and was then surrounded

  ice water and stirred 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 to 60) containing 2% acetic acid. . Evaporation of the appropriate eluate afforded the title compound (1.56 g); 2D1 + 36.2, (c 1.05, DMSO); Amax (EtOH) 269.2 nm (EI 184) Xinfl 2320 (EI cm 285),

  260.4 (Elcm 179) and 266.8 nm (Elem 183).

Example 4

  (6R, 7R, 2S) -7- [2- (2-Aminothiazol-4-yl) -2-].

  dihydroxyphenyl) (diphenylmethoxycarbonyl) methoxyimino7-

  diphenylmethyl acetamido-7-phenyl-3-e-4-carboxylate The compound of Example 3 (1.5 g) was stirred with methanol (15 ml) at 21 and acid was added.

  perchloric 60% (1 ml). After 2.5 hours, we have

  The solution was separated 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 brine, dried over magnesium sulfate and evaporated to give the title compound. in the title (1.34 g); RJD71 + 36.50 (c 0.96, DMSO);

  max (NdJol) 3600 to 3100 (broad); 1785, 1730 and 1680om-1.

Example 5

  (6R, 7R, 2'ZS) -7- (2- (2-aminothiazole) -2-carboxylic acid)

  (3,4-dihydroxyphenyl) méthoxyimino7acétamido7céph-3-em

  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 solution of sodium acetate (4 g) was added. , 8 ml). After 10 minutes, the mixture was filtered and the filter cake was washed well with

  ethanol four times, with ether at

  removed and dried under vacuum so as to obtain

  hold the title compound (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; L11.1 + 185.00 (c 0.78, DMSO); Xmax (pm6 buffer) 234.4 (Elm 38b); infl 250.4

  (E16 276); 276.8 (Es 184) and 294.4 nm (E 148).

I cm l om

Example 6

  Acid (6R.7R, 2'ZS) -7- / 2- (2-aminothiazol-4-yl) -2-

  (3,4-dihydroxylphenyl) methoxviniminoacetamido] -heph-3-th-4-carboxylic acid The compound of Example 5 (1.0 g) was mixed with water (4 ml) and added to the reaction mixture. sodium acetate (41 mg) so that a solution was formed. We have

  filtered this solution and scratching it began

  tallisation. The mixture was kept at 210 for 14.5 hours and then the crystals were collected by filtration, washed with water and dried under vacuum at 210 to give the title compound (250 mg). . Addition of 2N hydrochloric acid (6.9 ml) gave an additional amount of crystalline product (360 mg); + 136.270 (c 0, 54, DMSO); Xmax 234.4 nm (E1cm 408), Xinfl 249.6 (Elcm 295), 277.8% and 1% lm

(Elcm 192) and 295.0 nm (EBm 156).

1cm l 1m15)

Example 7

  (6R, 7R, 2'Z, S) -7- / 2- (2-aminothiazol-4-yl) -2- (2-aminothiazol-4-yl) acid

  Llcarboxy) (3,4-dihydroxyphenyl) méthoxvimino7acétamido7-

* ceph-3-th-4-carboxylic acid, salt with hydrochloric acid

  The compound of Example 4 (27.4 g) was dissolved in formic acid (110 ml) with stirring at room temperature.

  eC and 3 equivalents of hydrochloric acid were added

  than concentrated (8.2 ml). The mixture was stirred for an additional fifteen minutes and then was added dropwise over a period of six minutes to diisopropyl ether (1.1 liter) with stirring and stirring. The precipitate was collected by filtration, washed with diisopropyl ether (500 ml) and dried in vacuo to give the title compound (18.02 g); max (Nujol) 3600-2800 (broad) and 1780 cm-1; 3.3-3.7 (m, H-2), 5.05 (d, H-6), 5.4 (s, CHON), 5.8 (m, H-7), 6.46; (m, H-3) and 9.6 (d, NHCO).

Example 8

  (6R, 7R., 2 'Z, S) -7- / 2- (2-aminothiazol-4-yl) -2- (2-aminothiazol-4-yl) acid

  LTcarboxy) (3,4-dihydroxyphenyl) methoxyiminoacetamido7-

ceph-3-em-4-carboxylic acid.

  The compound of Example 7 (2.65 g), with stirring, was added to distilled water (10.6 ml) at 200 ml.

  and the mixture was stirred for thirty minutes,

  period during which crystallisation occurs

  Duisit. The suspension was vigorously cooled.

  in a mixture of ice and water for fifteen minutes and then the crystals were collected by

  filtration, they were washed with distilled water

  chilled (10 ml), dried in a circulating oven

  air at 30 ° C. to give the title compound (2.09 g); water content 12 6 (Karl Fischer); IR spectrum (NuJol) max 3700-2100 (broad), 1760, 1720, 1660v 1555, 1520,

  1350, 1300, 1290, 1240, 1215, 1170, 1155, 1120, 1050,

  1000, 920, 860 and 755 cm -1; X-ray diffraction grating (given as spacings in angstrom 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); 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); 3.48B (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

  (6R.7R, 2'ZS) -7- / 2- (2-Formamidothiazole-4-yl) -2- / T3.4-

  dihvdroxyphénvl) (diDhénvlméthoxvcarbonvl) méthoxyimino7-

  tert-butyl acetamido-7-t-th-4-carboxylate.

  Intermediate 5 (1.53 g), with stirring, was dissolved in methylene chloride (15 ml) and N, N-dimethylacetamide (2.9 ml) and the solution was cooled to -35.degree. And phosphorus oxychloride (0.41 ml) was added. The mixture was stirred at -25 to -20 for one hour and

  then added a solution of (bR, 7R) -7-aminocéph-3-

  tert-butyl e-4-carboxylate from its tosylate salt (1.0 g) under the action of a solution

  aqueous sodium bicarbonate, as described in

  Example 1 of diphenylmethyl ester in methylene chloride (15 ml) containing N, N-dimethylaniline (2.9 ml). We kept the mixture

  reaction at about 00 for 16 hours, it was

  washed with water, diluted hydrochloric acid (twice) and water; each time, the aqueous layer was extracted with methylene chloride. We have

  concentrated organic layers together until

  hold a foam that has been redissolved in chlorine

  Methylene chloride (15 ml) was added and the solution was poured down into a Sorbsil ™ U30 silica column (5g) eluting with methylene chloride (30 ml). The eluate was concentrated to one

  low volume and treated with diisopropyl ether

  propyl (15 ml) to precipitate the title compound as a white solid (1.2 g); (CDCl 3) 1.57 (s, CH 3) 3), 5.74 (s, OCHCO), 6.15 (m,

  H-7), 6.49 (d, H-3), 8.4-8.7 (m, NHCO and -OH).

Example 10

  (6R, 7R, 2'Z, S) -7 - / - (2-Aminothiazol-4-yl) -2- / 13.4-

  dihydroxyphenyl) (di-phenylmethoxycarbonyl) methoxyimino7-

  The compound of Example 9 (6.29 g) was stirred in methanol (64 ml) and 1,4-dioxane (16 ml) at 20 ° C. and added perchloric acid to

  % (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 silica '' Sorbsil '' U30 (65 g) which was then eluted

  with an additional amount of solvent.

  the appropriate fraction of the eluate has resulted in

  denote the title compound (4.0 g); 6 1.5 (s, CH 3) 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

  Acid (6R.7R.2'ZS) -7- / 2- (2-aminothiazol-4-Yl) -2-

  25 (carboxy) (3,4-dihydroxyphenyl) methoxyiminoacetamido).

  ceph-3-th-4-carboxylic acid, salt with hydrochloric acid

  than. The compound of Example 10 (1.5 g) was dissolved in formic acid (6 ml) with stirring at 20 and concentrated hydrochloric acid (0.35 ml, 2%) was added. 1 equivalents). 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 triturated with ethyl acetate (6 ml). The suspension thus obtained was stirred for 30 minutes at room temperature. The solid was collected by

  filtration, it was washed twice with acetic acid

  ethyl acetate and dried in vacuo to give the title compound (1.33 g)

  identical to the product of Example 7.

  Pharmaceutical example Dry powder for injection by vial

(6R, 7R, 2'Z, S) -7-amino-2-amino acid

  thiazol-4-yl7-2-carboxy) (3.4-500 mg)

dihydroxyphenyl) méthoxyimino7-

acétamido7céph-3-em-4-

carboxylic acid.

Sodium carbonate anhydrous 99 mg.

  Mix the two sterile components so

  aseptic and introduce them into sterile vials.

  Purge the top space of the flask with sterile nitrogen

  rile; close the vials using rubber stoppers and metal caps (applied by

  crimping). The product can be formed by dissolving

  in water for injections or any other suitable sterile vehicle, shortly before administration. - 44

Claims (13)

1. Compounds of the formula (I) HR3 H H Z / \ 1 __ r-ONH i iÀ OCHCOOR2 0; H OOR1   R 1 and R 2, which may be the same or different,   each represent a hydrogen atom or a   dical blocking the carboxyl function;   R3 represents a hydrogen atom or a radical   protecting the amino function; R4 and R5 each represent a hydroxyl or substituted hydroxyl radical, or R4 and R5 together represent a protected cyclic diol radical;   Z is -S- or -SO- (a- or O-); the line in broken lines   terminated bridge 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 the solvates (including   hydrates) and non-toxic salts of these compounds.   2. Compounds according to claim 1 of the formula (Ia) H2 NI; H 2xS _, H rONIQ1H N OCHCOOH O! H 1OOH \   (Ia) 1 / s, wherein R4a represents a hydroxyl or acetoxy radical; R5a represents a hydroxyl or acetoxy radical;   as well as metabolically labile esters, soil   vates (including hydrates) and non-toxic salts of these compounds.   3. Compounds of formula (Ia) according to   2, in which the etherifying group la.   oxime function has the S configuration.   4. (6R, 7R, 2'Z, S) -7-2- (2-aminothiazole) acid   4-yl) -2-carboxy (3,4-dihydroxyphenyl) methoxyimino   acetamido-7-phenyl-3-th-4-carboxylic acid and the   bolically labile solvates (including hy-   drats) and non-toxic salts of this compound.   5. A compound according to claim 4, crystalline form hydrated.   6. Hydrated crystalline compound according to the claim   5, characterized by an infrared spectrum   holding 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. Hydrated crystalline compound according to the claim   5, characterized by an X-ray diffraction grating (expressed as d-spacings in angstrom units and percent intensities) 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   (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 the formula (I) as defined in claim 1, or salts or solvates of these compounds, characterized in that a compound of the formula (II) is acylated H HZ HN -t fi (II OH COOR 1   (where R1, Z and the line in.   ruptured have the meanings ascribed to them in claim 1) or a salt or a 7-N-silyl derivative of such a compound, with a compound of the formula (III) NHR 3 I L - = .._ C.COOH 1 (III) NOT OîHCOOR2 II i 1 0 \ // \ R4   (wherein R2, R3, R4 and R5 have the meanings   fications attributed to them in the   cation 1), or a salt of such a compound, or with a corresponding acylating agent;   secondly, if it proves necessary and / or   In each circumstance, any of the following reactions can be carried out in any suitable order:   i) conversion of an A2 isomer to the desired A3 isomer you,   ii) reduction of a compound in which Z is -SO-   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, v) elimination of any blocking radicals the carboxyl and / or N-protecting function, and vi) elimination of any blocking radicals the hydroxyl function.   9. Process for the preparation of the crystal hydrate   Flax according to Claim 5, characterized in that an aqueous solution of the acid (6R, 7R, 2'Z,   S) -7-L2- (2-aminothiazol-4-yl) -2-Ljcarboxy) (3,4-di-   hydroxyphenyl) méthoxyimino_7acétamido7-ceph-3-em-4-   carboxylic acid, or an acid addition salt or a salt with a base of the acid in question, or a solvate of the salt concerned and crystallizes the hydrate in question.   10. Process for preparing the crystalline hydrate   tallin according to claim 5, characterized in that   that an aqueous solution of an additive salt is   acid or salt with a base of the acid   (6R, 7R, 2'Z, S) -7-L2- (2-aminothiazol-4-yl) -2-jcarboxy) -   -3,4-dihydroxyphenyl) méthoxyimino7-acétamido7-ceph-3-   e-4-carboxylic acid or a solvate thereof and the pH of said solution is adjusted to a varying value. from 1.0 to 4.0.   11. Pharmaceutical composition, characterized in that it contains, as active ingredient, a compound of the formula (Ia) as defined in the claim 2.   12. Pharmaceutical composition according to the claim   11, characterized in that the active ingredient   is a compound as defined in claim 4.   13. Pharmaceutical composition according to the   12, characterized in that the active ingredient is the crystalline hydrated compound of claim 5.