CS273350B2 - Method of cephalosporin's new derivatives production - Google Patents

Abstract

New compounds of formula I, where R<1> represents a substituted N-heterocyclic residue of formulas (a) or (b), Q represents a substituted quinoline group with up to 18 carbon atoms, whereas the N-heterocyclic residue is possibly substituted with at least one Cl-8-alkyl, R<2> represents hydrogen, C1-8-alkoxy, C1-8-alkylthio pr C1-7-alkanoylamino, R<3> represents acyl with up to 22 carbon atoms and A represents a pharmaceutically compatible anion, as well as pharmaceutically compatible salt of these compounds and hydrates of compounds of formula I, or hydrates of their salts, are prepared by reaction of a compound of formula III, where X represents a cleavable group, or its salts with a compound of formula IV or IVa, possibly the present protection groups are cleaved and for production of the salt or hydrates of the compound of formula I, possibly the hydrates of these salts with the compound of formula I are transformed to salt or to hydrate, possibly to the hydrate of this salt. The compounds have antimicrobial effect and can be used in medicaments.<IMAGE>

Description

The present invention relates to a process for the preparation of novel cephalosporin derivatives which are substituted with an N-heterocyclic radical at the 3-position. The novel compounds have valuable pharmacological properties and can be used as pharmaceuticals.

It is an object of the present invention to provide novel cephalosporin derivatives which are substituted with an N-heterocyclic radical at the 3-position of the general formula Γ.

COOH in which

R 6 represents a substituted N-heterocyclic radical of formula (a) or (b)

or

where

Q represents a substituted quinolinyl group having up to 18 carbon atoms, wherein the N-heterocyclic radical is optionally substituted with at least one alkyl group having 1 to 8 carbon atoms,

R is hydrogen, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio or C 1 -C 7 alkanoylamino;

R represents an acyl group of up to 22 carbon atoms, and

A is a pharmaceutically acceptable anion as well as pharmaceutically acceptable salts of these compounds and hydrates of the compounds of formula I, or hydrates of their salts.

CS 273350 02

The term C 1 -C 8 alkyl refers to straight or branched C 1 -C 8 hydrocarbon groups, preferably C 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, tert. butyl group and the like. >

The term (C 1 -C 8) alkoxy denotes straight or branched chain hydrocarbon oxy groups in which the alkyl group is as defined above. Examples include methoxy, ethoxy, n-propoxy and the like.

The term halogen refers to chlorine, bromine, iodine or fluorine unless otherwise defined.

The term aryl refers to an optionally substituted aromatic group such as phenyl, tolyl, xylyl, mesityl, cumyl (isoprapylphenyl), naphthyl, and the like, wherein the aryl group may carry, for example, 1 to 3 suitable substituents such as atoms halogen (e.g. fluorine, chlorine, bromine), hydroxy, and the like.

The term alkanoyl having 1 to 7 carbon atoms denotes a group of the general formula in which

R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

Examples of such groups include formyl, acetyl, propionyl, n-butyryl and the like.

The term substituted phenyl refers to a monosubstituted or disubstituted phenyl group, with halogen (for example, chlorine, bromine, fluorine), C1-C8alkyl, amino, nitro or trifluoromethyl substituents being suitable substituents.

The term substituted alkyl refers to an alkyl group having 1 to 8 carbon atoms which is optionally substituted, for example, by a halogen atom (e.g., chlorine, fluorine, bromine), trifluoromethyl, amino, cyano, and the like.

The term C 2 -C 6 alkenyl refers to a straight or branched hydrocarbon group having an olefinic double bond and 2 to 6 carbon atoms, i.e., the remainder of the compounds of the formula C 1-6 where n is a number from 2 to 6, such as an allyl group, a vinyl group, etc. The term aralkyl group refers to a hydrocarbon group having an aromatic and aliphatic structure, i.e. a hydrocarbon group in which one hydrogen of an alkyl group having 1 to 8 carbon atoms is substituted by a monocyclic aryl group such as phenyl, tolyl etc.

The term 5-, 6- or 7-membered heterocyclic ring having 1 to 4 oxygen, nitrogen and / or sulfur atoms denotes, for example, the following groups:

6-membered nitrogen-containing heterocyclic rings such as pyridyl, piperidyl, piperidino, N-oxidopyridyl, pyrimidyl, piperazinyl, pyridazinyl, N-oxidopyridazinyl, etc .;

5-membered nitrogen-containing heterocyclic rings such as pyrazolyl, pyrrolidinyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, ΙΗ- tetrazolyl, 2H-tetrazolyl, etc. These heterocyclic rings may be further substituted, taking into account, for example, the following substituents:

Λ-.

CS 273350 ο2 ο

(C až-C) alkyl group such as methyl, ethyl, n-propyl, etc., (C až-C alko) alkoxy such as methoxy, ethoxy, etc., halogen atom such as chlorine, bromine etc., haloalkyl C1-C8 such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxy, carbamoyl or carboxy, etc.

The term C 3 -C 7 cycloalkyl refers to a 3- to 7-membered saturated carbocyclic group such as cyclopropyl, cyclobutyl, cyclohexyl, etc.

The term acyl group with up to 22 carbon atoms (cf. substituent R1) denotes all organic groups which are formed by removal of the hydroxy group from the carboxylic acid. Certain acyl groups are preferred. Examples of such preferred acyl groups are those hitherto used to acylate β-lactam antibiotics, including 6-aminopenicillanic acid and derivatives thereof, as well as 7-aminocephalosporanic acid and derivatives thereof; cf. for example, Cephalosporins and Penicillins, Verlag Flynn, Academic Press (1972), Belgian Patent Publication No. 866 038, published Oct. 17, 1978, Belgian Patent Publication No. 867,994, Published Dec. 11, 1978, US Patent No. 4 No. 152,432, issued May 1, 1979, U.S. Patent No. 3,971,778, published July 27, 1976, and U.S. Patent No. 4,173,199, published October 23, 1979. These publications disclose various acyl groups that are used in this case. The following acyl groups further illustrate the term acyl, but do not limit it in any way. Examples of acyl groups include:

a) aliphatic acyl groups of the general formula

F? - CO - in which it represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkenyl group having 3 to 7 7 carbon atoms or a cyclohexadienyl group;

or is one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, mercapto, alkylthio of 1 to 8 carbon atoms or cyanomethylthio, substituted alkyl of 1 to 8 carbon atoms or alkenyl of 2 to 6 carbon atoms;

(b) aromatic acyl groups of the general formulas

R ⁶ i -coí

EN 273350 02 «

Wherein n is 0, 1, 2 or 3;

of 7 β

R, R and R are hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or aminomethyl,

R is amino, C 1 -C 7 alkanoylamino, hydroxy, carboxy in the salt form, protected carboxy such as benzyloxycarbonyl, formyloxy, azido or sulfo in the form of a salt and

M represents a cation.

Preferred carbocyclic aromatic acyl groups are those of the formulas

Particularly preferred is the second of the aforementioned groups (i.e., a phenoxyacetyl group). 90

R is preferably an amino, hydroxy or carboxy group present in the form of a salt or a sulfo group present in the form of a salt.

Examples of other acyl groups useful in the present invention include:

sulfophenylacetyl, hydroxysulfonyloxyphenylacetyl, sulfamoylphenylacetyl, (phenoxycarbonyl) phenylacetyl, (p-tolyloxycarbonyl) phenylacethyl, formyloxyphenylacptyl, carboxyphenylacetyl, formylaminophenylacetyl, benzyloxyphenylacetyl, benzyl

2- (Ν, Ν-dimethylsulfamoyl) -2-phenylacetyl, etc.

c) heteroaromatic acyl groups of the general formulas

101 • (CH _{2) n} - 00 101. - CH - CO - I90 101 - 0 - CH ₂ - co 101 S - CH ₂ - co 101 - what - what -,

in which ,

R is as defined above, n is 0, 1, 2 or 3;

R ³⁰ ' ¹ ' is optionally a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a C 1 -C 4 alkyl group or a C 1 -C 4 alkoxy group substituted with a 5-, 6- or 7-membered heterocyclic ring 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and / or sulfur atoms.

Examples of heterocyclic rings include thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl and tetrazolyl.

Preferred heteroaromatic acyl groups are those wherein R ³ is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyridin-2-yl, 2-amino-1, 3,4-thiadiazol-5-yl, 2-thienyl, 2-furanyl, 4-pyridinyl or 2,6-dichloro-4-pyridinyl.

d [[4-Substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] arylacetyl groups of general formula

R ¹²⁰ - N

N - CO - NH - CH - CO □ 111 in which

111 represents an alkyl group having 1 to 8 carbon atoms, a hydroxyalkyl group having 1 to 8 carbon atoms, or an aromatic group of the general formula

are as defined above, wherein

R ⁶ , R ⁷ and R ⁸ or R ¹¹¹ means the same heterocyclic radical as defined for R ¹⁰¹ ,

120 R optionally represents one or more substituents selected from the group consisting of halogen, cyano, nitro, amino and / or mercapto, substituted alkyl of 1 to 8 carbon atoms, such as 4-alkyl (preferably ethyl or methyl) A -2,3-dioxo-1-piperazinecarbonyl-O-phenylglycyl group in which the alkyl contains 1 to 8 carbon atoms.

e) (substoxyoxy) arylacetyl groups of the general formula

R ¹³⁰ -ON = C-CO101 in which _R 101 R ¹ ? ^O is as defined above and represents a hydrogen atom, a C 1 -C 8 alkyl group, a C 3 -C 7 cycloalkyl group, a C 3 -C 7 carboxy cycloalkyl group or a substituted C 1 -C 8 alkyl group, wherein the alkyl of 1 to 8 carbon atoms is substituted with one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, mercapto, alkylthio of 1 to 8 carbon atoms, an aromatic group as defined above by R ¹¹¹ , carboxy (including salts thereof), C 1 -C 7 alkanoylamino, carbamoyl, C 2 -C 9 alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, C 1 -C 8 hydroxyalkoxyphosphinyl, dihydroxyphenyl, dihydroxyphenyl a (phenylmethoxy) phosphinyl group or a (C1-C8) -alkoxyphosphinyl group in the alkoxy moieties.

As examples of groups of the general formula

R ¹³⁰ -ON = C-COR ¹⁰¹ :

[2- [chloroacetyl] amino] -4-thiazolyl] (methoxyamino) acetyl, (2-amino-4-thiazolyl) (1-methylethoxyimino) acetyl, (2-amino-4-thiazolyl) (methoxyimino) acetyl, (2 -furyl) (methoxyimino) acetyl, (4-hydroxyphenyl) (methoxyimino) acetyl, (methoxyimino) (phenyl) acetyl, (hydroxyimino) (phenyl) acetyl, (hydroxyimino) (2-thienyl) acetyl, [[(dichloroacetyl) oxy] imino] (2-thienyl) acetyl, [5-chloro-2 - [(chloroacetyl) amino] -4-thiazolyl] (methoxyimino) acetyl, (2-amino-5-chloro-4-thiazolyl) (methoxyimino) acetyl , [[[1- (1-dimethylethoxy) carbonyl] -1-methylethoxy] amino] -2-sulfoamino-4-thiazolyl) acetyl, [[[1- (1,1-dimethylethoxycarbonyl] -1-methylethoxy] imino] [ [2- (triphenylmethyl) amino] -4-thiazolyl] acetyl, (methoxyimino) (2-sulfoamino-4-thiazolyl) acetyl, [(1-methylethoxy) imino] [2 - [(methylsulfonyl) amino] -4-thiazolyl] Acetyl, [(3-methylsulfonyl) -2- [3H] -thiazolimino-4-yl] - [1-linethylethoxy) imino] acetyl, [[2- (chloroacetyl) amino] -4-thiazolyl] [[[[ (4-nitrophenyl) methoxy] carbonyl] methoxy] imino] acetyl;

(2-amino-4-thiazolyl) [(carboxymethoxyimidino) acetyl, (2-amino-4-thiazolyl) [1-carboxy- (1-methylethoxy) imino] acetyl, (2-amino-4-thiazolyl) [ [(aminocarbonyl) methoxy] imine] acetyl,

f) (acylamino) acetyl groups of the general formula

R ¹⁴⁰ - CO - NH - CH - CO

R ¹³³ is as defined above, and r ¹⁴¹³ is a group of formula

where f γ q

R, R, Ran are as defined above, hydrogen, C 1 -C 8 alkyl, halogen, trifluoromethyl, amino and / or cyano substituted C 1 -C 8 alkyl, amino, C 1 -C 8 alkylamino C 1 -C 8 dialkylamino, both C 1 -C 8 alkyl cyanalkylamino, hydrazino, C 1 -C 8 alkyl-hydrazino, phenylhydrazino or C 1 -C 7 alkanoylhydrazino.

Preferred (acylamino) acetyl groups of the above formula are those in which R ¹⁴⁰ is amino or acylamino. Also preferred are those wherein R 1 is phenyl or 2-thienyl.

g) (substituted oxyimino) acetyl groups of the general formula

R ¹⁴⁰ -CO-C-O-N = C-COR ²³ where:

R m and have the meanings given above and

23

R and R are each hydrogen or C 1 -C 8 alkyl;

23

R and R together with the adjacent carbon atom represent a carbocyclic ring of up to 7 carbon atoms, for example cyclopropyl, cyclobutyl or cyclopentyl.

Preferred substituted oxyiminoacetyl groups of the above formula are those in which R ^3-43 is amino. Also preferred are those in which R @ ³ = 2-amino-4-thiazolyl.

h) [[[3-Substituted-2-oxo-1-imidazolidinyl] carbonyl] amino] acetyl group of general formula

About »

M c

_b 15 - CO - NH - CH - CO. I · 1

HgC -, CHg R ¹¹¹ in which

R ¹¹¹ is as defined above and

R ¹⁵ represents a hydrogen atom, an alkylsulfonyl group having from 1 to 8 carbon atoms, a group

-NsCH-R ¹¹¹ (wherein R ¹¹¹ is as defined above), R ¹⁶ -CO (wherein R ¹⁶ represents hydrogen or optionally halogen substituted C 1 -C 8 alkyl), aromatic group as defined by R ¹¹¹ or optionally one or more substituents selected from the group consisting of halogen, cyano, nitro, amino and / or mercapto, a substituted C 1 -C 8 alkyl group.

Preferred [[[3-substituted-2-oxo-1-imidazolidinyl] carbonyl] amino] acetyl groups of the above formula are those in which R ¹¹¹ is phenyl or 2-thienyl. Also preferred are those groups wherein R ¹ is a hydrogen atom, methylsulfonyl, or two-fenylmethylenaminoskupinu furylmethylenaminoskupinu.

The substituent R ¹ in formula I representing either of the above mentioned substituted N-heterocyclic groups of the formulas (a), (b) and (c), in particular a group of formula (a) or a group of formula (c) wherein R ¹⁰ represents a group of formula (c1). The substituent R ¹ may be one of the following groups:

(i) groups (a) and (b) (quaternary piperazinium salts)

The symbol A denotes a pharmaceutically acceptable anion which is derived from a pharmaceutically acceptable organic or inorganic acid. Examples of such acids include hydrohalic acids (e.g. hydrochloric acid, hydrobromic acid and hydroiodic acid) as well as other mineral acids such as sulfuric acid, nitric acid, phosphoric acid or the like; lower alkanesulfonic acids and arylsulfenic acids such as ethane-, toluene- and benzenesulfonic acid as well as other organic acids such as acetic acid, trifluoroacetic acid, tartaric acid, maleic acid, malic acid, citric acid, benzoic acid, salicylic acid , ascorbic acid, and the like. The symbol A also includes an anion formed from the carboxy group at position 2 of the cephalosporin nucleus upon dissociation of the proton, forming a zwitterionic ion with a positive charge of the quaternary nitrogen atom.

Preferred embodiments of A are the anions: iodide anion, and the anion trifluoraoetátový 2-carboxylate anion to the cephalosporin nucleus, which forms a radical R ¹ piperaziniovým inner salt.

Q in groups (a) and (b) represents a substituted quinolinyl group, preferably a group of the formula

II in which R ³⁰

R ³⁰ and R ³¹

R ³³

represents a hydrogen atom or a halogen atom, a hydrogen atom, an alkyl group having 1 to 0 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms or mono-, dl- or trihalophenyl;

taken together are C 3 -C 5 alkylene, C 2 -C 4 alkylene monoxy, C 1 -C 2 alkylenedioxy, or -OCH (NCH 3) -; and represents a hydrogen atom or a halogen atom.

In a preferred embodiment of the process of the invention, R @ ³ represents a hydrogen, bromine, chlorine or fluorine atom, in particular a hydrogen or fluorine atom, and R @ ³ represents an alkyl group having 1 to 8 carbon atoms, in particular ethyl or halogen substituted alkyl. C 1 to C 8, especially fluoroethyl, or optionally C 3 to C 7 alkyl, especially cyclopropyl, and R is hydrogen, chlorine or fluorine, especially hydrogen or fluorine.

Examples of substituted piperazinium radicals R1 in the form of groups (a) and (b) are, for example, the groups of the following formulas:

Preferred compounds of the present invention are those compounds of formula (I) wherein R is hydrogen. Particularly preferred are compounds of formula Ia

NORWEGIAN

(la) in which:

R ' ¹ ' and R &lt; ³ & gt ^; are as defined above, R &lt; ² &gt; G is hydrogen or an amino protecting group such as trityl or chloroacetyl;

R represents a hydrogen atom, a C 1 -C 8 alkyl group or a group of the formula

R ²²

- C - COP i ²³

CS 273350 82 who

23

R and R are as defined above and

P is hydroxy or -NHR where »

R represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an amino group, an alkylamino group having 1 to 8 carbon atoms, a phenylamino group or an alkanoylamino group having 1 to 7 carbon atoms.

Particularly preferably, compounds of the formula Ia, 20 21 wherein R is hydrogen and R is methyl or _R 22 are prepared according to the process of the invention.

- C - COOH

R ²³ where

23

R and R are hydrogen or methyl.

Groups of general formulas

R ¹³⁰ -O-N = C-CO- ¹⁰¹

R ²²

R ¹⁴⁰ - CO - C - O - N = C - CO - and R ² 'R ^U1

NOR ²¹ i

- c - co are present preferably in the syn-form, i.e. in the Z-form, or in the form of mixtures in which the syn-form predominates.

62

A further preferred class of compounds are those of formula (Ib)

R ‘, 2

O - _CH2 - CONH

, 11

COOH (Ib) wherein 2

R is as defined above and rH is one of (a) and (b) above

Examples of salts of the compounds of formula I include alkali metal salts such as sodium salt and potassium salt, ammonium salts; alkaline earth metal salts such as calcium salt; salts with organic bases such as salts with amines, for example salts with N-ethylpiperidine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, alkylamines or dialkylamines, as well as 1 amino acid salts such as salts with arginine or lysine.

The compounds of formula I, when they contain a basic functional group, such as an amino group, also form addition salts with organic or inorganic acids. Examples of such salts include hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as salts with other mineral acids such as sulfates, nitrates, phosphates and the like, alkyl and monoarylsulfonates such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like. other organic acids such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula I, including their salts, may be hydrated. Hydration may occur in connection with the manufacturing process or may occur gradually as a result of the hygroscopic properties of the initially anhydrous product.

According to the invention, the compounds of formula I as defined above are prepared by reacting a compound of formula III

- N.

(III)

COOH in which 2 <3

R and R are as defined above and are a leaving group, and the amino, hydroxy and carboxy groups may optionally be protected, or a salt of this compound with a compound of formula IV or IVa

AND

1 '

in which

Q is as defined above, wherein the nitrogen atoms and the optionally present amino, hydroxy and carboxyl functions are optionally protected, the optionally present protecting groups are cleaved and, in order to produce the salts or hydrates of the compound of formula I, or the hydrates of these salts the compound of formula (I) per salt or hydrate or hydrate thereof.

The reaction of the compounds of the formula III and their salts with the piprazine derivatives of the formulas IV or IVa according to the invention is preferably carried out by first protecting the starting compounds of the formula III or their salts, preferably with a trimethylsilylating agent such as N-methyl -N- (trimethylsilyl) trifluoroacetomide (MSTFA) protecting any amino, hydroxy and carboxy groups present. The leaving group X is preferably a halogen atom, for example a chlorine, bromine or especially iodine atom, a lower alkyl or arylsulfonyloxy group, for example a mesyloxy or tosyloxy group, or an azido group.

The carboxy group of compounds of formula III may be optionally protected, for example by esterification to another readily cleavable aster such as the tert-butyl ester, the p-nitrobenzyl ester, the benzhydryl ester or the allyl ester. The carboxy group may also be protected by salt formation with an inorganic or tertiary organic base such as triethylamine. The amino groups present in the R groups may be protected. Possible protecting groups are, for example, hydrolytically, under acidic conditions, leaving groups, such as tert-butoxycarbonyl or trityl, or leaving groups under hydrolysis, such as trifluoroacetyl. Preferred protecting groups are chloroacetyl, bromoacetyl and iodoacetyl, especially chloroacetyl. The latter protective groups may be cleaved by thiourea.

The piperazine derivatives of the general formula IV and IVa are preferably protected on a nitrogen atom, for example by the MSTFA group.

The reaction is preferably carried out at a temperature of about 0 ° C to room temperature and in an inert organic solvent such as chloroforms, methylene chloride, or acetonitrile. The zwitterionic forms of the compounds of formula I are obtained by reacting the halide salt obtained with a base, for example, sodium bicarbonate or sodium hydroxide or sodium phosphate buffer.

The carboxy protecting groups are preferably those which, under mild conditions, can readily be converted to a free carboxyl group, such as a target. butyl, p-nitrobenzyl, benzhydryl, allyl, etc. Carboxy protecting groups are cleaved, for example, as follows;

v? 17. The p-nitrobenzyl group is cleaved by hydrolysis in the presence of sodium dart at. a temperature of Q ° C (or lower) -to room temperature in a solvent such as dimethylformamide (preferably in aqueous); the tepe, the hatyl group and the benzhydryl group are cleaved by reaction with trifluoroacetic acid, optionally in the presence of snisol, at a temperature of about 0 ° C to about room temperature, optionally in the presence of an additional solvent such as methylene chloride; The ellylic lupine is cleaved off with transallylsalkylated palladium in the presence of sodium or potassium 2-ethylcaproic acid λίβρον, eg 3.

Org. Chem. 1982, 47,. 5P7> - ... = · <'/' ·. '''- ^::

Possible amino protecting groups are those which are used in peptide chemistry, such as alkoxycarbonyl groups, especially tert-butoxycarbonyl groups, etc., substituted alkoxycarbonyl groups, such as trichloroethoxycarbonyl groups, etc., substituted aralkoxycarbonyl, such as, for example, nitrocarbonyl, e.g. an aralkyl group, such as a phenyl group, or a haloalkanoyl group, such as a chloroactyl group, a bromoacetyl group, an iodoacetyl group, or a trifluoroactyl group; <

Preferred amino protecting groups are _; The t-BOC, butoxycarbonyl group (t-BOC) and the trityl group. ,

The amino protecting groups are cleavable by, for example, acidic hydrolysis (such as a tert-butoxycarbonyl group or a trityl group), or else by bosic hydrolysis (for example, trifluoroacetyl). Chloro-, bpom-, iodoacetyl groups can be cleaved by treatment with thiophilia. . · ’··’? '·

The amino protecting groups which are cleavable by acid hydrolysis are preferably removed by lower alkanoic acid, which may optionally be halogenated. In particular, a formic acid, trifluoroacetic acid or working out usually at room temperature, although it may also use slightly higher or slightly lower temperature, for example ranging from about 0 C ^P dq .. +40 ° _C; * »'' -. ,

Protective groups which are cleavable under alkaline conditions are generally hydrolyzed with dilute aqueous lye at a temperature of from about 0 ° C to + 30 ° C, and chlorine, bromine and pyridyl protecting groups can be cleaved by treatment with thiourea in an acid, neutral or alkaline environment. *at. at about 0 C ^Q OF. + 30 ° C., » 'r'

The preparation of the salts of the hydrates of the compounds of the formula I or of the hydrates of these salts by the process according to the invention 6e can be carried out by reacting, for example, a carboxylic acid of general formula I with equilibrium. an organic solvent such as ethanol, methanol, qoetpnu APSD adequately implementing design ^- BÓ1Í addition of organic or anorganipké acids. the temperature during the salt formation is not critical and usually is carried BC | room temperature, although it is operated while teplqtáqh. Which The temperature is above or below room temperature, in the range of about 0 ° C to + 50 ° C.

Preparation of hydrates. It is carried out automatically in connection with the heating process or as a result of the hygroscopic properties of the initially anhydrous product, if it is intended to prepare a hydrate, the completely or substantially anhydrous product (carboxylic acid of formula I or one of its spirals) may be exposed to a humid atmosphere. for example at a temperature in the range of from about + 10 ° C to +40 ° C,

-. '·''In / * _in V' ·

The following reaction schemes illustrate the preparation of the compounds of the invention.

The compounds of formula (IV) to be used as starting materials R are represented by the substituted derivatives of plperazine of formula (IV);

i *

CS, 273350 B2 (IV)

wherein the piperazine core may be substituted with one or more alkyl groups of 1 to 8 carbon atoms, preferably alkyl groups of 1 to 4 carbon atoms.

Instead of these substituted piperazine derivatives of formula IV, substituted piperazines of formula IVa can also be used

HjC

(IVa)

In the following schemes, R 'represents a readily cleavable amino protecting group such as a tert-butoxycaponyl group; R, R and R are as defined above. The reactive groups are preferably protected; for example, amino groups may be protected by groups that are readily cleavable in peptide chemistry, for example, alkoxycarbonyl groups such as tert-butoxycarbonyl, etc .; substituted alkoxycarbonyl groups such as trichloroethoxycarbonyl and the like, substituted alkylcarbonyl groups such as monochloromethylcarbonyl groups, substituted aralkyloxycarbonyl groups such as p-nitrobenzyloxycarbonyl groups, or aralkyl groups such as triphenylmethyl.

Preferred protecting groups are t-butoxycarbonyl (t-BOC) or triphenylmethyl.

Protecting groups of the carboxyl function are, for example, ester forms which can be converted into free carboxyl groups under mild conditions. Examples of such groups include tert-butyl, p-nitrobenzyl, benzhydryl, allyl etc. Trimethylsilyl ester groups are also useful.

The compounds of formulas IIIa, i.e. the starting materials in Schemes I and III, are known and can be prepared by conventional procedures; some of these compounds are commercially available, such as 7-aminocephalosporanic acid. (Cf. Gordon, EM, and Sykes, RB in Chemistry and Biology of β-Lactam Antibiotiqs, Vol. 1, Morin, RB and Gorman, M., Academic Press, New York, 1982; Chapter 3, as well as literature references) and Ponsford, Rj and others in Recent Advances in Chemistry of β-Lactam Antibiotios, Proceedings of the Third International Symposium, Brown, AG and Roberts, SM, editors: Royal Society of Chemistry, Burlington House: London , 1985; Chapter 3 and references cited therein.)

Scheme I

1) MSTFA

2) WE ARE,

, CH,

3) IV + MSTFA

4) MeOK

C0 ₂ H

R ³ NH (lilac)

(Ic)

Scheme I:

The starting compound of formula IIIa is pre-protected by reaction with a trimethylsilylating reagent such as N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA) in an inert solvent such as chloroform or methylene chloride. The trimethylsilyl ester obtained, in which all potentially reactive sites, such as amino, hydroxy and carboxy, are protected with trimethylsilyl groups, is then reacted with iodotrimethylsilane at a temperature of about 0 ° C to about room temperature for about 20 minutes to about 2 hours. The reaction mixture is then evaporated under reduced pressure and the residue dissolved in a suitable solvent which does not contain hydroxyl groups, such as acetonitrile. Addition of a small amount of tetrahydrofuran (THF) decomposes the remaining amount of iodotrimethylsilane. The obtained protected, iodinated intermediate is then reacted in situ with a protected piperazine derivative of formula IV prepared from piperazine of formula IV by treatment with a trimethylsilylating agent such as MSTFA in a solvent which is compatible under the conditions, such as acetonitrile. The quaternization reaction is carried out for about 30 minutes to 24 hours, preferably for about 2 hours. Then a solvent containing CS 273350 B2 containing a hydroxyl group, such as methanol, is added under ice cooling, whereby the trimethylsilyl protecting group is lytically removed and the quaternary iodide of formula Ic is eliminated. After further treatment conditions, such as sodium bicarbonate or sodium hydroxide, or sodium sulfate buffer, the compound of formula Ic becomes a zwitterionic form.

Depending on the amount of the base added or the pH of the buffer 3 on salts, further functions in substituent R and substituent Q are employed.

solvobase groups by converting the ion of the formula can be converted

(Illb)

(Ic)

(Id)

Scheme II:

Compounds of formula IIIb are known and can be prepared, for example, according to U.S. Patent 4,266,049 (R. Bonjouklian, May 5, 1981). The piperazine derivative of formula IV is first protected by treatment with a trimethylsilylating agent such as MSTFA in a suitable solvent such as acetonitrile under anhydrous conditions. Other conventional protecting groups which can be cleaved under mild conditions may be used at will. Examples include the conversion of the carboxy group to the tert-butyl or p-nitrobenzyl ester form,

After reaction of the compounds of formula IIIb with a protected form of the piperazine derivative of formula IV in an inert form

Compound C: [6R- [6ώ, 7/1 (Z)]] - 1 - [[7 - [[[(2-amino-4-thiazolyl)] - [1- (1-carboxy-1-methyl) ethoxy]] imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -4- [3-carboxy-1- (2 (fluoroethyl) -6,8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl] -1-methylpiperazinium hydroxide (inner salt) in the form of the monosodium salt

Compound D: [6R- [6,1,7 / 1 (Z)]] - 1 - [[7 - [[(2-amino-4-thiazolyl) (methoxy imino) acetyl] amino] -2-carboxy- 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -4- (3-carboxy-1-ethyl-6-fluoro-1,4- dihydro-4-oxo-7-quinolinyl) -1-methylpiperazinium iodide

Compound E: (6R-trans) -4- [3-carboxy-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7-quinolinyl] -1 - [[2-carboxy-7] (Formylroino) -8-oxo-5'-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -1-methylpiperazinium trifluoroacetate.

J}

T a b u 1 k a 1

Minimum inhibitory concentration (yug / ml) as determined by the in vitro dilution series method

microorganism compounds 1 AND- (B) C D E E. coli ATCC 25922 0.25 0.5 0.25 0.5 0.5 E. ooli TEM 1 0/25 0.5 0.5 0.5 0.5 E. cloacae 5699 0.5 0.5 0.5 1 0.5 E. cloacae P99 0.5 0.5 2 1 0.5 S. marcescens 0.5 0.5 0.5 0.5 1 P. aeruginosa 8710 8 8 8 (B) 8 P. aeruginosa 18 S / H 8 4 8 32 8 E. faecalis ATCC 29212 64; 32 32 32 32 S. pneurooniae 6301 0,063 0.25 1 0,063 1 S. aureus 10598 2 0.5 8 2 0.5 S. aureus 4 ‘ 1 4 4 1 S. aureus ATCC 29213 4 0.5 4 4 0.5

In treating a bacterial infection in a mammal, the compound of the invention may be used at a daily dose of from about 5 to about 500 mg / kg, preferably from about 10 to 100 mg / kg, especially from about 10 to 55 mg / kg. Also suitable for the novel cephalosporins of the present invention are all routes of application that have hitherto been considered in the treatment of penicillins and cephalosporins. Thus, the administration forms are, for example, intravenous, intramuscular and enteral, for example in the form of suppositories.

The compounds of the invention may be used as medicaments, for example in the form of pharmaceutical preparations containing the compounds or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as water, gelatin, acacia, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules or in liquid form, for example in the form of solutions, suspensions or emulsions. . These preparations are optionally sterilized and optionally contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure, anesthetics or buffers. The compositions may also contain other therapeutically valuable substances. The carboxylic acids of the formula I and their salts or hydrates are preferably used for parenteral administration and are preferably prepared in the form of a lyophilisate or a dry powder for dilution by conventional means such as water and isotonic sodium chloride solution, co-solvents such as propylene glycol. Also readily hydrolyzable esters of the formula I are suitable for enteral administration.

The following examples illustrate the invention in more detail, but do not limit the scope thereof.

Example 1

Preparation of [R-trans] -4- [3-carboxy-1- (2-fluoroethyl) -6,8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl] -1 - [[2 -carboxy-8-oxo-7- [phenoxyacetyl] amino-3,5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -1-methylpiperazinium iodide

A mixture of 406 mg (1 mmol) of [(R) -trans] -3- (acetyloxy) methyl] -8-oxo-7-penoxyacetyl) amino] -5-thia-1-azabicyclo [4.2] was stirred under argon. O] oct-2-ene-2-carboxylic acid, 2 mL of absolute methylene chloride and 0.60 mL (3 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide (MSTFA) for 1 hour; after addition of 0.28 ml (2 mmol) of iodotrimethylsilane, the mixture was stirred for a further 2 hours. The solution was then evaporated to dryness under reduced pressure and the residual oil was dissolved in 2 ml of acetonitrile. After adding 5 drops of anhydrous tetrahydrofuran, the mixture is stirred for 5 to 10 minutes. After adding a solution of 111 mg (0.3 mmol) of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid acid, 0.11 mL (0.6 mmol) of MSTFA and 1 L of acetonitrile were stirred for an additional 2 hours. The mixture was cooled in an ice bath and about 100 mg of methanol was added. The precipitate obtained is filtered off, washed with acetonitrile and dried under reduced pressure. There was thus obtained the title compound.

NMR Spectrum (Perdeuterated Dimethylsulfoxide): cf values

3.15 (s, 3H, NCH 3), 3.45-3.85 (m, 9H, 4 x NCH ₂ and CH ₂ CH ₂ ), 3.95 (d, 1H, 3 gem = 16.5 Hz, CH of SCH ₂ ), 4.39 and 4.77 (AB, 2H, 3 gem = 13 Hz, NCH ₂ ), 4.61 and 4.64 (AB, 2H, 0 gem = 15 Hz, OCH ₂ CO) , 4.83 - 5.07 (Μ, 4H, NCH ₂ CH ₂ F), 5.24 (d, 1H, 3 = 5 Hz,

CH), 5.82 (dd, 1 H, 3 = 5 and 7 Hz, CH), 6.95 (d, 2 H, 3 = 8 Hz, Ar), 6.97 (t, 1 H, 3 = 8 Hz Ar), 7.29 (t, 2H, 3 = 8 Hz), 7.96 (d, 1H, 3 = 12 Hz, Ar), 8.91 (s, 1H, .dbd.CH-),

9.18 (d, 1H, J = 7 Hz, NH);

IR (KBr): 3400, 1788, 1728, 1700, 1612 cm ^- ^

Mass spectrum: m / z = 716 (cation).

Example 2

Preparation of monosodium salt of [6R- [6 ', 7' (Z)]] - 1 - [[7 - [[[(2-amino-4-thiazolyl)] - [1- (1-carboxy-1-methyl)] ethoxy] amino] acetyl] amino] -2-carboxy-8-oxo-5-thial-1-azabicyclo [4.2.0] oct-2-one-3-yl] methyl] -4- [3- carboxy-1- (2-fluoroethyl) -6,0-difluoro-1, N-dihydro-4-axocolinolin-1-yl] -1-methylpiperazinium hydroxide

A mixture of 5.12 g (8 mmol) of [6R- [6 < 1,7 > (Z)]] - 3 - [(acetyloxy) methyl] -7- (L '[(2- amino-4-thiazolyl) [1H-carboxy-1-methyl) ethoxy] imino] acetyl] amino] -O-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acids with trifluoroacetic acid, 48 ml absolute acetonitrile and 12 ml (64 mmol) N-roethyl-N- (trimethylsilyl) -trifluoroacetamide (MSTFA) for 30 minutes; after the dropwise addition of 2.0 ml (14 mmol) of iodotrimethylsilane, the mixture was stirred for an additional 30 minutes. The reaction mixture was then cooled in an ice bath and 1.12 mL (14 mmol) of absolute tetrahydrofuran was added. After 10 minutes, a solution of 2.27 g (6 mmol) of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo- Of 3-quinolinecarboxylic acid, 24 ml of acetonitrile and 1.28 ml (7.2 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide and the mixture is stirred for a further 1.5 hours. The mixture was then evaporated under reduced pressure and the residual oil was dissolved in 40 ml of acetonitrile. After cooling in an ice bath, 4 ml of methanol are added and a thick precipitate is formed. After a few minutes, the precipitate settles and is filtered off and washed four times with 10 ml of acetonitrile each time. After drying, the solid is triturated with 60 ml of methanol, then filtered off and washed four times with 10 ml of methanol each. The solid so obtained (5.7 g) was suspended in water, and an aqueous sodium bicarbonate solution was added until pH 7. This crude product solution is purified in 3 stages by reverse phase C-HPLC. _B> In a first step, a column packed with 50 g of silica gel (Waters C _1S ) is used, and water is used as the eluent, followed by 30¾ of the acetonitrile in water. In the second step, the product is further purified by high pressure liquid chromatography on a C18-Waters-Prep-500A column.

In the third step, the product column removes salt at the very rapid filling ohromatografii Nou 60 g _C18 silica gel, using water and 20% aoetonitrilu in water as eluent. Evaporation under reduced pressure and freeze-drying gave 1.0 g of the title compound.

Nuclear Magnetic Resonance Spectrum (Perdeuterated Dimethylsulfoxide - O ₂ 0): δ values

1.37 (s, 3H, _CH3), 1.44 (s, 3Ή, CHy), 3.10 (s, 3H, NCHj), 3.39 and 3.88. (AB, 2H, J gem = 16.5 Hz, _SCH2), 3.40-3.70 (m, 8H, 4 x _NCH2), 4.12 and 5.17 (AB, 2H, J gem = _12.5 tons Hz, _NCH2 ), 4.62 to 4.94 (m, 4H, NCH ₂ GH ₂ F), 5.15 (d, IH, □ = 5 Hz, CH), 5.73 (d, IH, <J = 5Hz, CH), 6.74 (s, 1H, Ar), 7.83 (d, 1H, J = 12 Hz, Ar), 8.47 (broad, s, 1H, = CH-);

IR (KBr): 3400, 1772, 1618, 1595 cm ^-1

Mass spectrum: m / z = 859 (M + H) &lt; + & gt ^; . ,

Example 3

Preparation of [6R- [ωώ, 7 (5 (Z)]] -1 - [[7- [X (2-amino-4-thiazalyl) (methoxyimino) acetyl] amino] -2-carboxy-8-oxo -5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -4- (3-carboxy-1-ethyl-6-fluoro-1,4-dihydro- 4-oxo-7-quinolinyl) -1-methylpiperazinium iodide

A mixture of 273 mg (0.6 mmol) of [6R- [6 < 1.7 / l (Z)]] - 3 - [] (acetyloxy) methyl] -7- [C (2-amino-4) is stirred under argon. -thiazolyl) (methoxyimino) acetyl] amino] -8-oxa-5-thial-1-azabicyclo [4.2.0] oct-2-enecarboxylic acid, 2 mL absolute methylene chloride and 0.45 mL (2, 4 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide for 2 hours. After addition of 0.17 ml (1.2 mmol) of iodotrimethylsilane, the mixture was stirred for a further 2 hours. The mixture was then evaporated under reduced pressure and the residual oil was dissolved in 2 ml of absolute acetonitrile. After addition of a few drops of absolute tetrahydrofuran, the mixture was stirred for an additional 15 minutes. A solution of 60 mg (0.18 mmol) of 1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid, 1 ml of absolute, is then added. of acetonitrile and 0.07 mL (0.36 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide and the mixture was stirred for an additional 2 hours. 125 mg of methanol are added dropwise to give the product. The solid was filtered off, washed four times with 1 ml of acetonitrile each time and evaporated under reduced pressure. Trituration with methanol under reduced pressure yields the title compound,

NMR spectrum (perdeuterated dimethylsulfoxide): .delta

1.45 (broad t, 3H, _CH? Group of NEt), 3.15 (s, 3H, NCHj), 3.50 to 3.95 (m, 9H, NCH ₂ 4 XX CH, SCH, and R, 3, 85 (s, 3H, OCH-j), 3.99 (d, 1H, 3 gem = 16.5 Hz, CH ₂ CH ₂ ), 4.43 and 4.70 (AB, 2H, 3 gem = 14 Hz) NCH ₂ ), 4.61 (broad q, 2H, CH ₂ of NEt), 5.31 (d, 1H, 3 = 5 Hz, CH), 5.94 (dd, 1H, 3 = 5 and 8 Hz) , CH), 6.76 (s, 1H, Ar), 7.30 (broad, 2H, NH ₂ ), 7.31 (d, 1H, 3 = 6.5 Hz, Ar), 8.03 (d @ 1 H, .delta. = 12.5 Hz, Ar), 9.03 (s, 1H, .dbd.CH--), 9.68 (dd, 1H, .delta. = 8 Hz, NH);

IR (KBr): 1785, 1720, 1680, 1628 cm ^- ^

Mass spectrum: m / z = 729 (cation).

Example 4

Preparation of [6R- [6 <, 7/5 (Z)]] - 1- [7 - [[[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-carboxy-8-oxo- 5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -4- [3-carboxy-6,8-difluoro-1- (2-fluoroethyl) -1], 4-Dihydro-4-oxo-7-quinolinyl] -1-methylpiperazinium iodide

CO ₃ H

A mixture of 84.6 mg (0.186 mmol) [[RC ^{] 6} > 7fl (Z)] 3 - 3 - [(acetyloxy) methyl] -7- [C (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -8, -oxo-5-thia-1-azabicyclo [4.2.0] oct-2-one-2-carboxylic acid, 4 mL of absolute methylene chloride and 0.148 mL (0.8 mmol) of N-methyl-N (Trimethylsilyltrifluoroacetamide was stirred for 1 hour. To this solution was added 0.0625 mL (0.46 mmol) of iodotrimethylsilane. The mixture was stirred for 2 hours and evaporated to dryness under reduced pressure. a few drops of absolute tetrahydrofuran was added, the mixture was stirred for 3 min and then a solution of 36.9 mg (0.10 mmol) of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro- 7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid, 0.040 mL (0.215 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide and 2.0 mL of absolute acetonitrile were stirred for 3 hours. A precipitate formed after the addition of 0.50 ml of methanol and the solid was filtered off and washed repeatedly is acetonitrile and dried to give 87.5 mg of the title compound.

NMR spectrum (perdeuterated dimethylsulfoxide): values /

3.15 (s, 311, NCIIj), 3.50 to 3.90 (in, 911, 4 × NCH ₂ CH groups of SCH ,,), 3.116 (t, 3H,

OCH 3), 3.96 (d, 1H, 3 gem = 17 Hz, CH ₂ CH ₂ ), 4.42 and 4.73 (ΛΒ, 2H, 3 gem = 14 Hz, NCH ₂ ), 4.48- 5.10 (m, 4H, NCH ₂ CH ₂ F), 5.29 (d, 1H, 3 = 5 Hz, CH), 5.93 (dd,

1H, J = 5 and 7 Hz, CH), 6.86 (s, 1H, Ar), 7.24 (s, 2H, NH ₂ ), 7.98 (d, 1H, 3 = 12 Hz,

Ar), 8.94 (s, -1H = CH-), 9.67 (d, 1H, 3 = 7 Hz, NH);

IR (KBr): 3420, 1775, 1720, 1675, 1618 cm ^1st

Example 1 a d 5

Preparation of 6R- [6,6,7,7] (Z) -1- [7 - [[[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-carboxy-8 monosodium salt -oxo-5-thial-1-azabicyclo [4.2.0] oct-2-en-2-yl] methyl] -4-Q-carboxy-6,8-difluoro-1- (2-fluoroethyl) - 1,4-dihydro-4-oxo-7-quinolinyl] -1-methylpiperazinium hydroxide.

r

A suspension of 900 mg of the compound produced in Example 4 in water was neutralized with 0.1N aqueous sodium hydroxide solution and the solution obtained was freeze-dried. The residue was purified by reverse phase HPLC on a Waters-Prep-500A column, eluting with a mixture of water and acetonitrile with a gradient of 0 to 40%. Evaporation and freezing of the appropriate fractions gave 344 mg of the title compound.

NMR Spectrum (Perdeuterated Dimethylsulfoxide): δ values

3.10 (s, 3H, NCH-j), 3.40-3.76 (m, 9H, 4 x NCH ₂ and CH of the SCH ₂ group), 3.84 (d, 1H, = 16 Hz, CH groups) SCH ₂ ), 3.84 (s, 3H, OCH-j), 4.10 and 5.19 (AB, 2H, 3 gem = 14 Hz),

4.70 to 4.94 m, 4H, NCH ₂ CH ₂ F), 5.13 d, 1H, 3 = 5 Hz, CH), 5.65 (dd, 1H, 3 = 5 and 7 Hz,

CH), 6.74 (s, 1H, Ar), 7.23 (s, 2H, NH ₂ ), 7.82 (d, 1H, 3 = 12 Hz, Ar), 8.55 (s, 1H, = CH-), 9.58 (dd, 1H, 3 = 7 Hz, NH);

IR (KBr): 3410, 1772, 1665, 1618 cm ^L MS: ro / z 787 (M + H) ^+.

Example 6

Preparation of (6R-trans) -4- [3-carboxy-6,8-difluar-1- (2-fluoroethyl) -1,4-dihydro-7-quinolinyl] -1 - [[2- (1,1- dimethylethoxy) carbonyl-7- (formylamino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

A mixture of 0.87 g (2.35 mmol) of 6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid acid, 0.51 mL (2.6 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide and 5 mL of absolute acetamide are stirred for 30 minutes. After addition of 1.00 g of [6R (6,7,7S) -7-formylamino-3-iodomethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-1,1-dimethyl ester, Of 2-en-2-carboxylic acid, the reaction mixture was stirred for an additional 24 hours. The precipitate obtained is filtered off and set aside. The mother liquor is absorbed onto a 5 g silica gel column. After eluting with water, 10¾ and 20¾ aqueous methanol, the appropriate fractions were combined and evaporated under reduced pressure. A precipitate was obtained, which was filtered off and dried. 380 mg of the title compound are obtained.

IR (KBr): 3440, 1785, 1720, 1610 cm ^- ^;

Mass spectrum: m / z = 666 (cation).

CS 273350 82

Example 7

Preparation of (6R-trans) -4- [3-carboxy-1,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7-quinolinyl] -1- [> - carboxy-7- (formylamino) 8-Oxo-5-thia-1-azabicyclo [4.2.0] act-2-en-3-yl] methyl] -1-methylpiperazinium trifluoroacetate

O! 1

HCNH

CO, H

A mixture of 200 mg of the compound prepared according to Example 6, 0.2 ml of anisole and 2.5 ml of trifluoroacetic acid was stirred at room temperature for 3 hours. After insoluble matter was filtered off, the solution was evaporated under reduced pressure. The residue was dissolved in 10 ml of acetonitrile and 200 ml of ether was added thereto to precipitate the product. The precipitate was filtered off and dried, yielding 135 mg of the title compound.

NMR Spectrum (Perdeuterated Dimethylsulfoxide): Values no

3.14 (s, 3H, NCH-j), 3.50-3.85 (m, 9H, 4 x NCH ₂ and CH ₂ CH ₂ ), 3.95 (d, 1H, gem = 16.5 Hz) CH of SCH ₂ ), 4.35 (d, 1H, J gem = 13 Hz, CH of NCH ₂ ),

4.82-5.05 (m, 5H, NCH ₂ CH ₂ F and CH of the NCH ₂ group, 5.23 (d, 1H, 3 = 5 Hz, · CH), 5.84 (double d, 1H, Δ = 5 and 7 Hz, CH), 7.96 (d, 1H, δ = 13 Hz, Ar), 8.17 (s, 1H, NCHO), 8.92 (s, 1H, = CH -) 9.11 (d, 1H, J = 7 Hz, NH);

IR: 3400, 1780, 1720, 1685 cm ^{- '1'.}

Mass spectrum: m / z = 610 (cation).

Example A

Production of dry ampoules for intramuscular application

1 g of the active ingredient is prepared in a conventional manner and filled into an ampoule. The sterile water ampoule contains 10% propylene glycol. 2.5 ml of a 2% aqueous lidocaine hydrochloride solution are added to the lyophilisate prior to application. Any of the end products produced according to Examples 1 to 7 can be used as the active ingredient.

Claims (14)

SUBJECT OF THE INVENTION CLAIMS 1. A process for the preparation of novel cephalosporin derivatives which are substituted with an N-heterocycle at the 3-position of the general formula I in which: R ¹ represents a substituted N-heterocyclic radical of formula (a) or (b) wherein Q represents a substituted quinolinyl group having up to 18 carbon atoms, wherein the N-heterocyclic radical is optionally substituted with at least one alkyl group having 1 to 8 carbon atoms; R is hydrogen, C 1 -C 8 alkoxy, C 1 -C 8 alkylthio or C 1 -C 7 alkanoylamino, R ⁷ represents an acyl group of up to 22 carbon atoms, and A is a pharmaceutically acceptable anion as well as pharmaceutically acceptable salts of these compounds and hydrates of the compounds of formula I, or hydrates of their salts, characterized in that a compound of formula III in which: R and R are as defined above and X is a leaving group, and the amino, hydroxy and carboxy groups may optionally be protected, or a salt of this compound with a compound of formula IV or IVa (IV) in which: Q is as defined above, wherein the nitrogen atoms and optionally present amino, hydroxy and carboxyl functions are optionally protected, Any protecting groups present are cleaved to produce salts or salts. hydrates of a compound of formula I or hydrates of these salts, the compound of formula I is converted into a salt or a hydrate or a hydrate thereof, 2. A process according to claim 1, wherein the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give compounds of the formula I213 wherein R is hydrogen and R and R are as defined in point 2. 3. A process according to claim 1 or 2, wherein the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give the compounds of the formula I in which the group I is where R ³⁰ represents a hydrogen atom or a halogen atom, R ³¹ represents a hydrogen atom, a C 1 -C 8 alkyl group, a C 2 -C 6 alkenyl group, a C 3 -C 7 cycloalkyl group, a C 1 -C 8 haloalkyl group or a mono-, di- or trihalophenyl group or R ( ³⁰⁾ and R ( ³¹⁾ together are (C3 -C5) alkylene, (C2 -C4) alkylene monoxy, (C1 -C2) alkylenedioxy or -OCH2NCCH3) - and R ³³ represents a hydrogen atom or a halogen atom, and 2 3 R and R are as defined in point 1 or 2. 4. A process according to claim 3, wherein the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give compounds of the formula I in which R @ ¹ is as defined in point 3 wherein R @ ³⁵ is hydrogen. , bromine, chlorine or fluorine, R ³¹ is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl or C 3 -C 7 cycloalkyl and R ³³ is hydrogen, chlorine or fluorine, and others the substituents have the meaning given in point 3. , 1 5. The method of claim 4; that starting from the corresponding compounds III and IV or IVa to give the compounds of formula I, wherein R ¹ is as defined in paragraph 3 -wherein R ³⁵ represents hydrogen or fluorine, 31 33 R is ethyl, fluoroethyl, or cyclopropyl, and R is hydrogen or fluoro and the other substituents are as defined in point 4. Process according to one of Claims 1 to 5, characterized in that the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give compounds of the formula I in which R ³ represents an aromatic acyl group of the formula CH ₂ - CO and the other substituents are as defined in any one of items 1 to 5. Process according to one of Claims 1 to 6, characterized in that the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give compounds of the formula I in which R ³ represents a (substoxyimino) arylacetyl group of the general formula formulas R ¹³⁰ -ON = C-COR ¹⁰¹ wherein R ¹⁰¹ represents a group of the formula wherein R represents a hydrogen atom or an amino protecting group and R @ ¹ = ³⁰ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a group of the formula R ²² - COP, l · ³ where 22 23 R and R represent a hydrogen atom or a C 1 -C 8 alkyl group or together with a neighboring carbon atom represent a C 3 -C 7 carbocyclic ring and P is hydroxy or -NHR in which R is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 amino, phenylamino or C 1 -C 7 alkanoylamino, and the other substituents are as defined in one of items 1 to 5. 8. A method according to claim 7, characterized in that starting from the corresponding compounds III and IV or IVa to give compounds of formula "I, wherein R ³ is as defined in paragraph 7, wherein R ²³ represents and R @ ³³ represents a methyl group or a group of the formula CS 273350 82 R ²² - C - COOH R ²³ wherein R ²² and R ²³ are hydrogen or methyl and the other substituents are as defined in point 7. Process according to either of Claims 7 or 3, characterized in that the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give the compounds defined in point 7 or 8 in a syn-form or in the form of mixtures, syn-form prevails. 10. A process according to claim 1, wherein the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give (6R-trans) -4- [3-carboxy-1- (2-fluoroethyl) -6 8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl] - [[2-carboxy-8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2] , 0] oct-2-en-3-yl] methyl] -1-methylpiperazinium iodide, monosodium salt of inner salt [6R- [6A, 7/5 (Z)]] - 1 - [[7 - [[[(2 amino-4-thiazolyl)] 1- (1-carboxy-1-methyl) ethoxy] imino] acetyl] amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -4- [3-carboxy-1- (2-fluoroethyl) -6,8-difluoro-1,4-dihydro-4-oxoquinolin-7-yl] -1 methylpiperazinium hydroxide and [6R- [6λ, 7/1 (Ζ)]] - 1 - [[7 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-carboxy-8-oxo -5-thial-1-aza-bicyclo [4.2.0] oct-2-en-3-yl] methyl] -4- (3-carboxy-1-ethyl-6-fluoro-1,4-dihydro -4-oxo-7-quinolinyl) -1-methylpiperazinium iodide. 11. A process according to claim 1, wherein the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give [> R- [6 < 7 &gt; / 1 (Z)]] -1- [[[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3- yl] methyl] -4- [3-carboxy-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7-quinolinyl] -1-methylpiperazinium iodide. 12. The process of claim 1, wherein the corresponding compounds of formula III and IV or IVa are used as starting materials to form the monosodium salt of the internal salt of [6R- [6 ', 7A (Z)]] -1- [ [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl methyl] -4- [3-carboxy-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-4-oxo-7-quinolinyl] -1-methylpiperazinium hydroxide. 13. A process according to claim 1, wherein the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give (6R-trans) -4- [3-carboxy-6,8-difluoro-1- ( 2-fluoroethyl) -1,4-dihydro-4-oxo-7-quinolinyl] -1 - [[2-carboxy-7- (formylamino) -8-oxo-5-thia-1-azabicyclo [4.2.1 &lt; 2,7 &gt; O] oct-2-en-3-yl] methyl] -1-methylpiperazinium trifluoroacetate. 14. A process according to claim 1, wherein the corresponding compounds of the formulas III and IV or IVa are used as starting materials to give [6R- [6a, 7 / i (Z)]] - 1 - [[7- [ [(2-amino-4-thiazolyl) - [[1,1-dimethyl-2- (1,1-dimethylethoxy) -2-oxo-ethoxy] imino] acetyl] amino] -2-carboxy-8-oxo 5-thia-1-azabicyclo [4.2.0] oct-2-en-3-yl] methyl] -4- [3-carboxy- (2-fluoroethyl) -6,8-difluoro-1,4- dihydro-4-oxoquinolin-7-yl] -1-methylpiperazinium iodide.