DE2653621A1 - CEPHALOSPORIN DERIVATIVES, PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

Cephalosporin derivatives, processes for their preparation and medicaments containing these compounds

claimed priorities:

Nov. 27, 1975 - Great Britain - No. 48719/75 April 13, 1976 - Great Britain - No. 14952/76

The invention relates to derivatives of cephalosporins, processes for the preparation of these derivatives and containing these derivatives Medicinal products as well as intermediate products suitable for the production of the cephalosporin derivatives.

The subject of the invention are cephalosporin derivatives of the general Formula (I)

7 0 9 0 2 3/1041

80

CH ₂ - S - Y - (CH ₂ J _n - CON

CO ₂ H

in the

R an ■ organic acylamino radical, a radical of the formula (Ha)

% - CH-

NH

CH.

C \

(Ila)

CH.

or a remainder of the general formula (lib)

N - CH = N -

(lib)

= 5 4
denotes, where R ^ and R are identical or different and represent alkyl radicals with 1 to 3 carbon atoms or together with the nitrogen atom to which they are bonded form a monocyclic ring,
Y stands for a 5-membered, nitrogen-containing ring,

η has the value 0 or 1 and

1 2
R and R are identical or different and represent hydrogen atoms or alkyl radicals with 1 to 6 carbon atoms,

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and their pharmacologically acceptable salts and esters.

The cephalosporin derivatives according to the present invention include pharmacologically acceptable, non-toxic esters of the general formula (I). Suitable esters hydrolyze easily in the human body and generate the parent acid. Examples of such esters are acyloxyalkyl esters, such as acetoxymethyl, Trimethylacetoxymethyl, oi-acetoxyethyl, oC-acetoxybenzyl and the oi.-Trimethylacetoxyäthylester, furthermore Alkoxycarbonyloxyalkylester, like the Ä'thoxycarbonyloxymethyl and the <* L-Ä * thoxycarbonyloxyethyl ester, also lactone, thiolactone and dithiolactone esters, i.e. esters with the group of the general formula

- CO.Oo - CH Z ¹

x «- c = γ»

in which X 'and Y ^{1 are} oxygen or sulfur atoms and Z ^{1 is} the ethylene or 1,2-phenylene group, the latter can be substituted by halogen atoms, nitro groups or lower alkoxy radicals.

Phthalide and 5 * 6-dimethoxyphthalides are preferred ter.

Examples of suitable salts of the cephalosporin derivatives of the general Formula (I) are metal salts, such as aluminum salts, alkali metal salts, for example sodium or potassium salts, furthermore Alkaline earth metal salts, for example calcium or magnesium

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salts, ammonium or substituted ammonium salts, for example those with lower alkylamino radicals, such as the triethyiarnino group. with hydroxy-lower alkylamino groups such as 2-hydroxyethylamino, bis (2-hydroxyethyl) amino or tri- (2-hydroxyethyl) amino groups, with cycloalkylamino groups such as the bicyelohexylamino group, or with the procaine, dibenzylamino, Ν, Ν-dibenzyl-ethylenediamino, 1-e-phenamine, N-ethylpiperidine, N-benzyl-ß-phenethylamino, dehydroabietylamino or the N, N ^f -bis-dehydroabietyl-ethylenediamino group, or salts with bases of Pyridine type, such as pyridine, collidine or quinoline, or finally salts with other amines, such as have been used to form salts with benzylpenicillin.

When the derivatives of the general formula (i) have a free amino group contain, pharmacologically acceptable acid addition salts of the derivatives of the general formula (I) are also included. Examples of acid addition salts of derivatives of the general formula (I) are inorganic salts such as sulfates, nitrates, Phosphates and borates, hydrohalides, for example hydrochlorides, hydrobromides and hydroiodides, and organic acid addition salts, such as acetates, oxalates, tartrates, maleates, citrates, succinates, benzoates, ascorbates, methanesulfonates, p-toluenesulfonates and trifluoroacetates.

When R is an organic acylamino group, specific examples include those acylamino side chains shown in known antibacterial penicillins and cephalosporins have been found. It has also been over the years

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found that by changing the identity of the 7-acylaraine residue of Ceph-j5-ems modified the spectrum and / or the level of antibacterial effectiveness of the respective Ceph-3-ems can be. In the same way, in the present case, for any given value of the 3-substituent with the general formula (I) a very large number of • 7-acylamino residues are introduced, creating a range of Compounds with widely scattered different activity spectra and levels is generated. In general, however the derivatives of the general formula (I) have which acylamino radical R they always have some efficacy, and those skilled in the cephalosporins are familiar with the area of acylamino radicals R that can be introduced.

Therefore, in general, the radicals R in general Formula (I) can be any organic acylamino radicals in the specified natural and semi-synthetic penicillins and cephalosporins are present. The acyl part can, for example have the structure of one of the following general formulas (lic) to (Hf):

R ^U (CH) CH - (CH,) -CO- I

(He) X

in which R ^{u is} a hydrogen atom, an alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl or heterocyclic radical, in particular a cycloalkyl radical with 3 to 6 carbon atoms, a phenyl

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or substituted phenyl radical,

X is a hydrogen or halogen atom, a carboxy, esterified carboxy, azido, amino, substituted amino group, including the ureido, substituted ureido, for example an acylureido, guanidino or substituted guanidino group, a triazolyl, tetrazolyl , Denotes cyano, an acyloxy (for example the pormyloxy or a lower alkanoyloxy group) or an esterified hydroxyl group and ρ and q are identical or different and have the numerical values 0, 1, 2 or J> ;

CO -

in which r has a numerical value from 1 to 4 and X the at general formula (lic) has given meanings;

R ⁷

R -Z-C-CO-

i ⁶

in the Pr an alkyl, aralkyl, aryl (especially a phenyl or substituted phenyl group), cycloalkyl (especially a cycloalkyl group having J5 to 6 carbon atoms or a substituted one Cycloalkyl group), cycloalkenyl (especially a cyelohexenyl or cyclohexadienyl group) or a heterocyclic group Remainder (especially the thienyl or pyridy group), R and R 'are identical or different and are hydrogen atoms, the phenyl, benzyl or phenylethyl group or a lower one

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- τ-

AlkyIrest mean and

Z represents an oxygen or sulfur atom;

R ^u - C - CO

(Hf)

in which R is a lower alkyl radical and R ^{u has} the meaning given above.

Specific examples of organic acylaraino radicals R which may be present in the derivatives of the present invention are 2-thienylacetamido-, J-thienylacetamido-, pheny lac et amido-, 2-hydroxyphenylacetamido, 2-aminophenylacetamido, 4-pyridylacetamido, 2-Amino ~ 2 - (^ - hydroxyphenyl) acetamido, 2-methoxyimino-2-fur-2 ' -yl-acetamido-, 2-carboxy-2-thien-j5-yl-acetamido-, 2-carboxy-2-phenylacetamido-, 2-carboxy-2- (4-hydroxyphenyl) -acetamido- and the 1-tetrazolylacetamido group, but are others Acyl radicals listed in detail in the examples of the present invention.

A class of derivatives of the general formula (I) includes those in which the acyl part of the radical R corresponds to that of the general formula (lic) in which ρ and q are O, R ^{u is} a cycloalkyl or cycloalkenyl radical or the Furyl, thienyl or phenyl group, which latter can be substituted by halogen atoms, hydroxy, nitro, amino or carboxy groups or lower alkyl or lower alkoxy groups, and X is a hydrogen atom, the hydroxy, amino, carboxy, a in salt form, carboxy, an esterified carboxy, the

7098 23/1041

Represents ureido or an acylureido group

Within this class, suitable radicals R ^{u are} the 2- and 3-furyl, 2- and ^ -thienyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexa-lj ^ -dienyl, phenyl, ^ -hydroxyphenyl, jJ-chloro- '4-hydroxyphenyl, 3,4-dihydroxyphenyl and the 4-methoxyphenyl group. The radical R preferably represents the 2- or 3-thienyl, phenyl or 4-hydroxyphenyl group.

The radical X can be a hydrogen atom, an esterified carboxy group, be the ureido or an acylureido group.

X is preferably a hydrogen atom, the amino or carboxy group or an acylureido radical. When X is acylureido, it can have the general formula (Hg)

NH

'(Hg)

N - CO.

in which R ^ is a hydrogen atom, the benzyl group or a lower alkyl radical, Z is an organic radical with up to 2Q carbon atoms or in which R ^y and Z together with the carbon atom and the nitrogen atom to which they are bonded form a 5- * Can form a 6- or 7-güedrigen ring. Z can, for example, be an alkyl or alkenyl radical each having 1 to 10 carbon atoms, an aralkyl or aralkenyl radical in which the alkyl and alkenyl radicals have 1 to 10 carbon atoms and the aryl radicals are the phenyl, thienyl, furyl or pyridy groups

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or a substituted phenyl radical, which is replaced by halogen atoms, Nitro or amino groups or by alkyl radicals with 1 to 3 carbon atoms or alkoxy radicals with 1 to 3 carbon atoms can be substituted, furthermore alkoxy radicals with 1 to 10 carbon atoms, cycloalkoxy radicals with 5 to 7 carbon atoms, Alkylamino radicals with 1 to 10 carbon atoms and be functionally substituted alkyl radicals having 1 to 10 carbon atoms, the functional substituents being for example Are alkylthio radicals having 1 to 3 carbon atoms, alkoxy radicals having 1 to 3 carbon atoms or phenoxy radicals.

Z is preferably an alkyl radical having 1 to 6 carbon atoms or an alkenyl radical having 1 to 6 carbon atoms, each of which substituted with a phenyl, halophenyl or nitrophenyl group can be, or Z is the phenyl or thienyl group or a phenyl radical containing up to 3 halogen atoms, Nitro groups, alkyl groups with 1 to 3 carbon atoms or alkoxy groups with 1 to 3 carbon atoms can be substituted can, or Ir and Z together with the carbon atom and the nitrogen atom to which they are attached form a 5- * 6- or 7-membered ring.

Appropriately, R ^ is an alkyl radical with 1 to 3 carbon atoms, preferably the methyl group.

The radical Z can, for example, be methyl, ethyl, n- or isopropyl, n-, sec, or tert-butyl, prop-2-enyl, but-2-enyl, Benzyl, 2-phenylethyl .. 3-phenylpropyl, p-chlorobenzyl, 2- (p-chlorophenyl) ethyl, 2-phenylethenyl, 2- (p-nitrophenyl) ~

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- 3-θ- -

ethenyl, 2- (p-chlorophenyl) -ethenyl-, phenyl-, 2-methoxyphenyl-, 2-chlorophenyl- , 2-methoxyphenyl-, 3,4,5-trimethoxyphenyl-, 4-nitrophenyl-, 2-methylphenyl -, 4-methylphenyl, puryl or the thienyl group.

If R ^y and Z together with the carbon atom and the nitrogen atom to which they are attached form a ring, they can, for example, have one of the following groupings CtIh) to (Hk):

p l

N-C-N-R

^(CH 2> u (Hi)

C-C

(Hk)

in which t is a number from 3 to 5, u has the value 2 to 4 and R ^{a is} a hydrogen atom, an alkyl radical having 1 to 3 carbon atoms, an acyl radical having 1 to 5 carbon atoms or an alkylsulfonyl radical having 1 to 5 carbon atoms. The ring formed is preferably an imidazolidin-2-on-1-yl-, 3-acetyl-imidazolidin-2-on-1-yl-, 3-methylsulfonyl-imidazolidin-2-on-1-yl-, hexahydroazepin-2 -on-1-yl- or a 4-oxo-1-piperazino ring. "

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The radical Z preferably denotes the phenyl, isopropyl or the 2-phenylethyl group.

Specific acylureido radicals for radical X are:

N-Benzoyl-N-methylureido-,

N- (2-chlorobenzoy1) -N-methylureido-,

N- (2-furoyl) -N-raethylureido-,

N-isobutyryl-N-methylureido-,

N- (3-thienoyl) -N-methylureido-,

N- (3-furoyl) -N-methylureido-,

N-cinnamoyl-N-methylureido-,

Imidazplidin-2-on-l-yl-carbonylamino- and the ^ -Ethyl ^ jJ-dioxo-l-piperazino-carbonylamino group.

If X is a carboxylic acid derivative, X can be a group of the general Formula -CC ^ r ", in which R ° is a hydrogen atom, an ion of a pharmacologically acceptable salt, a residue of an in vivo hydrolyzable ester, an alkyl, cycloalkyl, Alkenyl, alkynyl, aryl, aralkyl or a heterocyclic radical which can be substituted as desired.

Suitable salt-forming ions and in vivo hydrolyzable esters are discussed in connection with the cephem-4-carboxyl group.

In addition, the R- ⁷ radical can be an alkyl, _3- cycloalkyl, alkenyl, alkynyl, aryl, aralkyl or heterocyclic radical, which can be substituted as desired. Examples of suitable residues

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- YES -

(A) Alkyl radicals, especially lower alkyl radicals, such as Methyl, ethyl, η and isopropyl, η, sec.-, iso- and tert-butyl- or the Penty! group;

(B) substituted lower alkyl radicals, which are replaced by at least one chlorine, bromine or fluorine atom, a nitro or cyano group, a carboxyl (lower alkoxy), lower alkanoyl, lower alkoxy, lower alkyl mercapto, lower alkylsulfinyl, lower alkylsulfonyl, a

1-indanyl, 2 ~ indanyl, furyl, pyridyl, 4-imidazolyl, phthalimido, Azetidino-, aziridine-, pyrrolidono-, piperidino-, morpholine-, thiomorpholino-, N- (lower alkyl) -piperazino-, Pyriolo-, imidazolo-, 2-imidazolino-, 2,5-dimethylpyrrolidino-, 1, ^, 5,6-tetrahydropyrimidino, 4-methylpiperidino or a 2,6-dimethylpiperidino group or an alkylamino, dialkylamino, Alkanoylamino, alkylanilino or a substituted alkylanilino radical can be substituted, the latter by Chlorine or bromine atoms or can be substituted by lower alkyl or lower alkoxy radicals;

(c) Cycloalkyl radicals or cycloalkyl radicals substituted by lower alkyl radicals with 3 to 7 carbon atoms in the cycloalkyl part and the { 2,2-di- (lower alkyl) -l, 3-dioxolone-4 / -methyl group;

(d) alkenyl radicals with up to 8 carbon atoms;

(e) alkynyl radicals with up to 8 carbon atoms;

(f) Aryl radicals, such as the phenyl group or a substituted one Phenyl radical, which is characterized by at least one chlorine, bromine or fluorine atom, a lower alkyl, lower alkoxy, lower alkanoyl, Carbo (lower) alkoxy radical, a nitro group or a

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Di- (lower) alkylamino radical can be substituted, as well as radicals of the general formula (III)

(III)

in the Y means:

- CH = CH - 0 -

- CH = CH - S -

- CH ₂ - CH ₂ -S-

- CH = N ~ CH = CH -

- CH = CH - CH = CH -

- CO - CH = CH - CO -

- CO - CO - CH = CH -

or the rest of the general formula (Um)

(lim)

in which Z denotes a lower alkylene radical, such as the - (CH ₂ ), - or the - (CH ₂ ) ^ group or their derivatives substituted by chlorine or bromine atoms or methyl groups;

(g) Aralkyl radicals, such as the benzyl group or a substituted one Benzyl group, which by chlorine, bromine or fluorine atoms, lower alkyl, lower alkoxy, lower alkanoyl, carbo (lower) alkoxy or di (lower) alkylamino radicals or nitro groups may be substituted;

(h) heterocyclic groups such as furyl, quinolyl, methyl-substituted quinolyl, phenazinyl, 1,3-benzodioxolyl, 3-. (2-methyl - ² -pyronyl!) - 3- (4 ~ pyronyl ) - or the N- (methylpyri-

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dyl) group;

(j) other hydrocarbon radicals, such as the ac-Indany! group or their substituted derivatives in which the substituent is a chlorine or brora. atom or the methyl group, the ac-tetrahydronaphthy group and their substituted derivatives in which the substituent is a chlorine or bromine atom or the methyl group is, also the benzhydroyl, trityl, cholesterol or the .4 .o / decyl .group.

The radical R is preferably a lower alkyl radical, the benzyl, phthalidyl, indanyl, phenyl or a mono-, di- or tri- (lower) alkyl-substituted phenyl group, such as the o-, m- or p-methylphenyl, ethylphenyl, n- or isopropylphenyl or n-, sec-, iso- or tert-butylphenyl group.

Examples of the radical Y are the diazolyl, triazolyl, tetrazoly.1, thiazolyl, thiadiazolyl, thiatriazolyl, oxazolyl or the oxadiazolyl group.

Suitable examples for the radical Y are the oxadiazolyl, thiadiazolyl and the triazolyl group. Preferably Y is the tetrazolyl group.

The numerical value for η is preferably 1.

1 2
Suitable radicals for R and R are hydrogen atoms, methyl, ethyl, n- and isopropyl, n-, iso-, sec- and tert-butyl groups

1 2 pen. Both radicals R and R are preferably hydrogen atoms.

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12th

Accordingly, examples of the radical -Y- (CHg) _n -CONR R are the 2-carbamoylmethyl-1,3,4-oxadiazol-5-yl-, 2-carbamoyl-1,3,4-oxadiazol-5-yl- ,

1-Carbaraoyl-methyl-1H-tetrazol ~ 5-yl-i
1- (N-methylcarbamoylmethyl) -lH-tetrazol-5-yl-, 1- (N, N-dimethylcarbamoylmethyl) -IH-tetrazol-5-yl-, 2-carbamoylmethyl-1,3> ^ - thiadiazol-5- yl and the 2-carbamoylmethyl-1,3, ^ - triazol-5-yl group.

A preferred subclass of the cephalosporin derivatives of the present invention Invention are those of the general formula (IV)

(IV)

R ^Z - CH - CO - NH

Γ ² - (CH ₂ ) ^ 0.NR ¹ R ²

CO ₂ H

ρ ρ

in which X is the amino or an acylureido group, Y is the oxadiazole, thiadiazole or tetrazole group and R ^{z is} the phenyl or 4-hydroxyphenyl group, as well as their pharmacologically acceptable salts or esters.

Specific compounds falling under the general formula (IV) are:

7-25 ⁾ -oC- (3-Benzoyl-3-methyl-ureido) -phenylacetamido 7-3- (2-carbamoylmethyl-1,3 »4-oxadiazol-5-yl-thio) -methyl-ceph-3-em -4-carboxylic acid;

7 -, ^ D-3l- (3-Benzoyl-3-methyl-ureido) -phenylacetamidoy ⁷ - ^ -

.-1,3 * 4-oxadiazol-5-yl-thio) -methyl-ceph-5-em-

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4-carboxylic acid;

7- / D-oL- (3-Benzoyl-3-methyl-ureido) -phenylacetamido 7-3- (1-carbamoylmethyl-IH-tetrazol-5-yl-thio) -methyl-ceph-

5-em-4-carboxylic acid; 7- (D- ^ j-Amino-phenylacetamido) -3- (2-carbamoy! Methyl-1,3,4-oxa-

diazol-5-yl-thio) -methyl-ceph - ^ - em- ² ! -carboxylic acid; 7- (Dd - Atnino-phenylacetamido) -3- (2-carbamoyl-1,5j ^ -oxadiazole-

5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid; 7- (D-oL-amino-phenylacetamido) -3- (l-carbamoyltnethyl-lH-tetrazole-

5-yl ~ thio) methyl-ceph-3-em-4-carboxylic acid; Ί- / β- <L O-Benzoyl-5-methyl-ureido) -plienylacetamido / - ^ - (2-carbamoylmethyl-1,3,4-thiadiazol-5-y1-thio) -

methyl-ceph-3-etn-4-carboxylic acid; 7-JD-dt- _/ / 2- (2'-chlorobenzoyl) -3-methyl-ureidq / -phenylacetamido) - 3- (1-carbamoy! Methyl-1H-tetrazol-5-yl-thio) -methyl- ceph-3-em-4-carboxylic acid;

(l-carbamoylmethyl-IH-tetrazol-5-yl-thio) -methyl-ceph-

3-em-4-carboxylic acid; 7- / fi- <kr (3-isobutyryl-3-methyl-ureido) -phenylacetamido / -3- (1-carbamoylmethyl-IH-tetrazol-5-yl-thio) -methyl-ceph-

3-etn-4-carboxylic acid; 7- {D-ol- _ί / 3-methyl-3- (3 ¹ -thienoyl) -ureido ^ -phenylacetamidol 3- (1-carbamoylmethyl-IH-tetrazol-5-yl-thio) -methyl-ceph-

3-em-4-carboxylic acid; 7-iD-oO- / 3- (3'-furoyl) -3-niethyl-ureido7-phenylacetamido \ - 3- (1-carbamoylmethyl-IH-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid;

709823 / 10A1

7- (D-ot-amino-4-hydroxyphenylacetaraido) -3- (l-carbamoylmethyl-

1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid; 7- (D - ^ - AmInO- ¹ I-hydroxy-phenylace tamido) -3- (2-carbamoy / methyll, 3,4-thiadiazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid

and
7- / p, 2- (4-ethyl-2,3-dioxopiperazino-1-carbonylamino) -2-phenylacetamido 7-5- (1-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-5 -era-4-c8.rboxylic acid.

Another preferred class are compounds of the general formula (V) below or their pharmacologically acceptable ones Salts or Esters:

(V)

CO ₂ H

in the Y ^ the tutrazole, thiadiazole or the oxadiazole group int.

rpe>: ielle compounds falling under the general formula (V) are:

7- (Thien-2-yl-iicctarr.ido) -3- (2-carbamoylmethyl-1,3,4-oxadiazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid,

7- (Thien-2-yl-acetamido) -j? - (2-carbamoy 1-1,3 * ^ -oxadiazol-5-ylthio) -tethyl-ceph-3-em-4-carboxylic acid,

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7- (Thien-2-yl-acetamido) -3- (1-carbamoylmethyl-IH-tetrazol-5-yl-

thio) -methyl-ceph-3-em-4-carboxylic acid, 7- (Thien-2-yl-acetamido) -3- (carbamoylmethyl-1,3,4-thiadiazole-

5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid, 7- (Thien-2-yl-acetamido) -3- / Γ- (K-methyl-carbamoyimethyl) -1H-

tetrazol-5-yl-thio7-ynethyl-ceph-3-em-4-carboxylic acid, 7- (Thien-2-yl-acetamido) -2- / 1- (N, N-dimethyl-carbamoylmethyl) -

1H-tetrazol-5-yl-thio7-n-ethyl-ceph-3-em-4-carboxylic acid .. and 7- (thien-3-yl-e.cetamido) -3- (1-carbamoylmethyl-IH-tetrazole-5 -ylthio) -methyl-ceph-3-Gni- ⁱ } -carboxylic acid.

A particularly preferred subclass of compounds of the present invention are those of the following general ones Formula (VA) or their pharmacologically acceptable salts or esters

(VA)

R ^W - CH - CO - NH

CO ₂ H

CO ₂ H

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in the Y the tetrazole, thiadiazole ·, oxadiazole or the Is triazole and R is 2- or 5-thienyl, phenyl, 4-hydroxyphenyl or the 4-methoxyphenyl group.

Particularly preferred are compounds of the general formula (VA) whose radical R ^{w is} the 2- or 5-thienyl, phenyl or 4-hydroxyphenyl group, in particular the 3-thienyl group. Suitably, Y is the tetrazole, thiadiazole or the oxadiazole group.

A special compound that falls under the general formula (VA) is • 7- (2-Carboxy-2-thien-3 ^t -yl-acetamido) -5- (l-carbamoylmethyl-lH-tetrazol-5-yl- thi.o) -methyl-ceph-3-em-4-carboxylic acid,

\ W

i.e. compounds of general formula (VA) in which R is the

4th
3-thienyl group, Y is the IH-tetrazolyl group, η denotes

1 2
Has the value 1 and R and R are hydrogen atoms.

Other preferred compounds of the general formula (VA) are:

7- (2-carboxy-2-thien-3'-yl-acetamido) -3- (2-carbamoyl-1,3,4-

oxadiazol-5-yl-thio) -methyl-ceph-j5-em-4-carboxylic acid j 7- (2-carboxy-2-thien-3 ^t -yl-acetamido) -3- (l * N-methyl-carbamoyl-

methyl-IH-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid; 7- (2-Carboxy-2-thien-3 ^l -yl-acetamido) -3- (l, N, N-dimethylcarbamoylmethyl-1H-tetrazol-S-yl-thioJ-methyl-ceph-J-em-

4-carboxylic acid;
7- (2-carboxy-2-thien-3'-yl-acetamido) - ^ - (2-carbamoylmethyl-

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7 ~ ^ -Carboxy-2- (4-hydroxyphenyl) -acetamido / - ^ - (l-icarbamoyl-

methyl-1H-tetrazol-5-yl-thio) -methyl-ceph-; 5-em-4-carboxylic acid; 7- / 2-Carboxy-2- (4-methoxyphenyl) -acetamido / - ^ - (1-carbatnoyl-

methyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid; 7- / 2 "- (4-methyl ~ phenoxycarbonyl) -2-thien-3 ^f -yl-acetamidoy-J ;- (l-carbamo3 ^ 1methyl-lH-tetrazol-5-yl-thio) -methyl-eeph- 5 ~

em-4-carboxylic acid and
7- (2-Carboxy-2-thien-5'-yl-acetamido) -5- (3-carbamoylmethyl-1,3 * 4-triazol-5-yl-thio) -methyl-ceph-3-em-4 -carboxylic acid.

Other preferred compounds according to the invention are:

7- (D-, 2-Hydroxy-2-phenylacetamido) -J> - (1-carbamoylmefchyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid and

7- (2-Methoxy-imino-2-fur-2 '-yl-acetamido) -3- (1-carbamoylthiethyl 1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid.

The present invention also provides a process for the preparation of the cephalosporin derivatives of the general formula (I), their salts or esters in which R is an acylamino radical, which is characterized in that a compound of the general formula (VI) or its derivative protected on nitrogen atom ( ₀ )

(VI)

CH ₀ .S - Y - (CH_) -CON

^ Ct H

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in which -COpR ³⁵ "is the carboxyl group or a protected carboxyl group, m has the value 0 or 1, the dashed line denotes a bond in the 2- or 3-position and Y, n, R and R correspond to the general formula ( I) have given meanings, with an N-acylating derivative of an acid of the general formula (VII)

R ^q -0H. (VII)

in which R ^q denotes such an organic acyl radical that R in the general formula (I) represents the radical R ^q NH- and- wherein reactive groups such as the amino, carboxy and / or hydroxyl groups can be protected, converts and if necessary, then carry out one or more of the following stages:

(i) converting the Δ isomer into the desired £ χ isomer, (ii) removing the protecting group on the nitrogen atom, (iii) reducing the sulfoxide compound to the desired sulfide compound,
(iv) removing the blocking residues on the carboxyl group or acyl side chain and / or

(v) converting the compound obtained into a salt or an ester.

Examples of “derivatives protected on the nitrogen atom” of a compound of the general formula (VI) are on the nitrogen atom silylated or phosphoruslylated derivatives.

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- .2J- -

The expression "derivatives silylated on the nitrogen" of a compound of the general formula (VI) refers to the reaction product understood, in which the 7-amino group of a compound of the general formula (VI) with a silylating agent such as a Halosilane or a silazane of the following formulas has reacted:

L ₃ Si U; L ₂ Si U ₃ ; L ₃ Si NL ₃ ; L ₃ Si NH Si L ₃ TL ₃ Si.NH.COL; L ₃ Si.NH.CO.NH.Si L ₃ T

-L NHoCO.NHoSi L ₃ T LCOSi L ₃ .

NSiL ₃

in which U is a halogen atom and the various radicals L can be identical or different and are hydrogen atoms, alkyl, Can mean alkoxy, aryl or aralkyl radicals. Preferred Silylating agents are silyl chlorides, especially trimethylchlorosilane and dirnethyl dichlorosilane.

The expression “derivatives phosphorylated on the nitrogen” of a compound of the general formula (VI) is understood to mean the reaction product in which the 7-amino group of a compound of the general formula (VI) is substituted by a radical of the following general formula:

- ^P * ^R a ^R b

in which R _{0 is} an alkyl, haloalkyl, aryl, aralkyl, alkoxy,

a.

Haloalkoxy, aryloxy, aralkyloxy or a dialkylamino radical and R, has the same meaning as R or is a halogen atom, where R, _Q and R can also together form a ring.

α. Ο

709323/1041

Examples of radicals blocking the carboxyl group with the formation of the -COpR ^{x group} in compounds of the general formula (VI) are salts, esters and anhydride derivatives of carboxylic acids. These derivatives should preferably be able to be split off in a simple manner in a later stage of the process. Examples of suitable salts are tertiary amine salts, such as trisubstituted lower alkyl amines, N-ethylpiperidine, 2,6-lutidine, pyridine, N-methylpyrrolidine and dimethylpiperazine. The preferred salt is the triethylamine salt.

Examples of ester groups of the formula -COpR are:

(a) -COOCR R ^ R. where at least one of the radicals R, R,

C Cl 6 C Ct

or R. is an electron donor, e.g. the p-methoxyphenyl, 2,4,6-trimethylphenyl, ^ anthryl, methoxy, acetoxy or the Fur-2-yl group. The remaining radicals can either be hydrogen atoms or organic substituents. Examples of such Ester groups are the p-methoxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, Bis (p-methoxyphenyl) methoxycarbonyl and the 3> 5-di-tert-butyl-4-hydroxybenzyloxycarbonyl group;

(b) -COOCR R _H R ,,, where at least one of the radicals R ,,, R or R represents an electron-withdrawing group, for example benzoyl, p-nitrophenyl, 4-pyridyl, trichloromethyl, tribromomethyl, iodomethyl -, cyanomethyl, ethoxycarbonylmethyl, arylsulfonylmethyl, 2-dimethylsulfoniumethyl, o-nitrophenyl or the cyano group. The remaining radicals can be hydrogen atoms or organic substituents. Examples of such esters are the benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylffiethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and the

709823/1041

2, 2, 2-Tribromäthoxycarbonylester;

(ο) -COOCR R, R, where at least two of the radicals R, R, or

GdG G Ct

R represent hydrocarbon radicals such as alkyl radicals, e.g. Methyl or a'tbyl group, or aryl radicals, such as the phenyl group, and the remainder, if any, is a V / water atom. Examples of such esters are tert-butyloxycarbonyl, tert-amyloxycarbonyl, diphenylmethoxycarbonyl and triphenylmethoxycarbonyl ester;

(d). -COOR ^, where R _{f is} the adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl-

nnd is the pentachlorophenyl group;

groups

(e) Silylöxycarbony] /, which by reaction with a silylie-

agents have been obtained as described above for the carboxyl group;

(f) CO ₀ PR _Q R _K , where R ₀ and R are those given above

d you et D

Have meanings;

(g) triallcyltin ester; and

(h) Oxime esters of the general formula CO _p N = CH.R, where R

<- g B

is an aryl radical or a heterocyclic radical.

The carboxyl group can be restored from the abovementioned esters by customary processes, depending on the specific radical R ^x , for example by means of an acid and / or base catalyzed hydrolysis or an enzyme catalyzed hydrolysis. If necessary, the following work-up procedures can also be carried out:

709623/1041

Reaction with Lewis acids, such as trifluoroacetic acid, formic acid, Hydrochloric acid in acetic acid, zinc bromide in benzene and: aqueous solutions or suspensions of mercury (II) compounds, the reaction with a Lewis acid being facilitated by the addition of a nucleophilic compound such as anisole can;

Reduction with agents such as zinc plus aqueous acetic acid, zinc plus formic acid, zinc plus a lower alcohol, zinc plus Pyridine or with hydrogen and a palladium-carbon catalyst or other hydrogenation catalyst applied to support materials en;

Attack by means of nucleophilic compounds, such as those containing nuclephilic oxygen or sulfur atoms, for example Alcohols, mercaptans and water,

Oxidation, for example by using hydrogen peroxide and acetic acid; and

Exposure to light or UV rays.

In the aforementioned process, a reactive derivative of an acid acylated on nitrogen of the general formula is used (VII) used. The choice of a reactive derivative will, of course, be determined by the chemical nature of the substituents the acid affects.

Examples of suitable acylating agents are acid halides,

709823/1041

preferably acid chlorides or bromides. The acylation with .einem acid halide can be carried out in the presence of an acid-binding agent, for example a tertiary amine such as triethylamine or dimethylaniline, an organic base such as calcium carbonate or sodium bicarbonate, or an oxirane, which binds the hydrogen halide released during the acylation. The oxirane is preferably a 1,2-alkylene oxide, having 2 to 6 carbon atoms, such as ethylene oxide or propylene oxide. The acylation using an acid halide may be carried out at temperatures of -50 to + 5O ⁰ C, preferably from -20 to

C, in an aqueous or a non-aqueous medium, such as aqueous acetone, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane or their mixtures are carried out. Optionally, the reaction can also take place in an unstable emulsion with water immiscible solvent, in particular an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate, be performed.

The acid halide in question can be prepared by reacting an acid of the .general formula ("VII) or its salt with a halogenating agent, e.g. a chlorinating or brominating agent such as phosphorus pentachloride, thionyl chloride or oxalyl chloride, getting produced.

The derivatives of the acid of the general formula (VII) acylated on the nitrogen can optionally be a symmetrical or mixed anhydride. Examples of suitable mixed anhydrides are alkoxyformic anhydrides or anhydrides with two

709823/1041

- 'S6 -

for example carboxylic acid monoesters, trimethyl acetic acid, thioacetic acid, Diphenylacetic acid, benzoic acid, phosphoric acids, such as phosphoric acid or phosphorous acid, sulfuric acid or aliphatic or aromatic sulfonic acids, such as p-toluenesulfonic acid. The mixed or symmetrical anhydrides can be generated in situ. For example, a mixed anhydride by using N-ethoxycarbonyl ^ -ethoxy-l ^ -dihydroquinoline be won. If a symmetrical anhydride is used, the reaction can be carried out in the presence of 2,4-lutidine as a catalyst be performed.

Further examples of derivatives of an acid of the general formula (VII) acylated on the nitrogen are acid azides or activated ones Esters, such as esters with 2-mercaptopyridine, cyanomethanol, p-nitrophenol, 2 ·, 4-dinitrophenols thiophenol, halophenols, including pentachlorophenol, monoethoxyphenol or 8-hydroxyquinoline, also amides, such as N-acylsaccharines or N-acylphthalimides, and also alkylidene-imino esters, which have been prepared by reacting an acid of the general formula (VIl) with an oxime are.

Some activated esters, e.g. those made with 1-hydroxybenzotriazole or with N-hydroxysuecinimide are, can in situ by reacting the acid with a corresponding hydroxy compound in the presence of a carbodiimide, preferably Dicyclohexylcarbodiimide.

Other reactive derivatives acylated on nitrogen

. Acids of the general formula (VII) are reactive intermediate

709623/1041

- a? r H

products made by an in situ reaction with a condensing agent have been formed, such as a carbodiimide, e.g. with Ν, Ν-diethyl-, Ν, Ν-dipropyl- or Ν, Ν-diisopropylcarbodiimide, Ν, Ν'-cyclohexylcarbodiimide or N-A'thyl-N '- tf * -dimethylaminopropylcarbodiimide, also a suitable carbonyl compound, e.g. N, N'-carbonyldiimidazole or N, N'-carbonylditriazole, or an isoxazolinium salt, e.g. the N-ethyl-5-phenyl isoxazolinium-3-sulfonate or N-tert-butyl-5-methyl isoxazolinium perchlorate, or an N-alkoxy-carbonyl-2-alkoxy-1,2-dihydroquinoline, like the N-ethoxycarbonyl ^ -ethoxy-l ^ -dihydroquinoline. Other condensing agents are Lewis acids, e.g. BBr ^ -CgHg, or those based on phosphoric acids, such as diethylphosphoryl cyanide. The condensation is preferably carried out in an organic reaction medium, e.g. methylene chloride, dimethylformamide, Acetonitrile, alcohol, benzene, dioxane or tetrahydrofuran, carried out.

In the ways indicated above, it is preferred to become reactive Groups in the acyl side chain protected from acylation. If the group to be protected is an amino group, are those from the literature for the production of öt-aminobenzylpenicillin known protecting groups.

Examples of protected amino groups, including the protonated amino group NHt, which can be converted into the free amino group by simple neutralization after an acylation reaction, are the benzyloxy-carbonylamino group or substituted benzyloxy-carbonylamino groups, which are then converted into the NH by catalytic hydrogenation ₂ -Group over-

709823/1041

2853621

and numerous other groups that may result after an acylation reaction due to mild acid hydrolysis generate an amino group are the tert-butyloxycarbonyl group, the acid by treatment with trifluoroacetic acid, hydrochloric acid or p-toluenesulfonic acid can be removed.

• Another example of a protected amino group that subsequently can be converted into the NHp group due to mild acid hydrolysis are radicals of the general formula

. (VIII)

■ R
ι

^R B

in which R. is an alkyl, aralkyl or aryl radical, R _{ß is} an alkyl, aralkyl, aryl, alkoxy, aralkoxy or aryloxy radical and R _{c is} a hydrogen atom or an alkyl, aralkyl or an aryl radical represents or in which R, -, ″ together with either the radical R _fi or the radical R _{n complete} a carbocyclic ring.

Another example of a protected amino group that can be converted to the NHp group after an N-acylation reaction can is the azido group. In this case, the final conversion into the amino group takes place either by means of catalytic Hydrogenation or by means of electrolytic reduction.

709823/1041

The amino group can optionally also be blocked as a nitro group which can later be converted to the amino group by reducing.

When the compound obtained after N-acylation has a sulfoxide group in the 1-position, this can be done by usual Process can be reduced, for example with triphenylphosphine and acetyl chloride. In the aforementioned method, the Acylation cause a migration of the double bond into the 2-position of the cephem ring system, whereby a mixture of 2-cephem and J5 cephem isomers are formed. When this happens the mixture of 2-cephem and ^ -cephem isomers can be oxidized of the mixture can be converted into the sulfoxide and then converted into the 3-cephem isomer by reduction. This is of course the standard procedure for making 3-cephem compounds from 2-cephem compounds, as described, for example, in GB-PS 1,280,695. One of those procedures is again the treatment with triphenylphosphine and acetyl chloride.

The invention relates to a further method of production of the cephalosporin derivatives of the general formula (I), which is characterized in that a compound of the general Formula (IX)

(IX)

709823/1041

in which the radical -CO _p R is the carboxyl group or a blocked carboxyl group, m has the value 0 or 1, the dashed line denotes a bond in the 2- or 3-position and R has the meaning given for the general formula (I) and in which reactive groups such as amino, carboxyl and / or hydroxyl groups can be protected with a thiol of the general formula (IXA)

HS-Y- (CH,) -CON
^{2 n}

1 2
converts, in which Y, n, R and R have the meanings given for the general formula (I), and carries out one or more of the following stages:

(i) converting the Δ isomer to the desired z \ isomer; (ii) removing the protecting groups on the nitrogen atom; (iii) reducing the sulfoxide compound to the desired one

SuIfid compound;
(iv) Removal of the blocking residues on the carboxyl or

Acyl side chain and / or
(v) converting the compound obtained into a salt or an ester.

Process for isomerizing the Δ isomers to the / λ isomers and reducing the sulfoxide are described in more detail above. Those relating to protecting the nitrogen atom and the Amino protective groups made statements and the method for

709823/1041

so

Removal of the protective groups also apply in this case

The present invention also provides a process for the preparation of the cephalosporin derivatives of the general Formula (I) in which the radical R denotes an acylamino radical which is characterized in that one

(a) a protected cephem compound of the general formula (X)

R ° - m

CH ₂ .s - y - (CH) - con

in which R ° is an acylamino radical and in which R ^x , Y, n, R

and R are those given in the general formula (I) Have meanings, treated in such a way that on the 7-Aminos.tickstoffatom an imino bond is formed,

(b) the compound obtained with a compound, for introduction a group QR "converts on the imino carbon atom, in which Q is an oxygen, sulfur or nitrogen atom, and R ~ is an alkyl radical having 1 to 12 carbon atoms or denotes an aralkyl radical having 5 to 14 carbon atoms, and here an imino ether, an iminothioether or forms an amidine when Q is an oxygen, sulfur or nitrogen atom,

(c) the compound obtained is reacted with an acylating derivative of an acid of the general formula (VII),

(d) the compound obtained thereafter with water or a

709823/1041

Alcohol treats and

(e) then optionally carrying out one or more of the aforementioned steps (i) to (v).

The invention also relates to a fourth method for Preparation of the cephalosporin derivatives of the general formula (I) in which R is an acylamino radical, characterized in that is that one

(a) a compound of the general formula (X)

R ° - NH

CH ₀ .SY- (CH ₀ ) - CON

in which the radical -COpR is the carboxyl group or a blok-

is cated carboxyl group, R ^{0 is} an acid residue and

1 2

Y, n, R and R are those given in the general formula (I) Has meanings with an acylating agent to form an acyl radical R, where reactive groups can be protected in the presence of a. Trihydroxyearbylsilyl derivative of a sulfonamide, succinamide, phthalimide, Cyanoacetamids, trifluoroacetamides, benzamides, p-nitrobenzamides or a trichloroacetamide and

(b) for the compound of the general formula (XII) obtained

709823/1041

(XII)

S - Y -

(CH ₂ ) _n - CON

the radical R is replaced by a hydrogen atom and thus a Compound of the general formula (I) generated in which the radicals -COpH and R can be protected and then if necessary, the protective groups are removed.

The reagents and conditions for such a procedure are described in GB-PS 1 3 ^ 8,986.

The invention also relates to a fifth method for the preparation of the Cephalosporiri derivatives of the general formula (i), where R is a radical of the general formula (XIIl),

R ^U - CH - CO - NH -

(XIII)

in which X is an acylureido radical, which is characterized by that a compound of the general formula (XIV) or its derivative protected on the nitrogen atom

709823/1041

R - CH - CO - NH

(XIV)

CH ₉ S -Y- (CH_) -CON

-, U

in which R has the meaning given in the general formula (I) has the radical -COpR "" the carboxyl group or a blocked one Means carboxyl group, m has the value 0 or 1, the dashed line represents a bond in the 2 or J position

1 p

represents and Y, n, R and R in the general formula (I) have given meanings, with. an N-acylating derivative an acid of the general formula (XV)

y _

CO ₂ H

N - CO.Z

reacted, in which R ^y and Z have the meanings given above, and, if appropriate, then carries out one or more of the above-mentioned steps (i) to (v).

The cephalosporin derivatives of the general formula (I) in which R is a radical of the general formula (XIII), where X is the carboxyl group means, can by alkaline hydrolysis of a compound of the general formula (i) with a radical R of the general Formula (XIII) can be prepared in which the radical X is an esterified carboxyl group.

709823 / 104-1

2853621.

The hydrolysis is preferably carried out in an aqueous medium in the presence of a weak base, for example an alkali metal bicarbonate, carbonate or borate carried out. The preferred base is sodium borate. If the cephalosporin derivative, in which X is an esterified carboxyl group, in addition an esterified carboxyl group in the ^ position of the cephem ring system this diester is unlikely to be water-soluble and an appropriate solvent must be selected to bring the ester into solution. In such a case, the choice of the basic reactant to carry out the Hydrolysis will depend on the solvent used.

The cephalosporin derivatives of the general. Formula (I) in which R is a radical of the general formula (XVI)

R ^U - CH - CO - NH -

(XVI)

CO ₂ R

in which R ^{U has} the meanings given for the general formula (lic) and R denotes an ester radical, a compound of the general formula (XVII) or its reactive esterifiable derivative can be esterified

R ^U -CH-C0.NH

CO ₂ H

(XVII)

CH ₂ .sy- (CH ₂ ) _n -coN

709823/1041

-.96--

in which the radical -COpR ^{x is} the carboxyl group or a blocked carboxyl group, m has the value Ό or 1, the dashed line is a bond in the 2- or 3-position. and Y, n, R 'and R "have the meanings given for the general formula (I), with an esterifiable derivative

•, λ subsequent

Acid of the general formula R OH optionally with / avg.

by carrying out one or more of the aforementioned steps (i) to (v).

Numerous methods of esterification using a wide variety of combinations of reactive compounds are known from the literature esterifiable derivatives known. For example, the the aforesaid esterification by reacting a compound of the general formula (XVII) or its salt with an acid of the general Formula R, its alkyl sulfonate or aryl sulfonate or with a halide R -Hai, where Hai is a halogen atom,

will
implemented /. If appropriate, a mixed anhydride of a compound of the general formula (XVII) can be allowed to react with an acid of the general formula R OH. The mixed anhydride can be formed with any aliphatic or aromatic acyl radical which is derived from a secondary carboxylic acid, but alkoxycarbonyl radicals, for example the CpHp-O.CO group, generally give satisfactory results.

Usually it is considered satisfactory to use a sodium or potassium salt of a compound of the general formula (XVII) to react with a halide of the general formula R-Hai, especially if Hai is a bromine or chlorine atom.

709823/1041

Another reactive esterifiable derivative of the foregoing Compound of general formula (XVII) is an acid halide, especially the acid chloride. Such a connection can be reacted with an acid of the general formula R OH in the presence of an acid-binding agent to achieve the desired To prepare esters according to the present invention.

The antibiotics of the present invention can be administered in conventional manners for use in human or veterinary medicine be prepared or formulated in analogy to other antibiotics. The invention is therefore also directed to pharmaceuticals, those by a content of a compound of the general formula (i), optionally together with pharmacologically acceptable Carriers and / or diluents and / or auxiliaries and / or other active ingredients are labeled.

The drugs can be formulated for administration by any convenient route; they can be in the form of tablets, capsules, Powders, granules, lozenges or liquid or creamy preparations such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration can be in Individual doses are present and customary auxiliaries, such as binders, for example syrup, acacia gum gelatin, sorbitol, Tragacanth or polyvinyl pyrrolidone, then fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine, further lubricants such as magnesium stearate, talc, polyethylene glycol or silicon dioxide, as well as disintegration aids,

709823/1041

such as potato starch, or finally compatible wetting agents such as sodium lauryl sulfate. The tablets can after methods known per se in common pharmaceutical practice may be coated. Orally administrable liquid preparations can in the form of, for example, aqueous or oily suspensions, solutions, .Emulsions, syrups or elixirs or else as dry products' which are mixed with water or other suitable Vehicles to be reconstituted. Such liquid preparations can contain conventional additives, such as suspension aids, for example sorbitol, methyl cellulose, glucose syrup, gelatin, Hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hardened edible fats, emulsifying agents, for example Lecithin, sorbitan monooleate or acacia gum, furthermore non-aqueous vehicles including edible oils, for example Almond oil, fractionated coconut oil, fatty acid esters of glycerine, propylene glycol and ethanol, as well as preservatives, such as p-hydroxybenzoic acid methyl or propyl ester or sorbic acid, and optionally customary flavorings or Dyes.

Suppositories contain the usual suppository base, such as Cocoa butter, or other glycerides.

Liquid single doses are used for parenteral administration by the use of an appropriate compound and sterile vehicle, with water being preferred. The compound may vary depending on the vehicle used and the one employed Concentration either suspended or dissolved in the vehicle. When creating solutions, the

709823/1041

bonds are dissolved in water for injections and sterile filtered before they are filled into a suitable bottle or ampoule and capped. Other aids, such as a local aesthetic, a preservative or a buffer substance, can also be added to the solutions. To increase stability, the drugs can be frozen after they have been filled into the bottles or ampoules and the water can then be removed under reduced pressure. The dry lyophilized powders are then sealed in the ampoules or vials. Parenteral suspensions are prepared in essentially the same manner, but with the proviso that the compound is suspended rather than dissolved in the vehicle and that sterilization is not combined with filtration. The compound can be sterilized by exposure to ethylene oxide prior to suspending it in the sterile vehicle. A surface-active compound or a wetting agent is preferably added to the suspension in order to ensure uniform distribution of the compound.

The medicaments can contain 0.1 to 99 percent by weight, preferably 10 to 60 percent by weight, of active ingredient, depending on the method of administration If the medicaments consist of single doses, each single dose preferably contains 50 to 500 mg Active ingredient. The daily dose used for treatment of adults is preferably in the range of 100 to 3000 mg, for example 1500 mg, depending on the route and the frequency of administration.

• 7098 2 3/1041

The cephalosporin derivatives of the general formula (I) can be the only active ingredient in the medicaments of the present invention .his or they can also be used in conjunction with other antibiotics »They preferably contain drugs also a compound of the general formula (XVlII)

, 0

Γ V ^CH · '

.CH A ι / 2

N-V (XVIII)

0 *

in which A is a hydrogen atom or the hydroxyl group, or their pharmacologically acceptable salts or esters.

The compound of the general formula (XVIII) is preferred the clavulanic acid of the formula (XIX) or its pharmacologically acceptable salt or its ester

M _{/ C} H ₂ OH

The production of these compounds is described in BE-PS 827 926 and 836 652 as well as in DT-OS 26 16 088.

Of course, the side chain contains the cephalosporin derivatives of the general formula (I) a potentially asymmetric carbon atom. The present invention therefore completes all possible epimers of the cephalosporin derivatives of the all-

709823/1041

7653621

-into

common formula (I) and the mixtures of these epimers with a,

The examples illustrate the invention.

For example
(a) ^ -Mercapto-1,3,4- oxadiazol-2-yl- acetatnide

A solution of 25 g of crude 5-mercapto-1,3,4-oxadiazol-5-ylacetic acid ether ester in 150 ml of ethanol is saturated with ammonia gas and stirred for 70 hours at room temperature. The solvent is then evaporated off under reduced pressure, the residue is dissolved in water, acidified and extracted with ethyl acetate. The extracts are washed with water and saturated sodium chloride solution, dried and evaporated. The brown gummy substance obtained is extracted with a boiling mixture of ethyl acetate and petroleum ether boiling from 60 to 80 ° C., leaving a yellow solid which is heated in ethyl acetate and then allowed to cool. The insoluble residue is collected. Yield: 2.4 l g (= 12.7 % of theory). M.p. 160-163 ° C.

IR spectrum S) _m . (Nujol): 1675 cm ".
Max

Nuclear Magnetic Resonance Spectrum c5in (CD ₃ J ₂ SO: 3.68 (2H, s, -CH ₂ -); 7.52 (2H, d, J = 26 Hz, -CONH ₂ ): 14.4o (IH, broad singlet , -SH);

Analysis for C ^ H ₅ N ₃ O ₂ S: 'C (56) H (#) N. {%) S (#)

calc .: 30.19 3.1 * 26.42 20.13

Found: 30.66 3.21 25.50 20.28

709823/1041

(b) 7- (Thien-2-yl-acetamldo) -3- (2-carbamoylmethy1,3,4-oxadiazol-5-yl-thio) -methyl-ceph - ^ - em - ^ - carboxylic acid

2.09 g (5.0 mmol) sodium cephalothin, 0.84 g (5.5 mmol) 5-mercapto-1, 3,4-oxadiazol ~ 2-yl-acetamide and 0.42 g (5, be 6.5 hours 6O ⁰ C heated 0 mmol) of sodium bicarbonate in 25 ml of a Phosphatpufferlösung.vom pH 6.5. The reaction mixture is poured onto about 25 g of crushed ice, washed twice with 20 ml of ethyl acetate each time, acidified to pH 2.0 with 1N hydrochloric acid and extracted three times with 50 ml of ethyl acetate each time. The extracts are washed twice with 20 ml of water each time and once with 20 ml of saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The gummy substance obtained is extracted with 10 ml of hot ethyl acetate. An almost white solid is obtained in a yield of 1.23 g (= 49.8 % of theory).

Thin-layer chromatography - hereinafter abbreviated to TLC on SiOp as the support material with a mixture of n-butanol, acetic acid and water in the ratio of 12: 3: 5 as the mobile phase - gives an R _f value of 0.41.

UV spectrum X ", _QV (95 percent ethanol): 272 nm (€ = 9650).

Nuclear Magnetic Resonance Spectrum S in (CTu) ₂ SO: 3.5-4.0 (2H, m, Cg-methylene); 3.85 and 3.90 (4h, 2 χ s, 2 χ -CH ₂ CO-); 4.33 and 4.49 (2H, AB-quartet, J = 14Hz, -CH ₂ S-); 5.22 (IH, d, J = 5 Hz, Cg proton); 5.81 (IH, dd, J = 5.8 Hz, C "proton); 7.0-7.6 (JH, m, thienyl protons); 7.65 (2H, d, J = 26 Hz, -CONH ₂ ); 9.33 (IH, d, J = 8 Hz, -CONH-).

709823/1041

Example 2
(a) ^ -Mercapto-1,3,4-oxadlazo 1-2 -y 1- c .irboxamid

A solution of 45 g of crude 5-Mereapto ~ l, 3,4-oxadiazol-5-ylcarboxylic acid ethyl ester in 200 ral ethanol is saturated with ammonia gas and then stirred for 3 days at room temperature. The precipitate is filtered off, washed with ethanol and air-dried. 40.65 g of a cream-colored pesticide are obtained, which is dissolved in 150 ml of water. The solution is filtered and then acidified. The precipitate is filtered off, washed with water and dried under reduced pressure. Yield: 26.12 g (= 69.4 io of theory). Mp 208-210 ° C.

IR spectrum 0 iNujol): 1680cm " ¹ .
Max

Nuclear Magnetic Resonance Spectrum S in (CIX) ₂ SO: 8.47 (2H, d, J = 17 Hz, -CONHp): 13.75 (IH, broad singlet, -SH).

Analysis for C ₅ H ₅ N ₅ O ₂ S: C {%) H {%) N {%). S (#)

calc .: 24.83 2, o8 28.95 22.09 found: 24.46 2.12 28.57 21.51

(b) 7- (Thien-2-yl-acetamido) -3- (2-carbarnoyl-1,3,4-oxadiazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid

Sodium cephalothin and 5-mercapto-1,3,4-oxadiazol-2-yl-carboxamide are left react with one another as described in example l (b). The dried ethyl acetate extracts are reduced under reduced pressure Pressure evaporated to dryness. The residue is with

7 0 9 8 2 3/1041

265362V

rubbed with anhydrous ether. 1.85 g of the acid, which is free from cephalosporin, are obtained. The acid is dissolved in 20 ml of acetone and treated with 1.85 ml of a solution of 2N sodium 2-ethylhexanoate in methyl isobutyl ketone. The precipitated sodium salt is filtered off, washed with acetone and ether and dried. Yield: 1.48 g (= 58.9 % of theory).

TLC on siop with a mixture of n-butanol, acetic acid and water iin ratio of 12: 3: 5 ls ^a mobile solvent yields an R _f value 0.45.

UV spectrum λ _QV (95 percent ethanol): 272 nm (6 = 11200).

Nuclear Magnetic Resonance Spectrum S in (CD-J ₂ SO + D ₃ O: 3.3-3.9 (2H, m, Cg-methylene);

3.87 (2H, s, -CH ₂ CO-); 4,> 4.7 (2H, m, -CHgS-); 5.07 (IH, d,

J = 5 Hz, Cg proton): 5.4-5.9 (IH, m, C ^ proton); 6.9-7.7 (3H, m, Thienyl protons).

Example 3
(a) 5-mercapto-1H-tetrazol-ly! -acetamide

15.0 g of 5-mercapto-1H-tetrazol-5-yl-acetic acid ethyl ester are dissolved in 50 ml of ethanol. The solution is saturated with ammonia gas and allowed to stand for 36 hours. The precipitate is filtered off, washed with 20 ml of ethanol, dried and dissolved in 100 ml of water. The solution is treated with decolorizing charcoal, filtered, acidified with concentrated hydrochloric acid and cooled in an ice bath. The needle-shaped crystals are filtered off, washed with a little water and dried under reduced pressure. Yield: 9.51 g (= 75.0 % of theory). Mp. 214-216 ° C

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- 45 - (decomposition).

IR spectrum ϊ> fNujol): 1695 cm " ¹

lildX

Nuclear Magnetic Resonance Spectrum Sin (CD ^) ₂ SO: 7.72 (2H, d, J = 22 Hz, 5.02 (2H, s, -CH ₂ -).

Analysis for C ₅ H ₅ N ₅ OS: C (%) H (Ji) - N (56) S \ / o) calc .: 22.64 3.17 44, , 00 20.14 found: 22.39 2.18 43, , 82 20.16 (b) 7- (Thien-2-yl-acetamido) -3- (l-carbamoylmethyl-1H-tetfazole- 5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid

Sodium cephalothin and 5-mercapto-1H-tetrazol-1-yl-acetamide are reacted as in Example 1 (b). The dried ethyl acetate extracts are concentrated to about 15 ml and diluted with 15 ml of anhydrous ether. The precipitated free acid is filtered off, washed with ether and dried. Yield: 1.26 g. The acid is dissolved in acetone and treated with 2N sodium 2-ethylhexanoate in methyl isobutyl ketone. The sodium salt is obtained in a yield of 1.17 S (= 45.3 % of theory).

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3 > 5 as the mobile phase gives an .R _1. Value of 0.38.

UV spectrum A _max (95 percent ethanol): 273 nm ^ = 9550).

Nuclear Magnetic Resonance Spectrum Sin (CD,) ₂ S0: 3.3-3.8 (2H, m, Cg-methylene);

709 823/1041

3.83 (2H, s, -CH ₂ CONH-); 4.1-4.7 (2H, m, -CH S-); 5.04 (IH, d, J = 5 Hz, Cg proton); 5.17 (2H, S, -CHgg 5.75 (IH, dd, J = 5 and 8 Hz, C ₇ -Prοton); 6.9-7.6 (3H, m, thienyl protons); 7.92 (2H, d, J = 40 Hz, -CONH ₂ ); 9.20 (IH, d, J = 9 Hz, -CONH-).

Example 4
(a) S.

A solution of 8.20 g of 5-mercapto-l, 3,4-thiadiazol-2-yl-acetic acid ethyl ester in 25 ml of ethanol is saturated with ammonia gas and left to stand for 3 days. The black precipitate formed is filtered off and discarded. The filtrate is evaporated to dryness, dissolved in dilute sodium bicarbonate solution, treated with decolorizing charcoal, acidified and extracted twice with 25 ml of ethyl acetate. The extracts are concentrated to about 10 ml under reduced pressure. The precipitated crystals are filtered off. Yield: 1.21 g (= 17.2 % of the

_o about

Theory). Pp. 173-175 C. The aqueous phase is concentrated to / 20 ml and cooled. Further crystals are obtained in a yield of 0.72 g (= 10.2 % of theory). Pp. 174-176 ⁰ C.

IR spectrum v \, f Nujol): I655

Max

cm

-1

NMR spectrum Sin (CD,) _? S0: • 3.88 (2H, s, -CHpCQ); 7.60 (2H, d, J = ZJ Hz, -CONH ₂ ); 14.52 (IH, broad singlet, -SH).

Analysis for C ^ H ₅ N ₃ OS ₂ : C (#) H {%) N ' {%) S

at·.:. 27.42 2.88 23/98 36.60 * found: 27.2.4 3.00 24.25 36.28

70 98 23/1041

(b) 7- (Thien-2-yl-acetamido) -3- (carbamoylmethyl-1,3,4-thladia-- ₌ zol ^ -yl-thio ^ methyl-ceph ^ -em ^ -carboxylic acid

1.05 g (2.5 mmol) of sodium cephalothin and 0.48 g (2.75 mmol) of 5-mercapto-1,3,4-thiadiazol-2-yl-acetamide are mixed together as in Example 1 (b) implemented. The reaction mixture is poured onto ice, washed with ethyl acetate, covered with a layer of ethyl acetate and acidified. The resulting pale yellow precipitate is filtered off, washed with water and with ethyl acetate and dried. Yield: 0.87 g (= 68.1 % of theory).

TLC on SiO ₂ with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.41.

UV spectrum / I (95 percent ethanol): 276 nm- (g. = 12300). Max

Nuclear Magnetic Resonance Spectrum Sin (CD ₄ ) 2 SO: 3.85 (2H, s, C ₅ -Me thy I en); 3.95 (2H, s, -CH ₂ CONH-); 4.19 (2H, s, -CHgCONHg); 4.4l and 4.67 (2H, AB-quartet, J = 14 Hz, -CH ₂ S-); 5.22 (IH, d, J = 5 Hz, Cg proton); 5.90 (IH, dd, J = 5 and 8 Hz, C "proton); 6.8-8.1 (6h, m, -CO ₂ H, -CONH ₂ and thienyl protons); 8.85 (IH, d, J = 8 Hz, -CONH-).

Example 5

7- / Ώ - <- Q-Benzoyl - ^ - methyl-ureido) -phenylacetamidoy - ^ - (2-carbamoylmethyl-1,3j4-oxadiazol-5-yl-thio) -methyl-ceph-3-e ^ -4-carboxylic acid

1.42 g (2.5 mmol) D-0 <- (Benzoyl-3-methyl-ureido) -benzyl-cephalo-

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Sporin and 0.42 g (2.75 mmol) of 5-mercapto- _{1,3 J} ⁱ l-oxadiazol-2-ylacetamide are dissolved in 5 ml of 1N sodium bicarbonate solution and 20 ml of water and then heated to βθ C for 6.5 hours warmed up. The solution is then poured onto about 20 g of ice, washed twice with 20 ml of ethyl acetate each time, acidified and extracted three times with 20 ml of ethyl acetate each time. The combined extracts are washed twice with 25 ml v / ater and once with 20 ml of saturated sodium chloride solution, dried and concentrated to about 10 ml under reduced pressure. After adding 10 ml of anhydrous ether, the precipitate is filtered off with about 5 ml of ethyl acetate washed and dried. 0.88 g of a cream-like solid is obtained.

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 results in an R n value of 0.45.

NMR spectrum <5 in (CJX) ₂ CO: 3.20 (3H, s,> N-CH _V ); 3.6-4.0 (2H, m, C ₂ methylene) j 4.03 (2H, s, -CH ₂ CO-); 4.1-4.7 (2H, m, -CH ₂ S-); 5.13 (IH, d, J = 5 Hz, Cg proton); 5.8-6.2 (2H, m, PhCH <and C ₇ protons); 7.0-8.2 (I3 H, m, 2 χ Ph-, -CONH ₂ and -CO ₂ H); 8.62 (IH, d, J = 9 Hz, -CONH-); 10.28 (IH, d, J = 7 Hz, -CHNHCO-).

0.88 g of the free acid are dissolved in 10 ml of acetone and treated with a solution of 0.66 ml of 2N sodium 2-ethylhexanoate in methyl isobutyl ketone. The precipitated sodium salt is filtered off, washed with acetone and ether and dried under reduced pressure. Yield: 0.84 g (= 48.9 % of theory).

UV spectrum X “ _b (95 percent ethanol): 270 nm (g = I23OO). mdx

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Example 6

7 - £ ϊ) -? Άτ (3-Benzo y ± -3-ir.e thyl-uroπ do) -phony! Acetamid o / ^ - (2-carba- ΐϊΐθ7) Γΐ -1,3>, _4- q: xadiazole "5 - J l-fcni o) -1:. ethyl cc ph - 3-ei. * i ~ 4 -carboxylic acid

1.42 g (2.5 mmol) of Do (~ (3 ~ benzoyl ~ 3-raethyl ~ ureido) -benzyl-cephalosporin are added as described in Example 5 with 0.4-0 g (2.75 mmol) of 5-mercapto -l, 3,4-oxadiazole-2-3 ' ^r- l-earboxarnide, the dried stylacetate extracts are evaporated to dryness, the residue is triturated with anhydrous ether, and 1.1 g of a solid are obtained.

TLC on SiO "with a mixture of n-butanol, acetic acid and water in the ratio 12: 5: 5 FU results in a value 0, ² TJ.

NMR spectrum S in (CD ₅ ) ₂ C0: 3.20 (JH, s,> NCH,) j 3 / f7 (2H, broad singlet, C ₂ methylene) j 4.47 (2H, broad singlet, -CH ₂ S-); 5.12 (IH, d, J = 5 Hz, Cg proton); 5.7-6.2 (2H, m, PhCH <and C ^ proton); 6.6-8.2 (13H, m, -CO ₂ H, -CONH ₂ and aromatic protons); 8.57 (IH, d, J = 9 Hz, -CONH-); 10.27 (IH, d, J = 8 Hz, -CHNHCO-).

The free acid is dissolved in acetone and treated with 0.85 ml of a solution of 2N sodium 2-ethylhexanoate in methyl isobutyl ketone. The yield of the precipitated sodium salt is 0.83 g (= 49.4 % of theory).

UV spectrum iV (95% ethanol): 267 nm (£ = 14220).

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example

£ o ; / l-3-jneth y ^^

a-zol-S - ^ / l-thic /) -me thy1-ceph ~ 5- em- /! - carbons ξυ right

According to the information in Example 5,!, - '! 2 g (2.5 n- ^ ol D-oi- (5-benzoyl-3-methyl-ureido) -benzyl-eephalosporin and 0.44 g (2.75 mmol) 5-Moroapto-1H-tetrazol-1-yl-acetamide 0.95 g of free acid.

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.57.

Nuclear Magnetic Resonance Spectrum Sin (CD ^) ₂ CO: 5.21 (511, s,> NCH,) j 3.76 (2H, broad singlet, Cg-methylene): 4.46 (2H, broad singlet, -CH S- ); 5.10 (IH, d, J = 5 Hz, Cg proton); 5.28 (2H, S, 5.7-6.2 (2H, m, PhCH <and C ₇ -PrOtOn): 6.5-7 ^ 8 (15H, _{m, -CO 2} H, -CONH ₂ and aromatic protons); 8.63 (IH, d, J = 8 Hz, -CONH-); 10.29 (IH, d, J = 7 Hz, -CHNHCO-).

After treating the free acid in acetone with 2N sodium, -2-ethylhexanoate, the sodium salt is obtained in a yield of 0.98 g (= 58.8 % of theory).

UV spectrum K _Qv (95 percent ethanol): 264 nm (6 = 1082O). Max

Examples

(a) 'J-Zß-oL- (tert-Butoxycarbony lamino) -pheny lacetamido7-3- (1-carbamoy! methyl-1,5? 4-oxadiazol ~ 5-yl-thio) -methy1-ceph-5 -em-4-carboxylic acid

709823/1041

1.52 g (3.0 mmol) of N-tert-butoxycarbonyl-cephaloglycine. 0.48 g (3.0 mmol) of 5-mercapto-l, 3,4-oxadiazol-2-yl-acetamide and 0.50 g (6.0 mmol) of sodium bicarbonate in 20 ml of phosphate buffer solution at pH 6.5 are 3 * Heated to 70 G for 5 hours. The solution is poured onto 20 g of ice, washed twice with 25 ml of ethyl acetate each time, acidified and extracted three times with 20 ml of ethyl acetate each time. The combined extracts are washed twice with 25 ml of water each time and once with 20 ml of saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is triturated with anhydrous ether. A yield of 0.93 g (= 51.4 % of theory) of a cream-colored pesticide is obtained.

TLC on SiOp with a mixture of n-butanol, acetic acid and water / water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.36.

NiMR spectrum £ in (CD-J ₂ CO + D ₂ O: 1.45 (9H, s, -C (CH ₃ )); 3.72 (2H, broad singlet, C ₃ -methylene); 4.00 (2H, s, -CH ₂ CONH ₂ ); 4.37 (2H, broad singlet, -CH ₂ S-); 5.10 (IH, d, J = 5 Hz, Cg proton); 5.50 ( IH, s, PhCH <); 5.6-6.1 (IH, m, C ₇ -PrOtOn); 7.2-7.8 (5H, m, Ph-).

(b) 7- (D- ⁰ ^ -Ataino-phenylacetamido) -3- (2-carbamoylmethyl-l, 3,4-oxadiazol-5-yl-thio) methyl-ceph-3-em-4-carboxylic acid

0.93 g of the compound protected with the tert-butoxycarbonyIrest are suspended in 2 ml of anisole and cooled in an ice bath, during which 5 parts of chilled trifluoroacetic acid are added. The dark brown solution is stirred for 1.5 hours at room temperature and then in 400 ml of vigorously stirred anhydrous ether

709823/1041

dripped in. The precipitated trifluoroacetic acid salt is filtered off, washed with ether and dried under reduced pressure. Yield: 0.8 l g (= 85.0 % of theory).

UV spectrum λ, (95 percent ethanol): 266 nm (€. = 954θ).

Nuclear Magnetic Resonance Spectrum S in (CD ₄ ) 2 SO + D ₉ O: 3.62 (2H, broad singlet, C ₂ -methylene) j 3.89 (2H, s, -CH _{2 CONH 2} ); 4.32 (2H, broad singlet, -CH ₂ S-); 4.9-5.3 (2H, m, PhCH ^ and Cg proton); 5.7-6.0 (IH, m, C 1-4 proton); 7.57 (5H, s, Ph-).

Example 9

(a) 7 ~ / Ρ ~ ο {- (tert. - Butoxycarbony! amino) -pheny! acetamido7 ~ 3- (2-carbamoyl-l _? 3j4-oxadiazol-5-yl-thio) -methyl-ceph-3- em- Jj ₁ -Car b ons aur e

N-tert-Butoxycarboii3 ^r l-cephaloglycine is treated as in Example 8 with 5-mercapto-1,3,4-oxadiazol-2-yl-carboxamide. The compound is obtained in a yield of 33.8 %.

The DC gives an R _f value of 0.45.

NMR spectrum S in (CD ^) ₂ CO: 1.45 (9H, s, -C (CH ^) ₃ ); 3.76 (2H, broad singlet, Cg methylene) j 4.46 (2H, broad singlet, -CH ₂ S-); 5.12 (IH, d, J = 5 Hz, Cg proton); 5.4-5.6 (IH, m, PhCHC); 5.8-6.1 (IH, m, C 1-4 proton); 6.4-8.1 (1OH, m, -CO ₃ H, -CONH ₂ , -CONH-, Ph-); 8.40 (IH, d, J = 8 Hz, -CONH-).

7Q9R? 3/1 (H1

(b) 7- (D-ol-Amino-phenylaoetamido) -3- (2-carbamoyl-1,3,4-oxadia zo l-5-yl-thio) -methyl ^ ceph-3-em-4- carboxylic acid

The tert-butoxycarbony! Protective group is removed with trifluoroacetic acid in the presence of anisole. Analogously to Example 8 (b), the trifluoroacetic acid salt of the compound mentioned in the title is obtained in a yield of 88.2 %.

UV spectrum / 95% ethanol): 270 nm (£ = 10500). Max

Nuclear Magnetic Resonance Spectrum Sin (ClX) ₂ SO + D ₃ O: 3.4-3.8 (2H, m, Cg methylene); 4.36 (2H, broad singlet, -CH ₂ S-); 4.9-5.3 (2H, m, PhCH <and Cg proton); 5.88 (IH, d, J = 5 Hz, C _? Proton); 7.60 (5H, s, Ph-).

Example 10

(a) 7 -, / P-oC- (tert-Butoxycarbonylamino) -phenylacetamido7-3- (1-carbamoy! methyl-IH-tetrazol-5-yl-thio) -methyl-ceph-3-em-4- carboxylic acid

5-Mercapto-1H-tetrazol-1-ylacetamide is left in the same way as in Example 8 (a) and N-tert-butoxy-earbonyl-cephaloglycine with each other react. The compound mentioned in the title is obtained in a yield of $ 50.7>

The DC gives an R _f -four 0.48.

Nuclear Magnetic Resonance Spectrum Sin (CD,) ₂ CO: 1.44 (9H, s, -C (CH,),); 3.75 (2H, broad singlet, Cg methylene) j 4.3-4.6 (2H, tn, -CH ₂ S-) j 5, O8 (IH, d, J = 5 Hz, Cg proton) j 5.25 (2H, s, -CH ₂ CONH ₂ ); 5.4-5.7 (IH, m, PhCH ^); 5.93 (IH, dd, J = 5 and 9 Hz, C ^ proton); 6.5-7.8 (9H, m, -CO ₂ H, -CHNHCO-, -CON ^ and Ph-);

709823/10 41

8.44 (IH, d, J = 9 Hz, -CONH-).

(b) 7- (Dc ^ -amino-pheny! a cetamido) -3- (1 -car bam oy! methyl-IH-tetrazol ^ -yl-thio ^ ffiethyl-ceph ^ -em - ^ - carboxylic acid

Treatment of the compound obtained according to Example 10 (a) with trifluoroacetic acid and anisole analogously to Example 8 (b) gives the salt of the compound mentioned in the title in a yield of 94.7%.

UV spectrum λ (95 percent ethanol): 270 nm (β = 6090).

Nuclear Magnetic Resonance Spectrum Sin (CTu) ₂ SO + DgO: 3.65 (2H, broad singletfc, Cg-methylene), 4.35 (2H, broad singlet, -CHgS-); 5 * 0-5 * 3 (4h, m, -CH ₂ CONH ₂ , PhCHC and Cg-proton); 5 * 87 (IH, d, J = 5 Hz, C ₇ proton); 7 * 57 (5H, s, Ph-).

Example 11

7-Amino-3- (1-oarbamoylmethyl-1H-tetrazol-5-yl-thio) -methyloeph-3-eni-4-carboxylic acid

5 * 44 g (20 mmol) 7-amino-cephalosporanic acid and 3 * 50 g (2.2 mmol) 5-mercapto-1H-tetrazol-1-yl-acetamide in 200 ml of 50 percent suspended in aqueous acetone and mixed with solid sodium bicarbonate until a clear solution with a pH of approximately 7 * 0 receives. The solution is heated to 60 ° C for 6 hours, the flask being left open for the last hour to allow most of the To evaporate acetone. The mixture is then acidified to pH 4.0 and stirred for a further hour in an ice bath. The 'pest is filtered off, with washed a little cold water and subjected to reduced pressure

709823/1041

dries. Yield: 3 * 22 g (= 43.4 % of theory).

Nuclear Magnetic Resonance Spectrum & in CP ₃ CO ₂ H: 4.00 (2H, broad singlet, C ₂ methyl cn); 4.69 (2H, broad singlet, -CH ₂ S-); 5.56 (4li, s, -CH ₂ CO ₂ NH ₂ and ß-Lac tarn protons); 7.4-7.8 (2H, m, -CONH ₂ ).

Example 12
( ^a ) N-Methy1-5- mercap to -IH-tetrazol-1-y! -acetamide

2.0 g of 5-M ^e : rcapto-1H-tetrazol-l-yl-acetic acid ethyl ester are dissolved in 20 ml of 33 percent methylamine in ethanol and left to stand overnight at room temperature. The solution is evaporated to dryness under reduced pressure, the residue is dissolved in 20 ml of water, acidified and extracted six times with 50 K of ether each time. The extracts are dried and evaporated. After recrystallization from ethyl acetate, crystals are obtained in a yield of 0.59 g (= 32.0 % of theory) with a melting point of 167-168 ° C.

Nuclear Magnetic Resonance Spectrum 8 in (CD ₃ O ₂ CO: 2.88 (3H, d, J = 5 Hz, -NHCH ₃ ); 5.15 (2H, s, -CH ₂ CO-); 6.70 (IH , m, -NH-); 12.9 (IH, broad singlet, -SH).

Analysis for C ^ H ₇ N ₅ OS: C (56) H {%) N (#) S {%)

calc .: 27.74 4.07 40.44 18.51

Found: 27.53 4.17 40.07 18.38

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7- (Thien-2-yl-acetamido) -3- / 1- (N-meth yl-carbatnoy! Methyl) - 1H-tetr3ao! '.- 5-yl- thic; 7 "iriotliy 1 - ceph- 3 ~ Q ^ -4-carb onic acid

1.05 g (2.5 mmol) sodium cepha3othin, 0.48 g (2.75 mmol) N-methyl-S-mercapto-111-tetrazo! » 1-yl-ace / caraid and 0.21 g (2.5 millimoles) sodium bicarbonate in 15 ml of a phosphate buffer solution the pH 6.5 is heated to 60 C for 6.5 hours, then poured onto ice, washed twice with 20 ml of ethyl acetate each time, acidified and extracted three times with 20 ml of ethyl acetate each time. The extracts are saturated twice with 35 ml of water each time and once with 20 ml Saline solution washed, dried and under reduced Pressure evaporated to dryness. The residue is triturated with ether. 0.84 g of a cream-colored pesticide is obtained. The substance is dissolved in 50 ml of acetone and with 0.83 ml Treated 2-n sodium-2-ethyl-hexoate in 4-methyl-pentan-2-one.

anhydrous

After dilution with 200 ml / ether, the precipitated sodium salt is filtered off, washed with ether and dried under reduced pressure. Yield: 0.76 g (= 57.3 % of theory).

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.43.

UV spectrum λ (95 percent ethanol): 272 nm (£ 9700). NMR spectrum 5 (free acid) in (CD,) _p C0: 2.82 (3H, d, J = 5 Hz,

-NHCH ₃ ); 3.83 (2H, s, Cg-methylene); 3.98 (2H, s, -

₃ )

4.40 and 4.53 (2H, AB-quartet, J = 15 Hz, -CHgS-); 5.12 (IH, d, J = 5 Hz, Cg proton); 5.23 (2H, s, -CH ₂ COIiHCH ₃ ); 5.90 (IH, dd, J = 5 and 8 Hz, C ₇ proton); 7.0-7.6 (3H, m, thienyl protons); 7.8 (IH, m, -CONH-); 8.52 (IH, d, J = 8 Hz, -CONH-).

709823/1041

example

1.5 g of 5-Msrcapto-1H-tetrazol-1-yl-acetic acid-ether in 10 ml of ethanol and 6 ml of 33% dimethylamine in ethanol are mixed together and left to stand for 7 days. After adding a further 6 ml of 33 percent dimethylamine in ethanol, the solution is left to stand for a further 7 days and then evaporated to dryness under reduced pressure. The residue is dissolved in 50 ml of water, adjusted to pH 1.8 and concentrated to about 20 ml under reduced pressure. After the solution has been cooled in an ice bath, the crystals which have separated out are filtered off. Yield: 0.94 g (= 63.0 % of theory). Mp 204-205 ° C.

NMR spectrum S in (CD ^) ₂ CO: 3.02 and 3.28 (6H, 2 χ s, -N (CEL) ₂ ); 5.35 (2H, s, -CH ₀ CO-); 7.7 (IH, broad singlet, -SH).

Analysis for C ₅ H ₉ N ₅ OS: C (#) H (#) N (#) S {%)

at · .: 32.08 4.85 37.41 17.13 found i 32.21 5.01 37.63 16.99

(b) 7- (Thien-2-yl-acetamido) -3- / T- (N, N-dimethyl-carbamoy! methyl) lH-tetrazol-5-yl-thio7-methyl-ceph-3-em- 4-carboxylic acid

Analogously to the process of Example 12 (b), the compound mentioned in the title is obtained from sodium cephalothin and N, N-dimethyl ^ -mercapto-1H-tetrazol-1-yl-aeetamide in a yield of 44.1 %.

TLC on SiO ₂ in a mixture of n-butanol, acetic acid and water

709823/1041

• η

in a ratio of 12: 3: 5 as the mobile phase results in an R _f value of 0.55.

UV spectrum λ _m (95 percent ethanol): 271 nm (g = 8390).

Uiax

NMR spectrum 5 (free acid) in (CD ^) ₂ CO: 2.33 and 3.27 (6H, 2 χ s ,. -N (CH,) ₂ ) j 3.85 (2H, s, Cg- Methylene); 4.00 (2H, s, -CH ₂ CO-); 4.47 (2H, broad singlet, '- CHgS-); 5.20 (IH, d, J = 5 Hz, C ₆ proton); 5.55 (2H, s, -CH ₂ CON (CH- ^) ₂ ); 5.97 (IH, dd, J = 5 and 9 Hz, C ₇ -PrOtOn); 6.9-8.0 ( ² IH, m, thienyl protons and -CO ₂ H); 8.29 (IH, d, J = 9 Hz, -CONH-).

Example 14

7- / Po (.- (3-Benzoyl-3-methyl-ureido) -phe nyla cetamide Q7-3- (2-oarbamoyl-methyl-1,3,4-thiadiazol-5-yl-thio) -methyl-ceph -3-em-4-carboxylic acid

1.42 g (2.5 mmole) D-δ (- (3-Benzoyl-3-methyl-ureido) -benzylcephalosporin and 0.48 g (2.75 mmol) of 5-mercapto-1,3,4-thiadiazol-2-yl-acetamide in 20 ml of water and 5 ml of 1N sodium bicarbonate solution are heated to 60 ° C. for 6.5 hours. The reaction mixture is then poured onto crushed ice and washed twice with each 25 ml of ethyl acetate, acidify it and extract it three times 20 ml of n-butanol each. The extracts are washed twice with 20 ml of water each time and once with 20 ml of saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is triturated with anhydrous ether. You get the free acid in a yield of 1.31 g · The acid will dissolved in 40 ml of methanol, with 0.55 ml of 2N sodium 2-ethylhexoate treated in 4-Methy.lpentan-2-one, with 200 ml of anhydrous ether

709823/1041

added and filtered. The filtered sodium salt is washed with ether and dried under reduced pressure. Yield: 1.20 g (= 68.3 % of theory).

TLC on SiOo with a mixture of n-butanol, acetic acid and water in a ratio of 12: 5: 5 as a solvent gives an R _f value of 0.46.

UV spectrum A " _QV (95 percent ethanol): 275 nm <£ = 13700).

UlSLJi.

Nuclear Magnetic Resonance Spectrum Sin (CD ₄ ) 2 SO: 3.22 (3H, s,> N-CH ₃ ); 3.5-4.0 (2H, m, C ₂ methylene); 4.18 (2H, s, -CH ₂ CONH ₂ ) J 4.2-4.8 (2H, m, -CHgS-) 5.12 (IH, d, J = 5 Hz, C ₆ proton); 5.8-6.1 (2H, m, PhCEK and C ₇ proton); 7.0-8.0 (12H, m, -CONH ₂ , 2 χ Ph-); 9.38 (IH, d, J = 9 Hz, -NH-); 10.18 (IH, d, J = 8 Hz, -NH-).

Example 15

7- {D "t / - Z3- (2 ^l -Ch-lor-benzoyl) -3-methyl-ureido7-phenylacetamidof - 3- (1-carbamoy! Methyl-IH-tetrazol-5-yl-thio) - methyl-ceph-3-em-4-carboxylic acid

1.86 g (3.0 mmol) D - ^ - / 3- (2'-chloro-benzoyl) -3-methyl-ureido7-benzyl-cephalosporin and 0.59 S (3 * 7 mmol) 5-Mereapto- 1H-tetrazol-1-yl-acetamide in 30 ml of water is adjusted to pH 5.4 using 1N sodium bicarbonate solution and then ^{stirred for 3 hours at 70 °} C., then adjusted to pH 7 * 0, poured onto about 20 g of crushed ice , washed twice with 40 ml of ethyl acetate each time, acidified and extracted three times with 40 ml of ethyl acetate each time. The extracts are washed twice with 40 ml of water each time, dried and evaporated to dryness under reduced pressure.

709823/1041

The residue is triturated with ether. The free acid is obtained in a yield of 1.0 g.

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3 ' 5 as the mobile phase gives an R _f value of 0.35

The free acid is dissolved in 10 ml of acetone and treated with 0.71 ml of 2N sodium 2-ethylhexoate in 4-methylpentan-2-one. The precipitated sodium salt is filtered off, washed with acetone and with ether and dried. Yield: 0.90 g (= 4l, 6th the theory).

W spectrum λ _β (95 percent ethanol): '270 nm (£. = 9000). Max

Nuclear Magnetic Resonance Spectrum Sin (CDj) ₂ SO: 2.95 (3H, s, ^ CH ₅ ); 3.3-3.5 (2H, m, C ₂ methylene); 4.2-4.4 (2H, m, -CHgS-); 4.92 (IH, d, J = 5 Hz, Cg proton); 5.07 (2H, s, -CHgCONHg); % 5-5.8 (2H, m, PhCH <and C "-proton) j 7.2-8.1 (IH, m, -CONH ^ and aromatic protons); 9.3-9.5 (IH, m, -NH-); 9.8-10.0 (IH, m, -NH-).

Example 16

7- [P-c <-Z3- (2'-Fufoyl) -3-ynethyl-ureido7-phenylacetamido | -3-

(l-oarbamoyl-methyl-lH-tetrazol ^ -yl-thio ^ methyl-ceph ^ -em- 4-carboxylic acid

As indicated in Example 15, Dc <- / 3- (2'-FuTOyI) -3-methyl ureidoT-benzyl-cephalosporin and 5-mercapto-1H-tetrazol-1-ylacetamide are reacted with one another. The sodium salt is obtained in a yield of 25.6 %.

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- & h - UV spectrum λ, (95% ethanol): 2β9 nm (£ = 23200).

tilciX

Nuclear Magnetic Resonance Spectrum Sin (CD) ₂ S0: 3.32 (3H, s,> K ~CH,); 3.2-3.4 (2H, m, C ₂ methylene); 4.2-4.4 (2H, w, -CHgS-); 4.89 (IH, d, J = 5 Hz, Cg proton); 5.06 (2H, s, -CH ₂ CONH ₂ ); 5.5-5.8 (2Ii, m, PhCH <and Ο -, - proton); 6.6-6.8 (IH, m, furoyl proton); 7.3-7.6 (8h, m, -CONH ₂ , furoyl and aromatic protons); 7.97 (IH, m, furoyl proton); 9.2-9.5 (IH, m, -NH-); 9.6-9.8 (IH, m, -NH-).

Example 17

* [- / Ώ-οί- (3-isobutyr7 / l-3-tnsthyl-urcido) -pheny lace tamido / -3- (l-carbamoyl-raethyl-lH-tetrazol-.5-yl-thio) -m et hyl-c eph-3-em- 4-carboxylic acid

3.09 g (5.0 mmol) 7 ^ - ° <-aminopheny / acetamido) -3- (1-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-effl-4 -carboxylic acid trifluoroacetic salt in 25 ml of water and 10 ml of tetrahydrofuran are adjusted to pH 7.0 using 2.5N sodium hydroxide solution and then treated with 10 mmol of N-chlorocarbonyl-N-methylisobutyramide in 10 ml of tetrahydrofuran, prepared from N-methylisobutyramide the pH value is maintained at 6.5 by simultaneously adding 2.5 N sodium hydroxide solution. The mixture is diluted with 100 ml of water, then washed twice with 30 ml of ethyl acetate each time, acidified and extracted three times with 20 ml of ethyl acetate each time. The extracts are washed three times with 25 ml of water each time, dried, treated with 2N sodium 2-ethylhexoate in 4-methylpentan-2-one and diluted with ether. The precipitated sodium salt is filtered off, washed with ether and dried under reduced pressure. Yield: 0.80 g (= 27.0 % of theory).

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- & ± -.
'«I ■■

TLC on SiOg with a mixture of n-butanol, ethanol and water / water in a ratio of 2: 2: 1 as running agent gives an R _f value of 0.43.

IR spectrum P _mev (KBr): 1760 cm ".
Max

UV spectrum A ", _ov (95 percent ethanol): 270 nm (6 = 7900). Max

NMR spectrum in (CD ₃ ) ₂ S0: 1.06 (6H, d, J-7 Hz, (CPU) ₂ CH-); 3.05 (IH, m, (CH ^) ₂ CH-); 3, 18 (3H, s,>NCH,); 3.45 (2H, m, C ₂ methylene); 4.24 (2H, m, -CHgS-); 4.90 (IH, d, J = 5 Hz, Cg proton); 5.01 (2H, s, -CH ₂ CONH ₂ ); 5.4-5.7 (2H, m, PhCH <and C ₇ -PrO-ton); 7.0-8.0 (7H, m, -CONH ₂ and aromatic protons); 9.33 and 10.05 (2H, 2 χ d, 2 χ -NH-).

Example 18

7- | p-06- _; / 3-methyl-3- (3 * -thlenoyl) -ureido7-phenylacetamidoj-3- (l-oarbamoyl-methyl-lH-tetrazol-5-yl-thio) -methyl-ceph-3-em- 4-carboxylic acid

The 7- (Dc? <- Amino-phenylacetamido) -3- (1-carbamoy! Methyl-IH-tetra2ol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid trifluoroacetic acid salt is as in Example 17 acylated with N-chlorocarbonyl-N-methyl-3-thenoamide. The desired sodium salt is obtained in a yield of 30.3 %.

UV spectrum A _raax (95 percent ethanol): 240 nm (£ = 1580),

270 nm (ε = 10400).

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Nuclear Magnetic Resonance Spectrum in XCD ^) ₂ SO: 3.17 (JH, s, ^ CH ₅ ); 3.1-3.7 (2H, m, C ₂ -ethylene) j 4.2-4.4 (2H, m, -CH ₂ S-);, 4.87 (IH, d, J = 5 Hz , G ₆ proton); 5.06 (2H, s, -CH ₂ CONH ₂ ); 5.5-5.7 (2H, ra, PhCH <and C ^ proton); 7.40 (5H, s, Ph-); 7.2-8.2 (3H, m, -CONH ₃ and thienyl protons); 9.2-9.5 (IH, m, -NH-); 9.7-10.0 (IH, m, -KH-).

Example 19

Ί ~ ^ Τ> -οί- / 3- (3 '-Furoyl) -3-methyl-ureido7-phenylacetamide o | -3- (l-carbamoyl-methyl-lH-tetrazol-5-yl-thio) -methyl- ceph-3-em-4-carboxylic acid

The acylation of 7- (Do? -Amino-phenylacetamido) -3- (1-carbamoylmethy1-IH-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid with N-chloro-carbonyl N-methyl-3-i'uramid according to the process described in Example 17 gives the sodium salt in a yield of 19.9%.

UV spectrum A " _ov (95 percent ethanol): 270 nm (£ = 9500). Max

Nuclear Magnetic Resonance Spectrum δ in (CD ^) ₂ SO: 3.32 (3H, s,>NCH,); 3.2-3.7 (2H, xa, _C2 methylene); 4.2-4.4 (2H, s, -CH ₂ S-); 4.92 (IH, d, J = 5 Hz, Cg proton); 5.09 (2H, s, -CH ₂ CONH ₂ ); 5.4-5.8 (2H, m, PhCH <and C ₇ PrOtOn); 6.88-8.4 (1OH, m, Ph-, -CONH ₂ and furoyl protons); 9.3-9.5 (IH, ro, -NH-); 9.9-10.1 (IH, tn, -NH-).

Example 20

(a) 7 ~ (D - ^ - tert-Butoxycar bony lamino-4-hydroxy-ph.eny! acetamido) -3- (1-carbamoy! methyl-IH-tetrazol-5-yl-thio) -methy1- ceph-3-em-4-carboxylic acid

2.61 g (5'mMol) D-öi-tert-butoxycarbonylamino-4-hydroxy-benzyl-

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oephalos'porin, 0.795 g (5 ramol) of 5-mercapto-lH-tetrazol-i-yl-acetamide and 0.84 g (10 mmol) of sodium bicarbonate in 25 ml of a phosphate buffer solution of pH 6.5 to 4 hours is heated to 70 ⁰ C, then poured onto crushed ice, washed twice with 25 ml of ethyl acetate each time, acidified and extracted three times with 20 ml of ethyl acetate each time. The extracts are washed twice with 25 ml of water each time and then with saturated sodium chloride solution, dried and concentrated to about 10 ml under reduced pressure. The precipitated solid is filtered off, washed with about 2 ml of ethyl acetate and dried. Yield: 1.4-7 E (= ^ 7 A $ of theory).

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: J5: 5 as the mobile phase gives an R _f value of 0.45.

NMR ~ 3 spectrum <S in (CD ^) ₂ CO: 1.51 (9-H, s, -C (CH ₃ ),); 3 * 78 (2H, broad singlet, C ₂ methylene); 4.45 (2H, broad singlet, -CH ₂ S-); 5.15 (IH, d, J = 5 Hz, Cg proton); 5.27 (2H, s, -CH ₂ CONH ₂ ); 5.43 (IH, d, J = 9 Hz, PhCH <); 5.92 (IH, dd, J = 5 and 9 Hz, C ₇ proton); 6.5-9.0 (1OH, m, -OH, 2 χ -NH-, COgH, -CONH ₂ and aromatic protons).

(b) 7- (Dc ^ -amino-4-hydroxyphenylacetamido) -3- (1-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid

1.40 g of 7- (D- ° ^ -tert-butoxycarbonylamino-4-hydroxyphenylacetamido) -3- (l-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-cephj5-em-4- carboxylic acid are suspended in 2 ml of anisole, cooled in an ice bath, and treated with 5 ml of cooled trifluoroacetic acid

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delt. The solution is stirred for 1 hour at room temperature and then added dropwise to 350 ml of stirred anhydrous ether. The precipitated trifluoroacetic acid salt is filtered off, washed with ether and dried under reduced pressure. Yield: 1.20 g (= 83.8 % of theory).

UV spectrum λ, (95 percent ethanol): 275 nm (£ b = 8IOO). Max

NMR S & pect rum in (CD-J ₂ SO: 3.4-3.9 (2H, m, -C-methylene); 4.1-4.7 (2H, m, -CH ₂ S-); 4.90-5.4 (4H, m, -CH ₂ CONH ₂ ,> CHC0- and C ^ -proton); 5.7-6.1 (IH, m, Ο, -proton); 6.5- 9.0 (HH, m,

,, --CO ₂ H, -COMp, -OH and aromatic protons); 9.5-9.8 (IH, m, -CONH-).

Example 121

(a) 7- (Dc ^ -tert.-Butoxycarbonylamino-4-hydroxypheny! acetamido) 3- (2-carbamoylmethyl-1,3,4-thiadiazol-5-yl-thio) -methylceph ~ 3-etn- 4-carboxylic acid

D-oC-tert-butoxycarbonyl-amino-4-hydroxy-bensylcephalosporin is used and 5-mercapto-1,3,4-thiadiazol-2-yl-acetamide as in Example 20 (a) µm. A yield of 40.2 is obtained the connection named in the heading.

TLC on SiO ₂ with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an .R _f value of 0.43.

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- 66--

Nuclear Magnetic Resonance Spectrum <J-in '(CD ₅ ) ₂ CO: 1.42 (9H, "s, -C (CH ₅ ),); 3.75 (2H, m, C ₂ -methylene); 4.20 (2H, s, -CH ₂ COlIH ₂ ); 4.2-4 _; 8 (2Ii, m, -CHgS-5.12 (IH, d, J = 5 Hz, Cg proton); 5.43 (IH , d, J-8 Hz,> CHCO ~);

5.92 (IH, dd, J = 5 and 8 Hz, C "proton); 6.4-8.0 (9H, m, -OH, -COgH, -COInTH ₂ , -NH- and aromatic protons); 8.57 QH., D, J = 8 Hz, -NH-).

(fr) " 7- (D- ^ -amino -4- hydroxyphenylacetamido) -3- (2-carbarriqyl · 1- methyl-1,3,4-thiadiazol-5-yl- thio) -methyl-ceph -3-em-4- carboxylic acid

7- (D-oi-tert-Butoxyearbonylamino-4-hydroxy-pheriy / acetamido) -3- (2-carbamoylraethy1-1,3,4-thiadiazol-5-yl-thio) -methyl-ceph-3-em -4-carboxylic acid is treated with anisole and trifluoroacetic acid as in Example 20 (b). The compound is obtained in a yield of 88.5 %

UV spectrum X " (95 percent ethanol): 276 ran ^ = 12740). Max

Nuclear Magnetic Resonance Spectrum S in (CD ^) ₂ SO: 3.5-3.9 (2H, m, Cg-methylene); 4.10 (2H, s, -CH ₂ CONH ₂ ); 4.1-4.8 (2H, m, -CH ₂ S-); 4.9-5.4 (2H, m,> CHCO and C "protons); 5.6-6.1 (IH, m, C "proton);

6.93 and 7.42 (4h, AB-Q, uartette, J = 8 Hz, aromatic protons); 7.2-9.5 - (7H, m, -CONH ₂ , -AH ₅ , -COgH, -OH); 9.67 (IH, d, J = 8 Hz, -NH-).

Example 22

7- (2-Carboxy-2-thien-3 ^t -yl-acetamido) -3- (1-carbamoy! Methyl-IH-tetrazol-5-yl-thio) -me.thyl-ceph-3-em-4 -carboxylic acid

1.54 g (8.31 mmol). Thien-3-yl-malonic acid and 3.24 g (8.72 mmol) 7-Amino-3- (1-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-

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J-em - ^ - carboxylic acid in 40 ml v / water are adjusted to pH 6.0 using saturated sodium carbonate solution, cooled in an ice bath and treated with 1.68 g (8.72 niMol) 10-dimethylamino-propyl) -> -ätnyl-earbouiiniid hydrochloride treated. The solution is stirred at room temperature, during which the pH value, if necessary, is kept at pH 6.0 +0.1 by adding 5N hydrochloric acid. After 2 hours, the pH is adjusted by addition of sodium bicarbonate to 7 Λ. The solution is then washed with 50 ml of ethyl acetate, acidified to pH 4.0, washed twice with 25 ml of ethyl acetate each time, acidified to pH 1.8 and extracted three times with 20 ml of n-butanol each time. The extracts are washed twice with 20 tal of water each time and once with 20 ml of saturated sodium chloride solution, dried and evaporated to dryness. The residue is triturated with anhydrous ether. A yellow-brown solid which is dissolved in 25 ml of methanol is obtained in a yield of 1.72 g. The solution is treated with 3.2 ml of 2N sodium 2-ethylhexoate in 4-methylpentan-2-one and diluted with 50 ml of ether. The precipitated sodium salt is filtered off, washed with ether and dried under reduced pressure. Yield: 1.62 g (= 35 * 4 % of theory),

TLC on SiO ₂ in a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.24.

UV spectrum A _mov (95 percent ethanol): 272 nm (£ = 9840).

709823/10 4Ί

2 6 5 3 6 Z

NMR spectrum in DgO: 3.3-4.0 (2H, m, Cg-methylene); 4.24- and 4.46 (2H, 'AB-quartet, J = 14.5 Hz, -CH ₀ S-); 5.25 (IH, 2 χ d, J = 5 Hz, Cg proton); 5.50 (2H, s, -CH ₂ COfJHp); 5.87 (IH, d, J = 5 Hz, C ₇ PrOtOn); 7 * 2-7.7 (3H, ra, thienyl protons).

Example 23

(a) 7- Amino -3- (2-carb amoy 1-1,3,4-oxadiazol -5-yl-thlo) -cieth yl ceph- 3-em-4-carbonic acid

10.88 g (40 mmol) of 7-amino-cephalosporanic acid and 6.4O g (44 mmol) of 5-mercapto-1,3 * 4-oxadiazol-2-yl-carboxaraid in 500 ml of 50 percent aqueous acetone are mixed with solid Treated sodium bicarbonate at pH 7 and then heated to 6o ° C for 5 hours. The solution is acidified to pH 4.0 with 5N hydrochloric acid and cooled in an ice bath for 1 hour. The precipitated solid is filtered off, washed with 100 ml of water, then with 200 ml of ethanol and finally with 200 ml of ether and evaporated under reduced pressure. Yield: 5.87 g (= 41.1 % of theory).

NMR Spectrum _{5 in CP 3} CO ₂ H: 3.5-4.1 (2H, m, Cg-methylene); 4.4-4.9 (2H, m, -CH ₂ S-); 5.42 (2H, s, β-lactam protons); 7.89 (2H, d, J = 28 Hz, -CONH ₂ ).

(b) 7- (2-Carboxy-2-thien-3 ¹ -yl-acetarnido) -3- (2-carbamoyl-1,3,4-oxadiazol-5-yl-thio) -methyl-ceph-3- em-4-carboxylic acid

0.93 g (5 mmol) thien-3-yl-malonic acid and 1.87 g (5 mmol) 7 ~ Amino-3- (2-carbamoyl-1,3,4-oxadiazoi-5 ~ yl-thio) -methyl-ceph-3-em-4-carboxylic acid are dissolved in 20 ml of water by adding saturated sodium bicarbonate solution. The solution is in an ice bath

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cooled ,, adjusted with 5 N hydrochloric acid to pH 6.0 and then admixed with ₅ I 06 g (5.25 DiMoI) l- (5-dimethylamino-propyl) -3-ethyl-carbodiimide hydrochloride in XO ml of water. The solution is stirred at room temperature, during which the pH - if necessary - is maintained at 6.0 ± 0.1 by adding 5N hydrochloric acid. After 2 hours, the pH of the solution is adjusted to 7-5 by adding sodium bicarbonate solution. The solution is then washed with 50 ml of ethyl acetate. The aqueous layer is acidified to pH 4.0, washed twice with 25 ml of ethyl acetate each time, then covered with a layer of 25 ml of n-butanol, acidified to pH 1.8 and filtered. The n-butanol layer of the filtrate is collected and the aqueous layer is extracted again twice with 25 ml of n-butanol each time. The combined extracts are washed with 25 ml of water and then once with 25 ml of saturated sodium chloride solution, dried and evaporated to dryness under reduced pressure. The residue is triturated with anhydrous ether. A yield of 1.02 g of an almost white solid is obtained, which is dissolved in 20 ml of methanol, filtered, treated with 1.95 ml of 2N sodium 2-ethylhexoate in 4-methylpentan-2-one and with 100 ml anhydrous ether is diluted. The precipitated sodium salt is filtered off, washed with ether and dried under reduced pressure. Yield: 0.90 g (= 32.2 % of theory).

TLC on SiO ₂ with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an Rj value of 0.02.

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- ¹ TO W spectrum λ _a (95 percent ethanol): 269 nm (& = 10200).

ΓΠ3.Χ

NMR spectrum _{S'in D 2} O: 5 * 2-5.9 (2H, m, Cg-methylene) j 4.12 and k, k5 (2H, AB-quartet, J = II Hz, -CHgS-); 5.0-5.5 (IH, m, Cg proton); 5.95. (IH, d, J = 5 Hz, cu proton); 7.2-7.7 (5H> m, thienyl protons).

Example 24

(a) y> -Atnino-5 - (1-N-methyl-carbamoy! methyl-IH-tetrazol-5-ylthio) - methyl -ceph-5-em-4-carboxylic acid

7-Amino-cephalosporanic acid and N-methyl-5-mercapto-IH-tetrazoll-yl-ace.tamid are reacted as in Example 25 (a). The compound mentioned in the title is obtained in a yield of 44, p fo.

NMR spectrum S in CP ₅ CO ₂ H: 5.05 (5H, d, J = 5 Hz, -CONHCH ₅ ); 5.92 (2H, s, C ₂ methylene); h, 6j (2H, broad singlet, 5.47 (4h, s, -CH ₂ CO- and β-lactam protons); 7.5-7.8 (IH, m, -CONH- ').

(b) 7- (2-Carboxy-2-thien-5 ^t -yi-acetair.ido) -5- (l, N-methyl-Garbamoyimethyl-1H-tetrazol-5-yl-thio) -methyl-oeph- 5-em-4-carboxylic acid

Thien-5-yl-malonic acid and 7-amino-5- (Ι, Ν-methyl-carbamoylmethyl lH-tetrazol-5-yl-thio) -methyl-ceph-5-em-4-carboxylic acid are prepared according to the method described in Example 25 (b) described method coupled. The sodium salt of the compound mentioned in the title is obtained in a yield of $ 55.8>.

TLC on SiOp with a mixture of n-butanol, acetic acid and

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Water in the ratio 12: 3 '5 ^a ls eluent yields an R _f value 0.21.

TJV spectrum λ. (95 percent Gs ethanol): 271 nm (β = 8γ6θ). Biax

Nuclear Magnetic Resonance Spectrum S InD ₂ O: 2.67 (3H, s, -NHCH ₃ ); 3.0-3.9 (2H, rn, _C2 methylene); 4.01 and 4.25 (2H, AB-quartet, J = 14 Hz, -CH ₂ S-); 4.9-5.1 (IH, m, C ₆ proton); 5.13 (2H, s, -CH ₂ CO-); 5.55 (IH, d, J = 5 Hz, C "proton); 6.9-7.6 (3H, m, thienyl protons).

Example 25

(a) 7-Ainino-3- (1, N, N-dimethyl-arbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4- carboxylic acid

7-Amino-cephalosporanic acid and N, N-dimethyl-5-niercapto-1H-tetrazol-1-yl-acetamide are coupled to one another as in Example 23 (a). The compound is obtained in a yield of 40.6 %.

NMR spectrum & in CP ₃ CO ₂ H: 3.17 and 3.32 (6h, 2 χ s, -CON (CH ₃ ) ₂ ); 3.90 (2H, broad singlet, C ₃ methylene); 4.63 (2H, broad singlet, -CH ₂ S-); 5Λ5 and 5.58 (2H, 2H each, s + broad singlet, -CH ₂ CO- and ß-lactam protons).

(b) 7- (2-Carboxy-2-thien-3'-yl-acetamido) -3- (l, N, N-dimethylcarbamoy! methyl-IH-tetrazol-5-yl-thio) -methyl-ceph- 3-em-4-carboxylic acid

Thien-3-y! -Malonic acid and 7-amino-3- (Ι, Ν, Ν-.dimethyl-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid are coupled according to the procedure described in Example 23 (b). The sodium salt mentioned in the title is obtained.

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th compound in a yield of 50.8 %.

TLC on SiOp with a "mixture of n-butanol, acetic acid and water in the ratio 12: 5: 5 as the mobile phase gives an R _f value of 0.17.

UV spectrum λ (95 percent ethanol): 275 nm (£ = 9000).

Ul dA
/

NMR spectrum 8 in D ₃ O: 2.8l and 2.97 (6H, 2 χ s, -CON (CH ^) ₂ ); 5.1 to 3.8 (2H, m, C ₂ methylene); 5.9-4.4 (2H, m, -CH ₃ S-); 4.9-5.1 (IH, rn, C ₆ proton) j 5.57 (2H, s, -CH ₂ CO-); 5.54 (IH, d, J = 5 Hz, C ^ proton); 6.9-7.5 (5H, m, thienyl protons).

Example 26

( ^a ) 7-Amino-5- (2- carbamoy! m ethyl-1 , 5,4-thiadiazol-5-yl-thio) -methyl-ceph ~ 5-e ^ -4- carboxylic acid

7-Amino-cephalosporanic acid and 5-mercapto-1,5,4-thiadiazol-2-ylacetamide are reacted as in Example 25 (a). The compound mentioned in the title is obtained in a yield of 69.8 fo.

NMR spectrum S in CF ₅ CO ₂ H: 5.95 (2H, s, Cg-methylene) .; 4.65 (2H, s, -CH ₂ CO-); 4.82 (2H, broad singlet, -CH ₂ S-); 5.47 (2H, s, β-lactar protons) ;. 7.2-7.8 (2H, m, -CONH ₂ ) ..

(b) 7 ~ (2-Carboxy-2-thien-5'-yl-aoetarnido) -5- (2-carbamoyltnethyll, 5,4-thiadiazol-5-yl-thio) -tethyl-ceph-5-em- 4-carboxylic acid

Thien-5-yl-malonic acid and 7-amino-5- (2-carbamoylmethyl-1,5,4-thiadiazol-5-yl-thio) -methyl-ceph-5-em-4-carboxylic acid are coupled according to the procedure described in Example 25 (b). Man

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holds the sodium salt of the compound mentioned in the heading in a yield of 2b, 0 %, -

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3 · 5 as the mobile phase gives an R n value of 0.21.

UV spectrum λ _Qv (95 percent ethanol): 276 nm (£ = Γ34ΟΟ).

ETl et λ.

Nuclear Magnetic Resonance Spectrum S in D ₃ O: 3.1-3.7 (2H, m, Cg-methylene) s 4.04 (2H, s, -CH ₂ CO-); 4.1-4.6 (2H, m, -CH ₃ S-); 4.8-5.0 (IH, m, C ₆ proton); 5.4-5.6 (IH, m, C ₇ proton); 6.9-7.5 (3H, m, thienyl protons).

Example 27

7-Z2 "carboxy-2- (4-hydroxyphenyl) -acetamido7-3- (l-carbamoyl · - methyl-l · H-tetrazol-5-yl-thlo) -methyl-ceph-3-em-4-carboxylic acid

4-Hydroxy-phenyl-malonic acid and 7-amino-3- (1-carbamoy line thy 1-lH-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid are coupled according to the procedure described in Example 23 (b). The sodium salt of the compound named in the title is obtained in $ 25.3 yield

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.12.

UV spectrum A _max (95 percent ethanol): 273 nm (έ = 8100).

NMR spectrum in D S ₃ O: 3.1-3.7 (2H, m, C ₂ methylene); 3.96 and 4.24 (2H, AB-quartet, J = IJ Hz, -CH ₃ S-); 4.8-5.1 (IH, m, C ₆ proton); 5.13 (2H, s, -CH ₃ CO-); 5.50 (IH, d, J = 5 Hz, OpProton):

709823/1041

6.78 and, 7.17 (4H ^ AB-quartet, J = 8 Hz, aromatic protons). '

Example 28

7- / 2- Carboxy-2- (4- methoxy- phenyl) -acetamido y ⁷ ^ - (1-carbamoyl methy l -lH-tet razol-5-yl- thio) -methyl-ceph-3 -em-4-carbonic acid

4-Methoxy-phenyl-malonic acid and 7-amino-3- (1-carbamoylmethyl-1H-tetreszol-5-yl ~ thio) -methyl-ceph-3-em-4-carboxylic acid are prepared according to the method described in Example 23 ( b) described method coupled. The sodium salt of the compound mentioned in the title is obtained in a yield of 43.2 %.

UV spectrum λ ".. (95 percent ethanol): 274 nm (£ - 663Ο).

Nuclear Magnetic Resonance Spectrum S in D ₂ O: 3.2-3.8 (2H, m, Cg methylene); 3.77 (3H, s, -OCH-,); 4.0-4.6 (2H, m, -CHgS-); 4.9-5.2 (IH, m, Cg proton); 5.28 (2H, s, -CH ₂ CO-); 5.72 (IH, d, J = 5 Hz, C ₇ PrOtOn); 7.04 and 7.19 ( ² m, AB-quartet, J = 8 Hz, aromatic protons).

Example 29

7- (Thien-3-yl-acetamido) -3- (1-carbamoylmethyl-1H-tetrazol-5-ylthio) -methyl'-ceph-3-em-4-carboxylic acid

1.90 g (4.6 mmol) of the sodium salt of 7- (thien-3-yl-acetamido) -3-acetoxy-methyl-ceph-3-em-4-carboxylic acid, 0.81 g (5.1 mmol ) S-mercapto-lH-tetrazol-l-yl-acetamide and 0.42 g (5 mmol) of sodium bicarbonate in 25 ml of a phosphate buffer solution of pH 6.5 is heated for 6 hours at 6O ⁰ C. The reaction mixture is poured onto ice, washed with 25 ml of ethyl acetate, acidified to pH 1.5 and extracted three times with 20 ml of ethyl acetate each time. The extracts

70 9823/10 41

are washed with water _v and with saturated brine, dried and evaporated to dryness. The residue is triturated with anhydrous ether. The free acid is obtained in a yield of 1.59 g. The free acid is dissolved in 25 ml of acetone, treated with 1.5 ml of 2N sodium 2-ethylhexoate in 4-methylpentan-2-one and with 25 ml diluted with anhydrous ether. The precipitated sodium salt is filtered off, washed with ether and dried. Yield: 1.00 g (= 42.1 $ of theory).

TLC on SiOp with a mixture of n-butariol, acetic acid and water in a ratio of 12: 5: 5 as the mobile phase gives an R _f -4 0.40.

UV spectrum A _max (95 percent ethanol): 273 µm (Jg = 8200).

Nuclear Magnetic Resonance Spectrum £ In (CBx) ₂ SO: 3.2-3.7 (2H, m, Cg-methylene); 3.38 (2H, s, -CH ₂ CONH-); 4.04-4.25 (2H, AB-quartet, J = IjJ-Hz, -CH ₂ S-); 4.73 (IH, d, J = 5 Hz, Cg proton); 4.87 (2H, s, -CH ₂ CONH

5.50 (IH, dd, J = 5 and 8 Hs, C ₇ -PrOtOn); 6.9-8.2 (5H,. M, thienyl protons and -CONH ₂ ); 8.88 (IH, d, J = 8 Ha, -CONH-).

Example 30

(a) 7- (D, 2-pormyloxy-2-phenyl-acetamido) -3- (1-oarbamoylmethyllH-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid

A solution of 1.07 g (5.4 mmol) of D, 2-pormyloxy-2-phenyl-acetyl chloride in 12.5 ml of acetone becomes. -to a mixture of 1.86 g (5 mmol) 7-amino-3- (i-carbamoylmethyl-1H-tetrazol-5-yl-thio) -

5 ml of 1-N sodium hydroxide methyl-eeph-3-em-4-carboxylic acid, / and 7.5 ml of 1N sodium bicarbonate solution was added to 25 ml of 50 percent aqueous acetone. To

709823/1041

The acetone is removed under reduced pressure for 2 hours.

Residue
the aqueous / washed twice with 20 ml of ethyl acetate each time, covered with 15 ml of n-butanol, acidified to pH 1.5 and filtered. The n-butanol layer of the filtrate is collected. The aqueous layer is again twice with 15 ml each The combined extracts are then washed with water and with saturated sodium chloride solution, dried and evaporated to dryness. The residue is triturated with anhydrous ether. A pale brown solid is obtained in a yield of 1.53 ml of methanol is dissolved, the solution is treated with 1.4 ml of 2N sodium 2-ethylhexoate in 4-methylpentan-2-one and diluted with ether to give 1.20 g (= 43%) , 5 % of theory) the sodium salt of 7- (di2-formyloxy-2-phenylacetamido) -5- (1-carbamoylmethyl-1H-tetrazoi-5-yl-thio) -methyl-ceph-j5-em-4-carboxylic acid .

Nuclear Magnetic Resonance Spectrum in (CD-J ₂ SO: 3.0-3.6 (2H, m, Cg-methylene); 3.9-4.6 (2H, m, -CH ₂ S-); 4, 73 (IH, d, J = 5 Hz, Cg proton); 5.02 (2H, s, -CH ₂ CO-); 5.3-5.8 (IH, m, CU proton); 6, 15 (IH, s, PhCH ^); 7.1-8.2 (7H, m, Ph- and -CONH ₂ ); 8.32 (IH, s, -OCHO); 9.30 (IH, d, J = 8 Hz, -CONH-).

(b) 7- (D, 2-Hydrox.y-2-phenyl-acetamido) -3- (1-carbamoylmethyl- IH, -t. etrazol-5-yl-thio) -methyl-ceph-3-em- 4-carboxylic acid

■ 1.20 g (2 mmol) of the compound obtained according to Example 30 (a) become 25 ml of a solution of 1.53 g (4 mmol) of sodium tetraborate decahydrate given in water. The solution is stirred for 3 hours at room temperature and then worked up as in Example 30 (a). It is obtained in a yield of 0.20. g (= $ 17.6

709823/1041

.- ■ ft -

the 3w

der Theory) / Natriufflsalz of the Ver binding.'

Nuclear Magnetic Resonance Spectrum S in (CD ^) ₂ SO: 3.4-3.7 (2H, m, Cg-methylene); 3.9-4.3 (2H, m, -CH ₂ S-); 4.8 -5.2 (4H, m, Cg proton, -CH ₂ and PhCiK); 5.5 and 5.8 (IH, m, C ₇ -PrOtOn); 7.0-7.9 (8h, m, Ph-, -OH and -CONH ₀ ) Γ 8.45 (IH, d, J = 8 Hz, -CONH-).

Example Jl

7- (2-Methoxy-imino-2-f ur- 2'-y1-acetan ido) -3 - (1 -oarbarnoy Imethy 1-IH-tetrazol-5-yl-fchio) -me thy l-ceph -3 - g »n-4-carboxylic acid

With 6 nimoles of 2-syn-methoxy-imino-2-fur-2 ¹ -yl-acetyl chloride, 1.86 g (5 mmol) of 7-amino-3- (l-carbatnoylmethyl-lH-tetrazol-5-ylthio) - methyl-ceph-3-em-4-carboxylic acid acylated by the method described in Example 50 (a). The sodium salt of the compound mentioned in the title is obtained in a yield of 47.8 %.

TLC on SiOp with a mixture of n-butanol, acetic acid and water / water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.34.

UV spectrum λ _m - (95 percent ethanol): 277 mn (£ = 18900).

Ul CL Jt.

Nuclear Magnetic Resonance Spectrum S in D ₂ O: 3.41 and 3.72 (2H, AB-quartet, J = 12 Hz, C ₂ -ethylene), x 3.96 (3H, s, -OCH,), x 4 , 09 and 4.33 (2H, AB-quartet, J = II Hz, -CH ₂ S-); 5.16 (IH, d, J = 5 Hz, Cg proton); 5.27 (2H, s, -CH ₂ CONH ₂ ); 5.73 (IH, d, J = 5 Hz, C -proton); 6.5-6.9 and 7.6-7.8 (3H, m, puryl protons).

709823/1041

-Example 32

- (4-methyl-phenoxycarbonyl) -2-thien-3 ^> -yl-

(l ~ carbamoy! methyl-IH-tetrazol-5-yl-thio) -methyl-ce p h ~ 3-em- 4- carboxylic acid

With 6 mmoles of 2- (4-methyl-phenoxycarbonyl) -2-thien-3'-yl-acetyl chloride, 5 mmoles of 7-amino-3- (1-carbamoy! Methyl-IH-tetrazole-5-3 ^r l-thio ) i-methyl "Ceph-3-em-4-carboxylic acid is aeylated by the process described in Example 30 (a). The sodium salt of the compound mentioned in the title is obtained in a yield of 50.3 %.

TLC on SiOp with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.40. . .

NMR spectrum in D ₂ O: 2.15 (3H, s, -CH ₃ ); 3.2-3.8 (2H, m, C ₀ -ethylene); 3.9-4.4 (2H, m, -CHgS-); 5.03 (IH, d, J = 5 Hz, Cg proton); 5.20 (2H, s, -CH ₂ CONH ₂ ); 5.5-5.7 (IH, m, C ₇ proton); 6.58 and 6.99 (4H, AB-quartet, J = 8 Hz, aromatic protons); 7.0-7.6 (3H, m, thienyl protons).

Example 33

7- (2-Carboxy-2-thien-3 ^t -yl-acetamido) -3- (1-carbamoyimethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid

1.64 g of the sodium salt of 7- / 2- (4-methyl-phenoxycarbonyl) -2-thien-3'-yl-acetamido7-3- (1-carbamoylmethyl-IH-tetrazol-5-ylthio) -methyl-ceph -3-em-4-carboxylic acid are added to 100 ml of a solution of 1.92 g of sodium tetraborate decahydrate in water. The solution is stirred for 3 * 5 hours at room temperature, then on "

■ '" 709823/1041

pH 4.0 acidified, washed twice with 25 ml of ethyl acetate each time, then acidified to pH 1.8 and extracted three times with 20 ml of n-butanol each time. The n-butanol extracts are washed with 50 ml of water and with 25 ml of saturated sodium chloride solution, dried and evaporated to dryness. The residue is triturated with anhydrous ether. Μειη is obtained in a yield of 0.50 g of the free acid, which is dissolved in 20 ml of methanol, treated with 2N sodium 2-ethylhexoate in 4-methylpentan-2-one and diluted with ether. The sodium salt of the compound named in the title precipitates and is filtered off, washed with ether and dried. Yield: 0.47 g (= 32.0 % of theory).

TLC on SiO _Q with a mixture of n-butanol, acetic acid and water in a ratio of 12: 3: 5 as the mobile phase gives an R _f -Werf 0.25.

NMR spectrum in D ₃ O: 3.1-3.8 (2H, m, Cg-methylene); 4.02 and 4.26 (2H, AB-quartet, J = 8 Hz, -CH ₃ S-); 4.9-5.1 (IH, m, Cg proton); 5.22 (2H, s, -CH ₂ CONH ₂ ); 5.5-5.7 (IH, m, C ₇ proton); 7.0-7.5 (3H, m, thienyl protons).

Example 34

7- / D _J 2- (4-ethyl-2,3-dioxo-piperazino-1-carbonylamino) -2-phenylacetamido 7-3- (1-carbamoy! Methyl-IH-tetrazol-5-yl-thio) -methylceph -3-effl-4-carboxylic acid

1.15 g (2 RiMoI) of the sodium salt of 7- / D, 2- (4-ethyl-2,3-dioxopiperazino-l-carbonylamino) -2-phenylacetamido7-3-acetoxy-methylceph-3-em-4- carboxylic acid and 0.35 g (2.2 mmol) of 5-mercapto-1H-tetrazol-5-yl-acetamide in 15 ml of water are

• 709823/1041

carbonate adjusted to pH 7.0. The solution is warmed to 60 ° C. for 7 hours, then poured onto ice, twice with 10; ml of ethyl acetate · washed, acidified to pH 2.0 and extracted three times with 15 ml of n-butanol each time. The extracts v / earth with 20 ml water and washed with 20 ml of saturated sodium chloride solution, dried and evaporated under reduced pressure _f. The residue is triturated with ether free from water. The compound mentioned in the title is obtained in a yield of 0.73 g, which is dissolved in 20 ml of methanol, treated with 0.55 ml of 2N sodium 2-ethylhexoate in 4-methyl-pentan-2-one and treated with 50 ml of anhydrous ether is diluted. The precipitated sodium salt is filtered off, washed with ether and dried. Yield: 0.51 g (= 37.6 % of theory).

TLC on SiOp with a mixture of n-butanol, acetic acid and water / water in a ratio of 12: 3: 5 as the mobile phase gives an R _f value of 0.32.

UV spectrum A (95 percent ethanol): 268 nm (€? = 8580). NMR spectrum S in (CD ^) ₂ SO: 1.10 (3H, t, J = 7 Hz, -CH ₂₅ 2.9-3.8 (8h, m, piperazino and C ₂ -methylene protons, > NCH ₂ CH _T ); .3.8-4.4 (2H, m, -CH ₂ S-); 4.93 (IH, d, J = 5 Hz, Cg proton);. 5.08 ( 2H, s, -CH ₂ CONH ₂ ); 5.4-5.8 (2H, m, PhCH and C ^ proton)? 7.0-8.3 (7H, m, Ph and -CONH ₂ ); 9.41 (IH, d, J = 8 Hz, -CONH-); 9.87 (IH, d, J = 7 Hz, -CONH-).

Example 35

(a) 7-Amino-3- (3-carbamoylmethyl-1,2,4-triazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid

7-Amino-cephalospoic acid and 5-mercapto-1,2,4-triazol-3-yl ~

709823/1041

XOO

acetamide is reacted as in Example 23 (a). The compound mentioned in the title is obtained in a yield of 58.4 %:

KMil spectrum β in CP ^ CO ₂ H: 3.87 (2H, broad singlet, ^ -methylene) j 4.38 (2H, s, -CH ₂ GONH ₂ ) J 4.55 (2H, broad singlet, - CII ₂ S-); 5.40 (2H, s, β-lactam protons); 7.1-7.8 (2H, m, -CONH ₂ )

(b) 7- (2-Carboxy-P-thien-3 '-yl-acetamido) -3- (3-ca-rbamoylme thy l-1 , 2,4-triazol-5-yl-thio) methyl -ceph-J'-em- 4-carbo nic acid

Thien-3-yl-malonic acid and 7-amino-3- (3-carbamoylmethyl-l, 2,4-triaaol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid are prepared according to the example 23 (b) described method coupled. The sodium salt of the compound mentioned in the title is obtained in a yield of 27.1 %.

TLC on SiO ₂ with a mixture of n-butanol, acetic acid and water in a ratio of 2: 3: 5 as the mobile phase gives an ~ R _f value of 0.19.

UV spectrum / \ _max (95 percent ethanol): 271 nm (£ = 8270).

Nuclear Magnetic Resonance Spectrum (Sin D ₂ O: 3.55 (2H, broad singlet, Cg methylene) j 3.80 (2H, s, -CH _{2 CONH 2} ); 4.13 (2H, S, -CH ₃ S -); 4.9-5.2 (IH, m, C ₆ proton); 5.5-5.8 (IH, m, C ₇ proton); 7.0-7.6 (3H, m , Thienyl protons).

709823/1041

Claims (1)

Claims _or -, _M1 265362I 1. Cephalosporin derivatives of the general formula (I) (D CH ₀ - S - Y - (CH ₉ ) - CO.N .R in the R is an organic acylamino radical, a radical of the formula (Ha) CH- (Ha) CH ₃ CH ₃ or a radical of the general formula (Hb) «3 N - CH = N - (Hb) ■ a h denotes, where Br and R are identical or different and represent alkyl radicals with 1 to J> carbon atoms or together with the nitrogen atom to which they are bonded form a monocyclic ring,
Y stands for a 5-membered, nitrogen-containing ring, η has the value 0 or 1 and 1 p
R and R are identical or different and are hydrogen atoms 709823/10 41 i " or are alkyl radicals with 1 to 6 carbon atoms, and their pharmacologically acceptable salts and esters. 2. Derivatives according to claim 1, characterized in that the radical R has the general formula (Hn) R ^U .CH -CO-NH- Him) "X in which R is a cycloalkyl or cycloalkenyl radical or the Furyl, thienyl or fhenyl group, which is replaced by halogen atoms, Nitro, amino, hydroxyl or carboxyl groups or lower alkyl or lower alkoxy groups can be substituted, and X is a hydrogen atom, a hydroxy, amino, carboxy, in salt form is present carboxy, esterified carboxy, ureido or acylureido group. 3. Derivatives according to claim 2, characterized in that X is a hydrogen atom or esterified carboxyl -, - a ureido or an acylureido group. 4. Derivatives according to claim 2, characterized in that X is a hydrogen atom or an amino, carboxy or acylureido group is. 5. Derivatives according to claim 4, characterized in that X is the carboxy group. 709823/1041 6. Derivatives according to at least one of the preceding claims 2 to 5 i, characterized in that the radical R is the 2- or 3-thienyl, the phenyl or the 4-hydroxyphenyl group. ¹ J. Derivatives according to at least one of Claims 3 to 6, characterized in that Y is the oxadiazolyl, thiadiazolyl or the triazolyl group. 8. Derivatives according to at least one of claims 1 to 6, characterized characterized in that Y is the tetrazolyl group. 9. Derivatives according to at least one of claims 1 to 8, characterized in that η is 1. 10. Derivatives according to claim 1, characterized in that 1 2
R and R are hydrogen atoms. 11. Derivatives according to claim 1 of the general formula (IV) (IV) R ^S -CH-CO.Mi co.mp-R ² 2 2 in which X is an amino or acylureido group, Y is the oxadiazole, thiadiazoi or tetrazole group and R ^{z is} the phenyl or 4-hydroxyphenyl group, or their pharmacologically acceptable salts or esters. 709823/1 (U 1 12. Cephalosporin derivatives na.ch claim 11, namely 7-ZP-ÖC- (3-Benzoyl ~ 3-methyl-urGido) - pheny! Acetamido? -3 »- (2-carbamoylmethy1-1,3j ^ -oxadiazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid; 7- / bd.- (5-Benzoyl ~ 3-methyl-ureido) -phenylacetamido / ⁷ - ^ - (2 ~ oarbamoyl-1 _i 3,4-oxadiazol-5-yl-thio) -methyl-ceph-5 « era "4-carboxylic acid; Ί- / Ρ-Φ- (^ -Benzoyl-p-methyl-ureido) -phenylacetarnido7 ~ 5- (l-carbarnoylraethyl-lH-tetrazol-5-yl-thio) -methyl-ceph- 35-em — Ί— carboxylic acid;
7- (D-ÖC-amino-phenylacetamido) -J> ~ (2-carbaraoy line thyl-1,3,4-oxa- diazol-5-yl-thio) "methyl-ceph-3-a-4-carboxylic acid; 7- (D-d - Amino-pheny! Acetamido) -3- (2-carbamoyl-1,3i 4-oxadiazole- 5-yl-thio) -tethyl-ceph-3-em ~ ■ ^! · ^ -Carboxylic acid; 7- (Dd-Atnino ~ phenylacetamido) -3- (l-carbatnoylmethyl-lH-tetrazole- 5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid; 7-ZO-dC- (3-Benzoyl-3-methyl-ureido) -phenylacetamido7-3- (2-carbaffioylmethyl ~ l, 3j ⁱ l-thiadiazol-5-yl-thio) - methyl-ceph-3-eni-4-carboxylic acid;
7-] ü-dt- / 2- (2'-ChIo ^ eHZOyI) »3-methyl-ureido / -phenylace tamido | - 3- (l-carbamoylmethyl-lH-tetrazol ~ 5-yl-thio) -methyl- ceph- 3-βιΐι-4-carboxylic acid;
7- {p- <) l- / 3- (2 ^l -Puroyl) -3-methyl-ureido-7-phenylacetamido | -3- (l-carbaraoylmethyl-lH-tetrazol-5-yl-thio) -methyl-ceph - jj-ern- ¹ ! -carboxylic acid;
7- / S-Ob- (3-isobutyryl-3-m <3thyl-ureido) -phenylacetamido / -3- (l-carbamoylmethyl-lH-tetrazol-5-yl-thio) -methyl-ceph- 3-em-4-carboxylic acid; . . 709823/1041 7- | p-dl- ^ 3-methyl-3- (3 '-thienoyl) -ureido7-pheny! Acetamido] 3- (l-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-oeph- j5-em-4-carboxylic acid;
7— ^ D-oi .- / ^ - (3 '-Furoyl) ^ -methyl-ureidoZ-phenylacetamido) 3- (l-carbaraoylmethyl-1H-tetrazol-5-yl-thio) -raethyl-Geph- J> -eto-h- carboxylic acid; . 7- (D-c6-amino-4-hydroxyphenylacetamido) -> (l-carbamoylmethyl- 1H-tetrazol-5-yl-thio) -methyl-ceph-3-eni- ² } -carboxylic acid j 7> (D- (f _l 7Araino-4-hydroxyphenylacetamido) ~ 3- (2-carbamoylnietbyl "l, 3i ^j i-thladiazol-5-yl-thio) -methyl-ceph-3-em- ² l-carboxylic acid and
7- / p, 2- (4-ethyl-2,3-dioxopiperazino-1-carbonylamino) -2-phsnylacetamido7-3- (1-carbamoy! Methyl-1H-tetrazol-5-yl-thio) methyl - ceph-3-em- ² l-carboxylic acid »'' 709823/1041 Derivatives according to claim 1 with the general formula (v) (V) CH ₉ .SY ³ - (CH ₀ ) CO. in which Y ^ is the tetrazole, thiadiazole or oxadiazole group 1 2
and n, R and R have the meanings given in claim 1 own, and their pharmacologically acceptable salts or esters. 14. Cephalosporin derivatives according to claim I3, namely 7- (thien-2-yl-acetamido) -3- (2-carbamoylmethyl-l _J 3, ⁱ ! -Oxadiazole- 5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid, 7- (Thien-2-yl-aoetamido) -5- (2-carbamoyl-1,5,4-oxadiazol'-5-ylthio) -methyl-ceph-3 ~ em-4-carboxylic acid, 7- (Thien-2-yl-acetamido) -5- (l-carbamoylmeth3 "l-lH-tetrazol-5-yl- thio) -methyl-ceph - ^ - em-4-carboxylic acid _i 7- (Thien-2-yl-acetamido) -J> ~ (carbamoylmethyl-1,3, k- thiadiazole- 5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid, 7- (Thien-2-yl-acetamido) -3- / I- (N-methyl-carbamoy! Methyl) -IH- ^{tetrazol-5-yl-thio7-methyl-ceph-3-em-i} i-carboxylic acid; 7- (thien-2-yl-acetamido) -2 _/ / l- (N _i N-dimethyl-carbamoylmethyl) -IH -tetrazol-5-yl-thio7-nie thy l-ceph - ^ - em- ¹ ! -carboxylic acid, and 7- (Thien-3-yl-acetamido) -3- (1-carbamoylmethyl-1H-tetrazol-5-ylthio) -methyl-ceph-3 ~ em-4-carboxylic acid. 709823/1041 15 derivatives according to claim 1 of the general formula (VA) * ^W - CB-COJB CH ₂ .S - Y ⁴ - (CH ₂ J _n 00.NR ¹ R ² H.
in which Y the tetrazole, thiadiazole, oxadiazole or the tria- is zolgruppe, R ^w the 2 ~ or Jj-thienyl, phenyl, 4-hydroxy 1 ? denotes phenyl or the 4-methoxyphenyl group and n, R and R "have the meanings given in claim 1, and their pharmacologically acceptable salts or esters. 16. Derivatives according to claim 15, characterized in that R ^{w is} the 2- or 3-thienyl, phenyl or 4-hydroxyphenyl 4th
and Y is the tetrazole, thiadiazole or oxadiazole group. 17 · Derivatives according to claim 16, characterized in that R ^{w is} the 3-thienyl group. l8. 7- (2-carboxy-2-thien-3'-yl-acetamido) -3- (l-carbamoylmethyl 1H-tetrazol-5-yl-thio) -methyl-ceph-j3-em-4-carboxylic acid. 709823/1041 19 · cephalosporin derivatives according to claim 15 * namely 7- (2-Carboxy-2-thien-5'-yl-acetamido) -3- (2-carbamoyl ~ l, 3,4- oxadiazol-5-yl-thio) -methyl-ceph-5-em-4-carboxylic acid j 7- (2-carboxy-2-thien-3 ^t -yl-acetaraido) -3- (l, N-methyl-carbamoyl- methyl-1H-tetrazol-5-yl-thio) -methyl-ceph-5-em-4-carboxylic acid; 7- (2-9arboxy-2-thien-5 ¹ -yl-aeetamido) -3- (l / N, N - dimethylcarbamoylmethyl-1H-tetrazol-5-yl-thio) -raethyl-ceph-3-em- 4-carboxylic acid;
7- (2-Carboxy-2-thien-5 ^f -yl-acetamido) -3- (2-carbamoylmethyl-Ii3i ^ - thiadiazol-5-3 ^r l-thio) -meth3 ^r l-ceph-3-eni- ⁱ l-carboxylic acid; 7 - ^ / 2-carboxy-2- (4 ~ hydroxyphenyl) -acetamido7-3- (l-ß.2.rbamoyl- methyl-IH-tetrazol-5-yl-thio) methyl-ceph-3-eni-4-carboxylic acid; 7- / 2-carboxy-2 - (^ - methoxy-phenyl) -acetamido / - ^ - (l ~ carbamoyl- 7- / 2- (4-methyl-phenoxycarbonyl) -2-thien-3 '-yl-acetamido / "- ^ - (1-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3 -em- H- carboxylic acid and 7- (2-Carboxy-2-thien-3'-yl-acetamido) -5 ~ (5-carbamoyImethyl-1> 3 »4-triazol-5-yl-thio) -methyl-ceph-J-em- · ² ! - carboxylic acid. Other preferred compounds according to the invention are: 7- (D _J 2-Hydroxy-2-phenylacetamido) -5- (1-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-5-em-4-carboxylic acid and 7- (2-Methoxy-imino-2-fur-2 ^t -yl-acetamido) -5- (1-carbamoylmethyl 1H-tetrazol-5-yl-thio) -methyl-ceph - ^ - em- ^ l-carboxylic acid . 709823/1041 20. Derivatives according to claim 1, characterized in that the radical R has the general formula R ^U - C - CO.NH - il ο _u in which R is a lower alkyl radical and R is the 2- or 3-thienyl, phenyl or 4-hydroxyphenyl group means. 21. 7- (2-Methoxy-imino-2-fur-2'-yl-acetamido) -3- (1-carbamoylmethyl-1H-tet ■ razol-5-yl-thio) -methyl-ceph-3-em '- ^{^} ^ -carboxylic acid. 22. J- (D, 2-Hydroxy-2-phenyl-acetamido) -3- (1-carbarnoylmethyllH-tetra.zol-5-yl-thio) methyl-ceph-3-em-4-carboxylic acid. 23. Process for the preparation of the cephalosporin derivatives of General formula (I) according to claim 1, wherein the radical R is an acylamino radical, characterized in that one (A) a compound of the general formula (VI) or its am Nitrogen protected derivative ^(VI) CH ₂ .SY- (CH ₂ ) _n - 709823/1041 - 94- - in which the group -COpR ^ the carboxyl group or a blocked Is carboxyl group, m has the value 0 or 1, the dashed line is a bond in the 2- or 3-position 12th
and Y, n, R and R have the meanings given in claim 1, with an N-acylating derivative of an acid of the general formula R .OH, in which R ^ - is an organic acyl radical and reactive groups can be blocked, or (B) a compound of the general formula (X) (X) R ° - NH CH ₉ .SY- (CH ₀ ) -CON \ 2 CO ₂ R ^XR in which R is an acyl radical, reacts to form an imino bond on the 7-amino _{nitrogen atom, introduces a radical QR f} on the imino carbon atom into the compound obtained, where Q is an oxygen, sulfur or nitrogen atom and R _{f is} an alkyl radical having 1 to 12 carbon atoms or is an aralkyl radical having 5 to 14 carbon atoms, and here forms an imino ether, an iminothioether or an amidine, if Q is an oxygen, sulfur or nitrogen atom, the compound obtained with an N-acylating derivative of an acid of the general formula R ^q .0H converts and then treats the compound obtained with water or an alcohol, or 709823/1041 (C) a compound of the above general formula (X) with an acylating agent producing an acyl radical Pi, in which reactive residues can be blocked, in the presence of a trihydrocarbyl-silyl derivative of a sulfone_ amids, succinamids, phthalimides, cyanoacetamids, trifluoroacetamids, Berizamide, p-nitrobenzamide or a trichloroacetamide converts, and a compound of the general formula (XII) generated and then the radical R ° by a hydrogen atom replaced, and (D) after any of the above (A) to (C), if necessary performs one or more of the following stages: (i) converting the Δ "isomer to the desired one y / \ isomers, (ii) removal of the protecting group on the nitrogen atom, (iii) reducing the sulfoxide compound to the desired sulfide compound, (iv) Removal of the blocking residues on the carboxyl group or acyl side chain and / or (v) converting the compound obtained into a salt or an ester. 24. Process for the preparation of a cephalosporin derivative of the general formula (I) according to claim I, characterized in that a compound of the general formula (IX) 709823/1041 (ix) in which the group -COpR blocked the carboxyl group or one Is carboxyl group, m has the value O or 1, the dashed line denotes a bond in the 2- or J5-position and R denotes has the meaning given in claim 1, and wherein reactive groups can be protected with a thiol of the general Formula (TXA) HS-Y- (CH ₂ ) _n - CON (IXA) 1 2 in which Y, n, R and R have the meanings given in claim 1, and then, if necessary, one or performs several of the following stages: (i) converting the / \ -isomers into the desired (ii) removing the protecting group on the nitrogen atom, (iii) reducing the sulfoxide compound to the desired sulfide compound,
(iv) removing the blocking residues on the carboxyl group or the acyl side chain and / or (v) converting the compound obtained into a salt or an ester. 25. Process for the preparation of cephalosporin derivatives of 709823/1041 general formula (I) according to claim 1, in which R is the general Formula (XIII) has R ^U - CH - (XIII) CO
/ ι R ^y - N - COoZ in which R ^{y is} a hydrogen atom, the benzyl group or a lower alkyl radical, and Z is an organic radical with up to 20 carbon atoms or R ^y and Z together with the nitrogen atom and the carbon atom to which they are bonded form a 5-, 6 - Form or Y-membered ring, and R ^{u represent} a hydrogen atom or an alkyl, cycloalkyl, alkenyl, aryl or a heterocyclic radical, characterized in that a compound of the general formula (XIV) or its derivative protected on the nitrogen atom ^m (XIV) R ^U -CH-CO.HH S. CH ₂ -SY- (CH ₂ J _n -CON in which the group -COpR ^{x is} the carboxyl group or a blocked carboxyl group, m has the value O or 1, the dashed line denotes a bond in the 2- or ^ -position and Y, n, 1 2
R and R have the meanings given in claim 1, with an N-acylating derivative of an acid of the general formula (XV). 709823/1041 CO ₂ H - it- CO.Z ^(XV) implements and then, if necessary, one or more of the performs the following stages: (i) converting the / _S. Isomers into the desired Δ isomer, (ii) removing the protective group on the nitrogen atom, (iii) reducing the sulfoxide compound to the desired sulfide compound,
(Iv) removing the blocking residues on the carboxyl group or acyl side chain and / or (v) converting the compound obtained into a salt or an ester. 26. A process for the preparation of a cephalosporin derivative of the general formula (I) according to claim 1, in which R is a radical of the general formula (XIII) R ^U - CH - CO.NH - I (XIII) in which R ^{u is} a hydrogen atom or an alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl or heterocyclic radical and X is the carboxyl group, characterized in that a compound of the general formula (I) in which R is a radical of the general formula (XIII), where X represents an esterified carboxyl group, hydrolyzed under alkaline conditions. 27. Process for the preparation of a cephalosporin derivative of the general formula (I) according to Claim 1, in which R is a radical 709823/1041 2853621 AS of the general formula (XVl) R ^U - CH - CO.NH a V / ater toff ^u atom in R, or an alkyl, cycloalkyl, Alken'yl-, cycloalkenyl, aryl or a heterocyclic group and R represents a Estergruppe, characterized in that a compound of general formula ( XVII) or their reactive esterifiable derivative (XVII) R ^U -CH-CO.NH CH ₂ .SY- (CH ₂ J _n - CON in which the group -COpR ³⁵ "is the carboxyl group or a blocked carboxyl group, m has the value O or 1, the dashed line denotes a bond in the 2- or ^ -position and Y, n, 1 ?
R and R ~ have the meanings given in claim 1, esterified with an esterifying derivative of an acid of the general formula R OH and then, if necessary, carry out one or more of the following steps: (i) converting the £ \ -isomers into the desired Z \ - isomers, (ii) removing the protecting group on the nitrogen atom, (iii) reducing the SuIfoxidverbindung the desired sulfide compound,
(iv) Removal of the blocking residues on the carboxyl group 709823/1041 2653821 4h or the acyl side chain and / or (v) converting the compound obtained into a salt or an ester. 28. Medicament, characterized by a content of a cephalosporin derivative of the general formula (I) according to the claims 1 to 27, optionally together with a pharmacologically acceptable carrier material and / or diluent and / or auxiliaries and / or further active ingredients. 29. Medicament according to claim 28, characterized by an additional content of a compound of the general formula (XVIII) O. CH.CH "A \ / (XVIII) or their pharmacologically acceptable salt or ester. 30. Medicament according to claim 29, characterized by a Clavulanic acid content of formula (XIX) (XIX) or their pharmacologically acceptable salt or ester. 709823/1041 4> 31. Intermediate products of the general formula (VI) (VI) (CH ₂ ) _n - , χ in which the group -COpR ^{551 is} the carboxyl group or a blocked carboxyl group, m has the value O or 1, the dashed line denotes a bond in the 2- or 3-position and Y, n, 1 2
R - and R have the meanings given in claim 1. Intermediate products according to claim 3I, characterized in that m has the value O, the group -COpR ^{x is} the carboxyl group and the dashed line denotes a double bond in the 3 »position. 33 · Intermediate products according to Claims 31 and 32, thereby 12th
characterized in that R and R are hydrogen atoms. 3 ^. Intermediate products according to at least one of Claims 3I to 33 * characterized in that η has the value 1. 35 Intermediate products according to at least one of Claims 3I to y * t, characterized in that Y is the tetrazolyl group, 36. 7-Amino-'3- (1-carbamoylmethyl-1H-tetrazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid. 709823/1041 - 99 - Λ * 37 7-Amino-3- (2-earbamoyl-1,3,4-oxadiazol-5-yl-thio) -Kiethyl- ceph-3-em ~ 4-carboxylic acid. 38. 7-Araino-3- (1-N-methyl-carbamoylmethyl-1H-tetrazol-5-ylthio) -methyl-ceph-3 ~ em-4-carboxylic acid. 39. 7-Amino-3- (l ** N, N-dimethyl-carbamoylffiethyl-lH-tetrazol-5-yl-thio) -methyl-cepl-vO-em ^ -carboxylic acid. 40. 7-Amino-3- (2-carbarnoylraethyl-1,3,4-thiadiazol-5-yl-thio) -methyl-ceph-3-em-4-carboxylic acid. 41. Thiol intermediate compound of the general formula (IXA) N.CO. (CH _O ) "- Y - SH ₂ / (ΏΑ) 1 2 in which R, R, η and Y have the meanings given in claim 1 own. 42. 5-mercapto-1,3,4-oxadiazol-2-yl-acetamide. 43. 5-Mercapto-1,3,4-oxadiazol-2-yl-carboxamide. 44. 5-mercapto-IH-tetrazol-1-yl-acetamide. 45. 5-mercapto-1,3,4-thiadiazol-2-y1-acetamide. 46. N-Methyl-S-mercapto-1H-tetrazol-1-yl-acetamide. 47. NiN-dimethyl-S-mercapto-1H-tetrazol-1-yl-acetamide. 48. 5-mercapto-1,3,4-triazol-2-yl-acetamide. 709823/1041