DE2460537A1 - CEPHALOSPORIN ANTIBIOTICS - Google Patents

Description

Dr. F. Zumstein Sr. - Tue E. Dr. R. Koenigsberger - Dip! - Phys, R. Holzbauer - Dr. F. Zumstein Jun.

PATENT LAWYERS

TELEPHONE: COLLECTIVE NO. 22 53 41

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97 / n

Case Cephalosporin 19l / l99

GLAXO LABORATORIES LIMITED, Greenford, Middlesex / Great Britain

Cephalosporin antibiotics

Cephalosporin _r antibiotics in which the 7ß-acylamido group has the structure

R.C.CO.NH-

NR ^a

\ I

_z ) _m .C. (CH ₂ ) _n .COOH

has, wherein

R represents thienyl or furyl,

R and R are each selected from the group consisting of hydrogen, C 1 to C alkyl, C ₀ to C alkenyl, Co _{to C 7 cycloalkyl}} phenyl, naphthyl, thienyl, furyl, carboxy, Cp - to Cc-alkoxycarbonyl and cyano, or R ^a and R together with the carbon atom to which they are bonded form a C ₀ - to C ^ cycloalkylidene or cycloalkenylidene radical and

m and η each represent the numbers 0 or 1 such that the sum of m and η is 0 or 1,

5Ü9827 / 0946

_ 2 -

have a broad-spectrum antibiotic activity, which is characterized by a particularly high activity against gram-negative microorganisms, including those that produce β-lactamases. The compounds that are syn isomers or are present as mixtures of syn and anti isomers, which contain at least 90% of the syn isomer, have a particularly high activity in vitro against strains of Escherichia coli, Haemophilus influenzae and Proteus Organisms or species. Compounds in which at least one of R ^a and R is not hydrogen also have unusually high activity against Pseudomonas organisms. Important compounds of the above type include those in which the 7β-acylamido group is a syn-2-carboxymethoxy-2- (fur-2 ~ yl) -acetamido-, syn-2- (2-carboxyprop-2-yloxyitnino) -2- (fur-2-yl) acetamido or syn-2- (l-carboxycyclopent-l-yloxyimino) -2- (fur-2-yl) acetamido group.

The invention relates to improvements in the field of cephalosporin Compounds en and particularly relates to a new class of cephalosporin compounds that are valuable antibiotic Have properties.

The cephalosporin compounds of the present specification are named with reference to "Cepham" (J.Araer.Chem.Soc., 1962, 84 , 3400) and the term "cephem" refers to the basic cepham structure with a double bond.

Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria in humans and animals, for example in the treatment of diseases caused by bacteria resistant to other antibiotics, such as penicillin compounds, as well as treatment from patients who are sensitive to penicillin. In many applications it is desirable to be a cephalosporin antibiotic to use that an activity against both

has both gram-positive and gram-negative microorganisms, and much research has gone into developing

5 09 827/0946

lung of different types of broad-spectrum cephalosporin antibiotics performed *

There is currently ¹ substantial interest in the development of broad spectrum cephalosporin antibiotics which have high activity against gram negative organisms. The existing, commercially available β-lactam antibiotics tend to have relatively low activity against certain gram negative organisms, such as Proteus organisms, which are increasingly infectious agents in humans, and are also generally essentially inactive against Pseudomonas organisms. Certain Pseudomonas organisms are resistant to the majority of the existing commercially available antibiotic compounds, and the practical therapeutic use of aminoglycoside antibiotics such as gentamicin, which have Pseudomonas activity, tends to be limited due to the high toxicity of these compounds to be complicated. It is known that the cephalosporin antibiotics normally have low toxicity in humans, so that the development of broad spectrum cephalosporin antibiotics which have high activity against gram-negative organisms such as Proteus and Pseudomonas strains has met a chemotherapeutic need .

The invention provides Tβ-acylamidoceph-B-em- ^ carboxylic acid antibiotics and non-toxic derivatives thereof which are characterized in that the acylamido portion has the formula

R.C.CO.NH-

has, wherein

509827/0946

R represents a thienyl or furyl radical,

away
R and R, which can be the same or different, are each selected from the group consisting of hydrogen, CL- to C ₄ -alkyl (e.g. methyl, ethyl, n-propyl, isopropyl or butyl), C ₂ - to C.- Alkenyl (e.g. vinyl or allyl), C ₃ - bis (^ -Cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), phenyl, naphthyl, thienyl, furyl, carboxy, C ₀ - to Cc alkoxycarbonyl (e.g. ethoxycarbonyl) and cyano , or R and R together with —the carbon atom to which they are bonded, form a C 1-4 cycloalkylidene or cycloalkenylidene radical (eg a cyclobutylidene, cyclopentylidene or cyclohexylidene radical) and

m and η each represent the numbers O or 1 such that the sum of m and η is 0 or 1,

and wherein the compounds are syn isomers or are present as mixtures of syn and anti isomers which contain at least 90 % of the syn isomer.

These compounds have broad spectrum antibiotic activity, which are particularly characterized by high activity against gram-negative microorganisms including those that Form ß-lactamases, and also have a high stability towards ß-lactamases, which by some gram-negative Organisms are generated. A characteristic feature of the compounds is their high activity in vitro against gram-negative organisms such as Enterobacter clocae, Serratia marcescens and Klebsiella aerogenes. The connections have a particularly high activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms, e.g., strains of Proteus morganii and Proteus mirabilis.

Compounds in which at least one of R and R is not hydrogen also have an extraordinary one

high activity against Pseudomonas organisms, e.g. Pseudomonas aeroginosa strains.

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The compounds of the invention are with regard to the configuration of the rest

O. (CH) .C. (CH ₂₎ COOH

^b :

as the syn-isomeric form, with respect to the carboxamido group, having defined. In the present description, the syn configuration is structurally referred to as follows:

R. CCO. NH-

R ^a

_2m2n R ^b

this configuration is assigned on the basis of the work of Ahmad and Spenser (Can. J. Chem., 1961, 3 ^. »Ί34Ο). As mentioned above, the compounds can exist as mixtures of the syn and anti isomers, with the proviso that such mixtures contain at least 90 % of the syn isomer. It is preferred, however, that the compounds be syn isomers which are essentially free of the corresponding anti isomer.

The antibiotics according to the invention see compounds hence compounds of the general formula

R.C.CO.NH

COOH 0. (CH ₀ ) .C. (CH) .COOH

609827/0946

wherein R, R ^a, R, m and η the above meanings and Z represents a group the core sulfur atom and the carbon atom in the 4-position so connect at the 2 carbon atoms that the compound has an olefinic / \ -Unsättigung, as well as non-toxic derivatives thereof.

By "non-toxic derivatives" those derivatives which are physiologically tolerable in the administered dosage. Such derivatives can, for example, salts, biologically compatible esters, 1-oxides and solvates (especially Hydrates). Such derivatives as salts and esters can be obtained by reaction of either or both carboxyl groups, contained in the compounds of formula I are formed.

Non-toxic salt derivatives obtained from the compounds of general formula I include salts of inorganic bases, such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts), salts of organic bases (e.g. procaine, phenylethylbenzylamine, Dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine salts) and optionally Acid addition salts, e.g. with hydrochloric acid, hydrogen bromide acid, "sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, toluene-p-sulfonic acid and methanesulfonic acid. The salts can also be in the form of resinates, with, for example, a polystyrene resin or crosslinked polystyrene-divinylbenzene copolymer resin, the amino or quaternary amino groups or optionally sulfonic acid groups, or optionally with a resin containing carboxyl groups e.g., a polyacrylic acid resin. The use of highly soluble salts of the compounds of the Formula I with bases (e.g. alkali metal salts such as the sodium salt) is generally in therapeutic use This is advantageous because such salts are quickly distributed in the body when administered. However, if insoluble salts of compounds of the formula I are desired for special applications, e.g. for use in depot preparations

50 9 827/0946

460537

such salts can be formed in a conventional manner, for example with suitable organic amines.

Biologically compatible, metabolically labile ester derivatives, which can be formed from the compounds of the formula I include, for example, acyloxymethyl esters, for example lower alkanoyloxymethyl esters, such as acetoxymethyl or pivaloyloxymethyl ester.

If the radical R in the above formulas represents a furyl radical, this can be a fur-2-yl or fur-3-yl radical and when "R represents a thienyl radical, this can be a thien-2-yl or thien-3-yl radical.

When R ^a and R in the above formulas are different, the carbon atom to which they are attached may comprise a center of asymmetry. Thus, compounds of the invention in which R ^a and R are different can be diastereoisomeric. The invention includes the individual diastereoisomers of such compounds as well as mixtures thereof.

The cephalosporin antibiotics according to the invention can be unsubstituted in the 3-position or any in this position from the multitude of substituents described in the ■ literature relating to cephalosporin compounds wherein the characteristic feature of the present invention is the kind of 7β-acyl amido group. is. The invention thus includes compounds of the general formula

R.C.CO.NH

COOH

O. (CH_). C (CH ₀ ) .COOH 2 mj, zn

509827/0946

wherein R, R ^a , R, m and η have the above meanings and P is a hydrogen atom, a halogen atom such as fluorine, chlorine or bromine, or an organic radical, for example a saturated or unsaturated, substituted or unsubstituted organic radical with 1 to 20 Carbon atoms, and their non-toxic derivatives.

When P represents an unsaturated organic radical, R can, for example, be a radical of the formula

-CH = C

1 2

where R and R, which can be the same or different, are each selected from the group consisting of hydrogen, carboxy-, cyano-, C ₂ - to Cy-alkoxycarbonyl- (eg methoxycarbonyl- or ethoxycarbonyl-), and substituted or unsubstituted aliphatic (for example alkyl, preferably C _{1 to} Cg alkyl, such as methyl, ethyl, isopropyl or n-propyl), Cg to C ₇ cycloaliphatic (for example Cg to C ^ cycloalkyl -, such as cyclopentyl or cyclohexyl), C ^ - to C ^ -araliphatic (e.g. phenyl-C.- to C.-alkyl-, such as benzyl or phenylethyl) and Cg- to ^., - aromatic (e.g. mono- or bicyclic carbocyclic aryl, such as phenyl, nitrophenyl, tolyl or naphthyl) radicals. Typical substituted vinyl groups of the above formula include 2-carboxyvinyl, 2-methoxycarbonylvinyl, 2-ethoxycarbonylvinyl and 2-cyano vinyl.

P can also be a substituted methyl group of the formula

-CH ₂ Y

wherein Y represents an atom or a group, e.g. Residue of a nucleophile or a derivative of a residue of a nucleophile. Thus, for example, Y can be from a variety of nucleophilic Substances are derived that are characterized by the fact that they are a nucleophilic nitrogen, carbon-sulfur or oxygen atom and which is detailed in the patents and literature relating to the

509827/0946

Cephalosporin chemistry related, are described. Examples for such nucleophiles include:

NITROGEN NUCLEOPHILES

Examples of nitrogen nucleophiles include tertiary aliphatic, aromatic, araliphatic and cyclic amines, such as tri- (C ₁ - to Cg-alkyl) amines such as triethylamine, and heterocyclic tertiary amines. The heterocyclic tertiary amines can optionally contain one or more further heteroatoms in addition to the basic nitrogen atom, and they can be substituted or unsubstituted. The heterocyclic tertiary amines can thus be, for example, a pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, iinidazole, triazole or thiazole; a condensed bi- or poly-cyclic analogue of one of these heterocycles, for example purine or benzotriazole; and any of the above amines substituted by one or more aliphatic (e.g. lower alkyl such as methyl ·, ethyl, n-propyl or isopropyl · -), aryl ( e.g. Cc- to Cjp-mono- or bicyclic carbocyclic aryl- such as Phenyl or naphthyl), araliphatic (for example phenyl-lower rig-alkyl, such as benzyl or phenylethyl), lower alkoxymethyl (for example methoxymethyl, ethoxymethyl, n-propoxymethyl or isopropoxymethyl), acyloxymethyl - (e.g. lower alkanoyloxymethyl, such as acetoxymethyl, formyl, acyloxy (e.g. lower alkanoyloxy, such as Ac et oxy), carboxy, esterified carboxy (e.g. lower alkoxycarbonyl, such as methoxycarbonyl), carboxy low alkyl (e.g. carboxy methyl), sulfo, lower alkoxy (e.g. methoxy, ethoxy, n-propoxy or isopropoxy), aryloxy (e.g. phenoxy), aralkoxy (e.g. benzyloxy- ^, alkylthio - (e.g. methylthio or ethylthio), arylthio, aralkylthio, cyano, hydroxy, carbamoyl, N-mono-lower alkylcarbamoyl (e.g. N-methylcarbamoyl or N-ethylcarbamoyl -), N, N -Di-lower alkyl carb amoyl (e.g. Ν, Ν-dimethylcarbamoyl or N, N-diethylcarbamoyl), N-f-hydroxy-lower-alkyD-carbamoyl- (e.g. N- (hydroxymethyl) -carbamoyl or N- (hydroxyethyl) -carbamoyl) or carbamoyl -r-lower alkyl (for example carbampylmethyl or carbamoylethyl) groups. Examples of radicals Y, which are derived from nucleophilic heterocyclic tertiary amines of the above type

509827/0946

include pyridinium, 3- and 4-carbamoylpyridinium, 3-carboxymethyl pyridinium, 3-sulfopyridinium, thiazol-3-yl, Pyrazol-1-yl, pyridazinium and benzotriazol-1-yl.

Another class of nitrogen nucleophiles includes azides, e.g. alkali metal azides, such as sodium azide.

When the radical Y is a derivative of a radical of a nitrogen nucleophile it can be, for example, an amino radical or an acylamido radical be. Compounds in which Y is amino can be selected from the corresponding compound in which Y is azido, be derived by reduction, e.g. by catalytic hydrogenation of the azide using a noble metal catalyst, like palladium or platinum. Compounds in which Y is an acylamido group can be obtained by acylation a compound in which Y is amino, for example by any method capable of acylating an aminocephalosporin is suitable, e.g., reaction of the amino compound with an acid chloride, acid anhydride or mixed anhydride Acid corresponding to the desired acyl group and another acid.

Compounds in which Y is amino can also be reacted with a substituted isocyanate or isothiocyanate, to obtain urea or thiourea derivatives.

Other compounds in which Y is a derivative of a residue of a nitrogen nucleophile can be obtained by reacting a compound wherein Y represents azido, can be obtained with a dipolarophile. Examples of suitable dipolarophiles include acetylenic, ethylenic and cyano dipolarophiles.

Acetylenic dipolarophiles can be given by the formula

R ³ . C ^ C .R ^A

3 4
are denoted in which R and R, the same or different

can be, represent atoms or groups.

5038 27/0 94 6

3 In general, it is preferred that R and preferably also R are electronegative in nature. Examples of such Radicals include cyano, COpR, COR (where R is e.g. hydrogen, lower-alkyl, aryl or lower-aralkyl) and trihalomethyl, e.g. trifluoromethyl.

3 4

However, R and preferably also R can be electropositive,

e.g., alkoxy or alkylamino.

3 4
R and R can be taken together with the acetylenic group

Form a ring system, e.g. in an aryne.

3 4
If R and R represent individual atoms or groups that are identical, a single compound is formed in the reaction with the azidocephalosporin. However, if they are different, a mixture of positional isomers is generally obtained.

Ethylenic dipolarophiles can use the formula

~ 6

C = C

6 V 8 9
have, wherein R,. R, R and R, which are the same or different

6 which can be, represent atoms or groups. Although R, R,

OQ

R and R can all represent hydrogen, ethylene per se as well as acetylene reacts slowly or slowly with azido groups.

CO

pend. R and R together can have a cyclic structure, e.g. form a carbocyclic structure with the ethenoid group in such a way that the double bond is strained. examples for Ethylenic dipolarophiles that contain strained double bonds include norbornenes, trans-cycloalkenes, and acenaphthylenes.

503827/0946

Other Ethylenic Dipolarophiles that are used

6 7 8 Q can include compounds of the formula R .R C = CR .R,

6 7 8 9 wherein at least one of R, R, R and R is an electro-

/ - ρ

negative group is. R and R can therefore have identical elec-

7 9 tronegative groups, with R and R if desired

7 9
other groups are. R and R can thus be together

Form ring system. Examples of such dipolarophiles include benzoquinone and ring-substituted benzoquinones and

6 7 8 9 maleimide. Furthermore, R, R, R and R can all be identical

be electronegative groups. Electronegative groups that • can be used include those in the section on acetylenic dipolarophiles and examples of such compounds thus include dicyanoethylene and lower mono- and dialkoxycarbonyl ethylenes.

6 7 8 9

One or more of R, R, R and R can be used if desired be electropositive.

Cyano compounds, especially those produced by electronegatives Groups activated can act as cyano dipolarophiles. Examples of such dipolarophiles include lower alkoxycarbonyl cyanide and dicyan.

CARBON NUCLEOPHILES

Examples of carbon nucleophiles include inorganic cyanides, pyrroles and substituted pyrroles, e.g. indoles, and compounds which provide stabilized carbanions, e.g. acetylenes and compounds with ß-diketone groups, e.g. acetoacetic and Malonic acid esters and cyclohexane-l, 3-diones or enamines, inamines or enols.

The carbon nucleophiles can thus be cephalosporin compounds provide, which are characterized in that they have a substituent in the 3-position, in which one Carbonyl group with the cephalosporin nucleus through two carbons atoms is bound. Such compounds can thus be a radical of the formula as a substituent in the 3-position

5 0 9827/0946

R ¹⁰

¹ 12 eCH _o .C.C0.R

R ^U

wherein R and R, which may be the same or different, are selected from hydrogen; Cyano; lower alkyl, for example methyl or ethyl; Phenyl; Phenyl, substituted, for example by halogen, lower-alkyl, lower-alkoxy, nitro, amino or lower-alkylamino; Carboxy; lower-alkoxycarbonyl *, mono- or diaryl-lower-alkoxycarbonyi; -lower-alkylcarbonyli aryl-lower-alkyl or Ct-- or C _a -

12 db

Cycloalkyl and R is selected from hydrogen; lower alkyl, for example methyl or ethyl; Phenyl; Phenyl substituted by, for example, halogen, lower-alkyl, lower-alkoxy, nitro, amino or lower-alkylamino; Aryl-lower alkyl or C ₅ - or Cg -cycloalkyl.

SULFUR NUCLEOPHILES

Examples of sulfur nucleophiles include thioureas included the aliphatic, aromatic, araliphatic, alicyclic and heterocyclically substituted thioureas, dithiocarbamates, aromatic, aliphatic and cyclic .Thioamides, e.g. thioacetamide and thiosemicarbazide, thiosulfates, Thiols, thiophenols, thio acids such as thiobenzoic acid or thiopicolinic acid, and dithio acids.

One class of sulfur nucleophiles includes those

13 13

bonds of the formula R .S (O) H, in which R is an aliphatic radical, for example lower-alkyl, such as methyl, ethyl or n-propyl radical; an alicyclic radical, for example lower cycloalkyl, such as cyclohexyl or cyclopentyl radical; an aromatic radical, for example Cg to C * 2 ~ ^mon ° - or bicyclic carbocyclic aryl, such as phenyl or naphthyl radical; an araliphatic radical, for example phenyl-lower (for example C ^ - to C ₄ -) - alkyl, such as the benzyl radical; or represents a heterocyclic radical and η denotes the numbers 0, 1 or 2. A preferred class of nucleophiles of the above formula are those of

509827/0946

14 14

general formula R SH, where R is aliphatic, e.g. lower

rig-alkyl, such as methyl, ethyl or n-propyl, or lower alkanoyl, such as acetyl; araliphatic, e.g. phenyl-lower-alkyl, such as benzyl or phenethyl or substituted phenyl-lower alkyl; alicyclic, e.g., cycloalkyl such as cyclopentyl or cyclohexyl; aromatic, e.g., phenyl, substituted Phenyl; or a heterocyclic radical which contains at least one 5- or 6-membered ring and one or more heteroatoms is selected from O, N and S. Such

14th

heterocyclic radicals R can be substituted, and examples of suitable heterocyclic groups include thiadiazolyl, e.g., 5-methyl-1,3,4-thiadiazol-2-yl; Diazolyl; Triazolyl, e.g., triazol-4-yl; Tetrazolyl, e.g. 1-methyltetrazol-5-yl, 1-ethyl-tetrazol-5-yl or 1-phenyl-tetrazol-5-yl; Thiazolyl; Thiatriazolyl; Oxazolyl; Oxadiazolyl, e.g., 2-phenyl, 3,4-oxadiazol-5-yl; Pyridyl, e.g., N-methylpyrid-2-yl; Pyrimidyl; fused heterocyclic ring systems, such as Benzimidazolyl, benzoxazolyl, benzothiazolyl, such as benzothiazol-2-yl, Triazolopyridyl or purinyl ;. and substituted derivatives of such fused ring systems, e.g. nitrobenzothi'azol-2-yl, such as 5- or 6-nitrobenzothiazol-2-yl.

OXYGEN NUCLEOPHILES

Examples of oxygen nucleophiles include water, alcohols, e.g., alkanols such as methanol, ethanol, propanol and butanol, and lower alkanoic and alkene acids.

The term "oxygen nucleophile" thus includes compounds the general formula

R ¹⁵ OH,

15th
in which the radical R can be: lower-alkyl (e.g. methyl,

Ethyl, n-propyl, isopropyl, η-butyl or isobutyl); lower alkenyl (e.g. allyl); lower alkynyl (e.g. propynyl); lower cycloalkyl (e.g. cyclopropyl, cyclopentyl, or cyclohexyl); lower-cycloalkyl-lower-alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl or cyclohexylethyl); Aryl (e.g. phenyl or naphthyl); Aryl-lower alkyl (e.g. benzyl); a heterocyclic

509827/0946

shear radical (e.g. a heterocyclic radical / as defined for R, such as N-methylpyrid-2-yl); a heterocyclic lower alkyl radical (e.g. furfuryl); or any of these radicals substituted, for example, by one or more selected from lower alkoxy (e.g. methoxy or ethoxy), lower alkylthio (e.g. methylthio or ethylthio), halogen (chlorine, bromine, iodine or fluorine), lower-alkyl (e.g. methyl or ethyl), nitro, Hydroxy, acyloxy, carboxy, carbalkoxy, lower-alkylcarbonyl, lower-alkylsulphonyl, lower-alkoxysulphonyl, amino, lower-alkylamino or acylamino.

When water is the nucleophile, the 3-hydroxymethyl-cephalosporin compounds are obtained. Such 3-hydroxymethyl compounds and their non-toxic derivatives can have antibacterial activity, and it should be noted that they can be metabolites of compounds of the general formula II in which P is acetoxymethyl. 3-Hydroxymethyl-cephalosporins can be acylated to obtain derivatives containing the group 3-CH ₅ -O-CO-R ¹⁶ or 3-CH ₀ -O-CO-AR ¹⁷ on-

16, wherein A is 0, S or NH, R is an organic

17th
Represents a radical and R is hydrogen or an organic radical

represents.

The remainder of R CO- or R A.CO- ic can be under "the great class groups can be selected from those described in the literature and can have up to 20 carbon atoms. R and optionally R can thus each be a hydrocarbon radical or such a radical which is an or carries several atoms or groups as substituents, be and can thus, from the following, not be considered complete list 'can be selected:

i) CH where η is an integer from 1 to 7, e.g. 1 to 4. The remainder can be straight or branched chain and, if desired, through an oxygen or sulfur atom or an imino group or interrupted by cyano, carboxy, lower alkoxycarbonyl, hydroxy, carboxycarbonyl (HOOCCO.), Halogen (e.g. chlorine, bromine or iodine) or amino.

509827/0946

- 46 -

Examples of such groups include methyl, ethyl, propyl, isopropyl, η-butyl, tert-butyl, sec-butyl and 2-chloroethyl.

ii) CH ₀ ", where η is an integer from 2 to 7. η zn — χ ⁷

The remainder can be straight or branched and if desired be interrupted by an oxygen or sulfur atom or an imino group. Examples of such groups include vinyl and propenyl.

Λ R Ί R

iii) R, where R is carbocyclic aryl (e.g. Cg- to C ₁₂ -mono- or bicyclic carbocyclic aryl), heterocyclic aryl (e.g. comprising a 5- or 6-membered ring which contains at least one selected from O, N and S) , lower cycloalkyl, substituted aryl and substituted cycloalkyl. Examples of this radical include: phenyl; substituted phenyl, for example hydroxyphenyl, chlorophenyl, fluorophenyl, To-IyI, nitro phenyl, aminophenyl, methoxyphenyl or methylthiophenyl; Thien-2- and -3-yl; Pyridyl; Cyclohexyl; Cyclopentyl; Cyclopropyl; Sydnon; Naphthyl; and substituted naphthyl, for example 2-ethoxynaphthyl.

iv) R ^ ^CH 2 ^ m ' ^wor ^ - ^{n R} ^ - ^e has the meaning given above under iii) and represents an integer from 1 to 4.

Examples of "this radical include methyl, ethyl or butyl,

Ί R substituted by the various typical groups R listed above under iii), for example lower-cycloalkyl-C., - to C.-alkyl and carbocyclic or heterocyclic aryl-C ^ - to C ₄ -alkyl, such as benzyl and the suitable substituted benzyl groups.

The 3-position substituents of the above type include thus low-alkanoyloxymethyl radicals, such as acetoxymethyl and Isobutyryloxymethyl, lower alkenoyioxymethyl residues, such as Cro'tonyloxymethyl; Aroyloxymethyl residues such as benzoyloxymethyl; Carbamoyloxymethyl, N- (lower-alkyl) -carbamoyloxymethyl, such as N-methylcarbamoyloxymethyl, and N- (haloalkyl) -carbamoyloxymethyl, such as N- (2-chloroethyl) carbamoyloxymethyl.

509827/0 9-4

Another important class of cephalosporin compounds are those with the group -CHpHaI in the 3-position, in which Hai means chlorine, bromine or iodine. Such compounds can be used primarily as intermediates in the manufacture of active cephalosporin compounds can be valuable by passing the halogen atom through a nucleophile, e.g. a nitrogen, oxygen or sulfur-containing nucleophil as above described, is replaced.

The term "low" as used here to denote aliphatic Groups is used, unless otherwise stated, that the remainder contain up to 6 carbon atoms can. The term "lower" to denote cycloaliphatic radicals means that radicals 3 to 7 (e.g. 5 to 7). May contain carbon atoms.

A particularly interesting class of cephalosporin antibiotics according to the present invention includes compounds of the general formula

ΊΙΙ

COOH

where R has the above meaning, R is methyl, ethyl, propyl, Represents allyl or phenyl and R represents hydrogen, carboxy or, preferably, a radical as defined for R. became; or R and R together with the carbon atom to which they are attached form a cyclobutylidene, cyclopentylidene or form a cyclohexylidene radical, and W is selected under

509827 / 0-946

i) hydrogen,

ii) acetoxymethyl,

iii) benzoyloxyiiiethyl,

iy) carbamoyloxymethyl,

v) N-methylcarbamoyloxymethyl,

vi) a radical of the formula

-CH = CHR ^Z ,

wherein R is cyano, carboxy or a Cp- to Cc-alkoxycarbonyl radical, like methoxycarbonyl or xthoxycarbonyl, represents

vii) the residue -CHpG, in which G is the residue of a nitrogen newcleophile represents, selected from compounds of the formula

wherein R is hydrogen, carbamoyl, carboxymethyl or SuIfο, and pyridazine,

viii) azidomethyl and

ix) the radical -CHpSR ^W , in which R ^{W is} selected from pyridyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl and, for example, lower-alkyl or phenyl-substituted variants of these radicals, such as N-methylpyrid-2-yl, l -Methyltetrazol-5-yl, l-phenyltetrazol-5-yl, 5-methyl-l, 3,4-thiadiazol-2-yl and 5-phenyl-l, 3,4-oxydiazol-2-yl,

and also their non-toxic derivatives.

These compounds have broad spectrum antibiotic activity (including very high activity against Strains of Haemophilus influenzae and Proteus organisms) and a high ß-lactamase stability and are also characterized by a particularly high activity in vitro against Pseudomonas organisms, such as strains of Pseudomonas aeruginosa, the end.

509827/0946

Particularly preferred compounds of the above type Because of their particularly high activity against Proteus and Pseudomonas organisms, include the following:

(6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -3-pyridiniumraethylceph-3-em-4-carboxylic acid (syn isomer)

(6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -3- (5-methyl-1,3,4-thiadiazol-2 -ylthiomethyl) -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-Carbamoyloxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -7- [2- (2-carboxypropo-2-yloxyimino) -2- (fur-2-yl) acetamido] -3- (trans-2-methoxycarbonylvinyl) -ceph-3-era- 4-carboxylic acid (syn-isomer),

(6R, 7R) -7- [2- (2-Carboxypro-2-yloxyiniino) -2- (fur-2-yl) -acetarnido] -3-pyridaziniummethylceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -7 - [. 2- (2-Carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-eiti-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid _ (syn-isomer),

(6R, 7R) -7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamido] -3-pyridiniummethylceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -7- [2- (l-Carboxycyclopent-l-yloxyimino) -2- (fur-2-yl) -acetamido] -3- (trans-2-carboxyvinyl) -ceph-3-em- 4-carboxylic acid (syn-isomer),

(6R, 7R) -7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamido] -3- (1-methyltetrazol-5-ylthiomethyl ) -ceph-3 ^ -em-4-carbonic acid (syn-isomeres),

(6R, 7R) -3-Carbamoyloxymethyl-7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

509827/09 4 6

(6R, 7R) -7- [2- (1-Carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxybut-3-enyloxyirnino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-Isotneres),

(6R, 7R) -3-acetoxymethyl 1-7- [2 - (! - carboxyCyclobut-1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -7- [2- (1-carboxycyclobut-1-yloxyimino) -2- (fur-2-yl) acetamido] -3-pyridiniumethylceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -7- [2- (1-carboxycyclobut-l-yloxyimino) -2- (fur-2-yl) acetamido] -3- (1-methyltetrazol-5-ylthiomethyl) -ceph-3- em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-Carbamoyloxymethyl-7- [2- (1-carboxycyclobut-1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxypropoxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-acetoxymethyl-7- [2- (3-carboxypent-3-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

and their non-toxic derivatives, e.g., alkali metal salts such as the sodium and potassium salts.

Another interesting class of cephalosporin antibiotics of the invention includes compounds of the general formula ^ H "

N * " - ^W

RCCO.NH 1 r ί ■ _T v

COOH

O. (CH ₂ ) p.COOH

509827/0946

where R and W have the above meaning and ρ 1 or 2 and their non-toxic derivatives.

These compounds have broad spectrum antibiotic activity, paired with a high ß-lactamase stability. A characteristic feature of the compounds is their high activity against strains of Haemophilus influenzae, coupled with their particularly high activity against strains of Escherichia coli and Proteus organisms.

Particularly preferred compounds of the above type
Because of their particularly high activity against Escherichia coli and Proteus organisms, include the following:

(6R, 7R) -3-acetoxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-Azidomethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -7- [2-Carboxymethoxyimino-2- (fur-2-yl) acetamido] -3- (1-methyltetrazol-5-ylthiomethyl) -ceph-3-em-4-carboxylic acid (syn-isomer),

(6R, 7R) -3-carbemoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

(6R, 7R) -7- [2-Carboxymethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid Csyn isomer)

as well as their non-toxic derivatives, e.g. alkali metal salts, like the sodium or potassium salts.

The compounds according to the invention can be prepared by any suitable method, for example by techniques analogous to those in the BE-PS
783 449 described.

509 827/0946

Thus, according to an embodiment according to the invention a process for the preparation of an antibiotic compound of the above general formula I or a non-toxic derivative thereof has been provided, which is characterized in is that you can either

A) a compound of the formula

COOR ¹⁹

B ^ S or> S > 0 (α- or ß-),

19th
R is hydrogen or a carboxy1-blocking group, zE

the remainder of an ester-forming aliphatic or araliphatic alcohol or an ester-forming phenol, Silanols or stannanols (where the alcohol, phenol, silanol or stannanol are preferably 1 to 20 carbon atoms contains) or a symmetrical or mixed anhydride group derived from a suitable acid is, represents and

Z ^{1 represents} a radical in which 2 carbon atoms connect the core sulfur atom and the carbon atom in the 4-position in such a way that the compound has A - or / \ unsaturation,

or a salt such as an acid addition salt such as a hydrochloride, hydrobromide, sulfate, nitrate, phosphate, methanesulfonate or tosylate, or an N-silylated derivative thereof with a Acylating agent condenses that of an acid of the following formula

R.C.COOH

NR ^a

\ · 90

0. (CH ₀ ) .C (CH ₀ ) .COOR VI

ί Ι Ι, Δ Xi

509827/0946

. "· ..-. 2A6Q537

corresponds to, wherein R, R ^a , R, m and η have the preceding meaning and R is a carboxy 1-blocking group, for example

19th

represents a group as defined above with respect to R; or

B) when Z in formula I is the group

represents, wherein Y has the preceding meaning, a compound the formula

VII

R ^{a 1} COOR ^19th

I I Q

'0. (CH) .C (CHl) .COOR R ^b

wherein B, R, R ^a,. R, m and η have the meaning given above,

19th

each R independently of one another is hydrogen, or a carboxyl-blocking one Can represent group, γ «represents the replaceable radical of a nucleophile, e.g. an acetoxy or Dichloroacetoxy group or a halogen atom such as chlorine, bromine or iodine, and the broken line spanning the 2-, 3-, and 4- positions indicates that the compound is a Ceph-2-em- or Ceph-3-enw compound is

reacts with a nucleophile; after which, if necessary and / or Desirably, in each case any of the following reactions C) are carried out in any suitable order:

i) conversion of a ^ -isomer into a desired A -isomer,

ii) reduction of a compound in which B => S > 0 ,

to form a compound where B => S,

5 0 9 8 2 7/0 9 4 6

iii) Reduction of a 3-azidomethyl compound to form a 3-aminomethyl compound,

iv) acylation of a 3-aminomethyl compound to form a 3-acylaminomethyl compound,

v) reaction of a 3-azidomethyl compound with a dipolarophile to form a compound which has a polyazole ring which has a methylene group with the Carbon atom is connected in 3-position,

vi) deacylating a 3-acyloxymethyl compound to form a 3-hydroxymethyl compound,

vii) acylation of a 3-hydroxymethyl compound to form a 3-acyloxymethyl compound,

viii) carbamoylation of a 3-hydroxymethyl compound to form an unsubstituted or substituted 3-carbamoyloxymethyl compound and

ix) removal of carboxyl blocking groups; and finally

D) the desired compound of the formula I or a non-toxic derivative thereof, optionally after the separation of the Isomers is isolated.

Non-toxic derivatives of the compounds I can be applied to any be formed in a conventional manner, for example according to known methods. For example, salts of bases can be produced by reaction of the Cephalosporic acid with sodium 2-ethylhexanoate or potassium 2-ethylhexanoate getting produced. Biologically compatible ester derivatives can be obtained using conventional esterifying agents. 1-Oxides can be obtained by treating the corresponding cephalosporin sulfides with a suitable oxidizing agent, e.g. with a peracid such as metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid, or formed with tert-butyl hypochlorite, this the latter reagent is usually used in the presence of a weak base such as pyridine.

509827/0946

Acylating agents that can be used in preparing the compounds of Formula I include acid halides, in particular acid chlorides or bromides. Such acylating agents can be prepared by having a Acid VI or a salt thereof with a halogenating agent, e.g. phosphorus pentachloride, thionyl chloride or oxalyl chloride, implements. Treatment of the sodium, potassium or triethylammonium salt the acid VI with oxalyl chloride is advantageous insofar as the isomerization under these conditions is minimal.

Acylations using acid halides can be performed in aqueous or non-aqueous reaction media, advantageously at temperatures from -50 to +50 C, preferably from -20 up to +30 C, optionally in the presence of an acid-binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, Amides such as dimethylacetamide, nitriles such as acetonitrile, or mixtures of two or more such solvents. Suitable Acid binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. Calcium carbonate or sodium carbonate) and oxiranes, such as lower 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide), which contains the hydrogen halide that is present in the acylation reaction is released, bind.

Acids of the formula VI can themselves be used as acylating agents in the preparation of compounds of the formula I. Acylations using acids VI are advantageously carried out in the presence of a condensing agent, for example a carbodiimide, such as Ν, Ν'-diethyl-, -dipropyl- or -diisopropylcarbodiimidy N, N • -dicyclohexylcarbodiimide or N-ethyl-N ¹ -v ·· - dimethylaminopropylcarbodiimide; a carbonyl compound such as carbonyldiimidazole; or an isoxazolinium salt, such as N-ethyl-5-phenylisoxazolinium perchlorate. The acylation reactions of this type are advantageously carried out in an anhydrous reaction medium, for example methylene chloride,

■ 509827/0946

Dimethylformamide or acetonitrile, .. carried out.

The acylation can also be carried out with other amide-forming derivatives of the acids of formula VI, such as a symmetrical 'anhydride or a mixed anhydride (e.g. formed with pivalic acid or from a haloformate, such as a lower alkyl haloformate). The mixed or symmetrical Anhydrides can be generated in situ. For example, a mixed anhydride can be prepared using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline are formed. Mixed anhydrides can also be mixed with phosphorus-containing acids (e.g. phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. p-toluenesulfonic acid) are formed.

In the process for the preparation of the compounds of the formula I in which R ^a or R is carboxy, it may be necessary in many cases to remove the carboxy group, for example by substitution

with a carboxyl blocking group, e.g. a group,

19th

as defined above with respect to R.

Any conversions of substituents in the 3-position that in the preparation of particular compounds of the formula I may be necessary, for example, according to the in the literature procedures described are carried out.

For example, connections that are in the 3-position by a

-CH ₂ Y

are substituted, in which Y is an ether or thioether radical or represents a halogen atom as described in British Patents 1,241,656, 1,241,657, 1,277,415 and 1,279,402 Process are produced. Compounds in which Y represents the residue of a nucleophile can also be obtained by reaction a 3-acetoxymethyl-cephalosporin compound with a nucleophile, e.g., pyridine or other tertiary amine as described in GB-PS 912,541; a sulfur-binding,

50 9 827/0946

^ 2410537

--27 -

Nitrogen-linking or inorganic nucleophile, such as described in GB-PS 1,012,943; a sulfur-binding nucleophile, as in GB-PS 1 059 562, 1 101 423 and 1 206 305, or a nitrogen-binding one Nucleophile as described in UK Patents 1,030,630, 1,082,943 and 1,082,962. Links, in which Y is a derivative or a residue of a nucleophile for example where Y represents an amino or acylamido group derived from an azido group are manufactured according to GB-PS 1 057 883 and 1 211 694, these patents also describe the reaction of compounds in which Y is azido with a dipolarophile describe. Compounds in which Y is the residue of a nucleophile can also be obtained by reaction of a 3-halomethylcephalosporins with any of those in "the preceding References described nucleophiles, where such a process is described in GB-PS 1 241 657, or by reacting a 3-halomethylcephalosporin sulfoxide with any of the nucleophiles mentioned in the above references, such a method in GB-PS 1,326,531 is described. The contents of the aforementioned GB-PSs are incorporated herein by reference included on it.

When a 3-halomethylcephalosporin sulfide or sulfoxy ester with a tertiary nitrogen nucleophile, such as pyridine, is reacted according to the procedure described in British Patent 1,241,657 or 1,326,531, the reaction product becomes usually in the form of, for example, the corresponding 3-pyridinium methyl halide obtain. It has been found that the deesterification of compounds of this type by treatment with Trifluoroacetic acid tends to isomerize the oxyimino part to accelerate in the 7ß-acylamido side chain or to catalyze. Such isomerization is evident undesirable when a product containing at least 90% of the syn isomer without a subsequent step of Isomer separation is to be obtained.

509827/0946

However, it was also found that the tendency to isomerization can be significantly reduced if the 3-pyridinium methyl halide is converted into the 3-pyridinium methyl salt of a Non-hydrohalic acid (e.g. trifluoroacetic acid, acetic acid, Formic acid, sulfuric acid, or nitric acid Phosphoric acid) is transferred before de-esterification. The conversion of the halide salt to a non-hydrohalic acid salt is achieved with advantage with the help of the anion exchange. This is done, for example, by using a suitable Anion exchange resin, e.g. in the trifluoroacetate form. If an anion exchange resin is used, the 3-pyranium methyl halide passed through a column of the resin prior to deesterification. It can be advantageous to use an "inert to use an organic solvent system (e.g. a system that does not have a deleterious effect on the resin) to ensure adequate solubility of the cephalosporin compound. Organic solvent systems that are used may include lower alkanols such as ethanol, ketones such as acetone, and nitriles such as acetonitrile.

Compounds that have a 3-substituent

-CH ₂ Y

in which Y represents a hydroxyl group can be obtained according to those described in GB-PS 1 121 308 and BE-PS 841 937 Methods are made.

When Y is a halogen atom (e.g. chlorine, bromine or iodine), the Ceph-3-em starting compounds by halogenation of a 7β-acylamido-3-methylceph-3-em-4-carboxylic acid ester-lβoxide, followed by reduction of the Iβ-oxide group later in the sequence as described in GB-PS 1,326,531 will. The corresponding Ceph-2-em compounds can be prepared according to the method of the published NL patent application 69.02013 by reaction of a 3-methylceph-2-em compound with N-bromosuccinimide with formation of the corresponding 3-bromomethylceph-2-em compound getting produced.

5Ö9827 / O946

2460637

The carbamoylation of 3-hydroxymethyl compounds can be carried out by customary methods. For example, a 3-hydroxymethylcephalosporin can be reacted with an isocyanate of the formula R .NCO (in which R ^ represents a labile substituent radical or an alkyl group) in order to obtain a compound which has a substituent of the formula - CHpO.CONHR ⁶ contains, where R ^{e has} the preceding meaning. If R ^{e represents} a labile substituent, this substituent can, if desired, subsequently be cleaved off, for example by hydrolysis, in order to form a 3-carbamoyloxymethyl group. Labile radicals R, which are easily cleaved off in the subsequent treatment, include chlorosulfonyl and bromosulfonyl; halogenated lower alkanoyl groups such as dichloroacetyl and trichloroacetyl; and halogenated lower alkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. These labile groups R can generally be split off by acid-catalyzed or base-catalyzed hydrolysis (for example by base-catalyzed hydrolysis using sodium bicarbonate).

Another useful carbamoylating agent for the carbamoylation of 3-hydroxymethylcephalosporins is cyanic acid, which is advantageously generated in situ from, for example, an alkali metal cyanate such as sodium cyanate, the reaction being facilitated by the presence of an acid, for example a strong organic acid such as trifluoro * acetic acid will. Cyanic acid effectively corresponds to a compound of the formula R ^e .NCO, where R is hydrogen, and therefore converts 3-hydroxymethylcephalosporin compounds into their 3-carbamoyloxymethyl analogs.

3-Hydroxymethylcephalosporins involved in the above carbamoylation Sr eaktionen can be used, e.g. according to the in GB-PS 1 121 308 and BE-PSs 783 449 and 841 93 7 described method can be produced.

509827/0946

Cephalosporin compounds that have an acyloxymethyl group as Have substituents in 3-digit positions, for example, from a Cephalosporin compound which has a --CH-X radical in the 3-position has, in which X = OH or the remainder of an acid is HX-, which has a pKa value of not more than 4.0, preferably not more than 3.5, measured in water at 25.degree will. X can thus e.g. chlorine, bromine, iodine, formyloxy, an acetoxy group, which is at least: one electron-attracting group Has substituents on the α-carbon atom, or one nucleus-substituted benzoyloxy group, the nucleus substituent being of the electron-withdrawing type as in GB-PS 1,241,657 and the nucleophilic displacement reaction to form the desired acyloxymethyl in The 3-position can be carried out as described in GB-PS 1,241,657. Alternatively, when X is hydroxy, a 3-acyloxymethylcephalosporin by acylation ^ analogously to that described in GB-PS 1 141 293 obtained i.e., by aralkylation of the 4-carboxy group, acylation of the 3-hydroxymethyl group of the protected compound and then removing the aralkyl group.

Compounds with a vinyl or substituted vinyl group in the 3-position can be prepared according to that described in BE-PS 761,897 Procedures are obtained.

^ -Cephalosporin ester derivatives obtained by the process according to the invention can be converted into the corresponding j \ derivative, for example by treating the j \ -ester with a base.

Ceph-2-em-reaction products can also be oxidized to obtain the corresponding Ceph-3-em-1-oxides, e.g. Reaction with a peracid as described above. That The sulfoxide obtained can, if desired, then, as described below, be reduced to the corresponding Obtain Ceph-3-em-sulfide.

509 827/0946

If a connection is obtained in which B = > S > O, then so

this can be converted into the corresponding sulfide, for example by reducing the corresponding acyloxysulfonium or alkyloxysulfonium salt, which was prepared in situ by reaction with, for example, acetyl chloride in the case of the acetoxysulfonium salt, the reduction e.g. using sodium dithionite or the iodide ion, as in a solution of potassium iodide in a water-miscible solvent such as acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction may be carried out at a temperature of -20 to +50 ⁰ C.

If a compound of the formula I is obtained as a mixture of the isomers, the syn-isomer can e.g. by customary methods, such as crystallization or chromatography. The syn and anti isomers can by suitable Techniques, e.g. through their ultraviolet spectra, through thin-film or paper chromatography or by their NMR spectra. For example, this shows NMR spectrum of DMSO-dg solutions of the syn compounds of the Formula I the doublet for the amide-NH at a lower one Field as similar solutions of the corresponding anti isomers. These factors can be used to monitor or control reactions to be used.

Starting compounds of the formula V in which Z ^{1 is} the group

can be prepared, for example, by the processes of BE-PS 774 480 and FR-PS 2,165,834. Starting materials of the formula V, in which Z ^{1 is} a group of the formula

Shark

509827/0946

represents wherein Hal is a halogen atom such as fluorine, chlorine or Means bromine can be described / produced, for example, as in DT-OS 2 408 686.

Acids VI can be obtained by reacting a glyoxylic acid of the formula

R.CO.COOH ^VI11

wherein R is as defined above, or an ester thereof with a hydroxylamine derivative of the formula

R ^a -

'20

H ₂ N, O. (GH ₂ ) _m .C. (CH ₂ ) _n .COOR

wherein R ^a , R, R, m and η have the above meanings, are obtained. The acid or ester obtained can be separated into its syn and anti isomers, for example by crystallization, chromatography or distillation, after which ester derivatives can be hydrolyzed to form the corresponding acid.

Acids VI can also be obtained by etherification of an acid of the formula

R.C.COOH

Il

N X

OH

wherein R is as defined above, for example by reaction with a compound of the general formula

T. (CH ₀ ) ..C (CH ₀ ) .COOR ^υ XI R

wherein R ^a , R _5, R, m and η have the above meanings and T is halogen, such as chlorine, bromine or iodine, sulfate or sulfonate, such as tosylate. The isomers can be separated before or after the etherification. The etherification reaction

509827/0946

is suitably in the presence of a base such as potassium tert-butoxide or sodium hydride, and is preferably carried out in an organic solvent such as e.g. Dimethyl sulfoxide, a cyclic ether such as tetrahydrofuran or dioxane, or a Ν, Ν-disubstituted. Amide, like dimethylformamide. Under these conditions, the configuration of the oximino group is determined by the etherification reaction essentially unchanged.

Acids of the formula VI and acylating agents, which are derived from them derive (e.g. acyl halides, such as the chloride) are new and represent a feature of the invention.

Derivatives of compounds according to the invention, in which the carboxy Substituents of the 7β-acylamido side chain substituted by a carboxyl blocking group are also new and represent a feature of the invention. These monoester derivatives represented by the general formula

XII

"O. (CH) .C (CH ₉ ) .COOR ²⁰

R ^b ..

in which R, R ^a , R, Z, m and η have the above meanings and R is a carboxyl blocking group, such as tert-butyl or diphenylmethyl, are used as intermediates for the preparation of antibiotic compounds of the general formula I valuable. The compounds XII can themselves have antibiotic activity, although this is generally relatively low compared with the corresponding compounds I.

509827/0 946

460537

20 Ί9

Carboxyl blocking groups R and optionally R, the used in the preparation of the compounds of formula I or in the preparation of necessary starting materials Desirably, those groups that are readily present at an appropriate stage in the reaction sequence are desirably advantageous as the last stage, can be split off. However, in some cases it can be beneficial, biologically acceptable, metabolically labile carboxyl blocking groups such as acyloxymethyl groups (e.g. pivaloyloxymethyl) to be used and maintaining them in the final product to provide a biologically acceptable ester derivative of a compound of formula I. to obtain.

Suitable carboxyl-blocking groups are familiar to the person skilled in the art, with a list of representative blocked ones Carboxyl groups in BE-PS 783 449 is included. Preferred blocked or protected carboxyl groups include Aryl-lower alkoxycarbonyl groups, such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; lower alkoxycarbonyl groups, such as tert-butoxycarbonyl; and lower haloalkoxycarbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking resp. protecting group can then be removed by any suitable method described in the literature, e.g. by acid or base catalyzed hydrolysis or by enzymatically catalyzed hydrolysis.

The antibiotic compounds of the present invention, e.g., compounds of formula I and their non-toxic derivatives can be formulated for administration in any convenient manner which proceeds analogously to other antibiotics, and the invention therefore includes pharmaceutical within its scope Compositions containing an antibiotic compound of the invention adapted for use in human or Veterinary medicine included. Such compositions can be used in the usual manner with the help of any necessary pharmaceutical carriers or excipients.

509827/0946

The antibiotic compounds according to the invention can can be formulated for injection and may be in unit dosage form in ampoules or in multi-dose containers with one added preservatives are produced. The compositions can be in forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may include formulating agents such as suspending agents, Contain stabilizers and / or dispersants. Alternatively, the "active ingredient" may be in the form of a powder for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.

The antibiotic compounds can also be used in a suitable Form for absorption through the gastrointestinal tract are present. Tablets and capsules for oral administration can be in unit dosage form and conventional excipients, such as binders, e.g., syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Fillers, like Lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Lubricants such as magnesium stearate, talc, polyethylene glycol or silica; Disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate, contain. The tablets can be made according to the known Procedures are overdone. Oral liquid preparations can be in the form of e.g. aqueous or oily suspensions, Solutions, emulsions, syrups or elixirs are available or also as a dry product that can be remade with water or other suitable vehicle before use are present. Such liquid preparations can contain the usual additives, such as suspending agents, e.g. sorbitol syrup, methyl cellulose, Glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; Emulsifying agents such as lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles, which may include edible oils, e.g. almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol, and preservatives such as methyl or propyl p-hydroxybenzoates or sorbic acid. The antibiotic

509827/0 946

Compounds can also be formulated as suppositories, which contain, for example, common suppository raw materials such as cocoa butter or other glycerides.

In veterinary medicine the compositions can e.g. be formulated as intramammary preparations in either long-acting or quick-release bases.

In general, the compositions may contain from 0.1 % upwards, for example 0.1 to 99%, preferably from 10 to 60 %, of the active material, depending on the method of administration. If the compositions comprise dosage units J, each unit preferably contains 50 to 1500 mg of the active ingredient. The dosage used for the treatment of adult humans is preferably in the range of 500 to 5000 mg per day, depending on the route and frequency of administration, although higher daily doses may be necessary in the treatment of Pseudomonas infections.

The antibiotic compounds according to the invention can be used in Combination with other therapeutic agents, such as antibiotics, e.g. penicillins, tetracyclines or other cephalosporins, administered.

The following examples illustrate the invention. All temperatures are in ⁰ C. The structure of the compounds was confirmed by NMR spectroscopy (preparations and examples) and IR spectroscopy (examples only).

509827/0 9 46

2450537

Manufacture 1 '■ "

2-tert-butoxycarbonylniethoxyimino-2- (fur-2-yl) -essiq acid (s yn isomer)

The _pH value of a mixture of 4.2 g of 2-fur-ylglyoxylsäure, 4.5 g of tert-Butoxycarbonylmethoxyamin and 50 ml of water was adjusted with a 2N sodium hydroxide solution to 5.0. The resulting solution was stirred for 16 hours. The p n value of the solution was increased to 7.0 and the solution was washed twice with ether. The aqueous solution was acidified to an en p n value of 1.8 under ether and extracted further with ether. The combined ether extracts were washed (water, saturated brine), dried and concentrated to give 7.62 g of a solid which was crystallized from CCl * to give 3.67 g (46 %) of the title compound, mp 105.1 up to 106.2 ° C, · λ_ ₌ "(p _u 6 phosphate buffer) 277.5 nm (£ = 16,300).

Manufacturing 2

2-tert-butoxycarbonylmethoxyimino-2- (thien-3-yl) acetic acid (syn-isoneres)

Thien-3-ylglyoxylic acid and tert-butoxycarbonylmethoxyamine were reacted as described in Preparation 1, the title compound having a melting point of 102.6 to 104.4 ° C. (from CCl ₄ ); \ _mv (p "6 phosphate buffer) 258 nm (ε = 13 700).

max. rl

Manufacturing 3

2-RS-a-tert-butoxycarbonylbenzyloxyimino-2- (fur-2-yl) -acetic acid acid (syn isomer)

a) i) A mixture of 24.5 g of N-hydroxyphthalimide, 16.5 g anhydrous potassium carbonate, 41 g of tert-butyl-a-bromophenyl acetate and 225 ml of dimethyl sulfoxide was stirred for 18 hours and then poured into 1.2 l of water. The precipitated solid was filtered off, washed well with water, dried and off denatured alcohol (methylated spirits) crystallized, with 41 g (78%) of N- [a- (tert-butoxycarbonyl) -benzoyloxy] -phthalimide from F = 120.6 to 121.5 ° C.

-....., '_ 509 8 27/0946

ii) To a solution of 40 g of the above oxyphthalimide 11.4 ml of 100% hydrazine hydrate were added to 500 ml of dichloromethane joined. A precipitate formed immediately. The mixture was stirred for 1.5 hours, after which time sufficient 5N ammonium hydroxide solution was added to dissolve the precipitate. The two layers have been separated and the aqueous layer was extracted once with methylene chloride. The combined organic extracts were washed (Water, saturated saline solution), 'dried and concentrated, wherein 25, Og (98%) tert-butyl-α- (aminooxy) -phenyl acetate as colorless crystals of F = 48.2 to 49.6 C were obtained.

b) Fur-2-ylglyoxylic acid and tert-butyl-α- (aminooxy) phenyl acetate were reacted as described in Preparation 1, the title compound in 42% yield from 97.9 to 98.9 ° C (from CCl.); \ _m " _v (p _u 6 phosphate buffer) 278 nm ( L = 18,400).

Manufacturing 4

2-tert-butoxycarbonylmethoxyimino-2- (thien-2-yl) acetic acid (syn isomer)

To a stirred suspension of 0.96 g of sodium hydride (60% dispersion in oil) in 40 ml of tetrahydrofuran was added 1.71 g of 2-hydroxyimino-2- (thien-2-yl) acetic acid (syn-isomer). The mixture was stirred for 30 minutes, after which 25 ml of dimethyl sulfoxide were added and stirring was continued for an additional hour. 1.78 g of tert-butyl chloroacetate were added to the mixture, which was then stirred for 16 hours and then poured into 300 ml of water. After washing twice with ether, the aqueous phase was acidified to a p n value of 1.7. Extraction with ether and concentration of the washed (water, saturated saline) and dried extracts gave 2.71 g of a solid which was _{crystallized from CCl 4} to give 0.952 g (33%) of the title compound with an mp = 88.3 to 91 , 3 ° C; X _mzsv (p _H 6 phosphate buffer) 270.5 and 288.5 nm (ε = 9200 and 10,800).

509827/0946

Manufacturing 5

2- (2-tert-ButoxycarbQnylprop-2-yloxyimino) -2- (fur-2-yl) acetic acid (syn-isomer)

A solution of 14.1 g of 2- (fur-2-yl) ~ 2-hydroxyiminoacetic acid (syn isomer) in 100 ml of dimethyl sulfoxide became a solution of 22.4 g of potassium tert-butoxide, stirred with a magnetic stirrer added to 400 ml of dimethyl sulfoxide, the reaction mixture being kept under an atmosphere of dry nitrogen. A gel was formed which upon stirring became a finely divided yellow solid. Stirring was continued for 1 hour, and then a solution of 24.0 g of tert-butyl-bromo-methylpropionate in 50 ml of dimethyl sulfoxide was added to the reaction mixture over the course of 1 hour at room temperature. After the addition was complete, the resulting solution was stirred for an additional hour. The reaction was poured into 1.5 1 Eiswässer and acidified with 500 ml of ether with concentrated hydrochloric acid to a _pH value of 1.8. The two layers were separated and the aqueous layer extracted with more ether. The combined ether extracts were washed once with water and then extracted with an aqueous sodium bicarbonate solution. The combined alkaline extracts were acidified under ether to a p "value of 1.8 with concentrated hydrochloric acid, and the acidic solution was further extracted with ether. The combined ether extracts were washed (water, saturated salt solution), dried and concentrated to a yellow oil, which crystallized under high vacuum (22.41 g, 83%), λ_ (EtOH) 272.5 nm (£ = 15,400) .

ΙΪ13Χ ·.

The above solid (22.4 g) was _{recrystallized from 25 ml CCl 4 to give} 16.42 g (61%) of the title compound; F = 72.5 to 74.2 ° C (73.0 ° C).

Manufactures 6 to 20

Method A '

The dipotassium salt of 2- (fur-2-yl) -2-hydroxyiminoacetic acid (syn-isomeres) was under an atmosphere of dry

509827/0 946

Generated nitrogen and with the appropriate halogen tert-butyl ester alkylated as described in Preparation 5. The products were made by pouring into water, acidifying and extracting isolated in the usual way.

Method B.

As method A, but using a halodiphenylmethyl ester.

The half-esters obtained by this process are shown in Table I. listed.

509827/0946

co * σ>

Table I.

Manufacturing
No. RV _R 20 method F.
° c. λ IM
Max,
(Solution
middle) ε 6th > HCH ₃ * -C (CH), A. 69.8-73.4 ° 277 (pH6
Buffer) 15,500 7th -CH ₂ - It A. 107 ° 271 (EtOH) 13,700 8th It A. 106 "8-107.3 ° 277.5 (pH6
Buffer) 15,100 9; -CH (CH ₂ ) ₃ CH ₃ * -CHPh ₂ B. 102-104 ° 275 (EtOH) 12,700 10 ^ HCH ₂ CH ₃ * It B. - 271.5
(EtOH) 14,100 11 X ^C 2 ^H 5 It . B. - 269 (EtOH) 13,200 C ₂ H ₅

* Denotes (RS) isomers

• Table I (continued)

cn o co

co

O)

Manufacturing
No.

10

11

τ values in d.-DMSO ⁶ -20-

R ^q

5.31; 8.56

5.32

8.03; 8.30

5.1; 8.16; 8.7; 9.18

5.13; 8.11 9.07

8.08; 9.22

8.58

8.56

8 _t 63

3.07 (CH)

3.09 (CH)

3.10 (CH)

ro ι

'CT5 O Ul

O CD OO IO

CO -C-CD

Table I (cont R ^ R ²⁰ setting) ■ P
⁰ C. λ rim
Max
(Solution
middle) ε ^ CH (CH ₂ ) ₂ CH ₃ ^ -CHPh ₂ method 116-117 ° 270 (EtOH) 14,750 Manufacturing
No. > H-Q * -CHPh ₂ B. 270 (EtOH) 13,400 12th >: h-ch (ch ₃ ) ₂ * -CHPh ₂ • ..B - 270.5
266.5
(EtOH) 13,700
13,250 13th ^ CH-CH ₂ CH = CH *
X) -C (CH,)
Il B. 77.0-80.3 °
91.5 ° 276.5
(pH6
Buffer)
276.5
(pH6
Buffer) 17,500
16,700 14th > - ^CH 3
-CO ₂ C (CH ₃ ) ₃ »T A.
A. 91.5-93.8 ° 276 (pH6
Buffer) 15,800 15th
16 A. 17th

'CTD O

Table I (continued)

Crr ο co

Manufacturing
No. τ values (solvent) _R 20 12th R ^q 3.08 (CH) 13th 5.10; 7, .9-8 _r 9;
9.1 (d _& -DMSO) 3.07 (CH) ' 14th 5.32; 7.8-9.2
(d.-DMSO) 3.05 (CH) 15th 5.14; 7.68; 8.95
9.15 (CDCl ₃ ) 8.60 16 4.26; 4.86; 4.91
5.38; 7.44
(d, -DMSO) 8.57 17th 8.12; 8.50
(d ₆ -DMSO) 8.56 • 8.39; 8.56
(d ₆ -DMSO)

Manufacturing . · R ^q . Table I. (Continuation) "f • λ nm ε No. . R ²⁰ method ° G Max,
(Solution .20 middle) 18th > O 113-114 ° 278 (pH6
Buffer) 17,200 19th ~ -c " ³ * - Vj \ VjH, - ) _ '' A. "CO ₂ C ₂ H ₅ K cn
ο A. CD - - mm 00
ro -GHPh ₉ B. O CD * · * ■ ■ CD •

* Denotes (RS) isomers

+ N- Benzyl- 2-pheny la thy! Ammonium salt, F = 129 '

-cn co

Table I (continued)

err O CO 00 ro

CO

Manufacturing
No. τ values dg-DMSO R ²⁰ 18th
19th
20th R ^ 8.59
8.54
3.15 (CH) 7.4-8.3
5.76; 8.74; 8.33
(CH ₃ )
5.49; 8.6-8.9

cn ι

Manufacturing 21

2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (thien-2-yl) -essiq acid (syn-isomer)

The title compound was obtained from 2-hydroxyimino-2- (thien-2-yl) acetic acid (syn-isomeres) and tert-butyl 2-bromo-2-methylpropionate in a similar manner to that described in preparation 5 ″ in 78% yield as a colorless oil and was characterized as the N-benzyl-2-phenylethylammonium salt, F = 201.3 to 20 1.9 ° C (from ethanol).

Manufacturing 22

2- (2-tert-butoxycarbonylethoxyimino) -2- (fur-2-yl) acetic acid (syn isomer)

To a mixture of 8.9 g Acetohydroximinsäuremethylester [CH ₃ .C (: NOH) .OCH _3] and 12.8 g of tert-butyl acrylate · a solution of 0.1 g of potassium tert-butoxide in 1 ml was tert .-Butanol added. The mixture was kept at 0 ° C. for 65 hours, then washed with water, dried and distilled, 2.37 g (11%) of 2-tert.-butoxycarbonylethylmethylacetohydroximate having a melting point of 85 to 87 ° c / 1.2 mm Hg became.

2.15 g of 2-tert-butoxycarbonylethyl methylacetohydroximate and sufficient methanol were added to a solution of 1.26 g of fur-2-ylglyoxylic acid in 50 ml of water and sufficient methanol to obtain a homogeneous mixture, which lasted 30 minutes at a p "value of 1.5 was stirred. The ρ value was adjusted to 4.5 with 2N sodium hydroxide solution and the mixture was stirred for an additional 16 hours, after which the reaction was almost complete. Methanol was removed under reduced pressure, the ρ value of the residue was increased to 7.0, and the aqueous mixture was washed twice with ether. The aqueous phase was acidified in the presence of dichloromethane to a _pH value of 1.7 and the phases were separated. The aqueous phase was extracted twice with dichloromethane; The combined dichloromethane extracts were washed with water, dried and concentrated, whereby 1.53 g of a fawn solid (Mi

S09827 / 0946

schung der syn and anti isomers, 85:15) obtained from CCl. were recrystallized, whereby 0.975 g (34%) the title compound, m.p. 74.7-77.2 ° C;

Nnax ^(p H ^{6 buffer) 277 nm (ε = 16} 500)

Preparation 23 tert-butyl-1-bromocyclopentanecarboxylate

3.5 ml of concentrated sulfuric acid and then 150 ml of precondensed isobutene were added to a mixture of 36.99 g of l-bromocyclopentanecarboxylic acid and 35 ml of anhydrous ether in a 500 ml pressure bottle containing a magnetic stir bar. The bottle was sealed and stirred at room temperature for 20 hours. The bottle was then opened, excess butene evaporated, and the residue in ether was washed with an aqueous sodium bicarbonate solution and water, dried and concentrated. The residue was distilled under reduced pressure, whereby 33.6 g (70%) of the title ester (bp = 66 to 74 ° C / 0.5 to 2.0 mm Hg); V (CHBr ₇ ) 1702 cm "¹; ¹ C (CDCl.) 7.78, 8.20 (cyclopentane protons) and 8.54 [C (CH ₃ K]).

Preparation 24 Diphenylmethyl-g-bromohexanoate

1.95 g, oc-bromohexanoic acid in 25 ml of petroleum ether (bp. 40 ° to 60 ° C) were treated with a stock solution of diphenyldiazomethane in petroleum ether (ca. 3.8 mmol / l0 ml) under (b.p. 40 to 6O ⁰ C.) dropwise addition and treated with stirring until a pale purple color persisted. The mixture was stirred at room temperature for 2 hours after which the solvent was removed in vacuo. The obtained oil in ethyl acetate was washed with a saturated aqueous solution of sodium bicarbonate and then with water and dried. Removal of the solvent gave 3.0 g (90%) of the title ester, \ _maXi (EtOH) 252, 258, 263.5, 267.5 and 276 nm (£ = 1650, 1600, 1350, 1150 and 850 ).

509827/0946

Manufactures 25 to 34

, g-Halogen-substituted carboxylic acid ester Method A

The appropriate oc-Halogenc.arbonsäure was with isobutene and concentrated sulfuric acid in a pressure bottle at room temperature treated for 10 to 40 hours according to the method described in Preparation 23, the in Table II listed tert-butyl esters were obtained,

Method B.

The appropriate oc-halocarboxylic acid in a solvent, such as ether, petroleum ether, ethyl acetate, was mixed with a diphenyldiazomethane solution treated until faint persistent color was observed. The ester was with Washed alkali as described in Preparation 24, the diphenylmethyl esters listed in Table II being obtained became.

509.827 / 0946

Table II

XR ^q -CO ₂ R ²⁰

cn ο co oo ιό -4

O CD

Manufacturing
No. X τ R20 method Ester,
V cm ".
Max
(CHBr ₃ ) 25th Cl -CH ₂ - -C (CH ₃ ) ₃ A. 1735 26th Br iC (CH ₃ ) ₂ A. 1716 27 Br * HCH ₂ C < -CHPh ₂ B. 1737 28 Br H B. 1729 . 29 Br -CH (CH ₂ > _ft 1" B. 1730 30th Br fl B. 1725.1245 31 Br η B 1738

, to cn

■ * Denotes (RS) isomers

table II (continued)

on ο CjO OO ro

CD

cn

Manufacturing τ values (solvent) _R 20 ' No. ■ R ^q 8, 53 :. 25th 4.06 (CDCl ₃ ) 8.51 26th 5.74; 8.22 (CDCl ₃ ). 3 _; 10 (CH) .27 5.29; 7.97; 9.07
(d, -DMSO)
O 3.06 (CH)
X. 28 7.81; 9.10 (d ₆ ~ DMS0) 3.09 (CH) 29 5.24; 7.7-8.9; 9.12
(d, -DMS0)
D. 3.04 (CH) 30th . . 5.45.7.8-9.3- (d ₆ -DMS0) 3.10 (CH) • ³¹ ■ 5.40; 7.79; 9.0; 9.08
(d, -DMSO).
D.

cn

Table II (continued)

cn o co

Manufacturing
No. X ^Rq _R 20 method Ester,
v cm
Max
(CHBr ₃ ) 32
.33
• 34 Br
Br
Br > O
x> ti
-CHPh A.
A.
B. 1710
1714

Table II (continued)

CO-P-CD

Manufacturing
No. τ values (CHCl ₃ ) R ^q R ²⁰ 32
33
34 • 7.9; 8.0-8.9
6.9-7.6; 7.7-8.3
6 _r 29; 8.2-9.1 8.51.
8 _; 52
3.08 (CH)

Ut

Manufacturing 35

Di-tert-butyl-2-bromo-2-methylmalona t

11.52 g of di-tert-butylmethylmalonate were added to a stirred suspension of 1.7 g of sodium hydride (80% dispersion in oil) in 60 ml of tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred at 60 to 70 ° C. for 1.5 hours, a clear solution being obtained. This solution was cooled to -25 ° C. and a solution of 2.6 ml of bromine in 30 ml of methylene chloride was quickly added. The solution was allowed to warm to room temperature and then concentrated. The residue in ether was washed with water, dried and fractionally distilled under reduced pressure, 7.56 g (49%) of the title compound being obtained, boiling point 78 to 86 ° C./1.0 mm Hg; V (CHBr,.) 1730 cm " ¹ (COpBu); T (CDCl ₃ ) values include 8.05 [s, C (CHg) ₃ ] and 8.53 [2s, CH ₃ and C (CH ₃ J ₃ ].

Manufacture 36,. ·

tert-Butylathyl-2-bromo-2- methyl lmalonat

The title compound was prepared in a manner similar to that in the preparation 35 produced in 83% yield, b.p. 64 to 68 ° C / O, 0.3 mm Hg.

Manufacturing 37

l-bromomethylcyclopropane -! - carboxylic acid

The bromination of cyclobutane carboxylic acid resulted in the corresponding hydrobromic acid and the title compound (yield 15%), F = 83 to 84 ° C (petroleum ether, bp 60 to 8O ⁰ C.); T (dg-DMSO) values 6.25, 8.65 and 8.90.

509827/0946

246052?

example 1

a) (6R, 7R) -3-acetoxymethyl-7- [2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em - 4-carboxylic acid

(syn isomer)

0.45 ml of oxalyl chloride were added at 5 ° C. to a stirred solution of 1.35 g of 2-tert.-butoxycarbonylmethoxyimino-2- (fur-2-yl) -acetic acid (syn-isomer) in 50 ml of dry methylene chloride containing 0, 7 ml of triethylamine and 1 drop of dimethylformamide were added. The solution was stirred at 5 ° C. for 1 hour and then evaporated to dryness at 5 ° C. The residue was suspended in 50 ml of acetone and, within 30 minutes, added to a stirred, ice-cold solution of 1.36 g of (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid in 100 ml of water and 50 ml Acetone containing 1.0 g of sodium bicarbonate added. The reaction mixture was stirred for 1. hour, after which the acetone was removed under reduced pressure. The residue was acidified to a _pH value of 1.8, and this mixture was extracted with ether. The combined extracts were washed (water, saturated saline), dried and evaporated to give 2.52 g (95%) of the title compound as a pale yellow foam, [a] _D + 28.5 (c 0.96, DMSO); λ - (p "6 phosphate buffer) 276.5 nm (£ = 17,900)

- -ΓΠ9.Χ · ri

b) (6R, 7R) -3-acetoxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid, disodium salt (syn-isomer)

A solution of 1.422 g of (6R, 7R) -3-acetoxymethyl-7- [2-tert, -butoxycarbonylmethoxyiraino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-Isomeres) and 0.25 ml of anisole in 5 ml of trifluoroacetic acid was kept at room temperature for 5 minutes. The mixture was concentrated under reduced pressure 10 ml of ethyl acetate were added and the mixture was evaporated again. The residue was between ether and a Sodium bicarbonate solution distributed. The ethereal layer grew wider extracted with sodium bicarbonate solution, and the combined alkaline extracts were brought to a p "value under ether

509827/0946

acidified by 1.8. The acidic mixture was extracted with ether and the combined extracts washed (water, saturated saline), dried and evaporated to give the dicarboxylic acid corresponding to the title compound (942 mg, 74%); the T (d _g - DMSO) values include 0.24 (d, J 8Hz, NIi), 4.13 (dd, 7-H) and 5.31 (s,

900 mg of this diacid in 9 ml of acetone were neutralized with a solution of 700 mg of sodium 2-ethylhexanoate in 5 ml of acetone. The mixture was stirred for 10 minutes, then the precipitated solid was filtered off, washed with a little acetone and dried, 807 mg (60%) of the title compound being obtained, [α] _η + 15 ° (c 1.08, DMSO); v _{m v}

,. LJ ΙΪ13Χ *

(Nujol) 1766 cm (β-lactam).

Examples 2 to 26 General procedure for the production of (6R, 7R) -7-

(2-Aryl-2 ~ carboxy-R ^ -oxyiminoacetamido) -3- (substituted) -

ceph-3-em-4-carboxylic acids (syn-isornere) and their salts Method a

Following the procedure of Example 1, a solution of 1 equivalent was obtained the appropriate 2-aryl-2-tert-butoxycarbonyl-R ^ -oxyiminoacetic acid (syn isomer) in 1 equivalent of methylene chloride, which may contain a few drops of Ν, Ν-dimethylformamide and Containing 1 equivalent of triethylamine, treated with 1 equivalent of oxalyl chloride at 0 to 5 C for 1 hour. The mixture was then evaporated to dryness. The residue was suspended or dissolved in acetone and added to a stirred ice-cold Solution of 1 to 1.2 equivalents of (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid in water or a mixture of acetone and water containing 2 to 2.5 equivalents of sodium hydrogen carbonate. The reaction mixture was stirred for 0.5 to 2.5 hours, allowing the temperature to rise to room temperature, after which time the acetone was removed under reduced pressure. The ρ value was set to 1.5 to 2.0 and the product with Ethyl acetate extracted, alternatively ether or methylene

509827/0946

2490637

chloride can be used. The organic layer was washed with water and / or saturated saline, dried and evaporated, leaving the corresponding (6R, 7R) -3-acetoxymethyl-7- (2-aryl-2-tert-butoxycarbonyl-R -oxyiminoacetamido) -ceph-3-em-4-carboxylic acid (syn isomer) obtained by optical rotation and / or spectroscopic was characterized.

The tert-butyl esters were treated with trifluoroacetic acid, containing anisole, deprotected for at least 5 minutes at room temperature. The reaction mixture was evaporated in vacuo and the product by trituration or by partition between ethyl acetate (or ether) and an aqueous sodium hydrogen carbonate solution, separating off the aqueous extracts, acidifying these extracts under ethyl acetate and isolation of the title dicarboxylic acid in a conventional manner. The products are listed in Table III.

Method B.

It corresponds to method A, but the appropriate one 2-Ary1-2-diphenylmethoxycarbonyl-R -oxyiminoacetic acid (syn isomer) was used instead of the tert-butyl ester. The products are listed in Table III.

Method c

It corresponds to method A or B, but with the dicarboxylic acid by treating a solution of the acid in acetone with a solution of Na 2-ethylhexanoate in acetone in its ditrium salt was convicted. The precipitated disodium salt was washed and dried. The products are in table III listed.

Method D

It corresponds to method A, but with a (6R, 7R) -3- (substituted Methyl) -7-amino-ceph-3-em-4-carboxylic acid or a salt thereof instead of '(6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid was used. The products are listed in Table IV. · "

509827/0946

Table III

cn

CD OO ro

CD CD

at
game
No. Qj -CH ₂ - salt method [a] _D.
(dmSo) X _n J do _8x
(pH 6
buffer) ε ß-lactam,
(Nujöl) 2 Disodium A, C + 26.5 * 263 14,900 1762 C * -CH _n - 292 10,200 3 ■ xx-
^ CHPh - A. + 35 ° 262 19,700 1798 4th ■ X - X-
xCHCH ₃ A. + 48 ° 277.5 18,700 1778 5 ; c (ch ₃ ) ₂ Disodium A, C + 63 ° 275 16,800 1764 6th Disodium. A, C + 95 ° 274 16,800 1768

NJ

** 33

CO

K Ν3 O

Denotes (RS) isomers

crt ο to

Γ example
No. table III y * ^q 2 4.10 5.32 · 3 j (continued) 4 _r 05 5.27 ^4th τ values * "in dβ-DMSO at 100 MHz 4.08; 4.16 .4.28; 4.32 (CH)
2.3 - 2.6 (Ph) 5, _ · ·· · .. X 4.10 5.27 (CH)
8.54 (CH ₃ ) 6th 0.15 4.05 . δ, 4.7 • 6.26. 0.13; 0.20 0.29 . 0.32

(JI «5

Values for free acids

cn ο to 00 K) -J

O CO -C-

10 ^χ ο ^ ^Rq Tabel i III (Fc establishment) ^ • max ^^
(pH 6
Buffer) ε β-lactam ..
(Nujol) 11 > ο [a] _D
(DMSO) 276 16,800 1756 at
spat
No. 12th ** salt method -f62 ° 276 15,400 1760 7th Dinatriurr A, C 275 15,500 1756 8th ρ / Λ JJf
\ _c ^ CO ₂ H Disodium A, C + 76.5 ° 274.5 10,100 1760 9 κ> Dinatriura A, C + 43 ° 274 " 14,600 ■ 1780 _s ^ CO ₂ Et - A. + 28 ° 275.5 17,200 1790 ^N CH ₃ - ■ Α, Β + 21 ° A.

σι ο

Identifies (RS) -Isornere

Table III (continued)

CO ro

CD co

example
No. τ values * in dg-DMSO at 100 MHz y R ^q '■ 7th
8th ·
9
10
11
12th X 4.10
-4.15
4.13
4.16
i
4.09
4.16. 7,9.0 and 8.28
"4.1, -4.8, 5.34;
7.38
8.20; 8.50
8.36
7.56? 8.08
5>80; 8.33 · 8.80 0.38
0.29
'. 0.38
0.37
0.31
0.33

cn

ro

-ο cn

* Values for free acids

Table III (continued)

cn CD CO OO K)

co cn

at RP "- R * salt . method - B. Ca] X _max mm ε β-lactam game
No. B. (DMSO) (EtOH) ν cm * "- * ·
Max,
(Nujol) Λ B. 13th - B. 445 ° 274 19,150 1771 14th ^ ** · mm B. + 57 ° 274 18,000 1776 15th > C (C ₂ H ₅ ) ₂ - B. 444 ° 272.5 17,000 1773 16 -CH (CH ₂ ) ₂ CH ₃ - 4-53 ° 273 16,900 1780 17th Q- \ / —V "^ * - 441 ° 273 18,250 1782 18th ^ ■ ■ * ■ *
^ * KjU. \ JLI \ VjΠq / r) - 469 ° 273 18,100 1781

cn co

** Denotes (RS.) Isomers

Table III (continued)

*
τ values in y d ₆ -DMS0 at 100 MHz example 4.11 No. ' X 13 ' 0.31 4.10 '5.40; 8.2; 8.6; 4.13 9.1 14 ' 0.35 4.16 5.45; 5 _r 50 4.10 8.12; 9.01 .15 0.41 4.12 8.1 ;. 9.2 16 0.37 4.18 5.40; 5.42. 4.14 .8.2; 8.5; 9.1 ■ ·. ! «■■ ·" -. 0.4 • 5.65; 8.0-9.2 is; ■ ■■ ' 0.38 5.61; 5.69 7.85} 9.0

σι

iro

cn co

"Values for free, acids

Table III (continued)

cn ο co CX)

CD co -C - CD

at
game
No. ^ Λ · ( ΛΙΙ Λ salt method (DMSO) (pH6 ^}
Buffer) ε ß-lactam
(Nujol) 19th -CH ₂ CH ₂ - - A. 462.5 262 13,900 1784 20th Wk A. + 31 ° 276.5 15,800 1784 21 mä B. + 43 ° 276 17,250 1788

4 = »

cn CO

Table III (continued)

(Tt ο co

ro -j

CD (D

example
No. τ values in d ^ -DMSO at 100 MHz y 8.51
. 5.68; 7.34
5.68; 8.7-9 ^ 0. • 19th
20th
21 x. 4ilO
4.19
4.17 0.37
0.28
0.33

CTi

IS3

O CO

Table IV

R ^P - _1r - ~ CONH · - N

0-R ^q .C0 ₂ H

(y)

H H

-N

CH ₂ Y

CO ₂ H

At- RP R ^q Y salt method ΓαΊ Vax, ™ ¹ ε ß-lactam game
No. (Solution
middle) (pH6 buffer) ν cm ^
Max,
(Nujol) 22nd -CH ₂ - D. + 35 °
(Dioxane) 275 15,200 1770. 23 Ό OCONHCH ₃ - D. +41 _f 2 °
(DMSO) 277 17,850 1780 24 -CH ₂ - -OCONH ₂ Disodium D. +47.5 «
(DMSO) 264 13,900 1770 25th
26th ■ χ> -OCONH ₂
-OCONH ₂ Disodium D.
D. + 26 °
(DMSO)
+ 44 °
(H ₂ O) 277.5
274.5 15,100
14,950 SND
1788 * j>.
.C73
■ o
1773 <^

Table IV '(continued)

CD OO NJ -J

τ * .- values in dg-DMSO
at 100 MHz ^: y rS At-
game ' :
' No, 4.10 5.31
ί ί 22
! ■. ι O ₁ 14 4.18 -7.95? B, 3 j 23 ''
! 0.4 « 4.13 5.33 24 • Ό, 25. : 4.12 7.56j '8.10 ! "25 '- j • 0.34 i 4.15 ■ 8,52 · '■: 26th '0.44

Example 27

(6R, 7R) -7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -3- (1-methyltetrazol-5-ylthiomethyl) -ceph-3-era-4-carboxylic acid (syn- Isofneres)

A solution of 0.97 g of 2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn isomer) in 20 ml of methylene chloride was added dropwise at room temperature over the course of 15 minutes to a stirred solution of 1.484 g of dipheny! methyl (6R, 7R) -7-amino-3- (l-methyltetrazol-5-ylthiomethyl) -ceph-3-em-4-carboxylate and 0.743 g of dicyclohexylcarbodiimide in 45 ml of methylene chloride were added. After stirring for a further 2 hours, the solvent was removed by evaporation and the residue was stirred with 50 ml of ethyl acetate for 5 minutes and filtered. The filtrate was washed with saturated sodium bicarbonate solution, diluted with an equal volume of water and then with brine (25 ml each), dried and evaporated to 2.5 g of a foam which was dissolved in benzene and purified by chromatography on 70 g of silica gel. Elution with benzene: ethyl acetate (10: 1), combination of the appropriate fractions and evaporation to dryness gave 2.05 g of a foam which was dissolved in ethyl acetate and. was poured into low-boiling petroleum ether, where 2.02 g (90%) of diphenylmethyl- (6R, 7R) -> [2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -3- (l- methyltetrazol-5-ylthiomethyl) -ceph-3-em-4-carboxylate (syn-isomeres) as a white amorphous solid. [a] ^ ³ - 102 ° (c 0.99, CHCl.); \ _{m = v} (EtOH) 278 nm (& = 19,800).

A solution of 1.93 g of this diester in a mixture of 7.7 ml of trifluoroacetic acid and 1.9 ml of anisole were kept at 0 C for 10 minutes and then to 850 ml of a mixture of saturated Sodium bicarbonate and water (1: 3) added. After stirring for 10 minutes, the mixture was washed with ethyl acetate washed, covered with more ethyl acetate (200 ml) and treated with concentrated hydrochloric acid to a p "value of 2 acidified. The organic phase was separated, washed with water and brine, dried and added to 1.54 g of one Foam evaporates. Thin layer chromatography indicated that

5 0 9827/0946

the removal of the protective group was incomplete, and the product was treated again with 4.3 ml of trifluoroacetic acid and 1.1 ml of anisole for 15 minutes at 20 ° C., after which the product was isolated as a foam (1.3 g) as described above . This foam was dissolved in ethyl acetate was introduced into low-boiling petroleum ether to give 0.8 g (59%) of the title dicarboxylic acid as an amorphous white "solid, [α] !: ^3-99 ° (c 1.05, acetone) ; X _m (0.1 m-p "6 phosphate buffer) 277 nm (£ = 21,900); oo _V (Nujol) 1780 cm; the

IU cl-X-

τ (dg-DMSO) values include 0.19 (d, NH), 4.14 (dd, 7-H), .5.30 (s, CH ₂ CO ₂ H). '

Example 28

(6R, 7R) -3- (Carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer)

2.08 g diphenylmethyl- (6R, 7R-) -T-amino-S-carbamoyloxymethyl-ceph-S- em-4-carboxylate-toluene-p-sulfonic acid salt were in a mixture dissolved from 60 ml of ethyl acetate and 60 ml of a saturated aqueous sodium bicarbonate solution. The ethyl acetate layer was separated, washed with water, dried and evaporated to a foam.

1.0 g of 2-tert-butoxycarbonylmethoxyiraino-2- (fur-2-yl) acetic acid (syn isomer and 0.76 g of dicyclohexylcarbodiimide dissolved in a small volume of anhydrous methylene chloride were dissolved into a solution of the above amine The reaction mixture was stirred for 35 minutes at 3 ° C., Ν, Ν'-dicyclohexylurea crystallized out. This was filtered off and the filtrate evaporated to an oil which solidified on trituration with diisopropyl ether was dissolved in ethanol and decolorized with activated charcoal. Evaporation of the solution gave 2.08 g (86%) of diphenylmethyl- (6R, 7r) -3-carbamoyloxymethyl-7- [2-tert-butoxycarbonylmethoxyimino-2- ( fur-2-yl) -acetamido] -ceph-3-em-4-carboxylate (syn-isomer); F = 97 to 98 ° C; [a] _n + 5.5 ° (c 1.00, DMSO) ; λ _v (EtOH)

L) IUaLX *

276.5 nm (e = 17,250).

5098 27/094 6

6 ml of trifluoroacetic acid was added to a slurry of 2.08 g of the above diester ih 6 ml of anisole, and the reaction mixture was stirred at 20 ° C for 25 minutes. The solution was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution, the aqueous layer was separated and washed with ethyl acetate. 100 ml of ethyl acetate and 2N hydrochloric acid were added in order to reduce the pn value to 2. The organic layer was then separated, washed with water,

dried and evaporated to a yellow oil. By NMR spectroscopy the product was found to be the (6R, 7R) -3-carbamoyloxymethyl-7- [2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer).

This acid was treated with 4 ml of anisole and 4 ml of trifluoroacetic acid for 30 minutes at 20 ° C. and the reaction mixture was partitioned between ethyl acetate and an aqueous sodium bicarbonate solution. The aqueous layer was washed with ethyl acetate and acidified to a p "value of 2 with 2N hydrochloric acid under ethyl acetate. Evaporation of the ethyl acetate layer gave a solid which was purified by precipitation from ethyl acetate with isopropyl ether and filtering off to give 620 mg (44%) of the title dicarboxylic acid with a melting point of 159 ° to 161 ° C .; [oc] _D + 35 ° (c 1.0, DMSO); \ _{m = v} Cp "6 phosphate buffer) 275 nrn (B =

15 400): ν (NuIoI) 1778 cm. the τ (d --- DMSO) values by- * max. ο

hold 0.20 (d, NH) 4.15 (dd, 7-H _- ) 5.32 [s, C (CH ₃ ) ₂ ].

Examples 29 to 42

General procedure for the preparation of (6R, 7R) -7- [2-Carboxy-R -oxyimino-2- (fur-2-yl) -acetamido] -3- (substituted) - ceph-3-em-4— carboxylic acids (syn isomers) using dicyclohexylcarbodiimide

i) To a solution of diphenylmethyl- (6R, 7R) -7-amino-3- (substituted) -ceph-3-em-4-carboxylate (1 equivalent) and dicyclohexylcarbodiimide (1 to 1.3 equivalents) in dry Methylene chloride was a solution of the suitable

5 0 9827/0946

th 2-tert-butoxycarbonyl-R ^<3 -oxyimino-2- (fur-2-yl ^ acetic acid (syn-isomer) (1 to 1.15 equivalents) in dry methylene chloride. After stirring for 0.5 to For 5.0 hours the dicyclohexylurea was removed by filtration and the filtrate evaporated. The residue in ethyl acetate or methylene chloride was washed successively with aqueous sodium bicarbonate, water and brine, dried and evaporated. The diester was chromatographed on silica or, after decolorization with activated charcoal, purified by trituration or recrystallization The product was characterized by its NMR spectrum and thin layer chromatography.

When the 7-amino starting material is used as an acid addition salt was available, the free base was shaken with a mixture of ethyl acetate (or methylene chloride) and an excess of an aqueous sodium bicarbonate solution is released. After washing with water and saline, the organic layer evaporated to dryness and the free amine used as described above.

ii) Method A

The protecting group of the thus derived diester intermediates was obtained by dissolving in a mixture of trifluoroacetic acid (3 to 10 ml / g diester) and anisole (0.8 to 12 ml / g diester) and allowing to stand for 5 minutes to 2.5 hours between OC and room temperature. The mixture was taking concentrated under reduced pressure and to a mixture of " Ethyl acetate or ether and. excess aqueous sodium bicarbonate and the aqueous layer was washed with ethyl acetate. The aqueous phase was washed with ethyl acetate covered and with hydrochloric acid to a p "value acidified from 1 to 2. The organic layer was washed, dried and evaporated to give the desired dicarboxylic acid was obtained.

5Ό9827 / 0946

ii) Method B

In some cases that require treatment with trifluoroacetic acid was insufficient to achieve complete deprotection, the monoester intermediate became (in general, the tert-butoxycarbonyl group is split off more slowly than the diphenylmethoxycarbonyl group) again with Tirifluoroacetic acid and anisole were treated, and the acid was made isolated as described above.

iii) Method C

The 3-carboxyvinyl derivative described in Example 36 was used made from a 7-amino derivative in which both carboxyl groups were protected as diphenylmethyl esters. The distance the protecting groups from the obtained triester took place according to method B, whereby the desired tricarboxylic acid was obtained.

The properties of the reaction products are given in Table "V listed.

509827/0946

(χ)

.CONH -

(y)

N \

bJ_-ν

Table V

0-R ^q -C0 ₂ H

CO H 2

CD -P-

At-
qpiel
No. R ^q P. method (Solution
middle) (Solvent 3) ε β-lactam
^v rrax, ^οπΓΐ
(Nujol) . 29 NN
-CH ₂ SA _n / B. -12 °
(H ₂ O) 278
(pH 6 buffer) 20,050 1781 CH ₃ 30th ^ C (CH ₃ ) ₂ -CH ₂ OCONH ₂ B. + 62 °
(EtOH) 275
(pH 6 buffer) 14,850 1775 31 -CH ₂ - -CH = CHCO ₂ CH ₃
(trans) B. -108 °
(aq. NaHCO ₃ ) 295
(pH 6 buffer) 26,200 1775 32 ■> i f> / OU ^ NN
-CH ₂ sA _s A _CH -48 °
(DMSO) 278
(pH 5 buffer) 21,800 1780

■ CJ3 O

Table V (continued)

cn ο CD OO ro

CD

At- τ values in d.-DMSO
100 MHz 8.51 game
No. X I.
y 8.52. 29 0.33 4.1 5.32 30th 0.24 4.14 8.49; 8.57 31 0.20 4 _T 08 32 0.38

-J

CJD O CJ] OJ

Table V (continued)

CD CO OO

Example no.

33

34

35

36

C (CHJ

.3'2

> O

It

dd

Cl

^CH 2 ^S <

S-

-CH = CHCO ₂ C ₂ H ₅

(trans)

-CH = CHCO ₂ H (trans)

method

C «] _n ■

(Solvent)

+ 92.5 ° (CHCl,)

-89 °
(DMSO)

Nnax, ™ ¹

(Solvent)·

272.5
(EtOH)

221

283
(pH 6 buffer)

-8 °

(aq. NaHCO ₃ )

-15 ° (aq. NaHCO ₃ )

295
(pH 6
Buffer)

294.5
(pH 6
Buffer)

16,600

23,900 21,550

26,200

31,200

β-lactam

^V max, ^cm "(Nujöl)

1780

1772

1780.

1779

ST ¹ O

CTi O

■ cn

CO

Table V (continued)

cn CD CQ OO ro

CD CD

at
game
No. τ values in d, -DMSO at 100 MHz
■ ο . y R ^ 33 ■.:
34
35
36 X 4.11
4.10
4.09
4 _T 07 8.51
7.9; 8.3
7.9; 8.3
7.9; 8.3 0.34
0.42
0.38
0 _; 38

(Τι I

CTJ O CJl co ■ »■ J

ο co OD ro -j

CD

R ^q P. Tabel V (continued) λ nm
Max,
( Solution
middle) ε β-Lac camouflage
ν cm "* ^ -
Max,
(Nujöl) at
spat;
No. NN
-CE ₂ SA _N i method u \
(Solution
middle) 279
(pH 6 buffer) 22,000 1780 37 CH ₃ A. -71 °
(CHCl ₃ ) It -CH ₂ OCONH ₂ 274.5
(pH 6 buffer) 15,700 1778 38 ·· -CH = QICO ₉ CH
(trans) ^{λ ό} A. +52 «»
(EtOH) 295
(pH 6 buffer) 26,800 1780 39 ^ C (CH ₃ ) ₂ -CH = CHCO ₉ CH ₀
(trans) ² . B. -85 °
(5% NaHCO ₃ ) • 295
(pH 6P buffer) 27.200 1779 40 -CH ₂ - H. B. -104.4
(5% NaHCO ₃ ) 281.5
(pH 6 buffer) 15,100 1774 41 B. + 84 °
(5% NaHCO ₃ )

O what. co

T & belle V (continued)

cn ο co QO NJ -J

CD CO 4> -CT)

example
No. τ values in cL-DMSO at 100 MHz
b y . R ^q . 37
38
39
40
41. X 4.15
4.14
4.05
4.09.
4.08 7.9; 8.28
7.9; 8.25
7.90; 8.25
8.52; .8.60
5.31 0.42
0.45
0.33
0.34
0.19

■ «J

00

cn ο

CJ

Table V (continued)

o co OO «S3

O CO

at
game
No. R ^q P. Method. + 162O
(5% NaHCO ₃ ) λ Tim
Max. ε β-lactam
ν cm
Max,
(Nujol) 42 H B. 283
(pH 6 buffer) 13,800 1775

VD I

ro

CO O CJl GO

Table V- (continued)

cn ο co CX) Ni

CD CO

cn

at
game
No. τ - values in cL-DMSO at
100 MHz y R ^q 42 X 4.05 7.9; 8.25 0.37

O Ol GO -J

00 O

Example 43 . ·

(6R, 7R) -7- [2- (l-Carboxycy'clopent-1-yloxyimino) -2- (fur-2-yl) - acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

a) A stirred solution of 5.50 g of diphenylmethyl (6R, 7R) -7-aminoceph-3-em-4 ~ carboxylate and 5.23 g of propylene oxide in 100 ml of dry methylene chloride was added dropwise at -5 C within 20 minutes a solution of 2- (1-tert-butoxycarbonylcyclopent-1-yloxyimino) -2- (fur-2-yl) acetyl chloride (syn isomer) in methylene chloride (see below). The resulting solution was stirred at 0 C for 40 minutes and allowed to warm to 22 ° C with stirring for a further hour. 15 ml of methanol were added and stirring was continued for 15 minutes. The solution was washed with a 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated saline solution. After drying and clarifying with. Activated charcoal was obtained by evaporation, a foam which was dissolved in ether and added dropwise to petroleum ether, 8.3 g (83%) of diphenylmethyl- (6R, 7R) -7- [2- (l-tert-butoxycarbonylcyclopentr 1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylate (syn-isomeres) were obtained as a colorless powder. [oc] _n

+ 43 ° (c 0.1, CHCIo); λ ,,,. _v (EtOH) 277 nm (£ = 17,300).

b) 6 g of the diester prepared above under a) in 30 ml of anisole at 0 C were treated with 24 ml of trifluoroacetic acid, and the solution was stirred for 30 minutes. The reaction mixture was allowed to warm to 22 ° C. for a further 2 hours with stirring and was then increased to approx. 20 ml concentrated. The residual oil was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution distributed. The organic layer was extracted with a bicarbonate solution and the combined alkaline layers were washed with ethyl acetate and ether. The aqueous layer was covered with ethyl acetate and adjusted to a p "value adjusted from 1.5 with concentrated hydrochloric acid. The obtained organic layer was washed with saturated saline, dried and evaporated to a foam,

509827/094 6

containing the title acid.

The foam was dissolved in a buffer containing 0.1 mol of sodium acetate, 0.1 mol of acetic acid and 0.2 mol of sodium chloride (75 ml) with the aid of sodium bicarbonate. The solution was treated with Amberlite XAD-8 (50 ml) and the ρ value was adjusted to 4.8 with 2N hydrochloric acid. The resulting stirred suspension was treated with neutral aluminum oxide (Woelm) (20 g) while maintaining the ρ value at 4.8. The suspension was stirred for 20 minutes and applied to a column containing 25 g of neutral aluminum oxide (Woelm). The title acid was eluted with 300 ml of the above buffer and with 500 ml of a 2% aqueous sodium acetate solution. The eluates were freeze-dried and redissolved in a minimal amount of water. After adjusting the pn value to 1.5 with concentrated hydrochloric acid, the acidic liquids were extracted with ethyl acetate and the combined extracts were dried and evaporated to form a foam. Trituration with ethyl acetate, petroleum and ether gave the title acid as a colorless solid (3.5 g, 88%); [a] _D + 162 ° (c 0.01, 5% aqueous NaHCO ₃ ); λ (p "6 phosphate buffer) 282 nm ( t = 14,000); v _m , _v (Nujol)

fflclX rl IuclX

1775 (β-lactam), 1710 (CO ₂ H) and 1680 and 1528 cm " ¹ (CONH); the T (DMSO-dg) values include 0.37 (d, J 8 Hz, CONH), 2.10 , 3.24 and 3.31 (m, furyl protons), 4.05 (dd, J 5 and 8 Hz, 7-H), '4', 80 (d, J 5 Hz, 6-H) and 7.90 and 8.25 (2 χ wide m, cyclopentyl protons). The NMR spectrum also showed the presence of 1/2 mole each of ethyl acetate and water.

The acylating agent used in step a) above was obtained as follows:

A stirred suspension of 3.75 g of phosphorus pentachloride in 120 ml of dry methylene chloride and 6.53 g of dimethylacetamide was at -10 ° C with 2- (1-tert-butoxycarbonylcyclopent-1-yloxyimino) -2- (fur-2-yl) acetic acid (syn-Isomeres) (5.82 g) treated in small portions to keep the temperature below -5 C to keep. After stirring for 15 minutes, the solution became

509827/0946

Treated with 40 g of ice and stirred for 20 minutes to obtain the corresponding acid chloride in the organic layer became.

Examples 44 to 48

General procedure for the preparation of (6R, 7R) -3- (optionally substituted) -7- [2-carboxy-R ^ -oxyimino) ~ 2-fur-2-yl) -acetamidÖJ-ceph-3-em-4 -carboxylic acids (syn isomers) by treating an ester of a (6R, 7R) -3- (optionally substituted) -7-aminoceph-3-em-4-carboxylic acid with an acid chloride (syn isomer)

A 2- (tert-butoxycarbonyl-R ^ -oxyimino) -2- (fur-2-yl ^ acetic acid (syn isomer) was converted into its acid chloride as described in Examples 2 to 24. A solution from 1 to 1.3 equivalents of the acid chloride in methylene chloride was at -5 to + 5 ° C within a period of 10 to 30 minutes dropwise to a solution of 1 equivalent of diphenylmethyl- (6R, 7R) -3- (if necessary substituted) -7-aminoceph-3-em-4-carboxylate in dry methylene chloride, the Containing 5 to 20 equivalents of propylene oxide, added. The reaction mixture .wurde about 1 to 3 hours at 0 ° C to room temperature stirred and then successively with 2N hydrochloric acid, aqueous sodium bicarbonate solution, water and / or brine. The dried organic layer was evaporated and the residue purified by trituration, precipitation, chromatography or crystallization.

The obtained diphenylmethyl- (6R, 7R) -3- (optionally substituted) -7- [2- (tert-butoxycarbonyl-R ^q -oxyimino) -2- (fur-2-yl) -acetamido] -ceph-3 -em-4-carboxylate (syn isomer) was subjected to the removal of the protective group as described in Examples 29 to 42, Methods A and B, for the diesters. The products are listed in Table VI.

509827/0 946

cn ο co oo ro -j

CD CD

(X

(x)

CONH '

Table VI

OR ^q -CO ₂ H

at
game
No. -CH ₂ - P. N method UV
(Solution
middle) - λ. rim
Max,
(pH6 buffer) ε ' ß-lactam
ν cm
Max,
(Nüjol) ■ 44 -CH ₂ - -CH = CHCO ₂ Et
(trans) ._. N B. ■ -38 ° 294.5 26,300 1780 45 -CH - -CH = CHCN 2 ^ r ■ "
H B. (DMSO) 291.5 21 * 800 1785 46 2 -H A. + 113 °
(aq. NaHCO ₃ ) 277.5 23,600 1775 ? C (CH ₃ ) ₂ CH S— N-N 47 -CH ₂ S ^ _n /
CH ₃ B. -97.3 °
(CHCl-) 279.5 13,400 1777 XO 48 A. 279 21,900 1782

CD

GD

Ul OO

Table VI (continued)

cn o co

ro

ο co

05

Example ·
No. '" - τ values in cL-DMSO at 100 MHz
D. X y . R ^q 44
45
46
47
48 0.12
0.08
0.21
0.41
0.32 4.04
4.01.
4.19
4.09
4.11 5.30
5.29
5.30
8.5
7 _r 6; 8, l

cn

DG O Ol OJ

Example 49

a) (6R, 7R) -Benzoyloxyisethyl-7- [2 - (^ - tert-butoxycarbonyl- prop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4 -Carboxylic acid <syn isomer)

A suspension of 313 mg of phosphorus pentachloride in 4 ml of dry methylene chloride was treated at -10 C with 0.7 ml of Ν, Ν-dimethylacetamide, after which 446 mg of 2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetic acid (syn-isomeres) was treated. The resulting solution was stirred at -10 ° C. for 30 minutes, treated with about 1 g of ice and stirred at below 0 ° C. for 15 minutes. The organic phase was added dropwise to a solution of 502 mg (6R, 7R) -7-amino-3-benzoyloxymethylceph-3-em-4-carboxylic acid in 2 ml Ν, Ν-dimethylacetamide and 2 ml acetonitrile, containing 1.09 ml Triethylamine, added at below 0C. The solution was stirred at 0 ° to 5 ° C. for 2 hours, 0.3 ml of methanol was added and the mixture was stirred for a further 15 minutes. The solution was diluted with 20 ml of methylene chloride and washed successively with 2N hydrochloric acid, water and brine, dried and evaporated to 1.02 g of a gum. A solution of this gum in 6 ml of ethyl acetate was added dropwise to 200 ml of stirred petroleum ether of boiling point 40 to 60 ° C., the title acid being obtained as a cream-colored powder in a yield of 83 % (769 mg); [cc] _n + 26 ° (c 1.05, acetone); λ (p _u 6 phosphate buffer) 233.5 niti (ε =

ΓπθΧ rl -

19,200) and 274 ntn (6 = 18 6oO); v> _v (Nujol) 1790 cm

IU α. Χ ·

(β-lactam); the T (d _c -DMSO) values include 0.29 (d, J 8 Hz, NH), 4.03 (dd, J 8 and J 5 Hz, 7-H), 8.50 [s, C ( CH_ ₃ ) ₂ ] and 8.58 [s, C (CH ₃ J ₃ ].

b) 6R, 7R) -3-Benzoyloxymethyl-7- [2- (2-carboxyprop-2-yloxy- imino ) -2- (fu.r-2-yl) -acetam / ido] -ceph-3-em -4-carboxylic acid (syn isomer)

A solution of 620 mg (6R, 7R) -3-ben2oyloxymethyl-7- [2- (2-tert-butoxycarbonylprop-2 ~ yloxyimino) -2- (fur-2-yl) -acetamido] -

ceph-3-em-4-carboxylic acid (syn-isoneres) in 0.6 ml of anisole and

509827 / 0-9 46

3 ml of trifluoroacetic acid wurde'bei-2O ⁰ C stirred for 25 Hinuten. The solution was partitioned between ethyl acetate and an aqueous Nätriumbicarbonatlösung, - and the p _H ~ value was adjusted by adding sodium carbonate to firmer. 8 The aqueous phase was separated off, washed with ethyl acetate, covered with ethyl acetate, and the p ^ value was adjusted to 1.5 by adding concentrated hydrochloric acid. The organic phase was separated, washed successively with water and a brine solution, dried and evaporated to give an oily foam (584%). A solution of this foam in ethyl acetate was allowed to run in dropwise into stirred petroleum ether with a boiling point of 40 to 60 ° C., Tltel-dicarboxylic acid being obtained as a gray-white solid (384 mg, 67 %) ; [>] ._ + 30.4 ° (c I ₊ O, acetone); Cp _H 6 phosphate buffer) 234 nm (ε = 19,700) and 273 nm (18,450); ν (Nujol) 1784 cm " ¹ (ß-lactam) ·; the ^ (d

ITIcLX · O

Values include 0.30 (d, J 8 Hz, NH), 4.07 (dd, J 8 and J 5 Hz, 7-H) and 8.50 [s, C (CH _-3 ) ^ ₂ ].

Example 50 .

Potassium (6R, 7R) -7- [S-carboxymethoxyimino ^ - (fur-2-yl) acetamido] -3-pyridiniummethyl-ceph-3-em-4-carboxylate (syn isomer)

A mixture of 3.26 g of ^^ (6R, 7R) -3-acetoxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetmido] -ceph-3-em-4-carboxylate (syn -Isomeres ·), 5.25 g of potassium thibcyanate, 0.72 ml of pyridine and 2 ml of water were stirred and heated to 80 ° C. for 40 minutes. The cooled reaction mixture was diluted with 5 ml of water and adsorbed onto a column with 500 g of XAD-2 resin. The components of the reaction mixture were eluted first with water and then with aqueous ethanol (1: 3) and collected using an automatic fraction collector. The fractions with the characteristic ultraviolet absorption patterns for the desired product were combined and evaporated to dryness in vacuo at <35 ° C. The crude material (600 mg) was crystallized from aqueous acetone (1: 9) to give 295 mg of the title _{compound, λ (p u} 6 phosphate buffer) 261 nm (ε = 19,000):

^a * ^H 509827/0946

^λ 1ηί1 ^{275 η} ™ ⁽ * = 18 400).

Example 51 .

Potassium (SR, 7R) -7- [2-carboxyprop-2-yloxyimino-2- (fur-2-yl) acetamido] -3-pyridinium methyl ~ Geph-3-em-4-carboxylate (syn isomer)

A mixture of 4.0 g of (6R, 7R) -3-acetoxy methyl-7- [2- (carboxyprop-2-yloxyimino) - 2- (fur-2-yl) -acetamideQ] -ceph-3 - em- 4-carboxylic acid (syn isomer), 4 ml of pyridine and 40 ml of water were heated to 80 ° C. for 1 hour, after which the mixture was allowed to cool. The cooled mixture was diluted with 50 ml of water and extracted five times with 25 ml of methylene chloride, and the combined organic extracts were washed with water. The combined aqueous phases were evaporated to about 50 ml in vacuo at <35 C and acidified to a ρ value of 2 with 2N hydrochloric acid. The precipitated solid was removed by filtration, the filtrate was adjusted to a p n value of 6.5 with potassium bicarbonate, and the solution was concentrated to approx. 40 ml at <35 ° C. in vacuo. The product was purified on a column with 500 g of XAD-2 resin, eluting with water and then with aqueous ethanol (1: 3). The fractions showing the characteristic ultraviolet absorption of the product were combined and evaporated to dryness in vacuo at <35 C to give 880 mg of the title _compound , \ mv (H ₀ O) 261 and 277 nm (t = 17,000 and 16,950).

Example 52 ,

Sodium (6R, 7R) ~ 7- [2- (carboxyprop-2-yloxyimino) -2- (fur-2-yl) ■ acetamido] -3-pyridiniummethylceph-3-em-4-carboxylate (syn- isomer)

A mixture of 50.0 g of sodium iodide, 15.5 ml of water and 14 ml of pyridine was heated to 80 ° C. and during the addition within about 10 minutes of 14.4 g of (6R, 7R) -3-acetoxymethyl-7- [2- (carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acet-

5 0 9827/0946

245 05 37

amido] -ceph-3-em-4-carboxylate (syn-Isoraeres) stirred vigorously. The mixture was stirred at 80 ° C. for a total of 55 minutes and then cooled and diluted to approx. 400 ml with water. O, In sodium hydroxide was added to the. Adjust the Po value to about 6.5, and the solution was concentrated under reduced pressure at <40 C to a volume of about 100 ml. The resulting solution was diluted to 400 ml with water, it was added 0.3 ml of methyl isobutyl ketone was added, and the stirred solution was acidified with 2N hydrochloric acid (15 ml) to a _pH value 1 to 2 The solid was collected, washed with water and taken out. The filtrate and washings were treated with further 2N hydrochloric acid (approx. 10 ml) and extracted with ethyl acetate, the organic layer being re-extracted with a small amount of water. The aqueous phase was adjusted to a p n value of 6 with approx. 43 ral ln sodium hydroxide solution and concentrated under reduced pressure at <40 ° C. to a volume of approx. 175 ml. This solution was applied to a column with 700 g of XAD-2 resin (42 cm × 5.5 cm) which had previously been washed with 2 l of water. The column was eluted with water, the fractions being collected automatically and monitored by UV spectroscopy. When the inorganic salts and some impurities had been removed, the eluent was replaced with a mixture of ethanol and water (1: 4). The fractions with the characteristic UV absorptions of the product were combined, concentrated under reduced pressure at <40 C and then freeze-dried. The product was dried over phosphorus pentoxide in vacuo to give 4.10 g of the title salt; [a] _n + 10.5 ° (c 1.00, H ₀ O); X " " (p _u 6 buffer) 261.5 and 278.5 nm

c. ΓΠ3.Λ ·. Jri ^

(E. = 20 100; 19 200); Y _v (Nujol) 1770 cm " ^l (β-lactam; the

₂ O, 100 MHz) values include 1.03, 1.43, 1.91 (pyridinium protons), 4.12 (dd, 7-H_) and 8.50 [s _r C (CH ₃ ) ₂ ] ,

509827/0946

Examples 53 to 57

In the manner described in Example 52, the acetoxy group of (6R, 7R) -3-acetoxymethyl-7- [2- (carboxy-R -oxyimino) -2- (fur-2-yl) -acetamido] -ceph-3 -em-4-carboxylic acids- (syn isomers) displaced by treatment with pyridine or a substituted pyridine in aqueous sodium iodide solution at 80 ° C. for 45 to 60 minutes. The products were interpreted as sodium salts
XAD-2 chromatography purified, and its physical
Properties are listed in Table VII.

$ 09827/0946

Table VII

OO lsi ■ -j

at
game
No. -CH ₂ - P. CH ₂ -N ^ o) salt • Monosodium [«] _D (pH 6 buffer) ■ ε '' ■ β -L ·, apt am
^ max, ^
(Nuipl.); 53 Monosodium Disodium 260.5 14VSOO ) C (CH,) _? CH ₂ Nd) ^{CO NH} 2 278 14 * 100. 54 ; C (CH ₃ ) ₂ CH ₂ N ^ Monosodium. - M. 55 CH ₂ CO ₂ Na 270.5 19,100 O CH ₂ N ^) 56 Ml 260.5
280.5 19,100
19,100. . -

Table VII (continued)

cn ο to

example
No. τ values in D ₀ O at 100 MHz y R ^q 53
54
55
56 X 4.16
4.11
4.11
4.16 5 _f 45
8.48
8.48
7.92; 8.30 • I I I

VO (VJ

CD O <JT3 CJ

Table VII (continued)

στ ο to

at
game
No. R ^q P. salt + 14 °
(H ₂ O) λ run
Max,
(pH 6 buffer) ε ß-lactam,
ν, cm
Max'
(Nujol) X> Mononatriurr 260
280.5 19,400
18,550 1770

LO I

cn

Oil

Table VII (continued)

cn ο CD CD

O CO

at
game
No. τ - values in D-O at 100 MHz y R ^ · 57 X 4.11 7.58; 8.03 -

• fs »I

cn co

Example 58

(6R, 7R) -7- [2 ~ (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl ^ acetamido ] -3 ^ pyridaziumm ethyl ceph-3-em-4-carbonic acid-trifluoroacetate (syn-Lsomeres)

a) A suspension of 1.51 g of diphenylmethyl ~ (IS, 6R, 7R) -3-bromomethyl-7- [2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2 - (fur-2-yl ) -acetamid.o] -ceph-3-em-4-carboxylate-l-oxide (syn isomer) in 1 ml Ν, Ν-dimethylformamide was treated with 400 mg pyridazine. The mixture was stirred at 25 ° C. for 2 hours, a clear solution being obtained, which was then diluted with 50 ml of ether, which was slowly added with stirring. The precipitate obtained was filtered off. washed with ether and dried, the diphenylmethyl- (IS, 6R, 7R) -7- [2- (2-tert-butoxycarbonylprop-2-yloxyiinino) -2- (fur-2-yl) acetamido] -3 -pyridaziniummethylceph-3-em-4-carboxylate-1-oxydbromide (syn-Isomeres) was obtained as a pink powder (1.59 g, 94%); [a] ' _D + 13 ° (c 1.07, DMSO );

λ (EtOH) (277nm U = 21,200); ν (Nujol) 1790 cm " ¹

max. max »

(β-lactam); the T (dg-DMDO) values include 1.21 (d, J 8 Hz, NH), 3.76 (dd, J. 4 and 8 Hz), 8.51 [s, C {CHO ₉ ] and 8 , 61 [s, C (CH ₃ ) ₃ ],

b) 1.49 g of the above product obtained under a) in 5 ml of N, N-dimethylformamide were mixed with 1.33 g of potassium iodide at -10 ° C and then treated with 0.28 ml of acetyl chloride. The mixture was stirred for 1 hour while the temperature was slowly increasing rose to 0 C, "and then became a drop by drop stirred solution of 1 g of sodium metabisulphite in 50 nil of water joined. The resulting suspension was stirred for 10 minutes and then the solid was filtered off with water washed and dried over phosphorus pentoxide, 1.28 g of a “light brown powder. This material, in 20 ml of acetone: ethanol = 9: 1, was through a column with Deacidite FF resin (trifluoroacetate form, 15 cm χ 2.5 cm) passed, eluting with the same solvent mixture. The eluate fractions that absorb ultraviolet light Contained material, were combined and evaporated,

50 98 2 7/094 6

and the residue was triturated with ether, whereby 1.24 g (82%) of diphenylmethyl- (6R, 7R) -7- [2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (fur-2- yl) acetamido] -3-pyridaziniummethylceph-3-em-4-carboxylate trifluoroacetate (syn isomer); [a] _n -20 ° (c 0.76, DMSO); X _m ^ _v (EtOH) 278 nm (e = 18,300); v _max (Nujol) 1780 cm; the -T (dg-DMSO) values include 0.30 (d, J 8 Hz, NH), 3.95 (dd, J 5 and 8 Hz, 7-H), 8.55 [s, C (CH ₃ ) ₂ ] and 8.59 [s, C (CH ₃ ) ₃ ],

c) 1.13 g of the product obtained under b) above, mixed with 1.5 ml of anisole, were treated with 6 ml of trifluoroacetic acid for 5 minutes at 5 ° C. and then for 55 minutes at 20 ° C. The solution was evaporated in vacuo, the residue was triturated with ethyl acetate and the evaporation repeated. The resulting gum was triturated with ether to give the crude product as a pale brown solid which was filtered off, washed with ether and dried. This was extracted with 3 × 150 ml of water. The extracts were filtered, washed with ethyl acetate and then with ether and finally freeze-dried. The combined residues were triturated with ether to give the title salt as a white powder (586mg, 72%); [a] _n + 48 ° (c 0.98, DMSO); \ _{m = v} (p "6 phosphate buffer)

rl, *

277 nm (ε = 18,100); ν (Nujol) 1776 cm (β-lactam);

ITl 9lX

T (d ₆ -DMSO) 0.37 (d J 8 Hz, NH), 4.09 (dd, J 5 and 8 Hz, 7-H,) and 8.53 [s, C (CH ₃ > ₂ ] ,

Examples 59 to 64

The trifluoroacetate salts listed in Table VIII were by reacting the 3-bromomethyl ester (see below) with the appropriate tertiary base (or with the quaternary Mercaptan in Example 61), reduction of the sulfoxide and removal of both protective groups in a manner similar to that in Example 58 described manufactured. The starting material was obtained as follows:

509827/0 9 46

A solution of 5.20 g of phosphorus pentachloride in 60 ml of dry methylene chloride was mixed at -10 C with 12 ml of N, N-dimethylacetamide and then with 6.43 g of 2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetic acid (syn-isomeres), which were added in portions, treated. The solution was stirred for 15 minutes at -10 ° C, and then 14 g of ice were slowly added and the temperature within IO minutes at 0 ⁰ C allowed to rise. The organic layer was separated and added dropwise to a suspension of 10.62 g of diphenylmethyl (1S, 6R, 7R) -7-amino-3-bromomethylceph-3-em-4-carboxylate-1-oxide hydrobromide in 80 ml of methylene chloride , which contained 15 ml of propylene oxide, added at 0 C. The mixture was stirred for 1 hour, during which time the temperature rose to 20 ° C. and the suspension cleared. The resulting yellow solution was washed with 50 ml of 2.5% aqueous sodium bicarbonate solution and then with 50 ml of 2N hydrochloric acid, whereupon the solution was dried and evaporated to a yellow oil. This material, in 20 ml of ethyl acetate, was added dropwise to stirred petroleum ether, b.p. 40 to 60 ° C., to obtain a gummy precipitate. The supernatant was decanted and the gum was chromatographed on a silica gel column, eluting with methylene chloride containing 0-10% acetone. The eluate fractions containing the main product were combined and evaporated to a foam. On trituration with cyclohexane, the diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7- [2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylate-1-oxide (syn-isomeres) obtained as a pale yellow microcrystalline powder (13.61 g, 90%); [a] _D - 22 °. (c 1.0, DMSO); \ _mav (EtOH) 281 nm (£ = 22,200); γ » _v (CHBro) 1800 cm ~ (β-lactam); the r (dg DMSO) values include 1.26 (d, J 8 Hz, NH), 3.86 (dd, J 4 and 8 Hz, 7-H), 851 [s, C (CH ₃ ) ₂ ] and 8.61 [s, C (CH ₃ J ₃ ].

509827 / 09A6

O «D OO

. ty;

(x) H.

-CONH "

H S

Table VIII

. R ^q P. salt (DMSO) λ ran
Max,
(pH 6 buffer) CO ₂ H ε β-lactam.
ν cm
Max,
(Nuiol) at
game
No. CONH ₂ Trifluorine
acetate -57.5 ° 267 21,600 1775 $ 5 \ j \ VjIi ty J η ⁰ H ₂ ¹ C = J Trifluorine
acetate -43.5 ° 244
277 14,800
18,200 1784 60 ; c (cH ₃ ) ₂ CH S <@ Trifluorine -
acetate -14 ° 277 21,500 1782 61 ; c (cH ) T.rifluor-
acetate -58 ° 257 22.200 1780 62

Table VIII (continued)

O CD GO

-P-CO

τ values * in d, -DMSO at 100 MHz
D. 8.55 ' ' At- . ·
game
No. χ. y. 8.54 59 .... 0.38 4.11 8.53 60 0.4. 4.14 8.55 61 0.40 4.14 62 0.29 4.05

Values for the trifluoroacetate salt

Table VIII (continued)

cn CD CD OO »Ό

CD CO

CD

at
game
No. C (CH ₃ ) ₂ P. salt C «] _D
(DMSO) λ run
Max,
(pH 6 buffer) ε ß-L.actam ..
ν cm
Max, (Nujol) C (CH) ₂ + • Ν 3 63 CH ₂ NO) Trifluoro -79 ° 225.5 16,100 1778 acetate 271 18,400 64 CH ₉ NON-CH, Trifluoro -32 ° 274 18,100 1773 acetate

O O

■ CD CD

Table VIII (continued)

cn

CO OO

O CD -C-CJ)

example
No. τ values * in dg-DMSO at lOOMHz y 8.50
8.53 63
64 X 4.12
4.11 0.38
0.40

* "Values for the trifluoroacetate salt

Example 65

(6R, 7R) -3- ( Benzotriazol-1-y! Methyl) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3 -em-4 - carboxylic acid (syn isomer)

1.51 g of diphenylmethyl- (IS, 6R, 7R) -3-bromomethyl-7- [2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph -3 ~ em-4-carboxylate oxide (syn isomer) in 3 ml of N, N-diethyl form amide were stirred for 4 days with 480 mg of benzotriazole. The solution was diluted with methylene chloride and then washed twice with 2N hydrochloric acid. The solution was then dried and evaporated, and the main product was isolated from the residue by column chromatography on silica gel with chloroform containing 0-10% v / v acetone as the eluent. This material (700 mg) in 2 ml of N, N-dimethylformamide with 665 mg of potassium iodide was treated with 0.14 ml of acetyl chloride at -10 ° C. The suspension was stirred for 1.25 hours and allowed to warm slowly to 0 C and it was then added dropwise to 40 ml of water containing 0.5 g of sodium metabisulfite. The precipitate was filtered off, washed with water, dried and purified by chromatography on silica gel, eluting with methylene chloride containing 0 to 3% v / v acetone.

The diester obtained in this way (520 mg) was treated together with 0.5 ml of anisole and 2 ml of trifluoroacetic acid at 25 ° C. for 1 hour. The solution was then added dropwise with stirring to 50 ml of a saturated aqueous sodium carbonate solution and 25 g of ice. The mixture was stirred, after which ethyl acetate was added. The aqueous layer was separated and acidified to a p "value of 2 under ethyl acetate. The organic layer was separated and the aqueous layer extracted with more ethyl acetate. The combined extracts were dried and concentrated to an oil which was added dropwise to stirring b.p. 40-60 ° C. petroleum ether. The white precipitate was filtered off, washed with petroleum ether and dried, the title

509827/0946

Dicarboxylic acid was obtained as a white powder (350 mg, 31%); [a] _n + 37 ° (c 1.02, DMSO); \ _{m = v} (p "6 phosphate buffer) 269 nm (6 = 23,600); >? (Nujol) 1V80 cm "(β-lactam); the t (d ₆ -DMSO) values include 0.40 (d, J 8 Hz, WH), 4.11 (dd, J 5 and '8 Hz, 7 -H _- ) and 8.53 [s, C (CH ₃ ) ₂ J.

Example 66

The compound listed in Table IX was taken from the corresponding Nucleophile prepared using the procedure of Example 65-

509827/0946

<U

Λ id

β-L ac tarn ..
ν cm
Max,
(Nujol) 1780. ω 18,100 (U
Β ?. ZLZ Q t / 3
ι—> p
Ö O ο CD I. CM
K
O CM
pi CM
O
CJ
* \ at
game
No. % Λ
Co

509827/0946

τ values in d _c -DMSO at 100 MHz he m
OO 4.11 X O at
game
No. vO
VO

509827/0946

2A60537

Example 67

Pivaloyloxymethyl- (6R, 7R) -3-carbamoyloxymethy1- T- [2-carboxymethoxyiroino-2- (fur-2-yl) -acetamido] -ceph-3-e m-4-carboxylate (syn-isomer)

A stirred solution of 8.50 g of sodium (6R, ■ / RX-S-icarbamoyloxymethyl-y- [2-tert-butoxycarbonylmethoxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em -4-carboxylate (syn isomer) in 100 ml of dimethylformamide was treated with 4.68 ml of chloromethyl pivalate. The solution was stirred at room temperature for 25 hours and partitioned between ethyl acetate and water. The aqueous layer was further extracted with the ethyl acetate and the combined extracts were washed successively with brine, saturated sodium bicarbonate solution and brine and were then dried and evaporated to a small volume. The residue was slowly added to 1.5 1 of stirred petroleum ether with a boiling point of 40 to 60 ° C. and the precipitate was collected, washed with petroleum ether and dried in vacuo, 8.32 g of a mixture of the tert-butyl ester of the title compound and its / \ Analogue (A 'Ά ratio ~ 3: 2, determination by NMR spectroscopy).

8.1 g of this mixture of isomers, dissolved in 75 ml of methylene chloride, were cooled to -40 C and stirred, while dropwise 2.41 g of m-chloroperbenzoic acid in 65 ml of methylene chloride were admitted. The solution was stirred for 1.25 hours at -40 ° C., and a further 1.2 g of m-chloroperbenzoic acid were added added in methylene chloride. After stirring for an additional 40 minutes, the solvent was evaporated and the residue partitioned between ethyl acetate and a salt solution. The ethyl acetate solution was made with sodium bicarbonate solution and brine washed, dried over sodium sulfate and added to 9.77 g of one yellow foam evaporates. This was triturated with ether, and a yellow solid was filtered off, which was washed with ether washed and dried in vacuo to give 7.27 g of the 1-oxide of the title compound.

509827/0946

A solution of 7.07 g of this sulfoxide and 14.34 g of potassium iodide in 100 ml of dimethylformamide was surrounded by a salt-ice bath and while adding 3.08 ml of acetyl chloride stirred in 15 ml of dimethylformamide. The solution was stirred for 3.5 hours and an additional 1.54 ml of acetyl chloride was added in Dimethylformamide added. The solution was stirred for 1 hour and between a sodium metabisulfite solution and ethyl acetate distributed. The organic layer was washed with sodium metabisulfite solution and water and then dried and evaporated to a small volume. The solution obtained was slowly added to excess stirred petroleum ether with a boiling point of 40 to 60 ° C, and the solid obtained was collected, washed with petroleum ether and dried in vacuo, 7 g of pivaloyloxymethyl- (6R, 7R) -3-carbamoyloxymethyl-7- [2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] - ceph-3-em-4-carboxylate (syn-isomeres); λ

Max .

(EtOH) 277 nm (S = 16,540); λ> _v (Nujol) 1782 (β-lactam), 1740 and 1720 cm (CONH ₂ ); the . (dg-DMSO) values include 0.25 (d, NH_), 3.40 (s, NH_ ₂ ) and 8.8 [s, C (CH ₃ J ₃ ].

The above diester (1.0 g) was dissolved in 5 ml of trifluoroacetic acid and this solution was stirred at room temperature for 15 minutes and then diluted with ether, washed with water and evaporated. The residue was partitioned between ethyl acetate and a sodium bicarbonate solution and the organic layer was extracted again with sodium bicarbonate solution. The combined aqueous extracts were washed with ethyl acetate, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to give an oil. This was dissolved in a little ethyl acetate volume, and added slowly to excess stirred petroleum ether, bp. 40 to 6O ⁰ C. The gray-white precipitate was collected, washed with petroleum ether and dried in vacuo to give 0.645 g of the title ester; λ

> t ΠΙ 3.X

(EtOH) 278 nm (£ = 16,900); \? (Nujol) 1778 cm "(ß-lactam>; the r (d ₆ -DMS0) values include 0.25 (d, NH_), 2.16, 3.26, 3.38 (fur-2-yl- Protons) and 4.10 (dd, 7-H_).

509 827/0946

The sodium salt starting material for the above procedure was prepared as follows:

2.58 ml of triethylamine and 2 drops of dimethylformamide were added to a solution of 5 g of 2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn isomer) in 200 ml of dry methylene chloride. The stirred solution was cooled to 0 ° C and 1.58 ml of oxalyl chloride was added. the
Solution was stirred for 1 hour and then evaporated. The residue was suspended in 150 ml of acetone and added to a stirred, ice-cold solution of 5.08 g of (6R, 7R) -3-carbamoyloxymethyl-7-aminoceph-3-em-4-carboxylic acid within half an hour
in 150 ml of acetone and 300 ml of water containing 3.74 g of sodium bicarbonate added. The reaction mixture was stirred for 1 hour and evaporated to remove acetone. The aqueous residue was reduced to a p "value of 1.8 under ether
Using dilute hydrochloric acid acidified,
and the layers were separated.

The aqueous layer was further extracted with ether, and
the combined extracts were made with water and saline
washed, dried and evaporated, whereby the (6R, 7R) -3-carbamoyloxymethyl-7- [2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-carboxylic acid (syn-isomer) was obtained; \ _{m = v} (p "6 phosphate buffer) 274.5 nm (ε = 17 520);

V (CHBr-.) 1785 (β-lactam), 1686 and 1530 cm (CONH); max. ό ⁷

the tf (d ₆ -DMSO) values include 0.29 (d, NH), 4.19 (dd, 7-H_) and 4.79 (d, 6-H).

A stirred solution of 9.02 g of the above acid in 40 ml of acetone was treated with a solution of 2.86 g of sodium 2-ethylhexanoate in 40 ml of acetone. The resulting solution was slowly added to 1600 ml of stirred petroleum ether with a boiling point of 40 to 60 ° C., and the precipitate was collected, washed and dried in vacuo, the sodium (6R, 7R) -3-carbamoyloxymethyl-7- [2- tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) -acetamidoJ-ceph-S-em-A-carboxylate (syn-isomeres) (8.71 g)
was obtained; X _{m = v} (p "6 buffers) 274.5 nm (& = 17,650);

509827/0946

^ m _v (Nujol) 1755 (ß-lactam) and 1608 cm " ¹ (CO ₀ -): the

T (d _g -DMS0) values include 0.4 (d, NH), 4.4 (dd, 7-H) and 4.98 (d, 6-H). . ■

Example 68

(IS, 6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyimino 2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylic acid 1-oxide (syn isomer)

a) A solution of 1.21 g of (6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3 -em-4-carboxylic acid (syn isomer in 25 ml of pyridine and 1 ml of water was treated with 0.3 ml of tert-butyl hypochlorite at -45 ° C., with vigorous stirring. After 2 minutes, 1 ml of 2n- Sulphurous acid was added to the solution, and the mixture was immediately poured into 100 ml of a 20 v / v 3% aqueous phosphoric acid solution, the aqueous solution was extracted with ethyl acetate, and the organic extracts were mixed with 0.5N hydrochloric acid solution (50 ml), an aqueous sodium bicarbonate solution (50 ml> and water, then dried and concentrated in vacuo. The crude product was chromatographed on preparative silica gel plates using ethyl acetate: petroleum ether of b.p. 60 to 80 ° C in a ratio of 4: 1 as eluent The slower running band was extracted with ethyl acetate, whereby 505 mg of the di-tert-butyl ester of the title compound ung were obtained; \> (Nujol) 1798 (β-lactan), 1738, 1727, 1715 (acetate and CO ₂ .tBu), 1680 and 1542 cm "(CONH); the r (DMS0-dg) values include 0.28 (i.e. , J -8 Hz, NH), 4.19 (dd, J 5 and 8 Hz, 7-H), 5.02 (d J 5 Hz, 6-H), 5.71 and 6.38 (ABq, J 18 Hz, 2-H).

0.38 g of the di-tert-butyl ester in 5 ml of trifluoroacetic acid, which contained a few drops of anisole, were 15 minutes at room temperature touched. The solution was concentrated in vacuo to a red oil, diluted with 2 ml of ethyl acetate and added dropwise added to vigorously stirred petroleum ether with a boiling point of 60 to 80 ° C. (50 ml). The precipitated solid was collected, with 5 ml Ether washed and dried, 185 mg (60%) of the title

509827/0946

Acid were obtained; \ _{m = v} (ethanol) 276 nm ( t = 16 600):

(Nujol) 1790 (β-lactam), 1730 (acetate), 1720 (CO ₀ H), 1680 and 1523 (CONH) and 1040 cm (S - Y 0); the (DMSO-dg) values include 0.21 (d, J 8 Hz, NH), 4.17 (dd, J 5 and 8 Hz, 7-H), 5.01 (d, J 5 Hz, 6 -H_), 5.71 and 6.32 (ABq, J 18 Hz, 2-H), 8.49 [s, C (CH ₃ ) ₂ ].

The starting material for the above oxidation process was made as follows:

A solution of 1.05 g of tert-butyl (6R, 7R) -7-amino-3-acetoxymethylceph-3-one-4-carboxylate in 10 ml of dry methylene chloride was added to a solution of 0.99 g of 2- ( 2-tert-Butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetic acid (syn isomer) and 0.69 g of dicyclohexylcarbodiimide in 10 ml of dry methylene chloride, and the mixture was stirred at room temperature for 1 hour - The solution was filtered and concentrated in vacuo. The crude product was passed through a column of silica gel (MFC, 2 × 20 cm, particle size 0.149 to 0.074 mm (100 to 200 mesh)] using ethyl acetate: petroleum ether with a b.p. 60 to 80 ° C in a ratio of 1: 1 as the eluent The combination of the appropriate fractions, determined by thin layer chromatography, gave 1.29 g of (6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid di-tert-butyl ester (syn isomer); ν _m ■ (CHBr.,) 1776 (ß-lactam), 1725, 1712 (acetate and C0 ₂ - tBu), 1678 and 1512 cm (CONH); the X (CDCl ₃ ) values include 1.90 (d, J 8 Hz, NH), 4.08 (dd, J 5 and 8 Hz, 7-H) and 4.98 (d, J 5 Hz, 6-H).

Example A.

This example illustrates the formulation of a pharmaceutical Composition.

509827/0946

- Ill -

Dry powder for injections

Sterile disodium salt of (6R, 7R) -3-acetoxymethyl-7- [2- (1carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylate (syn-isomeres) is filled into glass vials, ' the content of antibiotic in each container being 500 mg or 1.00 g as desired. The filling takes place under aseptic conditions under a nitrogen blanket. The vials are made using rubber washers or Plugs, which are held in place by aluminum sealing rings, are closed, causing gas exchange or the Penetration of microorganisms is prevented. The product can be reconstituted or reconstituted for injections with water or other suitable sterile vehicle shortly before administration. be turned on again.

509827/0946

Claims (1)

- 112 claims 1. 7β-Acylamidoceph-3-em-4-carboxylic acid antibiotics and their non-toxic derivatives, characterized in that the 7β-acylamido group has the formula R.C.CO.NH- 'ra' .C. (CH «V .COOH |, £ Xl has, wherein R represents thienyl or furyl, R ^a and R, which can be the same or different, are each selected from hydrogen, C ^, - to C, -Alkyi, C ₂ - to C ₄ -alkenyl, C ₃ - to C _? -Cycloalkyl, Phenyl, Naphthyl, Thienyl, Furyl, Carboxy, Cpbis Cg-Alkoxycarbonyl und Cyano or R ^a and R together with the carbon atom, to which they are attached, a C ^ - to C ^ -Cycloalkyliden- or -Cycloalkenyliden- Make up the rest and m and η each represent the numbers 0 or 1 in such a way that that the sum of m and η is 0 or 1, where the compounds are syn isomers or as mixtures of the syn and anti isomers are present which contain at least 90% of the syn isomer. 2 «compounds according to claim 1, characterized in that the syn isomer is essentially free of the anti isomer. 3. Compounds according to claim 1 or claim 2 of the general formula 509827/0 9 46 R.C.CO.NH- (ID COOH ... '. (CH ₀ ). C. (CH_) .COOH 2 m ^ 2 η wherein R, R ^a , R, in and η have the meaning given in claim 1 and P is selected from a) hydrogen,. b) halogen, c) a radical of the formula 1 'P wherein R and R, which can be the same or different, are each selected from hydrogen, carboxy, cyano, Cp- to C ^ -alkoxycarbonyl, C 1 - to Cg-alkyl, C ₅ - to Cy-cycloalkyl, phenyl-C ^ - to C ₄ ~ alkyl and Cg- to C ^ 2 ~ ^mon ° - or bicyclic carbocyclic aryl, and d) a radical of the formula -CH ₂ Y wherein Y is selected from i) the remainder of a nitrogen nucleophile which is a TrI- (C ^ - to Cg-alkyl) -amine or a heterocyclic it is tertiary amine, ii) azido, iii) amino, - iv) acylamido, " 509827 / 09A6 ν) a derivative obtained by reacting a compound in which Y is azido with a acetylenic, ethylenic or cyano-dipolarophile, vi) a radical of the formula R ¹⁰ 'ι C. CO. R ¹² 10 11
wherein R and R, which can be the same or different, are selected from hydrogen; Cyano; lower alkyl; Phenyl; Phenyl substituted by one or more of halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino; Carboxy; lower alkoxycarbonyl; Mono- or diaryl-lower alkoxycarbonyl; lower-alkylcarbonyl; Aryl low 12 rig-alkyl; and C ₅ and C 6 cycloalkyl; and R is selected from hydrogen; lower alkyl; Phenyl; Phenyl substituted by one or more of halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino; Aryl-lower-alkyl; and Cj- and Cg-cycloalkyl; vii) the remainder of a sulfur nucleophile which is a thiourea, such as dithiocarbamate, thioamide, thiosulfate, a thio acid or ditnio acid, viii) a radical of the formula -S (O) _n R ¹³ 13th
wherein R is a lower-alkyl, lower-cycloalkyl, phenyl-lower-alkyl, C _g - to C ^ or bicyclic carbocyclic aryl or represents heterocyclic radical and η represents the numbers 0, 1 or 2, 509827/094 6 ix) a radical of the formula 15 -OR wherein R is hydrogen, a lower alkyl, lower alkenyl, lower alkynyl, lower cycloalkyl, lower-cycloalkyl-lower-alkyl-, aryl-, aryl-lower-alkyl-, heterocyclic, heterocyclic-lower-alkyl radical or any of the preceding radicals means, by one or more selected from lower-alkoxy, lower-alkylthio, halogen, lower-alkyl, nitro, hydroxy, acyloxy, carboxy, lower-alkoxycarbonyl, lower-alkylcarbonyl, lower-alkylsulphonyl, lower-alkoxysulphonyl, amino, lower alkylamino and acylamino can be, x) a residue of the formula -O.CO.R ¹⁶ . wherein R is selected from the group consisting of Cs, - can -C ₇ -alkyl which may be interrupted by an oxygen or sulfur atom or an imino group or be substituted by cyano, carboxy, lower-alkoxycarbonyl, hydroxy, carboxycarbonyl, halogen or amino; Cp- to C ₇ - · alkenyl, which can be interrupted by an oxygen or sulfur atom or an imino group; lower cycloalkyl; carbocyclic or heterocyclic aryl which can be substituted by hydroxy, halogen, nitro, amino, lower-alkyl or lower-alkylthio; alkyl low-cycloalkyl-C-to C _4; and carbocyclic or heterocyclic! Aryl-C ^ - to C ₄ -alkyl, and xi) a radical of the formula. " -O.CO ^ AR ¹⁷ 17th
where R is hydrogen or a radical as defined above for R and A is>0,> S or> NH, -. 5 09827 / 0946- - 116 and their non-toxic derivatives. 4. Compounds according to claim 3, characterized in that P is a radical of the formula -CH ₂ Y < where Y is the residue of a nitrogen nucleophile which comprises a pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, imidazole, triazole, thiazole, purine, benzotriazole, or any of these compounds represented by one or more lower alkyl, Cg - To C ₁₂ - ^1110110 - or bicyclic carbocyclic aryl, phenyl-lower alkyl, lower alkoxymethyl, acyloxymethyl, formyl, acyloxy, carboxy, esterified carboxy, carboxy-lower alkyl, suIfο- , lower alkoxy, phenoxy, phenyl lower alkoxy, lower alkylthio, phenylthio, phenyl lower alkylthio, cyano, hydroxy, carbamoyl, N-mono- (lower alkyl) carbamoyl , N, N-di (lower-alkyl) -carbamoyl, N- (hydroxy-lower-alkyl) -carbamoyl or carbamoyl-lower-alkyl groups are substituted. 5. Compounds according to claim 3, characterized in that that P is a residue of the formula -CH ₂ Y, where Y is a radical -SR ¹⁴ 14th
represents, wherein R is a diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, pyridyl, pyrimidyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, trxdazolopyrinyl, trxdazolopyrinyl is. 6. Compounds according to claim 3, characterized in that P is an acetoxymethyl or carbamoyloxymethyl group. 50 98 27/0946 7. Compounds according to claim 1 or 2 of the general formula (III) COOH wherein R has the meaning given in claim 1, R is methyl, ethyl, propyl, allyl or phenyl and R is hydrogen, carboxy or a radical as ^{defined for R c} , or R and R together with the carbon atom, to which they are bound form a cyclobutylidene, cyclopentylideri or cyclohexylidene radical and W is selected from i) hydrogen, ii) acetoxymethyl, iii) benzoyloxymethyl, iv) carbamoyloxymethyl, v) N-methylcarbamoyloxymethyl, vi) a group of the formula -CH = CHR ² wherein R is cyano, carboxy or C ^ - to Cc -alkoxycarbonyl represents, _. vii) a radical of the formula -CH ₂ G wherein G is the residue of a nitrogen nucleophile under compounds of the formula - O- 509827/0946 wherein R is hydrogen, carbamoyl, carboxymethyl or sulfo, and is pyridazine, viii) azidomethyl and ix) a radical of the formula -CH ₂ SR ^W wherein R is a pyridyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl or oxadiazolyl radical or a lower alkyl or phenyl substituted one Is an analogue of such a residue, and their non-toxic derivatives. 8. Compounds according to claim 7, characterized in that W is a radical of the formula -CH ₂ SR ^W where R ^{w is} N-methylpyrid-2-yl, 1-methyltetrazol-5-yl or 5-methyl-1,3,4-thiadiazol-2-yl. 9. Compounds according to claim 7 or 8, characterized in that R is not hydrogen. 10. Compounds according to claim 1 or 2 of the general formula R.C.CO.NH- J Kf J T.T (IV) . (CH) .COOH COOH 2 P wherein R has the meaning given in claim 1, W is as defined in claim 7 and ρ represents 1 or 2, and their non-toxic derivatives. 509 8 2 7/0946 11. Compounds according to claim 10, wherein W is a radical as in Claim 8 means defined. 12. (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido J-S-pyridiniummethylceph-S-eni- ^ carboxylic acid (syn isomer). 13. (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -3- (5-methyl-1, 3,4-thiadiazol-2-ylthiomethyl) -ceph-3-em-4-carboxylic acid (syn isomer). 14. (6R, 7R) -3-carbamoyloxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2-fur-2-yl ) -acetamido] -ceph-3-ern-4-carboxylic acid (syn-isomer). 15. (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetatnido] -3- (trans-2-itiethoxycarbonylvinyl) -ceph-3— em-4- carboxylic acid (syn isomer). · 16. (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -3-pyridaziniummethylceph-3-em-4-carboxylic acid (syn isomer). 17. (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 18. (6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). , 19. (6R, 7R) -7- [2- (1-carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) acetamido] -3-pyridiniummethylceph-3-em-4-carboxylic acid (syn isomer). 20. (6R, 7R) -7- [2- (l-Carboxycyclopent-l-yloxyimino) -2- (fur-2-yl) -acetamido] -3- (trans-2-carboxyvinyl) -ceph-3- em-4-carboxylic acid (syn isomer). 5098 27/0 94 6 21. (6R, 7R) -7- [2- (l-carboxycyclopent-l-yloxyimino) -2- (fur-2-yl) acetamido] -3- (l-methyltetrazol-5-ylthiomethyl) -ceph- 3-em-4-carboxylic acid (syn isomer). 22. (6R, 7R) -3-carbamoyloxymethyl-7- [2- (1-carboxycyclopent-lyloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 23. (6R, 7R) -7- [2- (1-Carboxycyclopent-1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 24. (6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxybut-3-enyloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-a-4-carboxylic acid (syn isomer). 25. (6R, 7R) -3-acetoxymethyl-7- [2- (i_carboxycyclobut-1-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 26. (6R, 7R) -7- [2- (1-carboxycyclobut-1-yloxyimino) -2- (fur-2-yl) -acetamido] -3-pyridiniummethylceph-3-em-4-carboxylic acid (syn isomer). 7. (6R, 7R) -7- [2- (1-carboxycyclobut-1-yloxyimino) -2- (fur-2-yl) -acetamdiö] -3- (l-methyltetrazol-5-ylthiomethyl) -ceph- 3-em-4-carboxylic acid (syn isomer). 28. (6R, 7R) -3-carbamoyloxymethyl-7- [2- (l-carboxycyclobut-lyloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carbon- acid (syn isomer). 29. (6R, 7R) -3-acetoxymethyl-7- [2- (1-carboxypropoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 30. (6R, 7R) -3-acetoxymethyl-7- [2- (3-carboxypent-3-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 509827/09 46 31 .- (6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyirnino) -2- (thien-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn- * isomer). 32. (6R, 7R) -3-acetoxy methyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). 33. (6R, 7R) -3-Azidomethyl-7- [2-carboxymethoxyiinino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer). ο " 34. (6R, 7R) -7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -3- (l-methyltetrazol-5-ylthiometh.yl) -ceph-3-em-4- carboxylic acid (syn-Isoraeres). 35. (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetainido] -ceph-3-em-4-carboxylic acid (syn-iso- raeres). 36. (6R, 7R) -7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetamidoJ-ceph-3-em-4-carboxylic acid (syn-Isorneres). 7. The sodium and potassium salts of the acids according to any one of the preceding claims. 38. Method of making an antibiotic compound the general formula R. C. CO. NH- (I) COOH O. (CH ₂ ) _m ._C. (CH ₂ ) _n. COOK 5 D9827 / 0946 R represents thienyl or furyl, R and R, which can be identical or different, are each selected from the group consisting of hydrogen, C.- to C.-alkyl, C ₂ - to C ₄ -alkenyl, C ₃ - to Cy-cycloalkyl, phenyl, naphthyl , Thienyl, furyl, carboxy, C ₂ - to C ₅ -alkoxycarbonyl and cyano, or R and R together with the carbon atom to which they are attached form a C ₃ - to C ^ cycloalkylidene or cycloalkenylidene radical, m and η each represent the numbers O or 1 in such a way that that it is the sum of m and η O or 1, and Z represents a group in which 2 carbon atoms the core sulfur atom and the carbon atom connect in 4-position with each other in such a way that the connection has a / \ -saturation, or a non-toxic derivative thereof, the compound is a syn isomer or as a mixture of the syn- and anti isomers are present which are at least 90% of the syn isomer contains, characterized in that dass.man either A) a compound of the formula “B (V) 0OR 19 in which B> S or>S-> 0, R is hydrogen or a carboxyl blocking group and Z ^{1 is} a group in which 2 carbon atoms connect the core sulfur atom and the carbon atom in the 4-position in such a way. / 2 λ 3 denotes that the connection has / \ or / N _{1 unsaturation} 509827/09 46 or an acid addition salt thereof or a N-silyl derivative thereof with an acylating agent which an acid of the formula R.C.COOH N R ^a 0. (CH ₀ ) .C. (CH ₀ ) .COOR ^u ₀ ) .C it ₀ ) (VI) corresponds to wherein R, R ^a , R, m and η have the above meanings and R represents a carboxyl blocking group, condensed; or B) when Z in formula I is the group represents wherein Y is the residue of a nucleophile or a Is derivative of the residue of a nucleophile, a compound of the formula (VII) wherein B, R, R, R, m and η have the above meanings 19th each R is independently hydrogen or a carboxyl blocking group, Y ^{1 is a} replaceable residue of a nucleophile, and the broken line bridging the 2-, 3- and 4-positions indicates that the compound is a Ceph-2-em- or is Ceph-3-em compound, reacts with a nucleophile; after which 509827/0946 one, if necessary and / or desired, in any case
carries out any of the following reactions C) in a suitable sequence, namely i) Conversion of a / \ -isomer into the desired one
-Isomers, ii) reduction of a compound where B > S > O to form a compound where B> S
means, iii) Reduction of a 3-azidomethyl compound to form a 3-aminoethyl compound, iv) acylation of a 3-aminomethyl compound to form BiI-. formation of a 3-acylaminomethyl compound, v) reaction of a 3-azidomethyl compound with a Dipolarophile to form a compound with a polyazole ring attached to the carbon atom in the 3-position is linked via a methylene group, vi) deacylation of a 3-acyloxymethyl compound to Formation of a 3-hydroxymethyl compound, .: - .. "vii) acylation of a 3-hydroxymethyl compound to form a 3-acyloxymethyl compound, viii) carbamoylation of a 3-hydroxymethyl compound to form an unsubstituted or substituted one 3-carbamoyloxymethyl compound and ix) 'removal of carboxyl blocking groups, and finally D) the desired compound of formula I or a non-toxic derivative thereof, if appropriate after separation of the isomers, wins. 39. The method according to claim 38, characterized in that a 'compound (V) or an acid addition salt or an N-silyl derivative thereof with an acid halide, the
Acid (VI) corresponds, is condensed. 9827/0946 40. The method according to claim 39, characterized in that the condensation is carried out in the presence of an acid-binding agent, which is a tertiary amine, an inorganic one Base or an oxirane. 41. The method according to claim 38, characterized in that a compound (V) or an acid addition salt or a N-silyl derivative thereof with an acid (VI) in the presence a condensing agent which is a carbodiimide, carbonyldiimidazole or an isoxazolinium salt includes. , _ "■. ·! ■■ 42. Antibiotic compounds according to claim 1, produced by a method according to any one of claims 38 to 41. 43. A pharmaceutical composition containing an antibiotic A compound according to any one of claims 1 to 3 to 7 or 42 in one for human or veterinary medicine. fit shape. 44. Acids of the formula VI according to claim 38 and derived therefrom Acylating agents. 45. Compounds of the general formula R.G.CO..NH (XII) N '0. (CH) .C (CHj .COOR ²⁰ 2 m ι 2 η wherein R, R ^a , R, R ²⁰ , Z, m and η have the meanings given in claim 38. 509827/0946