DD263064A5 - PROCESS FOR THE PREPARATION OF NEW CEPHALOSPORINES - Google Patents

Abstract

The invention relates to a process for the preparation of new cephalosporins for use as medicaments in human and veterinary medicine and as animal feed. The aim of the invention is the provision of new cephalosporins with strong and broad antimicrobial activity against Gram-negative and Gram-positive bacteria. According to the invention, new cephalosporins of the formula (I) are prepared in which, for example: R 1 is straight-chain or branched, saturated or unsaturated, optionally substituted by carboxy-substituted alkyl having up to 6 C atoms, R 2 is straight-chain or branched alkyl having up to 6 C atoms , which is optionally substituted by hydroxy, carboxy, alkoxy, alkoxycarbonyl each having up to 3 C atoms u. a. Formula (I)

Description

-A-

 o x "i η ι

Process for the preparation of new cephalosporins

Field of application of the invention

The invention relates to a process for the preparation of new cephalosporins and their use as medicaments, in particular in antibacterial therapy. .

Characteristic of the known technical solutions

Cephalosporins bearing a 2- (2-aminothiazol-4-yl) -2-alkoxyiminoacetic acid residue as the acyl side chain and a pyridiniummethyl radical in the 3-position are known from EP-PS 64 740. .

Object of the invention

The aim of the invention is to provide novel compounds with strong and broad antimicrobial efficacy, especially against Gram-negative and Gram-positive bacteria. , ,

Explanation of the essence of the invention

The object of the invention is to develop new cephalophores

218.86-368922

-Ia-

rine with the desired properties and processes for their preparation.

According to the invention, new cephalosporins of the general formula (I)

^ r- S

N.

(I)

⁰ coc ©

made in which

2 63

R ¹ - represents straight-chain or branched, saturated or unsaturated, optionally substituted by carboxy alkyl having up to 6 C atoms,

R - represents straight-chain or branched alkyl having up to 6 C atoms, which is optionally substituted by hydroxyl, carboxy, alkoxy, alkoxycarbonyl having in each case up to 3 C atoms, halogen or cyano,

- the remainder of * _v s, if applicable, to the

Ringmethylene groups substituted groups

or ^N - '

r> 2

/ ^N NR * stands.

R ³ - represents straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 10 C atoms, which is optionally substituted

by -OH, CHO, OCONH ₂ , NHCONH ₂ ,

- By the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , where

R ⁵ - for hydrogen, alkyl with up to 8 C-

Atoms, aryl having 6 to 10 C atoms, or C ₇ -C ₁₄ aralkyl,

by halogen, cyano, SO3H, 35

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2 630 A A

- through the groups -N

"R ^{6 V} >'R ⁶ ""

-SO ₂ -N ^) or -CON. /

• where . ^J

R and R are independently hydrogen or together or individually Cj-C ₆ -AlkVl, C ₂ -C ₆ alkenyl or phenyl, or wherein the

Substituents R ^6, R ⁷ optionally mi-t the nitrogen atom a 5- to 7-membered ring, which can contain further hetero atoms oxygen, sulfur and / or 1-2 nitrogen atoms and optionally substituted by C ^ -C ^ -Alkyl, or - by the group -SO ₂ -Y or -O-Y, wherein Y - is Cj-CQ-alkyl, aryl having 6 to 10 C-atoms or - is C ₇ -C ₁₄ -aralkyl .

and

R * a) represents straight-chain, branched or cyclic saturated or unsaturated alkyl with bis

to 10 carbon atoms, which is substituted at least once is.t - by OH, CHO, OCONH ₂ , -NHCONH ₂ ,

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- by the groups COOR ⁵ . NHCOR ⁵ , COR ⁵ ,

in which

R ⁵ - for hydrogen. Alkyl having up to 8 carbon atoms, aryl having 6 to 10 carbon atoms or C ₇ -C ₁₄ -aralkyl,

'ο '.' '

by halogen, cyano, .SO3H,

R ⁶ N / *

- through the groups -N /.

_R 6s p6-.

- SO _? -N j or -CON

V '' ^X r7 - '"

in which

R ⁶ and R 'independently of one another represent hydrogen or together or individually represent C 1 -C 4 -alkyl, C ₂ -C 18 -alkenyl or phenyl, or where the substituents R ⁶ , R' optionally together with the nitrogen atom have a 5-7th -glie-

form a ring containing, as further heteroatoms, an oxygen, sulfur and / or 1 to 2 nitrogen atom and which is optionally substituted by C 1 -C 4 -alkyl,

or

by the group -SO ₂ -Y or -O-Y where

Y - for C ₁ -C ₈ -alkyl, aryl having 6 to 10 carbon atoms or

- represents C ₇ -C ₁₄ -aralkyl,

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OO ¹ J r) //

b) CHO, SO ₃ H,

c) stands for COOR ^, where R ^ is the one given above

Meaning, or d) represents the group -ZR ⁸ ,

in which

v Z - is C or -SO ₅ - and

ι / ^ά

R ° _ fyj- straight-chain, branched or

is cyclic saturated or unsaturated alkyl having up to 8 carbon atoms, optionally substituted by halogen, hydroxy, cyano, alkoxy, alkylthio each having up to 6 C atoms, aryloxy, arylthio with up to

10 C atoms, carboxy, C ^ -C ^ alkoxycarbonyl, -OCONH ₂ , -NHCONH ₂ , SO 3 H or

-Ni, -CO-N; or -SO ₂ -N

R ⁶ χ

or -SO ₂ -N 7 /

is substituted. where R ⁶ , R 'have the abovementioned meaning, - for aryl having 6 to 10 C atoms

- for C ₇ -C ₁₄ aralkyl

for heterocyclyl or

R ⁶ v

- for the group -N, where ^V r7 <'

R ^, R 'have the abovementioned meaning.

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-4, υ ο - 6 -

O 5 If the radicals R ' Q _y - ^ _R * $. _s

^ N NR ³ , ^ N NR *

substituted on the ring methylene groups, then by up to four, preferably up to two identical or less than 10 different substituents such as:

a> straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 10 C atoms, which is optionally substituted again 15

by -OH, CHO, -OCONH ₂ , -NHCONH ₂

- By the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , where

R ⁵ - for hydrogen, alkyl up to 8

20 C atoms, aryl with 6 to 10 carbon atoms

or C7-Ci ₄ is aralkyl,

- by halogen, cyano, SO3H

R ⁶

25 - through the groups -NJ

-SO ₂ -N. · ^ Or -CO-N) 30 N ^'X

in which

R and R are each independently of one another water or together or individually for

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C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl or phenyl

or wherein the substituents R ⁶ . R '' optionally with the nitrogen atom form a 5 * * to 7-membered ring containing as further heteroatoms an oxygen, sulfur and / or 1-2 nitrogen atoms

and optionally substituted by Cj-C ^ -alkyl, or

by the group -SO ₂ -Y or -O-Y where

Y - for C ₁ -C ₆ -alkyl, aryl having 6 to 10 C-

Atoms or

- is C ₇ -C ₁₄ -aralkyl or 20

b) the group -Z-R ^, where

Z - represents C or -SO ₂ - and II

R® - represents straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 6 C atoms, which is optionally substituted by halogen, hydroxy, cyano, alkoxy, alkylthio

in each case 6 C atoms, aryloxy, arylthio (6-10 C atoms), carboxy, Cj-C ₆ -alkoxycarbonyl, -OCONH ₂ -, -NHCONH ₂ , -SO 3 H,

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2 63 04-4

-N ι, -CON. ι or ^X R ^ r7 /

- SOp-N

A

is substituted, wherein R, R have the meaning given above

- for aryl having 6 to 10 carbon atoms

- for C ₇ -Cj ₄ aralkyl

for heterocyclyl or 20

for the group -N.

A

where R, R again have the abovementioned meaning.

c) -OH, CHO, OCONH ₂ , NHCONH ₂ ,

d) the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , 30

where R ^{5 is} hydrogen, alkyl having up to 8 C atoms,

Aryl having 6 to 10 C atoms, or C ₇ -C ₁₄ aralkyl, 35

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e) halogen, cyano, SO3H

f) the group -H. where

r6 and R ^{7 have} the abovementioned meaning, g.) the group -O-Y, where

Y - for C ₁ -C ₆ -AlKyI, aryl having 6 to 10 C atoms or

- represents C ₇ -C ₁₄ -aralkyl.

Preferred compounds of general formula I are those in which 2.0

R * represents straight-chain, branched, saturated or unsaturated, optionally substituted by carboxy alkyl having up to 4 carbon atoms,

r 2 -fUr is straight-chain or branched alkyl having up to 4 C atoms, which is optionally substituted by hydroxyl, carboxy, methoxy, methoxycarbonyl, fluorine, chlorine or bromine,

R ^ ® - >> ^ ¹ "^^ ^e SjeSJebenenfalls sub-

^ - \ situated

V ** '- \ \ vti-ν

Radicals _NN _ _R 3 _or V NR * is.

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2 6 3 υ α

in which

R- represents straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 8 C atoms, which is optionally substituted by OH, CHO, OCONH ₂ , NHCONH ₂

- by the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , where R ⁵ - is hydrogen, alkyl having up to 6 C atoms, phenyl or benzyl, - by fluorine, chlorine, bromine or SO 3 H,

R ⁶ v R ⁶ \

- η ι,

- By the groups - ηι , -SO ₂ -N ^ ^r6x

or

in which

R ⁶ and R ⁴ independently of one another represent hydrogen, C 1 -C 3 -alkyl or phenyl or where the substituents R ⁶ , R 'optionally together with the nitrogen atom form a 5- or 6-membered ring which, as further heteroatoms, forms an oxygen, Sulfur and / or 1-2 nitrogen atoms and optionally substituted by C ^ -C ₂ ~ alkyl, or - by the group -SO ₂ -Y or -O-Y, wherein

Y - represents C 1 -C 4 -alkyl, phenyl or benzyl,

and

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ö3 ö s 4

- 11 -

R ⁴ a) represents straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 8 C atoms, which is substituted at least once

by OH, CHO, OCONH ₂ , NHCONH ₂

- By the groups COOR ⁵ , NHCOR ⁵ , COR ⁵

in which

R ^{5 represents} hydrogen, alkyl having up to 6 C atoms, phenyl or benzyl,

by fluorine, chlorine, bromine or SO 3 H 15

- through the groups -N! , -SO ₂ -N ',

R / R- '

CON

where Έ and R 'are as defined above

by the group -SO ₂ -Y or -O-Y

in which

Y - is C ₁ -C ₆ -Alkyl, phenyl or benzyl, or

b) is CHO or SO3H,

c) stands for COOR ⁵ , where

R ^{5 has} the meaning given above, or

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d) the group -ZR ⁸ , wherein Z - is C or -SOg- and

R ⁸ - represents straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 6 C atoms, which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, carboxy, alkoxy or, alkylthio having up to 3 C atoms, phenyloxy , Phenylthio, alkoxycarbonyl with up to 3

C atoms, through

OCONHo, -NI, -CO-N ) 20

or -SO ₂ -N /, is substituted,

where R ⁶ and R 'are as defined above

to have,

- for phenyl,

for benzyl,

for pyridyl, furyl, thienyl, thiazolyl,

Pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, oxazolyl, morpholinyl, piperidinyl, imidazolyl, pyrazolyl, thiazolyl or piperazinyl,

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4 » \ JO 'J

or R ⁶ \

for the group -N ', where

^{r7 //}

R ^ and R "have the meaning given above

 10

Particularly preferred compounds of the formula I are those in which

* R ¹ - is methyl, ethyl, allyl or 1-carboxy-1-methylethyl,

R ² - is methyl, ethyl, 2-hydroxyethyl or carboxymethyl,

R ^a ff) the radical \>-> s for the optionally substituted

^ ^ -> groups

ff) & -al

stands in which

R ^ - for straight-chain, branched or cyclic, saturated or unsaturated alkyl with bis

to 6 carbon atoms, which is optionally substituted

by OH, CHO, OCONH ₂ , NHCONH ₂

- By the groups COOR ⁵ , NHCOR ⁵ , or COR ⁵ , where

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R ⁵ - for hydrogen, alkyl with up to 4 C

Atoms, phenyl or benzyl, by fluorine, chlorine or SO3H,

- by the groups -N 1, SO ₂ -N

Rl.- '

or CON]

wherein R °, R 'independently of one another represent hydrogen, methyl, ethyl, phenyl or form a ring with the nitrogen atom, such as pyrrolidine, piperazine, piperidine, morpholine or thiomorpholine, or

- by the group -SC ^ -Y or -O-Y, where

Y represents alkyl (to C ₄ ), phenyl or benzyl,

and

R a) is straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 6 C atoms, which is substituted at least once

by OH, CHO, OCONH ₂ , NHCONH ₂

- by the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ being

R ^{5 is} hydrogen, alkyl (C ₄ -alkyl, phenyl or benzyl,

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by fluorine, chlorine or SO3H

through the groups -N j, -SO 2 -N

or CON '

R? '

in which

R ^ and R 'have the meaning given above

ben or

- by the group -SO ₂ -Y or -O-Y, where

Y - represents alkyl having up to 4 C atoms, phenyl or benzyl,

or

b) is CHO or SO3H,

c) COOR ⁵ , where Br has the meaning given above, or

d) represents the group -ZR ⁸ , where

Z - stands for C or -SO? - and

Il

R ⁸ - for straight-chain or branched, saturated or unsaturated alkyl with

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UJ Ü

up to 4 C-atoms, the given

if by chlorine, fluorine, hydroxy, carboxy, OCONH ₂ , NHCONH ₂ , SO 3 H,

-NJ -CO-N! or SO ₂ -NR? ' ⁷ R ^ ^y

is substituted, wherein R ^ and R ^ have the abovementioned meaning, - for phenyl,

for benzyl,

- is pyridyl, furyl, thienyl, thiazolyl, isoxazolyl, imidazolyl, pyrazolyl or

^ ^ R6

- stands for the group -N}, where

R, R 'again have the abovementioned meaning. 25

If the leftovers

_N _ _R ³ V NR ⁴

are then substituted in both the preferred and the most preferred compounds of general formula I by a substituent such as:

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2 6 3 O A j

- 17 -

a) straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 6 C atoms, which is optionally substituted again

by OH, CHO, OCONH ₂ , NHCONH ₂

- by the group COOR ⁵ , NHCOR ⁵ , COR ⁵ where

R ⁵ - for hydrogen, alkyl with up to 4 C atoms. Phenyl or benzyl,

- by fluorine, chlorine, SO3H

R ⁶ ^ s R ⁶ -

- by the group -N 1, SO ₂ -N '

or CON ^ ι, ^^ rZ ''

wherein R and R are independently hydrogen, methyl, ethyl, phenyl or wherein R ⁶ , R 'together with the nitrogen atom form a ring such as pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, or - by the group -SO ₂ -Y or 0-Y, where Y is - for alkyl of up to 4 carbon atoms, phenyl or

Benzyl stands, 30

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 2 63 OS

b) the group -ZR ⁸ where Z - is C or -SO ₂ - and

R® - represents straight-chain, branched, saturated or unsaturated alkyl having up to 4 C atoms, which is optionally substituted by fluorine, chlorine, hydroxyl, carboxy, OCONH ₂ , NHCONH ₂ , SO 3 H, R ⁶ R ⁶ R ⁶

-NJ, -CO-N \ or SO ₂ -N ) \ 7 / ^^ v _e 7, / ^ 1 = 7 '

substituted, wherein R ⁶ , R ^{7 have} the meaning given above, 20

- for phenyl,

for benzyl,

for pyridyl, thienyl, furyl, thiazolyl,

Oxazolyl, isoxazolyl, imidazolyl, pyrimidyl,

Morpholinyl, piperidinyl or

- stands for the group -N ', where

R ⁶ , R ⁷ again have the abovementioned meaning 30

to have,

c) OH, CHO, OCONH ₂ , NHCONH ₂ ,

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d> the groups COOP ⁵ , NHCOR ⁵ , COR ⁵ , where R has the abovementioned meaning

e) fluorine, chlorine, SO3H, 10

f) the group -N j

^ r ⁷ - '

where R * ¹ , R ⁷ in turn have the abovementioned meaning

WU

have, or

g) the group -0-Y where

Y- is alkyl of up to 4 C atoms, phenyl or benzyl.

Of the compounds of the formula I according to the invention, a plurality of isomers can be formed which

are biotactically effective and can be separated by chromatography or crystallization as needed.

The compounds of general formula I can thereby

that compounds of general formula 30

* OH ^N

S ₁

OR ¹

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2 * 3 US4

wherein

R has the meaning given above,

in which the amino group may be protected or unprotected, after activation of the carboxyl group by conversion into a mixed anhydride, for example with ethyl chloroformate or methanesulfonyl chloride by conversion into the acid halide or by conversion into an activated ester with, for example, N-hydroxybenzotriazole and dicyclohexylcarbodiimide, with compounds of the general Formula III,

J-

ο-I

COO ~ ^IU

R ² ® ^ - ^

in which - * * ν , which has the abovementioned meaning,

are reacted, then optionally cleaved protecting groups and the desired salts or salts of the free acids are prepared.

For the coupling of carboxylic acids <II) to B-lactams of

A large number of methods known from cephalosporin or penicillin chemistry can be used in formula (III). It has proven advantageous to use the carboxylic acids of the general formula (II) without amine.

Activate protection group and then with the fJ-Lactairen 35

of formula (III) which have been solubilized as salts with an amine.

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The activation with sulfonic acid derivatives of the formula V to give anhydrides of the formula IV is particularly advantageous

H-

(II)

OH

OR ¹

H ₁ N

0-Sun ₂ -R

OR ¹

in which

T- is the radical R ^ -SC ^ -O- or halogen, and

R ⁹ - is alkyl having up to 10 carbon atoms, which is optionally substituted by fluorine, chlorine, cyano, phenyl, alkoxycarbonyl, alkoxy or alkyl each having up to 4 carbon atoms, or - is phenyl which is optionally substituted is by fluorine, chlorine, bromine, cyano, alkyl, alkoxy, alkylthio, alkoxycarbonyl each having up to 4 carbon atoms, nitro, Trifluormethyi or phenyl.

When R 1 is substituted, preferably 1 to 3 substituents, more preferably those mentioned, are present.

Most preferably, R represents a methyl or p-tolyl radical.

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2 6 3'O j; j

The mixed anhydrides of formula (IV) are prepared by dissolving the carboxylic acids of formula (II) and 1-1.4 equivalents of an amine in a solvent and reacting with 1 to 1.2 equivalents of a derivative of the formula (V) leaves.

Suitable solvents are all solvents which are stable under the reaction conditions, e.g. Diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloroform or dimethylformamide.

Suitable amines are tertiary amines such as e.g. Triethylamine or tributylamine, but also sterically hindered secondary amines such as e.g. Diisopropylamine, or mixtures of these amines.

,

The reactions can be carried out at temperatures between -80 * C and room temperature. Advantageously, the activation with CI-SO2CH3, in dimethylformamide at -40 * C to -60 * C within 0.2 to 24 hours, preferably 0.5 to 5 hours performed.

To dissolve the compounds of the formula (III), the solvents or water mentioned in the preparation of the compounds of the formula (IV) and also the amines mentioned there may be used as the base.

Activation of the carboxylic acids of the general formula (II) by conversion into an activated ester with, for example, N-hydroxysuccinimide and dicyclohexylcarbodiimide or 1-hydroxybenzotriazole and dicyclohexylcarbodiimide is also particularly advantageous.

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Suitable solvents are all solvents which are also suitable for the preparation of anhydrides of the formula (IV).

The reactions can be carried out at temperatures between -30 * C and + 100'C. Advantageously, activated with 1-hydroxybenzotriazole and dicyclohexylcarbodiimide in dimethylformamide at room temperature for 2 to 6 hours, then filtered with suction from the precipitated Dicyclohexylharnstoff and reacted with a compound of formula (III) in the form of a solution of its amine salt within 2 to 24 hours. To dissolve the compounds of the formula (III) it is possible to use the solvents mentioned in the preparation of the compounds of the formula (IV) and also the amines used there as the base. 20

The compounds of the formula (III) are obtained by cleaving the amine protecting group R ¹⁰ from compounds of the formula (VI).

R ¹⁰ -NH

NX (III)

VI

In this case, R 1 can be either an acid-labile protective group such as the t-butyloxycarbonyl group or, advantageously, an enzymatically removable protective group. Preferred enzymatically cleavable protecting groups are phenylacetyl or 2-thienylacetyl.

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2 63 O'A J!

10 15

The enzymatic cleavage is carried out at room temperature in water or a mixture of water and a polar organic solvent, e.g. Acetonitrile or tetrahydrofuran, with immobilized penicillin G acylase at pH 7-8, preferably at pH 7.5-7.8.

During enzymatic cleavage, the pH is adjusted by adding a base such as lithium hydroxide, sodium hydroxide, potassium hydroxide or a tert. Amines such as e.g. Triethylamine, tripropylamine, tributylamine or pyridine, kept constant.

20

The compounds of the formula (VI) can be prepared from esters of the formula (VII) via intermediate compounds of the formula (VIII).

COOR (VII)

ι ι

30

35

COOH

(VIII)

-> vi

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In the esters of formula (VII) X represents a leaving group such as mesylate, tosylate, brosylate, triflate, nonaflate, iodide, bromide, chloride and R ** an acid protecting group common in cephalosporin chemistry, preferably an acid-cleavable protecting group such as e.g. Benzhydryi, 4-methoxydiphenylmethyl, t-butyl.

The compounds of the formula (VII) are converted by cleavage of the acid protecting group R ** into the reactive free acids of the formula (VIII). In the preferred

acid labile protecting groups R **, the protecting group is cleaved off in an organic solvent. Preferably, the removal of the benzhydryl protecting group in methylene chloride with Tr ifluoressigsäure possibly with the addition of an alkoxybenzene, preferably methoxybenzene. The cleavage takes place at -20 * C to +30 "C, preferably at 0 * C within 5 minutes to one hour, preferably within 20 minutes.

The acid of the formula (VIII) can be isolated after removal of the protective group. Advantageously, however, not isolated, but reacted directly and without purification to compounds of formula (VI). This is the

in the reaction (VII)> (VIII) resulting solution

of (VIII) gently concentrated in vacuo. The residual crude acid is taken up in an organic solvent, preferably in tetrahydrofuran, and treated with from 2 to 50 equivalents, preferably from 5 to 20 equivalents, of a tert. Amines of the formula

R ² -NX,

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2 6 3 O y $ 4

wherein R ^ -N X has the abovementioned meaning. converted into compounds of formula (VI).

The reaction is carried out at temperatures between -20 * C and 40 ^# C, preferably at 25 * C, within 10 minutes to 2 hours, preferably within 30 minutes. The product can be precipitated by the addition of diethyl ether after completion of the reaction. The crude product thus obtained can be purified on a resin such as Diaion HP 20 or XAD 7. It is also advantageously possible to further react the crude product directly to compounds of the formula (III).

The compounds of the formula (VI) can alternatively also be prepared from acids of the formula (IX) in which R has the abovementioned meaning and R * represents an optionally substituted alkyl or aryl, such as methyl, ethyl, propyl, chloromethyl, dichloromethyl , Trichloromethyl, trifluoromethyl, phenyl. Most preferably, R 1 represents a methyl group.

ο ι

COOH

(IX)

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 2 6 3

- 27 -

R ¹⁰ -NH

O Il

O-C-R

CH ₃ COOSi -CH ₃

1

(X)

R ¹⁰ -NH

N X

, N

(VI)

(XI)

COOSi-CH ₃ ^X CH ₃

The starting compounds of formula (IX) are suspended in a suitable organic solvent and solubilized by silylation to silyl ester X. Particularly suitable organic solvents are chloroform, methylene chloride, dichloroethane. The silylation is carried out using a conventional silylating agent such as trimethylchlorosilane (TMCS), hexamethyldisilazane (HMDS), N, O-bis- (trimethylsilyl) acetamide (BSA), N, O-

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Bis (trimethylsilyl) trifluoroacetamide (BSTFA), N-methyl-N-trimethylsilylacetamide (MSA), N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA), 1,3-bis (trimethylsilyl) urea or trimethylsilyl trifluoromethanesulfonate

 10

In this case, several silylating agents can be used in a mixture.

The silylation is carried out at -30 * C to * 70 * C, preferably at -10'C to + 10 * C, within 5 minutes to 30 minutes. Advantageously, an up to tenfold excess of the Si IiIierungsmittels is used, preferably a two to five times excess.

The resulting solution of the trimethylsilyl ester of formula (X) is at -40 * C to + 30'C, preferably with three to four equivalents of a trialkylsilyl iodide, more preferably TrimethylsiIyI iodide, within 15 minutes to 2 hours, preferably within 30 minutes to 1 hour, converted to compounds of formula (XI).

The compounds of the formula XI are advantageously not isolated, but directly without purification with amines

R ²

^ NX ^to the compounds of formula VI

implemented

 35

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4

The compounds of the general formula I can alternatively also be prepared by "compounds of the formula (XII)

Ί1 """^ l Γ Λ _12

(XII)

H ₂ N- ^ Jl "Ν. y -, ν COOH 11 0 R ¹² TN ^ OR ¹ sbenaena might »Η Β where R ^ - and R ¹² 'the ι

analogously as described above for the reaction of compounds of the formula VI, directly without isolation of the intermediates after silylation and conversion into the iodide with amines

^ H χ to compounds of the formula I.

be implemented.

The compounds according to the invention have a strong and broad antimicrobial activity, especially against Gram-negative and Gram-positive bacteria. These properties enable their use as chemotherapeutic agents in medicine.

The compounds of the invention are particularly effective against bacteria and bacteria-like microorganisms. They are therefore particularly good for prophylaxis and

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Chemotherapy of local and systemic infections in human and veterinary medicine, which are caused by these pathogens.

For example, local and / or systemic diseases caused and / or prevented by the following pathogens or by mixtures of the following pathogens can be treated and / or prevented:

Micrococcaceae, such as staphylococci, e.g. Staphylococcus aureus, Staph. epidermidis, Staph, aerogenes and Graffkya tetragena (Staph. = Staphylococcus);

Lactobacteriaceae such as streptococci, e.g. Streptococcus pyogenes, or β-hemolytic streptococci, non-hemolytic streptococci, St. viridans, Str. Faecalis (enterococci) and Dipolococcus pneumoniae (pneumococci) CStr. = Streptococcus);

Enterobacteriaceae, such as Escherichiae bacteria of the Coli group: Escherichia bacteria, e.g. Escherichia coli, Enterobacter bacteria, e.g. E-aerogenes, Ε-cloacae, Klebsiella bacteria, e.g. K. pneumoniae, Serratia, e.g. Serratia marcescens (E. = Enterobacter) (K. = Klebsieila), Proteae bacteria of the Proteus group, e.g. Proteus vulgaris, Pr. Morganii, Pr. Rettgeri, Pr. Mitabilis, (Pr. = Proteus);

Pseudomonadaceae, such as Pseudomonas bacteria, e.g. Pseudomonas aeruginosa, (Ps. = Pseudomonas); 35

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Bacteroidaceae, such as Bacteroides bacteria. e.g. Bacteroides fragilis (B. = Bacteroides).

The above enumeration of pathogens is merely exemplary and by no means restrictive, 10

As diseases which can be prevented, ameliorated and / or cured by the compounds according to the invention, mention may be made, for example:

Respiratory and pharyngeal diseases; Otitis, pharyngitis; Pneumonia; Peritonitis, pyelonephritis; cystitis; endocarditis; Systemic infections; Bronchitis, arthritis, local infections.

The present invention includes pharmaceutical preparations which, in addition to non-toxic, inert pharmaceutically suitable excipients, contain one or more compounds according to the invention or which consist of one or more active substances according to the invention and processes for the preparation of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations are in the form of individual parts, e.g. Tablets, dragees, capsules, pills, suppositories and ampoules, the active substance content of which corresponds to a fraction or a multiple of a single dose. The dosage units may be e.g. 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose.

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A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to one whole, one half or one third or one quarter of a daily dose.

Non-toxic inert pharmaceutically suitable excipients are solid, semisolid or liquid diluents, fillers and formulation auxiliaries of any kind.

Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tablets, dragees, capsules, pills and granules may contain the active ingredient (s) in addition to the usual excipients such as (a) fillers and extenders, e.g. Starches, lactose, cane sugar, glucose, mannitol and silica.

<b> binders, e.g. Carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone <c> humectants, e.g. Glycerin, (d) disintegrants, e.g. Agar-agar, calcium carbonate and sodium carbonate, (e) solution retarder, e.g. Paraffin and <f) absorption enhancer, e.g. quaternary ammonium compounds, <g> wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h)

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€ - ^ λ

° J ° 6 4

- 33 -

Adsorbent. e.g. Kaolin and bentonite; and (i) lubricants, e.g. Talc, calcium or magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under <a> to (i).

The tablets, dragees, capsules, pills and granules may be provided with the usual optional opacifying agents contained coatings and shells and also be composed so that they deliver the active substance or only optionally or preferably delayed in a particular part of the intestinal tract, vobei as embedding masses eg Polymer substances and waxes can be used.

The active substance (s) may optionally also be present in microencapsulated form with one or more of the excipients specified above.

Suppositories may contain in addition to the active substance or the usual water-soluble or water-insoluble excipients, for example polyethylene glycols, fats, eg cocoa fat and higher esters (eg C ₁₄ alcohol with C ^ fatty acid) or mixtures of these substances.

For parenteral administration, the solutions may also be in sterile and blood isotonic form.

The therapeutically active compounds should preferably be present in the abovementioned pharmaceutical preparations in a concentration of about 0.1 to 99.5, preferably of about 0.5 to 95 wt .- * of the total mixture.

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• 5 6 3 O a 4

The pharmaceutical preparations listed above may contain, in addition to the compounds according to the invention, other active pharmaceutical ingredients.

The preparation of the abovementioned pharmaceutical preparations is carried out in a customary manner by known methods, e.g. by mixing the active substance (s) with the excipient (s).

The active substances or the pharmaceutical preparations can be administered locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally or parenterally, such as intravenously or intramuscularly.

In general, it has proven to be advantageous both in human and in veterinary medicine, the active ingredient (s) according to the invention in total amounts of about 1 to about 1,000, preferably 1 to 200 mg / kg body weight every 24 hours, optionally in the form of several individual doses to achieve the desired results. A single dose contains the active substance (s) according to the invention, preferably in amounts of about 1 to 250, in particular 1 to 60 mg / kg of body weight. However, it may be necessary to deviate from the stated dosages, depending on the type and body weight of the object to be treated, the nature and severity of the disease, the nature and preparation and the application of the drug and the period or Interval within which the administration takes place. That's the way it works

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2 oo ₆

be sufficient in some cases, with less than the above-mentioned amount of active ingredient, while in other cases, the above-mentioned amount of active ingredient must be exceeded. The determination of the respectively required optimal dosage and mode of administration of the active ingredients can be done easily by any specialist due to his expertise.

The compounds of the invention may be used for the purpose of extending the spectrum of action with another β-lactam antibiotic or with aminoglycoside antibiotics, such as e.g. Gentamicin, sisomicin, kanamicin, amikacin or tobramycin are combined.

The active compounds of the invention can be used in all areas of animal breeding as a means of promoting and accelerating growth and improving feed utilization in healthy and diseased animals.

The effectiveness of the active ingredients is largely independent of the species and sex of the animals. The active ingredients prove particularly valuable in the rearing and keeping of young and fattening animals. As animals, where the active ingredients can be used to promote and accelerate growth and improve feed conversion. For example, the following farm animals and animals called:

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k ό JVA 4 - 36 -

Warm-blooded animals, cattle, pigs, horses, sheep, goats, cats, dogs, rabbits; Fur animals, e.g. Mink and chinchilla; Poultry, e.g. Chickens, geese, ducks, turkeys, pigeons, parrots and canaries, and cold-blooded animals such as fish, e.g. Carp, and reptiles, e.g. Snakes.

The amounts of the active ingredients that are administered to the animals to achieve the desired effect, can be largely varied because of the favorable properties of the active ingredients. It is preferably about 0.01 to 50, especially 0.1 to 10 mg / kg of body weight per day. The duration of administration can be from a few hours or days to several years.

The amount of active substance to be administered and the corresponding duration of administration depends in particular on the type, sex, state of health and the type of keeping and feeding of the animals and can be easily determined by any person skilled in the art.

The active ingredients are administered to the animals by the usual methods. The mode of administration depends in particular on the type, behavior and state of health of the animals. Thus, the administration can be made once or several times daily at regular or irregular intervals oral or parental. For convenience, oral administration, especially in the rhythm of food and / or beverage intake of the animals, is preferable in most cases. For the purposes of the present invention, food means both solid and liquid food and also drinks and water.

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The active compounds may be in the form of pure substances or in formulated form, ie in admixture with non-toxic inert carriers of any kind, e.g. with carriers and in formulations as are customary in nutritive preparations.

The active ingredients are optionally administered in formulated form together with pharmaceutical agents, mineral salts, trace elements, vitamins, proteins, fats, dyes and / or flavorings in a suitable form.

It is recommended to administer the oral solution together with the feed and / or drinking water, adding the active ingredient to the total or only parts of the feed and / or drinking water as needed.

The active compounds are added to the feed and / or drinking water by conventional mixing by simple mixing as a pure mixture, preferably in finely divided form or in formulated form in admixture with edible non-toxic carriers, optionally in the form of a premix or feed concentrate.

The feed and / or drinking water may contain, for example, the active ingredients in a weight concentration of about 0.01 to 50, in particular 0.1 to 10 ppm. The optimal level of the concentration of active ingredients in the feed and / or drinking water is particularly dependent on the amount of feed and / or drinking water intake of the animals and can be easily determined by any expert.

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The type of food and its composition is irrelevant here. Any customary or special feed compositions may be used which preferably contain the usual balance of energy and builders necessary for a balanced diet. The feed may, for example, be composed of vegetable substances, eg hay, beets, cereals, cereal ^by- products, animal substances, eg meat, fats, bone meal, fish products, vitamins, eg vitamin A, D complex and B complex, proteins, amino acids, eg DL-methionine and inorganic substances, eg lime and common salt.

Feed concentrates contain the active ingredients besides edible substances, e.g. Rye flour, maize flour, soybean meal or lime, optionally with other nutrients and nutrients and proteins, mineral salts and vitamins. They can be prepared by the usual mixing methods.

Preferably in premixes and feed concentrates, the active ingredients, optionally also suitable agents covering their surface, e.g. protected from air, light and / or moisture with non-toxic waxes or gelatine.

Example of the composition of a chick rearing feed containing an active substance according to the invention:

200 g wheat, 340 g corn, 361 g soybean meal, 60 g beef tallow, 15 g dicalcium phosphate, 10 g calcium carbonate,

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¹ ^ ^w ° ^v ö 4

4 g of iodized salt, 7.5 g of vitamin-mineral mixture and 2.5 g of active ingredient premix yield, after careful mixing, 1 kg of feed.

One kg of feed mixture contains:

600 IU vitamin A, 100 IU vitamin D ₃ . 10 mg vitamin E, 1 mg vitamin K3, 3 mg riboflavin. 2 mg pyridoxine, 20 mcg Vitamin B ₂ , 5 mg calcium pantothenate, 30 mg nicotinic acid, 200 mg choline chloride, 200 mg MnSO ₄ χ H ₂ O, 140 mg ZnSO ₄ χ 7 H ₂ O, 100 mg FeSO ₄ χ 7 H ₂ O and 20 mg CuSO ₄ χ 5.H ₂ O.

The drug premix contains the active ingredients in the desired amount, e.g. 10 mg and additionally Ig DL-methionine as well as soybean meal, as & 2,5 g Praemix arise.

Example of the composition of a piggery feed containing an active ingredient according to the invention:

630 g of cereal meal (composed of 200 g maize, 150 g barley, 150 g oat and 130 g wheat grits), 80 g fish meal, 60 g soybean meal, 60 g tapioca flour, 38 g brewer's yeast, 50 g vitamin-mineral mixture for pigs (Composition eg as with chick feed), 30 g Zuckerrohrme.lasse and 2 g active substance preemix (composition eg as with chick feed) give after careful mixing 1 kg food.

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2 6 3

The specified feed mixtures are preferably adapted for rearing and fattening of chicks or pigs, but they can also be used in the same or similar composition for the rearing and fattening of other animals.

embodiment

The invention will be explained in more detail below with reference to some examples.

us. υ ο "

Manufacturing Example 1

a) 3-C, 4-Dimethyl-3-oxo-piperazinium-methyl-76-phenylacetamido-3-C8-phen-4-carboxy la t

Under nitrogen, 9.36 g <24 mmol) of 3-Acetoxymethy1-7 β-phenylacetamido-3-cephem-4-carboxylic acid at room temperature in 100 ml of absol. Slurried methylene chloride and brought by the addition of 15.2 ml (72 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) in solution. After cooling to 0 ° C., 14 ml (96 mmol) of trimethylsilyl iodide are added and the reaction solution is stirred at 0 ° C. for 1 h.

Subsequently, 15.3 g (120 mmol) of 1,4-dimethyl-3-oxo-piperazine are added and the solution is stirred for 30 minutes. Then 4.8 ml of water are added and after a further 5 minutes is poured onto 400 ml of ether. The ether is decanted from the oily residue, the residue is stirred again with ether and taken up again after decanting in water and chromatographed over absorbent resin HP 20 (eluent: acetonitrile / water 5/95). Yield 5.3 g of a mixture of 2 isomers.

¹ H NMR (D ₆ -DMSO)

6 (ppm) = 9.20 Cllbd, J = 7 Hz, 7.32 C53m, 5.61

CUdd, 3 = 7 Hz, J = 5 Hz, 5,12 and 5,10 end, J = 5 Hz, 5,02 C13bd, J = 13 Hz, 4,33 and 4,18 ClDd, J = 13 Hz, 3.34 to 4.24

C103m, 3.10 C3] s, 2.92 C3] s.

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b) 7-AmJnO-S- (1,4-Dimethv-3-oxopiperazinium) methyll-3-cephem-4-carboxvlate

5.0 g of 3- (1,4-dimethyl-3-oxopiperazinitime) methyl-7β-phenylacetamido-3-cephem-4-carboxylate are dissolved in ml of water, adjusted to pH 7.8 with 4N triethylamine in ethanol After completion of the enzymatic cleavage, the acylase is filtered off and the filtrate is adjusted with concentrated hydrochloric acid to pH 2. The resulting precipitate is filtered off with suction through silica gel and the filtrate is filtered off with suction is added dropwise to 2 1 of acetone.The desired product is crystallized out as the hydrochloride and is filtered off with suction and dried.

Yield: 3.3 g (χ HCl χ H ₂ O) as a mixture of two I someren.

¹ H-NMR (D ₂ O) -

6 (ppm) = 5.40 and 5.39 C13d, J = 5 Hz, 5.19 and

5.18 [13d, J = 5 Hz, 4.86 and 4.76 tl3d J = 13 Hz, 4.24 and 4.21 ClDd, J = 13 Hz, 4.24 ClDd, J = 18 Hz, 4, 06 C13m, 3.62 4.00 [53m, 3.56 and 3.54 C13d, J = 18 Hz, 3.17 and 3.15 C3] s, 2.98 C3] s.

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c) 78-C (Z) -2- (2-aminothiazol-4-vl) -2-methoxymiminoacetamido3-3- (l, 4-dimethyl-3-oxopiperazinium) methyl-3-cephem-4-carboxylate

1.1 g (5.3 N, N) (Z) -2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid are dissolved under nitrogen at room temperature in 8.1 ml of absolute. Dissolved dimethylformamide. After addition of 339 μl of N-ethyldiyopropylamine, 369 μl of tripropylamine and 456 μl of tributylamine, the mixture is cooled to -50 ° C. 435 U of methanesulfonic acid

Chloride are added and the solution is stirred for 30 minutes at -50 * C. This solution is then rapidly added to a solution of 1.6 g (4.0 mmol) of 7-amino-3- (1-dimethyl-S-oxopiperazinium) methyl-3-cephem-4-carboxylate cooled to 0 ° C. ( x HCl χ H ₂ O)

in 2.55 ml of water and 2.1 ml of triethylamine. After 5 minutes, the reaction solution is added to 500 ml of acetone. The resulting precipitate is filtered off with suction, dried and chromatographed on adsorbent resin HP 20 (eluent: acetonitrile / water 5/95). Yield 700 mg of a mixture of two isomers.

¹ H NMR (D ₆ -DMSO)

6 (ppm) = 9.63 ClDbd, J = 7Hz, 7.26C23bs, 6.76

[ils, 5.71 Clndd, y = 7 Hz, J = 5 Hz,

5.17 / 5.15 C13d, J = 5 Hz, 5.08 / 5.03 C13d,

J = 12 Hz, 4.32 C13d, J = 16 Hz, 4.13 ClDd, J = 16 Hz, 4.13 / 4.07 C13d, J = 12

Hz, 3.87 C33s, 3.30-4.00 C63m, 3.09 C33bs, 2.92 C33s.

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Example 2

a) 7-Amino-3- (4-methylsulfonyl-1-methylpiperazinium) -methyl-3-cephem-4-carboxylate

4.68 g of S-acetoxymethyl-β-phenylacetamido-3-cephem-4-carboxylic acid are reacted analogously to Example 1a with 21 g of 4-methylsulfonyl-1-methylpiperazine. The product is precipitated from acetone and directly cleaved analogously to Example Ib with penicillin G acylase and worked up.

Yield: 1.05 g (x HCl χ H ₂ O).

¹ H NMR (D ₂ O)

«(Ppm) = 5.39 C13d, J = 5 Hz, 5.17 C13d, J = 5 Hz, 4.78 C13d, J = 13 Hz, 4.14 ClDd, J = 13

Hz, 3.92 end, J = 18 Hz, 3.40-3.80 C9] m, 3.10 C33s, 3.06 C33s.

b) 76- [Z-2- (aminothiazol-4-vl) -2-methoxyiminoacetamido 3-3- (4-methylsulfonyl-1-methylpiperazinium) methyl] 3-cephem-4-carboxylate

0.5 g of the product from Example 2a are reacted with 0.34 g of Z-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid analogously to Example 1c. Yield after chromatography on adsorbent resin HP 20 0.56 g.

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263

¹ H NMR (D ₆ -DMSO)

6 (ppm) = 9.55 ClDd, 3 = 7 Hz, 7.25 C23bs, 6.73 ClDs, 5.66 ClDdd, J = 7 Hz, J = 5 Hz, 5.13 C13d, J x 5 Hz, 5 , 14 C13bd, J = 13 Hz, 4.06 C13bd, J = 13 Hz, 3.83 C33s, 3.26 C33s, 3.20-4.00 ClODm, 3.04 C33s.

Example 3

a) 7-Amino-3- (4-formyl-1-methylpiperazinium) methyl-3-cephem-4-carboxvlate

Analogously to Example 1a, 4.68 g of S-acetoxy-ethyl-β-6-phenylacetamido-3-cephem-4-carboxylic acid are reacted with 15 g of 4-formyl-1-methylpiperazine. The product is precipitated from acetone and directly cleaved analogously to Example Ib with penicillin G acylase and worked up. Yield 1.2 g (x HCl χ ^ 0).

¹ H NMR (D ₂ O)

6 (ppm) = 8.02 C13s, 5.38 C13d, J = 5 Hz, 5.17 C13d,

J = 5 Hz, 4.78 C13d, J = 13 Hz, 4.14 E23d, J = 13 Hz, 3.70-3.98 C33m, 3.30-3.64 C63m, 3.13 C33s.

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b) 76-Cz-2- (2-aminothiazo1-4-vl) -2-methoxymiminoacetamido3-3- <4-formyl-1-methylpiperazinium) methyll-3-cephem-4-carboxylate

Analogously to Example 1c, 0.6 g of the product from Example 3a are reacted with 0.47 g of Z-2- <2-aminothiazol-4-yl) -2-methoxyiminoacetic acid. Yield after purification Over adsorbent resin HP 20 0.2 g .. '

¹ H-NMR (D ₆ -DMSO) 6 (ppm) 9.62 C13d, J = 7 Hz, 8.12 C13S, 7.26

C23bs, 6.77 CIiIs, 5.20C13dd, J = 7Hz, J = 5Hz, 5.17Cl3d, J = 5Hz, 5.14C13bd, J = 13Hz, 4.07C13bd, J = 13 Hz, 3.87 C33s, 3.10 C33s, 3.00 - 4.00 C83m

 20

Example 4

a) 7-Amino-3- (4-aminocarbonyl-1-methylpiperazinium) methyll-3-cephem-4-caerboxylate

9.4 g of S-acetoxymethyl-β-phenylacetamido-3-cephem-4-carboxylic acid are reacted analogously to Example la with a solution of 34 g of 1-aminocarbonyl-4-methylpiperazine in 150 ml of dimethylformamide. The product is precipitated from ether and directly cleaved analogously to Example Ib with penicillin G acylase and worked up. Yield 3.1 g (x HCl χ H ₂ O).

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5 ¹ H-NMR (D ₂ O)

(Ppm) = 5.39 tl3d, J = 5 Hz, 5.16 ClId, J = 5 Hz. 4.80 [lld, J = 13 Hz, 4.14 ClDd, J = 13 Hz, 3.85 - 4.02 C33m, 3.35-3.72 C73m. 3.22 C33s

 10

b) 7 & EZ-2- (2-aminothiazol-4-vl) -2-methoxymiminoacetamido 3,3'- (4-aminocarbonyl-1-methylpiperazinime) methyl-3-cephem-4-carboxylate

Analogously to Example 1c, 0.98 g of the product from Example 4a are reacted with 0.68 g of Z-2- <2-aminothiazol-4-yl) -2-methoxyiminoacetic acid. Yield after chromatography on adsorbent resin HP 20 0.9 g.

20 ¹ H NMR (D ₆ -DMSO)

Ö (ppm) = 9.58 did, J «7 Hz, 7.53 C23bs, 6.72 ClIs, 6.29 C2] bs, 5.66 Clldd, J = 7 Hz, J = 5 Hz, 5.13 C13d, J = 5 Hz, 5.09 C13bd,

J = 13 Hz, 3.99 C13bd, J = 13 Hz, 3.82

25 C33s, 3.18 - 3.92 C103m, 3.00 C33s.

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Example 5

a) 7-AmJnO-S- (4-dimethyaminosulfonyl-1-methylpiperazinium) methyl-3-cephem-4-carboxvlate

Analogously to Example la, 9.4 g of

phenylacetamido-3-cephem-4-carboxylic acid with 49 g of 1-Dimethy1aminosu1fonyl-4-methyl-piperazine reacted. The crude product is cleaved directly analogously to Example Ib with penicillin G acylase.

Yield 2.0 g (x HCl χ H ₂ O).

¹ H NMR (D ₂ O)

5 (ppm) = 5.39 tl] d, J = 5 Hz, 5.96 ClDd, J = 5 Hz.

4.82 C13d, J = 13 Hz, 4.18 CUd, J-13Hz, 3.98 C13d, J = 18Hz, 3.48-3.80

C93m, 3.13 C3Ds, 2.89 C63s.

b) 7B-CZ-2-C 2-aminothiazole-4-vl) -2-methoxviminoacet amido3-3- (4-methylpiperazin-1-dimethvlaminosulfonvl ium) Methyl-3-cephem-4-carboxvlat

0.9 g of the product from Example 5a are reacted with 0.55 g of Z-C2- <2-aminothiazol-4-yl) -2-methoxyiminoacetic acid analogously to Example Ic. Yield after chromatography on adsorbent resin HP 20 0.45 g.

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¹ H NMR (D ₆ -DMSO)

6 (ppm) = 9.59 [13d, J = 7 Hz, 7.24 [23bs, 6.74

[13s, 5.67 [13dd, J = 7 Hz, J «5 Hz, 5.13 [13d, J = 5 Hz, 5.14 [13bd, J« 13 Hz, 4.03 Cllbd, J = 13 Hz, 3 , 84 C3] s, 3.81 ClId, J = 18 Hz, 3.20-3.60 [93m, 3.04

[33s, 2.82 C63s.

Example 6

a) 7-Amino-3- (4-acetyl-1-methylpiperazinium) methyl-3-cephem-4-carboxylate

Analogously to Example la, 9.4 g of 3-acetoxymethyl-7-β-phenylacetamido-3-cephem-4-carboxylate are reacted with 34-gl-acetyl-4-methylpiperazine. After chromatography of the crude product precipitated from ether on adsorbent resin HP 20, 7.5 g of 3- <4-acetyl-1-methylpiperazinium) methyl-7-.beta.-phenylacetamido-3-cephem-4-carboxylate are obtained, which is analogous to Example Ib with penicillin G. Verify acylase cleaved. Yield 3.2 g (x HCl χ H ₂ O).

¹ H NMR (D ₂ O)

((Ppm) = 5.31 C13d, J = 5 Hz, 5.08 C13d, J = 5 Hz, 4.80 C13d, J = 13 Hz, 4.10 C13d, J = 13

Hz, 3.20 - 4.00 C103m, 3.05 [33s, 2.03 t33s.

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b> 7B-CZ-2- (2-aminothiazo-1-4-yl) -2-methoxymiminoacetamido-1,3-4-acetyl-1-methvloperazinium) methYl-3-ceohem-4-carboxylate

Analogously to Example Ic, 1.59 g of the product from Example 6a with 1.24 g

Z-2- <2-aminothiazol-4-yl) -2-methoxyiminoacetic acid. Yield after chromatography on adsorbent resin HP 20 0.8 g.

¹ H NMR (D ₆ -DMSO)

6 <ppm) = 9.61 ClId, J = 7 Hz, 7.26 C23bs, 6.75

C13s, 5.69 C13dd, J * 7 Hz, J «5 Hz, 5.16 Cl 3d, J = 5 Hz, 5.15 C13bd, J * 13 Hz, 4.03 C13bd, J = 13 Hz, 3, 86 C33s, 3> 2 -4.0 C103m, 3.07 C33s, 2.07 C33s.

Example 7

a) 7-amino-3- <4-tert-butoxycarbonyl-1-methylpiperazinium) methyl-3-cephem-4-carboxvlate

9.4 g of S-acetoxymethyl -? - fi-phenylacetamido-3-cephem-4-carboxylate with 48 g of 1-methyl-4-tert. reacted butoxycarbonylpiperazine. The crude product is cleaved directly analogous to Example Ib with penicillin G acylase. Yield 1.9 g (x HCl χ H ₂ O).

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263

¹ H NMR (D ₂ O)

Β (ppm) β 5.29 ClId, J = 5 Hz, 5.06 C13d, J = 5 Hz,

4.64 CUd, J = 13 Hz, 4.00 ClDd, J = 13 Hz, 3.75-4.00 C33ro, 3.20-5.5 C73m, 2.98 C33s, 1.32 [93s

 10

b) 7-fl-CZ-2- <2-aminothiazol-4-vl) -2-methoxymiminoacetamido3-3- (4-tert-butoxycarbonyl-1-methylpiperazine ^Λ ium) Methyl-3-cephem-4-carboxvlat

0.85 g of the product from Example 7a are reacted with 0.52 g of Z-2- <2-aminothiazol-4-yl> -2-methoxyiminoacetic acid analogously to Example Ic. Yield after chromatography on adsorbent resin HP 20 0.2 g.

¹ H NMR (D ₆ -DMSO)

6 (ppm) = 9.64 C13d, J = 7 Hz, 7.30 C23bs, 6.77

C13s, 5.70 C13dd, J = 7 Hz, J = 5 Hz, 5.17 C13d, J «5 Hz, 5.14 C13bd, J = 13 Hz, 4.03 C13bd, J = 13 Hz, 3.87 C33s, 3.24-3.95 C103m, 3.05 t33s, 1.45 C93s.

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Example 8

a) 7-AmJnO-S-CA- (3-hydroxypropyl) -1-methylpiperazinium] Methyl-S-cephem-'l-carboxvlat

4.68 g of 3-acetoxymethyl-7β-phenylacetamido-3-cephem-4-carboxylic acid are reacted analogously to Example 1a with 19 g of 4- (3-hydroxypropyl) -1-methylpiperazine. The product is precipitated from acetone and directly analogous to Example Ib with penicillin G acylase

IS split and worked up. Yield: 2.3 g (x HCl χ H ₂ O).

¹ H NMR (D ₂ O)

(Ppm) = 5.47 ClId, J = 5 Hz, 5.26 C13d, J = 5 Hz, 4.97 C13d, J = 15 Hz, 4.37 C13d, J = 15

Hz, 4.02 did, J = 18 Hz, 3.70-3.90 ClOIm, 3.64 ClId, J = 18 Hz, 3.45 C23m, 3.33 C33s, 2.04 C23m.

b) 76-C-C-2- (2-aminothiazol-4-vl) -2-methoxviminoacet amidoü-3-C4-C3-hvdroxvpropvl) -l-methvlpjperazinium3-Methyl-S-

1.0 g of the product from Example 8a is reacted with 0.66 g of Z-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetic acid analogously to Example 1c. Yield after chromatography on adsorbent resin HP 20 0.68 g.

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¹ H NMR (D ₆ -DMSO)

6 (ppm) = 9.60 CUd, J = 7 Hz, 7.27 C2] bs, 6.74 Cl] s, 5.66 Cl] dd, J = 7 Hz, J = 5 Hz, 5.15 Cl ] d, J = 5 Hz, 5.08 CUd, J = 14 Hz, 4.02 Cl] d, J = 14 Hz, 3.83 C3] s, 3.81

Cl] d, J = 18 Hz, 3.30 - 3.50 C7] m, 2.97

C3] s, 2.40 - 2.80 C6] m, 1.55 C23m.

Example 9

7B-CZ-2- <2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3- <4-aminocarbonvl-l-ethvlDiDerazinium) Methyl-3-cephem-4-carboxylate

¹ H NMR (D _A -DMS0>

δ (ppm) = 9.64 Cl] d, 3 = 7 Hz, 7.29 C2] bs, 6.77 Cl] s,

6.33 C2] bs, 5.68 Cl] dd, J = 7 Hz, J = 5 Hz, 5.10 Cl] d, J = 13 Hz, 5.08 Cl] d, J = 5 Hz, 3, 96 Cl] d, J = 13 Hz, 3.88 C3] s, 3.20-3.92 C12] m,

1.26 [3] m

 25

Example 10

78 ~ CZ-2- (2-aminothiazol-4-vl) -2-methoxviminQacetaniido] -

3-C4- (2-hydroxyethyl) -1-methylpiperazinium] methyl-3-30

cephem-4-carboxyl at

¹ H NMR (D ₆ -DMSO)

δ (ppm) = 9.64 Cl] d, J = 7 Hz, 7.30 C2] be, 6.78 Cl] s, 5.70 Cl] dd, 3 = 7 Hz, J = 5 Hz, 5, 18 Cl] d, J = 5 Hz, 5.12 Cl] d, J = 13 Hz, 4.01 Cl] d, J = 13 Hz, 3.88 C3] s, 3.85 Cl] d, J = 18 Hz, 3.20 - 360 C7] m, 3.01 C3] s, 2.40 - 280 C6] m.

Le A 23 586

Example 11

76-CZ-2- (2-Aminothiazo1-4-vl) -2-methoxyiminoacetamido] -3-Cl-methyl-4- (2-oxoimidazolidino) carbonvlpiperazinium]

methyl-3-cephem-4-carboxylate 10

¹ H NMR (D ₆ -DMSO)

δ (ppm) = 9.61 Cl] d, 3 = 7 Hz, 7.50 Cl] bs, 7.28 C2] bs, 6.76 Cl] s, 5.69 Cl] dd, 3 = 7 Hz, J = 5 Hz, 5.16 Cl] d, J = 13 Hz, 5.15 Cl] d, J = 5 Hz, 4.05 Cl] d, J = 13 Hz, 3.88 C3] s, 3, 20 - 3.96 C14] m, 3.08 C3] s.

Example 12

7B-CZ-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] - 3-C 1 -methyl-4- (3-methylsulfonyl-2-oxo-imidazolidino) carbonyl-piperazinium-methyl-3-cephem-4-carboxvlate

¹ H NMR (D _A -DMSO)

δ (ppm) = 9.58 Cl] d, 3 = 7 Hz, 7.24 C2] bs, 6.73 Cl] s,

5.67 Cl] dd, 3 = 7 Hz, J = 5 Hz, 5.15 Cl] d, J = 13 Hz, 5.12 Cl] d, J = 5 Hz, 4.04 Cl] d, J = 13 Hz, 3.84 C3] s, 3.20-3.98 C14] m, 3.35 "[3] s,

3.08 [3] s.

Example 13

7B-CZ-2- (2-aminothiazol-4-yl) -2-methoxyiminoacetamido] -3-C1-methyl-4- (methylphenylsulfonyl) piperazinium]

methyl-3-cephem-4-carboxylate 35

Le A 23 586

¹ H NMR (D ₆ -DMSO)

δ (ppm) = 9.62 Cl] d, J = 7 Hz, 7.69 C2] d, J = 8 Hz, 7.47 C2] d, J = 8 Hz, 7.23 C2] bs, 6, 72 Cl] s, 5.76 Cl] dd, J = 7 Hz, J = 5 Hz, 5.19 Cl] d, J = 5 Hz,

¹⁰ 4.78 Cl] d, J = 13 Hz, 4.16 [1] d, J = 13 Hz, 3.84f37s, 3.00 - 3.95 ClO] m, 2.92 C3] s, 2, 43 C3] s.

Le A 23

Claims (2)

invention claim 1 or CON R ⁶ . wherein R, R independently of one another are hydrogen, methyl, ethyl, phenyl or form a ring with the nitrogen atom, such as pyrrolidine, piperazine, piperidine, morpholine or thiomorpholine, or - by the group -SO ₂ -Y or -O-Y, where Y - represents ^ alkyl having up to 4 C atoms, phenyl or benzyl, R a) is straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 6 C atoms, which is substituted at least once 2 63 OS - 13 - · by OH, CHO, OCONH ₂ , NHCONH ₂ - by the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ being R ^{5 is} hydrogen, alkyl is up to 4 C atoms, phenyl or benzyl. by fluorine, chlorine or SO ₃ H, - by the groups -N ^ j, -SO ₀ -N _v · » or CON ^ ' where R and R are as defined above have, or - by the group -SO ₂ -Y or -O-Y, 'where Y- is alkyl having up to 4 C atoms, Phenyl or benzyl, or b) CHO or SO ₃ H, c) stands for COOR ⁵ , where>. R has the meaning given above, or 263Og ₄ 8th
d) represents the group -ZR, where Z - represents C or -SO ₂ - and Il. ο _ · R is straight-chain or branched, saturated or unsaturated alkyl having up to 4 C atoms, which is optionally substituted by chlorine, fluorine, hydroxyl, carboxy, OCONH ₂ , NHCONH ₂ , SO ₃ H R ⁶ \ .R ⁵ ». '; -CO-N ^ J or SO ^ -N R / is substituted, ♦ where R and R are those given above Have meaning for phenyl,
for benzyl, is pyridyl, furyl, thienyl, thiazolyl, isoxazole, imidazolyl, pyrazolyl
or for the group -Nr <, where R, R in turn have the abovementioned meaning. 2-63 5. The method according to item 1, characterized in that cephalosporins of the general formula I are prepared, wherein R ² the radicals U NR ° ^ N NR ^ are substituted, composed by a substituent from the group consisting of: a) straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 6 C atoms, which is optionally substituted again - by OH, CHO, OCONH ₂ , NHCONH ^ - by the group COOR ⁵ , NHCOR ^, COR ⁵ where R - represents hydrogen, alkyl having up to 4 C atoms, phenyl or benzyl, - by fluorine, chlorine, SO ₃ H - by the group -Nn. ', SO ₀ -N or wherein R and R are independently hydrogen, methyl, ethyl, phenyl or wherein R "R together with the nitrogen atom form a ring such as pyrrolidine, piperidine, piperazine, morpholine or thiomorpholine, or - through- the group -SO ₂ -Y or 0-Y, where 263 ÖS 4 Y - represents alkyl having up to 4 C atoms, phenyl or benzyl, ' 8th
b) the group -ZR in which Z - represents C or -SO ₂ - and R - represents straight-chain, branched, saturated or unsaturated alkyl having up to 4 C atoms, which is optionally substituted by fluorine, chlorine, hydroxyl, carboxy, OCONH ₂ , NHCONH ₂ , ⁵ \ .R ⁵ ' -CO-Nv !, or SO ₀ -N ^ \ is substituted, where R, R have the meaning given above, for phenyl, for benzyl, for pyridyl, thienyl, furyl, thiazolyl, oxazolyl *, isoxazolyl, imidazolyl, pyrimidyl, morpholinyl, piperidinyl or - for the group -N _v ! stands, where R, R in turn have the abovementioned meaning, C) OH, CHO, OCONH ₂ , NHCONH ₂ - > 7 - d) the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , where R has the abovementioned meaning e) fluorine, chlorine, SO ₃ H, f) the group - where R, R again have the abovementioned meaning, g) the group -O-Y where Y- represents alkyl having up to 4 C atoms, phenyl or benzyl. 3 06 6. The method according to item 1 to 5 ,, characterized in that the carboxylic acids of the general formula (II) are activated without amine-protecting group and then with the ß-lactams of the formula (III), which brought as salts with an amine in solution were coupled. 7. The method according to item 1 to 5, characterized in that the carboxylic acids of the general formula (II) with Sulfonsäurederiyaten of the formula (V) to give anhydrides of the formula (IV) according to the scheme, , (II) (IV) in which 9
T - the radical R is -SO ₅ -O- or halogen, and R represents alkyl having up to 10 carbon atoms, optionally substituted by fluorine, chlorine, cyano, phenyl, alkoxycarbonyl, alkoxy or alkyl each having up to 4 carbon atoms, or - is phenyl which is optionally substituted is fluorine, chlorine, bromine, cyano, Alkyl, alkoxy, alkylthio, alkoxycarbonyl, each having up to 4 C atoms, nitro ,. Trifluoromethyl or phenyl. 8. The method according to item 7, characterized in that one dissolves the carboxylic acids of the formula (II) and 1-1.4 equivalents of an amine in a solvent and with 1 to 1.2 equivalents of a sulfonic acid derivative of the formula (V,) reacts * 9. The method according to items 1 to 8, characterized in that are used as the solvent diethyl ether, tetrahydrofuran, acetonitrile, acetone, methylene chloride, chloroform, or dimethylformamide for the reaction. 10. The method according to points 6 to 9, characterized in that are used as amines triethylamine, tributylamine or diisopropylamine, or mixtures of these amines. 11. The method according to the items 1 to 9, characterized in that the reactions are carried out at temperatures between -80 ⁰ C and room temperature 12. Method according to item 6, characterized by that the activation of the carboxylic acids of the general formula (II) by conversion into an activated 263 Os 4 Ester with N-hydroxysuccinimide and dicyclohexylcarbodiimide or. With 1-hydroxybenzotriazole and dicyclohexylcarbodiimide takes place. 13. Method according to. Item 12, characterized in that one carries out the reactions at temperatures between -30 ⁰ C and +100 ⁰ C. " 14 · Use of cephalosporins of the general formula (I) in which 2 63 0 $ 4 - Ba R - represents straight-chain or branched, saturated or unsaturated, optionally substituted by carboxy-substituted alkyl having up to 6 C atoms » R - represents straight-chain or branched alkyl having up to 6 C atoms, which is optionally substituted by hydroxyl, carboxy, alkoxy, alkoxycarbonyl having in each case up to 3 C atoms, halogen or cyano, R ₂ ^^ Λ - the radical ^ * N X for the optionally , 'Λ ο- ο ι '· substituted groups "^ N '·' N-R -SL- or ^R ^ <9r - x ₄
/ stands, R ³ - for straight-chain, branched or cyclic-10 sehes saturated or unsaturated alkyl having up to 10 carbon atoms, which is optionally substituted by -OH, CHO, OCONH ₂ , NHCONH ₂ , 15 - through the groups COOR ⁵ . NHCOR ⁵ , COR ⁵ , in which R ^{5 is} hydrogen, alkyl having up to 8 C atoms, aryl having 6 to 10 C atoms, or Cy-Cj-aralkyl, 20-by halogen, cyano, SO ₃ H,  R?. · ' - by the groups -N _v 25 ° ⁶ -. R ⁶ - SO ₂ -N: or CON 30 where R ^ and R ^ are independently hydrogen or together or individually Cj-C ^ alkyl, C ₂ -C ^ alkenyl or phenyl, or where the 35 Le A 23 586 263 O S 4 5 substituents R ⁶ . R ⁷ optionally together with the nitrogen atom form a 5- to 7-membered ring which may contain as further heteroatoms an oxygen, sulfur and / or 1-2 nitrogen atoms and which is optionally substituted by C ₁ -C ₄ 10, or by the group -SO ₂ -Y or -O-Y, where 15 is Y- for C ₁ -C ₈ -alkyl, aryl having 6 to 10 C atoms or
- represents C ₇ -C ₁₄ -aralkyl, and _% R ⁴ a) represents straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 10 C atoms which is substituted at least once 25 * - by OH, CHO, OCONH ₂ , -NHCONH ₂ , - By the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , where R ⁵ - for hydrogen, alkyl up to 8 C atoms, aryl having 6 to 10 C-Ato-30 men or C ₇ -C ₁₄ aralkyl, by halogen, cyano, SO3H, Le A 23 586 263 Os 4 - SH - J6. - through the groups -N - SO ₂ -N: or CON _i in which R ⁶ and R ~ independently of each other for hydrogen or jointly or individually for C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or phenyl or in which the substituents R 1, R 4 optionally together with the nitrogen atom form a 5- to 7-membered ring which, as further heteroatoms, forms an oxygen, May contain sulfur and / or'1 to 2 nitrogen atoms and which is optionally substituted by Cj-C ^ alkyl, or - by the group -SC ^ -Y or -O-Y where Y - for Cj-Cg-alkyl, aryl with 6 to 10 men or - represents Cp-Cj ^ aralkyl. Le A 23 586 , si. 243 OS b) for CHO. SO3H stands. c) COOR ⁵ , where R ^{5 has} the meaning given above, or d) stands for the group -ZR ⁸ . in which \ /
Z stands for C or -SO ₂ "and R ⁸ - is straight-chain, branched or cyclic saturated or unsaturated alkyl having up to Cg, optionally substituted by Halogen, hydroxy, cyano, alkoxy, alkylthio each having up to 6 C atoms, aryloxy, arylthio having up to 10 C atoms. Carboxy, Cj-C ^ - Alkoxycarbonyl, -OCONH ₂ , -NHCONH ₂ , SO3H or R ⁶ , r \ R ⁶ -N), -CO-N, 'or -SO ₂ -N ^ ^ R ^{7' 'X} R ^7' ^ R ⁷ is substituted, wherein R ^., R ^{7 have} the meaning given above, - for aryl having 6 to 10 carbon atoms - for C ₇ -C ₁₄ aralkyl for heterocyclyl or Le A 23 586 1. Process for the preparation of cephalosporins of the general formula (I), in which   \, 63064 - 57 - R ^{1 represents} straight-chain or branched, saturated or unsaturated, optionally substituted by carboxy alkyl having up to 6 C atoms, R ² - represents straight-chain or branched alkyl having up to 6 C atoms, which is optionally substituted by hydroxyl, carboxy, alkoxy, alkoxycarbonyl having in each case up to 3 C atoms, halogen or cyano, - the rest; | "χ for the optionally substituted groups R, / / N _{N. R} 3 ^λ or ^Κ ^ Φ ν , N NR * stands. R ^ - for straight-chain, branched or cyclic is a saturated or unsaturated alkyl having up to 10 carbon atoms, which is optionally substituted - by -OH, CHO. OCONH ₂ . NHCONH ₂ . by the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , in which R ⁵ - for hydrogen, alkyl up to 8 C atoms, aryl having 6 to 10 C atoms, or C ₇ -C _{1 4} aralkyl group,
35 by halogen, cyano, SO3H, Le A 23 586 * 6 3 OS 4 - SS - through the groups "N ^). -SO ₂ -N or -CON; in which R ⁶ and R ⁴ are each independently hydrogen or together or individually C ₁ -C ₆ -AlkVl, C ₂ "C ^ -alkenyl or phenyl, or wherein the substituents R °, R optionally with the nitrogen atom, a 5- to Form a 7-membered ring which may contain, as further heteroatoms, an oxygen, sulfur and / or nitrogen atom and which is optionally substituted by C 1 -C 4 -alkyl, - or by the group -SC ^ -Y or -0-Y. where Y - for Cj-Ce-alkyl, aryl having 6 to 10 carbon atoms or
- represents C ₇ -C ₁₄ -aralkyl, and
30 R ⁴ a) represents straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 10 C atoms which is substituted at least once - by OH, CHO, OCONH ₂ , -NHCONH ₂ , - through the groups COOR ⁵ , NHCOR ⁵ . COR ⁵ , where Le A 2 3 586 - 55 - R ⁵ - for hydrogen, alkyl up to 8 C atoms, aryl having 6 to 10 C-Ato men, or C ^ -C ^ -Aralkyl stands. by halogen, cyano, SO3H10 - by the groups - - SO ₉ -N! Or -CO in which R ^ and R 'independently of each other for what or together or individually stand for ~C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl or phenyl or where the substituents R ⁶ . R ⁷ optionally form, with the nitrogen atom, a 5- to 7-membered ring which may be mentioned as further heteroatoms may contain an oxygen, sulfur and / or 1 to 2 nitrogen atoms and which is optionally substituted by C ₁ -C ₄ -alkyl, or - by the group -SO2-Y or -0-Ywöbe i
Y- for C ₁ -C ₈ -alkyl, aryl with 6 to 10 men or
- represents C ₇ -C ₁₄ -aralkyl, Le A 23 586 2 63 OS 4 -. bo - b) CHO, SO ₃ H, c> is COOR ^, where R ^ has the meaning given above, or d) represents the group -ZR ⁸ , in which
15 Z - represents C or -SO ₂ - and R ° - for straight-chain, branched or cyclic saturated or. unsaturated alkyl with up to C ₈ optionally substituted by halogen, hydroxy, cyano, alkoxy, alkylthio each having up to 6 C atoms, aryloxy, arylthio with up to 10 C atoms, carboxy, Cj-C ^ alkoxycarbo- nyl, -OCONH ₂ , -NHCONH ₂ , SO 3 H or -N,, -CO-N is substituted, wherein R ⁶ , R ^{7 have} the meaning given above, - for aryl having 6 to 10 carbon atoms - for C ₇ -C ₁₄ aralkyl for heterocyclyl or Le A 23 586 63 06 R ⁶ Y - stands for the group -N ^ j , where R, R have the abovementioned meaning * characterized in that compounds of general formula II (II) R has the meaning given above, in which the amino group may be protected or unprotected, after activation of the carboxyl group by conversion into a mixed anhydride, by top conduction into the acid halide or by conversion into an activated ester, with compounds of the general formula III, COO 263 06 where ^ N X is the abovementioned meaning has been reacted, then optionally cleaved protecting groups and the desired salts or salts of the free acids are prepared. - 63 06 2. The method according to item 1, characterized in that cephalosporins of the general formula I are prepared, wherein the radicals R ² K®r < -NR ⁴ are substituted by up to four identical or different substituents from the group consisting of a) straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 10 C-Atomeri, which is optionally substituted again by -OH, CHO, -OCNNHg, -NHCONH ₂ , through the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , in which R - for hydrogen, alkyl with bis to 8 C atoms, aryl having 6 to C atoms or Cy-C ₁₄ aralkyl, by halogen, cyano, SO ₃ H, -by the groups - - ii - SO ₀ -N ^ ^J or - in which . .- · R and R are independently hydrogen or together or individually ^ C -CG alkyl, ^C 2 ~ ^C 6 "alkenyl or phenyl or where the substituents R, R, optionally, a form with the nitrogen atom ^ 5-to 7-membered ring, which may contain, as further heteroatoms, an oxygen, sulfur and / or nitrogen atom and which is optionally substituted by C ₁ -C ₄ -alkyl, or - by the group -SO ₂ -Y or -O-Y where
Y - for C ₁ -C ₆ alkyl, aryl riiit 6 to 10 C atoms or
- is C ₇ -C ₁₄ -aralkyl, or 8th
b) the group -ZR, in which Z - for. ei or -SO ₂ - stands and R - is straight-chain, branched or cyclic saturated or unsaturated alkyl having up to 6 C atoms, which is optionally substituted by halogeno, hydroxy, cyano, alkoxy, alkylthio having in each case 6 C atoms, aryloxy, arylthio (6-10 C) Atoms), carboxy, C 1 -C 6 -alkoxycarbonyl, -OCONH ₂ -, -NHCONH ₀ , -SO, H, ι , -υυην 'or   · _R 6, Ό '. is substituted, wherein R, R have the meaning given above _N for aryl having 6 to 1.0 C atoms for C ₇ -C ₁₄ aralkyl
for heterocyclyl
or 26306 - te - - stands for the group -N ^ '. where R, R again have the abovementioned meaning. c) -OH, CHO, OCONH ₂ , NHCONH ₂ , d) the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , in which R - for ^Wass% erstoff, alkyl having up to carbon atoms, aryl having 6 to 10 carbon atoms, or C ₇ -C ₁₄ aralkyl group, f · e) halogen, cyano, SO ₃ H f) the group -N ^^, 'where R ⁷ / R and R have the meaning given above. g) the group -0-Y, where ν Y - for C ^ -Cg-alkyl, aryl having 6 to 10 carbon atoms or
«- stands for Cy-C ^ .- aralkyl. 63 Os 4 3. The method according to item 1, characterized in that cephalosporins of the general formula I are prepared, wherein R - is straight-chain, branched, saturated or unsaturated, optionally substituted by carboxy-substituted alkyl having up to 4 C atoms, R - represents straight-chain or branched alkyl having up to 4 C atoms, which is optionally substituted by hydroxyl, carboxy, methoxy, methoxycarbonyl, fluorine, chlorine or bromine. the rest R>. © - · for the if necessary ^ substituted Radicals ^ N N-R ° or ^ "N N-R, R ' in which _{; β} R - represents straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 8 C atoms, which is optionally substituted by OH, CHO, O, CONH ₂ , NHCONH ₂ , COR ⁵ , - through the groups COOR ⁵ , NHC0R5, where R - represents hydrogen, alkyl having up to 6 C atoms, phenyl or benzyl, by fluorine, chlorine, bromine or SO_H, 2630S 4 - by the groups - N ^ J, -SO ₂ -N, ' or CON ^ L. ' ' \ ⁷ in which R and R independently of one another represent hydrogen »for C ₁ -C_-alkyl or phenyl or 6 wherein the substituents R, R optionally with the nitrogen atom form a 5- or 6-membered ring which may contain as further heteroatoms an oxygen, sulfur and / or 1-2 nitrogen atoms and optionally substituted by C ^ j-Cp Alkyl is substituted, or - By the group -SO ₂ -Y or -O-Y, where ι Y ρ is CL-Cg-alkyl, phenyl or benzyl, '* R a) represents straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 8 C atoms, which is substituted at least once by OH, CHO, OCONH ₂ , NHCONH ₂ , - By the groups COOR ⁵ , NHCOR ⁵ , COR ⁵ , where R ^{5 is} hydrogen, alkyl up to 6 C atoms, phenyl or benzyl, '-. - by fluorine, chlorine, bromine or SO-H - through the groups - -N. ^J , -SO_-N R ⁶ N CON wherein R and R have the meaning given above
- by the group -SO ₂ -Y or -OY in which " Y - represents C 1 -C 8 -alkyl, phenyl or benzyl, or b) is CHO or SO_H, c) stands for COOR ⁵ , where R ⁵ is d or R has the meaning given above. - Τ-ΰ - d) represents the group -Z-R, where . ,
ν
Z - represents C or -SO ₂ - and 8th
R - represents straight-chain, branched or cyclic, saturated or unsaturated alkyl having up to 6 C atoms, which is optionally substituted by fluorine, chlorine, bromine, hydroxyl, carboxyl, alkoxy or alkylthio having up to 3 C-atoms, phenyloxy, phenylthio , Alkoxy • carbonyl with up to 3 carbon atoms, by OCONH ₂ , -N ^. ' , -CO-N or -SO ₀ -N ^ ', is substituted, S 7 '
wherein R and R have the meaning given above. for phenyl,. for benzyl, is pyridyl, furyl, thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl, isoxazolyl, oxazolyl, morpholinyl, piperidinyl, imidazolyl, pyrazolyl, thiazolyl or piperazinyl. 630 $ 4 or ^ R · for the group -N · stands, where \ 7 ' R and R have the abovementioned meaning. 4. The method according to item 1, characterized in that cephalosporins of general formula I are prepared, wherein R ¹ - represents methyl, ethyl, allyl or 1-carboxy-1-methylethyl, R ² "- is methyl, ethyl, 2-hydroxyethyl or carboxymethyl,. .r2 -v  ν Λ «" '"» ^ the rest. ^ / N X for the optionally substituted groups ₃ N? 4 NR- ³ .or ^ NN-R, in which - for straight-chain, branched or "is cyclic, saturated or unsaturated alkyl having up to 6 carbon atoms, which is optionally substituted by OH, CHO, OCONH ₂ , NHCONH ₂ , - By the groups COOR ⁵ , NHCOR ⁵ , or COR ⁵ , where R ^{5 is} hydrogen, alkyl having up to 4 carbon atoms, phenyl or benzyl, by fluorine, chlorine or SO ₃ H, - through the groups -N 2 63 ÖS 4 R ⁵ ·. - for the group -Γ \ τ; stands, where R and R are as defined above to have, characterized in that they are used in the manufacture of medicaments.