CS270227B2 - Method of new acyl derivatives production - Google Patents

Abstract

Cephalosporin derivatives of the formula <IMAGE> in which m represents 0, 1 or 2, R<1> represents hydrogen or an acyl group, R<2> represents hydrogen, lower alkoxy, amino, lower alkylthio or lower alkanoylamino, R<3><1> represents hydrogen, lower alkyl, lower alkenyl, C3-C7-cycloalkyl, halogen-lower alkyl or halophenyl; Z represents R<3><0>-C or nitrogen, R<3><0> represents hydrogen or halogen, or R<3><0> and R<3><1> together represent a C3-C5-alkylene group, a C2-C4-alkylene- monooxy group or a C1-C2-alkylenedioxy group, R<3><2> represents hydrogen, halogen, lower alkyl or an optionally substituted 5- or 6-membered heterocyclic ring having one, two or three oxygen, nitrogen and/or sulphur atoms and R<3><3> represents hydrogen or halogen or R<3><2> and R<3><3> together represent a C1-C4-alkylenedioxy group, and easily hydrolysable esters and salts of these compounds and hydrates of the compounds of the formula I or of their esters and salts are described. The products have antimicrobial activity.

Description

R @ 1 and R @ 2 are epoxy, respectively, C1-4alkylene CS270227 B2 dioxo. As well as the salts of these compounds and the hydrates of the compounds of the formula I or the hydrates of the compounds thereof, this is based on this. A compound of formula IV in which R is an ester protecting group which is useful in the chemistry of cephalosporin and which is cleavable under mild conditions, for example tert-butyl, pnitrobenzyl or allyl. cleaves the ester protecting group R, preferably a p-nitrobenzyl group by hydrolysis in the presence of sodium carbonate, a tert-butyl group by reaction with tri-fluoroacetic acid in the presence of anisole or an allyl group by transellylation of catalysed palladium. of the carboxylic acids of formula X, whereupon the compound obtained is optionally isolated in the form of salt, hydrate or salt form. · The compounds produced are antibacterial and can be used as medicaments ·

(IV)

CS 270 227 B2

The present invention relates to a process for the preparation of the novel aoyl derivatives of the following general formula I having valuable pharmacological properties.

New acyl derivatives of the general formula X have been found

(X>

in m '

R ^1, which is 0, 1 or 2, represents a hydrogen atom or an acyl group useful for the aoylation of β-γ-γ-type antibiotics of β to 21 carbon atoms, such as the formula group

up to 8 carbon atoms which is a substl?

_H 101 _B 120 _H 130

R ² kterýoh is hydrogen or alkyl of 0 tuována kyanoekupincu means an optionally amino substituted pétiélenný hetorooyklický ring having 1 or 2 nitrogen and / or sulfur, represents an alkyl group 1 1 d 8 carbon atoms and is optionally carboxy substituted alkyl group and one has a value of 0, 1, 2 or 3, which is hydrogen, C1-C8alkoxy, amino, C1-C8alkylthio or C1-C7alkanoylamino,

CS 270 227 B2 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 halophenyl group,

Z represents a group R ^C-C or an atom of the atom, wherein

R (10) is hydrogen or halogen, or and iP ( ¹⁾ is a C 3 -C 5 alkylene group, C 2 -C 4 alkylene monoxy or C 1 -C 2 alkylenedioxy,

R ^ ² represents a hydrogen atom, a halogen atom, a C 1 -C 8 alkyl group or optionally a C 1 -C 8 alkyl group or a formyl group substituted with a five- or six-membered N-heterocyclic ring optionally containing an oxygen atom or an additional nitrogen atom R33 represents a hydrogen atom or a halogen atom;

R (2 ⁾ and R (2) together are C1 -C4 alkylenedioxy, the salts of these compounds and the hydrates of the compounds of formula (I) or the hydrates of their salts. The term alkyl ¹¹ refers to straight and branched chain hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, tert-butyl group or under ·

The term alkoxy refers to straight or branched hydrocarbon oxy groups in which the alkyl moiety is as defined above. Examples include methoxy, ethoxy, n-propoxy, and the like.

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

The term aryl "refers to an optionally substituted aromatic group such as phenyl, tolyl, xylyl, masityl, cumyl (isopropylphenyl), naphthyl, and the like, wherein the aryl group may contain, for example, 1 to 3 suitable substituents such as a halogen atom (such as fluorine, chlorine, bromine), hydroxy, etc. ·

The term C 1 -C 7 alkanoyl refers to a group of the formula

R ²⁵ - CO in which

R ² represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, ·, examples of these groups are uvéet асеtylovou, formyl, propionyl, n-butyryl and the like *.

Substituted phenyl refers to a mono- or disubstituted phenyl group, ** wherein the substituents are halogen (e.g., chlorine, bromine, fluorine), (C 1 -C 8) alkyl, amino, nitro, or trifluoromethyl;

The term substituted alkyl means an alkyl group having 1 to 8 carbon atoms which is optionally substituted by halogen (e.g. chlorine, fluorine, bromine), trifluoromethyl, amino, cyano, etc. ·

The term C 2 -C 6 alkenyl refers to straight or branched hydrocarbon groups having an olefinic double bond and 2 to 6 carbon atoms, i.e. the remainder of the compounds of the formula С _д Н _2п in which n is a number from 2 to 6, such as allyl group CS 270 227 B2 full, wool group etc ·

The term aralkyl refers to a hydrocarbon group having an aromatic and aliphatic structure, i.e. a hydrocarbon group in which one hydrogen atom of a C 1 -C 8 alkyl group is substituted by a monocyclic aryl group, for example a phenyl group, a tolyl group, etc. ·

The term * five-, six *, or seven-membered heterocyclic ring of 1 to 4 oxygen, nitrogen and / or sulfur * denotes, for example, the following groups: six-membered, nitrogen-containing heterocyclic rings such as pyridyl, piperidyl, piperidino, N-oxidopyridyl, pyrimidyl, piparazinyl , pyridazinyl. N-oxidopyridazinyl etc .; five membered nitrogen containing heterocyclic rings such as pyrrolidinyl, pyrazolylimidazyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl. 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-trlazolyl,

1,2.4-triazolyl, 1H-tetrazolyl. 2H-tetrazolyl etc. These heterocyclic rings may be further substituted, for example with the following substituents: alkyl of 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, etc. ·, alkoxy of 1 to 8 carbon atoms, such as methoxy , ethoxy, etc. ·, halogen such as chlorine, bromine, etc., haloalkyl and 1 to 8 carbon atoms, such as trifluoromethyl · trichloroethyl, etc. ·, amino, mercapto, hydroxy, carbamoyl or carboxy, etc. ·

The term ^w cycloalkyl of 3 to 7 carbon atoms "refers to a 3- to 7-membered saturated karbooyklický residue such as cyclopropyl, cyclobutyl, etc. oyklohexyl · ho _mo lpi and together be alkylene having 3-5 C atoms, for example - (CH ) ^ -, _{-CH2) 4} "" _^(CH2) 5 or -CH (CH.j) - (CH _{2) 2,} or also alkylenmonooxyskupinu with 2-4 carbon atoms, e.g., - (CH _{2) 2} -O -, ~ (CH ₂ ) 3 -O-, - (CH ₂ ) ₄ -O or -CH (CH ₂ -O-) or else C 1 -C 2 alkylenedioxy, such as -O-CHg-O ", - O- (CH ₂ ) ₂ -O- or -O-CH (CH 2) -O-, preferably form a five- or six-membered fused ring,

R ² and _m represent the common ohou alkylendioxyskupimi β 1 to 4 carbon atoms such as the group -, -O- (CH ₂ 0- ^ · "θ" (0Η ₂₎ ^ - 0-. ^ -O- CH) 4-O-, -O-CH (CH3) -O-, -043H (CH3) 4H (CH3) -O- or similar groups. In this case, a five or six-membered fused ring is preferred.

The term acyl (R ¹⁾ comprises organic groups ktevé is formed by removing the hydroxyl group with a carboxylic acid containing up to 21 carbon atoms. Examples of such groups are those which have been used to date with acyl-alpha-lactam antibiotics, including 6-aminopenicilic acid and derivatives thereof, as well as 7-aminocephasporic acid and derivatives thereof, cf. e.g. Cephaloeporins and Penicillins, Verlag Flynn, Academie Press (1972), Belgian Patent 866 038, published Oct. 17, 1978, Belgian Patent No. 867,994, published Dec. 11, 1978. 1978, U.S. Patent No. 4,152,432, published January 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. In these publications, U.S. Pat. disclose various acyl groups which are used in the present case. The following aoyl groups are further illustrated by the term acyl group, but are not intended to limit it in any way. Examples of acyl groups include:

(a) an aliphatic group of the formula R ⁵ - CO in which:

R ⁵ represents a hydrogen aram or an alkyl group of 1 to 8 carbon atoms which is substituted by a cyano (b) carbocyclic aromatic group of the formulas

CS 270 227 B2 ti

0CH ₂ - C -

COOH (s) a heteroaromatic group of the general formula

R ¹⁰¹ - (CH ₂ ) _n - CO -.

where n is 0, 1, 2 or 3 and

R ¹⁰¹ represents an optionally substituted 5-membered five-membered heterocyclic ring having 1 or 2 nitrogen atoms and / or

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

Preferred heteroaromatic acyl groups are those in which R ¹⁰¹ is 2-amino-4-thiazolyl or 2-thienyl * (d) [[(4-substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] arylactyl a group of the general formula

in which

R ¹²⁰ is C ₁ -C ₈ alkyl, for example 4r (C ₁ -C ₈ alkyl, especially ethyl or methyl) -2,3-dioxor-1-piperazine-carbonyl-D-phenylglycylf (e) (subst * oximino) ) an arylacetyl group of the general formula

R ¹³ ° -O-N-C-CO ¹⁰¹ where _R 10 °,.

is as defined above and

R @ ¹ = ^O is optionally carboxy substituted by a C1 -C8 alkyl group.

As examples of groups

R ¹³ ° -O-HC-COR ¹⁰¹ include the following groups:

2- (2-Aminothiazol-4-yl) -2-isopropoxyiminoacetyl,

CS 270 227 B2

2- (2-aminothiazol-4-yl) -2-methoxyiminoacetyl,

2- (2-aminothiazol-4-yl) -2-hydroxyiminoacyl, 2-thienyl-2-methoxyiminoacetyl, 2-thienyl-2-hydroxyiminoacetyl, 2-thienyl-2- (dichloroacetoxyimino) acryl, 2- ( 2-aminothiazol-4-yl) -2-carboxymethoxyimino) acetyl; 2- (2-aminothiazol-4-yl) -2- (carboxyisopropoxyimino) acetyl, etc. *.

In a preferred selection of the 3-quinolinyl or azaquinolonyl substituents in the 3-position, Z represents a group in which R 50 represents a hydrogen atom, a chlorine or fluorine atom, preferably hydrogen or a fluorine atom.

R @ ¹ is preferably an alkyl group having from 1 to 8 carbon atoms, particularly preferably an ethyl group or a haloalkyl group having from 1 to 8 carbon atoms, in particular a fluoroethyl group, or a cycloalkyl group having from 3 to 7 carbon atoms; group

R @ ² is preferably an alkyl group having from 1 to 8 carbon atoms, in particular a methyl group, or a piperazinyl group which is optionally substituted on the nitrogen atom in the 4-position by an alkyl group having 1 to 8 carbon atoms, preferably a methyl group | ·

R @ 1 preferably represents a hydrogen, chlorine or fluorine atom, in particular a hydrogen or fluorine atom;

CS 270 227 B2

Ή

CS 270 227 B2

CS 270 227 B2

CS 270 227 B2

CS 270 227

A preferred group of compounds of the invention are those of formula Ib

(Ib) in which it is as defined above,

R ²⁰ represents an amino-protecting group, such as a trityl or chloroacetyl group, or preferably a hydrogen atom, and

R represents a hydrogen atom, an alkyl group of β 1 to 8 carbon atoms or a group of the formula

R ²²

AND

- C - COOH where

R ( ²²⁾ and R ( ²¹ ) are hydrogen or alkyl of 1 to 8 carbon atoms;

R @ ²² and R @ ² together represent e carbon atom to which they are attached, a 3- to 7-membered carbocyclic ring, for example, cyclopropyl ring, cyclobutyl or cyclopentyl ring.

Particularly preferred are compounds of formula Ib in which

R ²⁰ represents a hydrogen atom and

R ²¹ is methyl or formula

COOH taking

R @ ²² and R @ ² represent hydrogen or a methyl group ·

Groups

N - O - R ¹³⁰ N - O - R ttII a

- C - C are preferably present in the syn-form, ie in the Z-form, or in the form of mixtures in which the syn-form predominates ·

Examples of salts of the compounds of formula I include alkali metal salts such as sodium and potassium salts, ammonium salt salts in alkaline earth metals such as calcium, and salts with organic bases such as salts in amines such as salts with N-ethylpiperidine, procaine, dibenzylamine, N, N'-dibenzylethylenediamine, alkylamines or dialkylamines, as well as salts with amino acids such as salts 8 of arginine or lysine.

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

The compounds of formula I, including their salts, can be hydrated. K hydrataoi may occur during the manufacturing process or gradually as a result of the hygroscopic properties of the initially anhydrous product ·

The present invention relates to a process for the preparation of novel acyl derivatives of the formula I which comprises:

CS 270 227 B2

in which m, R ¹ , R ² , R · * ¹ , R? ² and are as defined above, and

R is an ester protecting group which is used in the chemistry of cephalosporins and which is cleavable under mild conditions such as a tert-butyl group, a p-nitrobenzyl group or an allyl group cleaves the ester protecting group R, preferably a p-nitrobenzyl group by hydrolysis in the presence of straw sodium, tert-butyl by reaction with trifluoro-acetic acid in the presence of anisole or a palladium-catalyzed allyl transallylalo group in the presence of sodium or potassium salt of 2-ethylcaproic acid to give the carboxylic acid of formula I, optionally recovering the compound as a salt, hydrate or in a salt hydrate blower ·

The protecting groups of the ester group R of the esters of formula IV which are used in the process according to the invention are preferably those which, under mild conditions, can be converted into a free carboxyl group, such as a target, butyl, p-nitrobenzyl, benzhydryl, allyl The above-mentioned easily hydrolyzable ester moieties can also be used. The protecting groups of the ester group are cleaved, for example, by the following methods, the p-nitrobenzyl group by hydrolysis in the presence of sodium sulfide at 0 ° C (or lower) to room temperature in a solvent such as for example in dimethylformamide (preferably aqueous dimethylformamide); tert-butyl group by reaction with trifluoroacetic acid in the presence of anisole at a temperature of about 0 ° C to room temperature, with or without an additional solvent such as palladium- (O) -methylene chloride / allyl transallylalkyl group in the presence of sodium or potassium salt of 2-ethylcaproic acid (cf. for example J. Org · Chem · 1982. 47 · 587) · '

The preparation of the salts and hydrates of the compounds of the formula I or of the hydrates of these salts according to the invention can be carried out in a known manner, for example by reacting the carboxylic acid of the formula I with an equimolar amount of the desired base, suitably in a solvent such as water or an organic solvent such as ethanol, · Salt formation temperature is not a critical condition and varies around room temperature, but can also be operated at a temperature slightly above room temperature or at a temperature slightly below room temperature, for example from 0 ° C to +50 ° C ·.

Hydroscopic production is usually carried out automatically as a result of the manufacturing process or as a result of the hygroscopic properties of the initially anhydrous product. In the deliberate production of the hydrate, the zoela or partially anhydrous product (carboxylic acid of formula I or one of its salts) may also be exposed to a humid atmosphere, for example at temperatures +10 ° C to +40 ° C ·

The starting compound of formula IV can be prepared by reacting the compound of formula IV

CS 270 227 B2 (II) of formula II

wherein m ₉ R ¹ , R ² and R are as defined above and

Hal represents a halogen atom with a carboxylic acid salt of the general formula III

0 R ³³ HOCO - 1 i | l JI ( ⁴ Z ^ _R 32 1 R ³¹

(III) wherein

R ³¹ , R ³² and R ³³ are as defined above.

Reacting a halide of model II is a carboxylic acid salt of pattern III is preferably carried out in rozpoufrtědle _t which do not contain hydroxyl groups · · as in dimethylfoxuamidn · of methylene chloride or N, R * -dimethylaoetamidu · Suitable salts of the carboxylic acid III pattern as sodium · potassium · · cesium Tero · butylamine or tetraethylammonium · Hal in the general pattern sloučenináoh П · represents a halogen especially bromine or iodine · This reaction is preferably carried out at temperatures of about 0-80 ° 0 _t particularly at rt ·

Compounds of formula I with groups

NOR ¹³⁰

NOR ²¹ II or - C -

(cf. above) are preferably present in the form of syn-forms · Such α-forms can be obtained using starting materials · in which this syn-form is already present · If desired, the obtained syn / anti-forms of the compound of formula I can be separated in conventional manner to the corresponding syn- and anti-forms, for example by recrystallization or chromate by ographic techniques using a suitable solvent · or solvent mixture ·

Compounds pattern I ₉ and also the corresponding salts or hydrates of these compounds are antibiotic, especially bakterioidně active · can be used as agents к combat bacterial infections (including infekoí urinary tract dýohaoíoh vessels) in mammals · eg dogs _t cat · horses, etc. · as well as humans · These oephalosporins are effective against a wide range of both gram-negative and gram-positive bacteria ·

The in vitro potency of the compounds of the invention against a variety of gram-positive and gram-negative microorganisms, expressed as the minimum inhibitory concentration in microgram / ml and ascertained using the dilution series (liquid) method, is as follows:

CS 270 227 B2

Compound A: [6R- (6R, 7A)] 3R [[E (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyljoxy] hydrate] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thiar-1-azabicyclo [4.2.0] ract-2-ene-2-carboxylic acid

Compound B: [6R- (6R, 7A)] - 3T [[[[(5-ethyl-5,8-dihydro-e-oxo-1,3-dioxolo [4,5-g] quinolin-7]] monosodium salt -yl) carbonyl] oxy] methyl] -8-O, O - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] -2-ene-2-carboxylic acid.

Compound C: sodium sůlpR- (6tf, 7 (i) (z) j [£ 2-amino-47thiazolyl) (methoxyimino) aoetylj -amino -3 - [[[(l-1-1 _t βthy 4-dihydro-7 methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyl-oxylmethyl-8-oxo-5 * thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

Compound D: sodium sd1 [6R- (6,7,7A) (Z) -? - (2-amino-4-thlazolyl) (methoxyimino) acetyl] amino] -3 - [[[(5-ethyl-5 »8) -dihydro-8-oxo-1,3-dioxo [4,5- g (quinolin-7-yl) carbonyl] oxy] methyl-3-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -27 carboxylic acids.

Compound E: 6R- (6tf, 7 (J)] - 3-E-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4- oxoquinolin-3-yl] carbonyl-oxy-methyl-8-oxo-7-f (phenoxyacetyl) amino-5-thia-17-azabioyklo [4.2.0] oct-2-ene-2-carboxylic acid.

Compound F: [6R- (6α, 7β)] -3- [δ-5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl] sodium salt yl) carbonyl] oxy] methyl] -8-oxo-7 - [(2-thienylacetyl) amino] -5-thia-1-azabioyclo [4.2.0] oct-2-ene-2-carboxylic acid.

Compound G: Sodium £ 6R- (6 H, 7 / J) -3- £ j [£ _l-ethyl-6-t řluor-L-744-4rdihydro formyl71piperazinyl) -4roxochinolin-3-yl] karnonyl] oxy methyl] -8- (2-thienylacetyl) amino-8-oxo-5-thia-1-azabioylclo [4.2.0] oct-2-ene-2-carboxylic acid.

Compound H: Sodium [6R (6o & 7/3)] -3- ££ _{[l-ethyl-6-fluoro-4-t-dihydro} 7r (l-pyrrolidinyl) -4-oxoquinoline-3-yl carbonyl] oxy] methyl] -8-oxo-7- (phenoxyacetyl) amino] -S-thiaScazabioylclo [4.2.0] oct-2-ene-2-carboxylic acid

Compound I: δ 6 R- (6 ', 7/3) (Z) -7- E 2 (amino-4-thiazolyl) (methoxy) amino) acetyl-2-amino-3-EMI sodium salt [[1-ethyl-6] -fluoro-1,4-dihydro-7R- (1-pyrrolidinyl) -4-oxoquinolin-3-ylcarbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acids.

Table

Minimum In vitro Inhibitory Concentration in (µg / ml) microorganism minimum inhibitory concentration of compounds

AND В 0 D E E. coli 32 2 0.5 0.25 8 K. pneumoniae A 16 1 0.5 0.25 2 E. cloacae 957OA 64 2 2 1 8 E. cloacae 948-1 «Β 2 8 1 8 E < cloacae 236772 7 1 16 2 4 E. cloacae 7099 16 θ · 5 8 0.5 2 E. cloacae 128 2 8 0.5 8 P. vulgaris ATCO 6380 8 0.5 0.25 0,063 4 P. mirabilis 8 0.5 0.16 0.008 0.5 S. marcescens SM 16 1 1 0.5 4 P. aeruginosa Stone 128 32 128 16 16 P. aeruginosa 503-56 128 64 128 32 32 S. aureus Smith 0.25 0.25 2 2 0,063 S. aureus - 4 8 4 2

CS 270 227 B2 table continuation:

microorganism minimal inhibitory concentration of compounds

F G H AND E * coli 2 8 32 0.5 Pneumoniae 1 4 32 0.5 E, cloacae 957OA 2 8 32 2 E * cloacae 948-1 1 8 32 4 · £ cloacae 2367-2 1 32 32 4 E * cloacae 7099 0.5 2 2 2 E * cloacae 2 64 32 4 P. vulgaris ATCC 6380 0.5 4 32 0.5 P * mirabilis 190 0 * 5 4 0.5 0,031 S. Marceecena SM 1 4 32 1 P * aeruginoea Stone 130 32 32 32 8 P. aaruginosa 503-56 64 64 64 32 S · aureue Smith. 0.25 0.25 0.25 0.25 S * aureus 4 4 0.5 0.5

For controlling bacterial infections, the compound of the invention can be administered to mammals at a daily dose of from about 5 to about 500 mg / kg, preferably at a dose of from about 10 to 100 mg / kg, especially at a dose of about 10 to 55 mg / kg. the types of applications that are currently contemplated in the treatment of penicillin and oephalosporins are also applicable to the novel cephalosporins of the invention. Thus, the administration can be carried out, for example, by intravenous, intramuscular and entoral administration.

The compounds of the invention may be used as medicaments, for example in the form of pharmaceutical preparations containing these compounds or their salts in admixture with a farm? oeutic, organic or inorganic inert carrier materials suitable for enteral or parenteral applications such as water, gelatin, acacia, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline etc. · Pharmaceutical preparations they may be present 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 auxiliary substances such as preservatives, stabilizers, wetting agents, emulsifiers, salts for varying the osmotic pressure, anesthetics or buffers. These preparations may also contain other therapeutic agents. Carboxylic acids of the formula I and their salts or hydrates are preferably suitable for parental application and are preferably prepared for this purpose in a parenteral form. except for lyophilisates or dry powders for dilution with conventional means such as water and isotonic sodium chloride solution, co-solvents such as propylene glycol. Easily hydrolysable esters of formula I are also suitable for enteral application *

The following examples illustrate the invention but do not limit it in any way.

Example 1

1,1-dimethylethyl [6R- (6 <* 7 β)] -3 - [[[(5-ethyl-5 _t 8-dihydro-8-oxo-3-dloxolo [4,5-g] 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid-5-thia-1-azabicyclo [4.2.0] octin-7-yl) carbonyl] oxy] methyl] -7-

A solution of the sodium salt of 5-ethyl-5,8-dihydro-8? _T oxo-3-ůioxolo [4,5-g] quinoline-7-carboxylic acid (1 nrnol) in 12 ml of dimethylformamide was stirred under nitrogen for 1 hour in 1.5 g of molecular sieve (4 · 10 · 4 ° m) and then a solution of [6R- (6tf, 7 / J)] -3r (Joethyl) -ethoxo-7 1,1-dimethylethyl ester was added. - [(phenoxyaoethyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (1 mmol) in 6 ml of absolute dimethylformamide and stirred for 5 hours · The mixture is then evaporated to dryness.

CS 270 227 B2 with ethyl acetate / methylene chloride, the solution obtained is then washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulphate and evaporated to dryness. ethyl acetate / methylene chloride 8: 2 as eluent ·

Example 2

[6R- (6 (7070) (Z)] -3-LCt (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3- 1, 1-dimethylethyl ester) yl) carbonyloxy] methyl] -7-1C (methoxyimino) - [2- (t-riphenylmethyl) amino-4-thiazolyl] acetyl-amino] -8-oxo-5-thia-1-ezabicyclo [4.2.0] oct -2-en-2-carboxylic acids · ·

The title compound ee is obtained by repeating the reaction described in Example 1 using 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid sodium salt and C6R- 1,1-dimethyl-ethyl ester. (6 (ft7A) (Z)) -3-iodomethyl-7- (C (methoxyimino) -2- (triphenylmethyl) amino-4-thiazolyl) acetyl 1 amino] -8-oxo-5-thia-1-azabicycloC4, The residue was purified by flash chromatography using a 9: 1 mixture of ethyl acetate and methylene chloride as the solvent system.

Example 3

C 6 R- (6 rf, 70) (Z) -3-tEE (5-Ethyl-5,8-dihydro-8-oxo-1,3-dioxolo) 4,5-quinoline-7- 1,1-dimathylethyl ester yl) -carbonyloxy oxy-7-CC (methoxyimino) -E 2- (triphenylmethyl) amino-5-thiazolyl) acetyl] amino] -θ-o-5-thia-1-azabicyclo 4,2.0 1 oct-2-ene -2-carboxylic acids · *

The title compound is obtained by repeating the reaction described in Example 1 using

5-ethyl-5,8-dihydro-8-oxo-1,3-dioxoloE 4,5-g-quinoline-7-carboxylic acid and 1,1-dimethylethylether 6R- (6 < 70 &gt;, 70) - (Z) 3 -3-iodomethyl-7- [X (methoxyquinino) -? 2- (triphenylmethyl) amino-4-thiazolyl-acetyl-amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct- 2-en-2-carboxylic acid starting materials · The residue is purified by flash chromatography using a 9: 1 mixture of ethyl acetate and methylene chloride as the solvent system.

Example 4

E 6R- (6,66,71) -3-CLE 11-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinoline 1,1-dimethylethyl ester 3-yl] carbonyloxy-3-methyl; -β-οχο-7-C (phenoxyacstyl) amino-5-thia-1-azabicyclo-C4,2,0J-oct-2-ene-2-carboxylic acid

The title compound is obtained by repeating the reaction of Example 1 using 1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid and 1, C6R- (6 <C ₉ 7β) -3-Q-iodomethyl] -8-oxo-7- (2 (phenoxyacetyl) amino-5-thia-1-azabicyclo [4.2.0] oct-2-ene-1-dimethyl-ethyl ester) 2-carboxylic acid starting materials The residue is purified by flash chromatography using a 20: 1 mixture of methylene chloride and methanol as solvent system.

Example 5

6R- (6,6,7) -3- (5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo) -4,5-g quinoline-

oct-2-ene-2-carboxylic acid

To a solution of 3.00 g (4.52 mmol) of the reaction product of Example 1 in 15 ml of anisole is added, while stirring at room temperature, 10.6 ml of trifluoroacetic acid. The reaction mixture is stirred for 4 hours and then evaporated to dryness under reduced pressure. · The residue is obtained as an oil which is dissolved in methylene chloride and water is added to the obtained solution. The pH of the reaction solution was adjusted to pH 7.5 by the addition of sodium bicarbonate. The mixture was stirred for 20 min and then the aqueous phase was removed. Water addition and pH adjustment to 7.5 with hydrogen

CS 270 227 B2 sodium carbonate was repeated twice with stirring. The three aqueous extracts were combined and freeze dried. The residue is purified by chromatography on a non-polar, stationary phase (reverse phase C ^ _Q ) using 50% aqueous methanol as solvent. After evaporation and freeze-drying, the title compound is obtained.

The compound obtained has the following properties:

IR spectrum (KBr technique):

3410, 1765, 1692, 1635, 1528 cm

Mass spectrum:

m / z 630 (M ⁺ H), 652 (M * H) ·

He does

E 6R- (6cC, 7β) (Z) -7- (2-Amino-4-lhlazolyl) - (methoxyxino) acetyl amino-3-CLE (1-ethyl-1,4-dihydro-7-methyl) sodium salt -4-oxo-1,8-naphthyridin-3-yl) carbonyl] oxy] methyl 3-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

A suspension of 0.31 mmol of the reaction product of Example 2 in 0.66 ml of aniaol was cooled to 0 ° C under a nitrogen atmosphere and 3.3 ml of trifluoroacetic acid was added to the cooled suspension. The solution thus obtained was kept at 0 for 18 hours. ° C and then evaporated under reduced pressure at room temperature · After the addition of methylene chloride, the evaporation under reduced pressure is repeated · The residue is triturated with ethyl acetate to give a solid, if possible, before being converted to the sodium salt. In both cases, the solid or oil obtained is dissolved in 9 ml of methylene chloride, and then an aqueous solution of sodium bicarbonate is added dropwise to the solution thus obtained in methylene chloride at a temperature of 0 to 3 ° C. contains a sufficient quantity of sodium bicarbonate to achieve a final pH of 7,2 to 7 ^ 4 freeze-drying and then purified by high-performance liquid chromatography using a reversed-phase column using an aqueous-methanol mixture and a methanol gradient (0 to 100% methanol, 20 minutes) as the eluent. with the following characteristic values:

IR spectrum (KBr technique):

3405,3300, 3200, 1766, 1716, 1681, 1617,

1537 cm * ¹ ·

Example 7

6R- (goC, 7β) (Z) J -7-EE (2-amino-4-thiazolyl) - (methoxy-amino) acetyl] amino-J -3-ECC (5-ethyl-5,8-dihydro-B) -oxo-1,3-dioxolo [4,5-g (quinolin-7-yl) carbonyl] oxy] methyl-8-oxo-5-thia-1-azebicyclo [4.2.0] oct-2-ene- 2-carboxylic acids

The title compound is obtained according to the procedure described in Example 6, but using the reaction product of Example 3.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3400 - 3200, 1767, 1715, 1685, 1635, 1616, 1533 cm ^-1 .

Mass spectrum:

m / z 679 (M * H), 701 (M * H) ·

Example 8

Sodium salt [2,6R- (6 (E, 7β) -3-CLE1-ethyl-6-fluoro-1,4-dihydro-7- (4-forsyl-1-piperezinyl) -4-oxoquinolin-3-yl) carbonyl methyl-7-E (phenoxyacetyl) amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Using the procedure described in Example 6 and using the reaction product of Example 4, the title compound is obtained having the following characteristics:

CS 270 227 B2

IR spectrum (KBr technique):

3420, 1768, 1668, 1620 cm ^-1 ;

Mass spectrum:

m / z 716 (M @ ⁺ + H), 738 (M @ + + Na).

Example 9

1,1-dlmethylethyleeter £ 6R- (6ťÉ 7 / J)] -3- £ ££ _(5-ethyl-5-F 8-dihydro-8-oxo-l, 3-dioxolo

Q4,5-quinolin-7-yl) -carbonyl-3-oxy-methyl-8- 8-oxo-7- (2-thienylacetyl) -amino-5-thia-1- 8-bicyclo [4.2.0} oct-2- en-2-carboxylic acids

Procedure as described in Example 1 but using 1,1-dimethylethyloethanol Q6R- (6R, 7β)] -3- (iodomethyl) -8-oxo-7- (2 (2-thienylacetyl) amino) -5-thia 1-esabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and 5-ethyl-5,8-dihydro-7-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl ) carboxylic acid starting material to give the title compound ·

Example 10

[6R- (6tf, 7β)] -3-C- (5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo-4,5-g-quinolin-7-yl) sodium salt carbonyl-3-methoxy-3- (8-oxo-7- (2-thienylacetyl) amino) -5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylic acid

The title compound is obtained as described in Example 6, but using the reaction product of Example 9.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3410, 1763, 1682, 1632, 1608 cm ^-1}

Mass Epectrum:

m / z 620 (M ⁺ H), 642 (M ⁺ H). .

Example 11

6R- (6C, 7β) -3- [[[1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4- oxoquinoline-3-yl oxy-3 with methyl karbonyl3 £ 7- (2-thienylacetyl) amino-3 -8-oxo-5-thia-4 azabicykloE _f 2.03 OTR-2-ene-2-carboxylic acid

The procedure described in Example 1, but using 1, l-dimethylethyl £ 6R- (6tf ⁷ β)] -3- (iodomethyl) -8-oxo-7- £ (2-thienylacetyl) amino-5-thia-l -azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and sodium salt of 1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxo-3- quinolinecarboxylic acid starting materials gave the title compound. ,

Example 12

Sodium are 6R- (6d, 7β)] -3- C-1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3 -yl-3-carbonyl-oxy-ethyl--7- (2-thienylacetyl-amino-8-oxo-5-thia-1-azabicyclo-4,2,0-oct-2-ene-2-carboxylic acid)

Following the procedure described in Example 6, but using the reaction product of Example 11, the title compound was obtained.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3430, 1765, 1715, 1662, 1623 cm ¹ .

Mass spectrum:

m / z 706 (M + H).

Example 13

6R- (6'S, 7β) (Z) -3-? LLC 1-ethyl-6-fluoro-1,4-dihydro-7- (4-forCS 270 227 B2 myl-1) -1-dimethylethyl ester -piperazinyl) -4-oxo-quinolin-3-yl] carbonyl-oxy-methyl-7- (methoxyimino) -2-trifluoromethyl) amino-4-thiazolyl-3-acetyl-amino-3-8-oxo-5-thia-1-azab ± cyclo C4,2, Oocok-2-ene-2-carboxylic acid

Using the procedure of Example 1, but employing? 6R- (6?, 7β) (Z) -3- (iodomethyl) -7-? (Methoxyimino) -? 2- (triphenylmethyl) aeino-4, 1,1-dimethylethyl ester -thiazolyl-3-acetyl-amino-3-8-oxo-5-thla-1-azabicyclo-C4,2,0-oct-2-ene-2-carboxylic acid and 1-ethyl-6-fluoro-1,4-dihydro-7-sodium salt - (4-formyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid starting material to give the title compound.

Example 14

Sodium salt 6R- (6R, 7R) (2)] -7- (2-amino-4-thiezolyl) (methoxyimino) acetyl 3 amino 3-3-ethyl-6-fluoro-1,4- dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3-yl (2-carbonyl) oxy] methyl-8-oxo-5-thia-1-azabicyclo C 4,2.03 oct-2-ene -2-carboxylic acids

The title compound is obtained as described in Example 6, but using the reaction product of Example 13.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3420, 1765, 1712, 1622 cm ^-1 .

Finished spectrum:.

m / z 764 (M * H) ·

Example 15

1,1-dimethylethyl £ 6R- (6 H / ₉ 7β)] -3- ££ ££ 1-ethyl-6-fluoro-1,4-dihydro-7- (lpyrrolidlnyl) -4-oxoquinoline-3-yl3 karbonyljoxylmethy 13-7-8- (phenoxyacetyl) -mino -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The title compound (ee) was obtained according to the procedure of Example 1 but substituting E6R- (6 < 0.7 &gt; D)] -3- (iodomethyl) -8-oxo-7- (phenoxyacetyl) amino] -5-thiae 1,1-dimethylethyl ester -1-azabicyclo-4,2,0-3-oct-2-ene-2-carboxylic acid and 1-ethyl-8-fluoro-1,4-dihydro-4-oxo-7- (1-pyrrolidinyl) -3- sodium salt quinolinecarboxylic acids as starting materials ·

Example 16

Sodium salt of C6R- (6 (7β)) -3- [QQ [1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl- 7-f (Phenoxyacetyl-amino-8-oxo-5-thia-1-azabicyclo-C4,2,0-oct-2-ene-2-carboxylic acid

The title compound is obtained as described in Example 6, but using the reaction product of Example 15.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3410, 1770, 1695, 1628 cm ¹ .

Mass spectrum:

m / z 673 (M + + H), 695 (M + + No).

Example 17

C 6 R- (6?, 7 (i) (Z)) -3-CCCCl-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinoline-3, 1-dimethylethyl ester -yl-3-carbonyl-oxy-methyl-7-E - ((ethoxy) amino) - (2- (triphanylmethyl) amino-4-thlazolyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct -2-an-2-carboxylic acids

CS 270 227 B2

Using the procedure described in Example 1 but employing 1,1-dimethylethylether 6R- (6o, 7β)] - 3- (iodomethyl) -7-C (methoxyimino) -E 2- (triphenylmethyl) amino-4- thiazolyl-3-acatyl-3-amino] -8-oxo-5-thia-1-azabicyclo-4,2,2-oct-2-ene-2-carboxylic acid and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- sodium salt (1-pyrrolidinyl) -3-quinolinecarboxylic acid starting material, 8a to obtain the title compound ·

Example 18

E6R- (6 Ф, 7ft) (Z) J -7- (2-Amino-4-thiazolyl) - (methoxyimino) acetyl-3-amino] -3-CEEC-ethyl-6-fluoro-1,4-dihydro- 7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl-3-carbonyl-3-oxymethyl 3 -8-oxo-5-thia-1-azabicyclo-4,2,03-oct-2-ene-2-carboxylic acid

The title compound is obtained as described in Example 6, but using the reaction product of Example 17.

The compound obtained has the following characteristics:

IR spectrum (KBr technique):

3455, 3430, 1768, 1682, 1630 cm ^-1 .

Mass spectrum:

m / z 722 (M * H) ·

Example 19

66R- (6d, 7β) -3- (η 1 -ethyl-6-fluoro-1,4-dihydro-7- η 4 - (1,1-dimethylethoxy) carbonyl-, 1,1-dimethylethyl ester) 1-Piparazinyl-4-oxoquinolin-3-yl] kerbonyl-oxy-3-methyl-8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo E4,2.0 3-oct-2-ene-2-carboxylic acid kyeeliny

Using the procedure described in Example 1, but using £6R- (6,7β) -3-iodomethyl-8-oxo-7- (phonoxyacetyl) amino] -5-thia-1-azabicyclo [1,1-dimethylethyl ester 4,2] , 3-oct-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1,1-dimethylethoxy) carbonyl-1-piperazinyl] -4-oxo -3-quinolinecarboxylic acids as starting materials to give the title compound ·

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3420, 1787, 1730, 1698, 1510 cm ¹ .

Finished spectrum:

m / z 822 (M ⁺ H) ·

Example 20

6-R- (6d, 7β)] - 3- (1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1,1-dimethylethoxy) carbonyl) -1- Piparazinyl-4-oxoquinolin-1-yl-3-carbonyl-oxy-3-methyl-6-oxo-7E (phenoxyacstyl) amino-5-thia-1-azabicyclo-E4,2,0-3-oct-2-ene-2-carboxylic acid

Using the procedure described in Example 1, but using 2-propenylether (6R- (6R, 7β) -3-iodo-methyl-8-oxo-7- (phenoxyacetyl) amino) -5-thia-1-azabicyclo 4,2,0J oct-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1,1-dimethyl-ethoxy) carbonyl-1-piperazinyl] 4-oxo-3-quinoline-carboxylic acid starting materials and yields the title compound. .

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3415, 3300, 1789, 1729, 1694, 1622 cm * ¹ ·

Mass spectrum:

m / z 806 (M ⁺ H) ·

Example 21

[6R- (6β, 7β)] -3- [EL [1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1-propenoxy)] - 2-propenyl ester

CS 270 227 02 carbonyl-1-piperazinyl} -4-oxoquinolin-3-yl] carbonyl] oxy 2-methyl] -8-oxo-7-C (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.1] O] oct-2-one-2-carboxylic acid

Using the procedure described in Example 1, but using 2-propenylether E 6R- (6?, 7?) -3-iodomethyl-8-oxo-7- (phenoxyacotyl) amino] -5-thia-1-azabicyclo E 4, 2,0 3-oct-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-7-1 4- (2-propenoxy) carbonyl-1-iperazinyl] -4- oxoquinoline-3-carboxylic acid starting materials to give the title compound.

The compound obtained has the following characteristic data:

iC spectrum (KBr technique) i

3410, 1789, 1725, 1699, 1622 cm ^-1 .

Mass spectrum;

m / z 790 (M * H) ·

Example 22

2-propenyl £ 6R- (6c £ _t 7 (J), J C-3-CC (5-ethyl-1-5,8-dihydro-8-oxo-3-dioxolo £ 4,5-g] quinoline 7-yl) carbonyl] oxy] methyl] -8-oxo-7-f (phenoxyacetyl) amino] -8oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid acid

Using the procedure of Example 1, but using 2-propenyl E 6R- (6?, 7β)] -3-iodomethyl-8-oxo-7- (phenoxyacetyl) amino] -5-thi-1-azabicycloE4,2, O] oct-2-one-2-carboxylic acid and 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo-4,5-g] quinoline-7-carboxylic acid potassium salt as starting materials, to give the title compound ·

Example 23

Alternative synthesis of the sodium salt of 66R- (6,, 7β)] -3-CC ((5-ethyl-5,8-dihydro-8-oxo-

1,3-dioxolo [4,5-g] quinolin-7-yl) carbonyl] oxy] methyl-8-oxo-7- E (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids

To a solution of 337 mg of the reaction product of Example 22, 0.03 ml of tri-ethylphaphite, 5.6 mg of palladium acetate, 3.9 ml of ethyl acetate and 5.6 ml of methylene chloride, 1.68 ml of 0.5 M are added dropwise with stirring over 15 minutes. of a solution of sodium 2-ethylhexanoate in ethyl acetate · The mixture is then stirred for 30 minutes and added with 11 ml of acetone, followed by stirring for 10 minutes · The reaction product is filtered, washed with ether and air dried · After purification reversed-phase high-performance liquid chromatography ( _C18 ) yields the title compound. The spectral data of this product are identical to those obtained in Example 5.

Example 24

[6R- (6dz, 7β)] - [(6-fluoro-1,4-dihydro-1,4-dihydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] sodium salt] methyl] -8-oxo-7- (phenoxyacotyl) amino-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

A solution of 0.187 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-oxo-7- (4-thiomorpholinyl) -3-quinolinecarboxylic acid sodium salt in 8 ml of dimethylformamide is stirred for 1 hour. hours with molecular sieve and size 4 · 10 “ ⁰ m · After adding 0.257 g of £ 6R- (6 ', 7β) -3- (iodomethyl) -8-oxo-7- (phonoxyacetyl) amino-2-propenyl ester] - 5-Thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 8 ml of DMF was stirred for 5 hours and then evaporated under reduced pressure. The residue solution in ethyl acetate was washed successively. aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and concentrated in vacuo. The residue is purified by preparative layer chromatography to give the intermediate allylostor corresponding to the title compound.

To a solution of 63.5 mg of this allyl ester in 1.1 ml of methylene chloride and 0.75 ml of ethyl acetate is added 5.1 µl of triethylphosphite, 1 mg of palladium acetate and 0.28 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate. The mixture was stirred for 1 hour, then added to the mixture

CS 270 227 B2 ml of acetone and then evaporated to dryness under reduced pressure · The residue is triturated with ether to give a solid · Purification by reverse-phase high performance liquid chromatography yields the title compound ·

The compound obtained has the following characteristic data:

iC spectrum (KBr technique):.

3420, 1768, 1695, 1622 ся * ¹ .

Mass spectrum:.

m / z 705 (M + H), 727 (M + Na) ·

Example 25

Sodium salt [6R- (6d, 7β) -3 - [[[(1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1H-pyrrol-lyl)) quinolin-3-yl] carnonyl] oxy] methyl-8-oxo-7- (phenoxyacetyl) amino-5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylic acid

A solution of 0.845 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1H-pyrrol-1-yl) -3-quinolinecarboxylic acid potassium salt in 30 ml of methylformamide is stirred for 1 hour with a molecular size of approx. Then, 1.54 g of [6R- (6d, 1,7β-3-iodomethyl-8-oxo-7- (phenoxyacetyl) amino) -5-thia-1-azabicyclo 2-propenyl ester is added. E4,2,0 □ oct-2-ene-2-carboxylic acid and then stirred for 2.5 hours. The reaction mixture is then evaporated under reduced pressure, ethyl acetate is added to the residue and the ethyl acetate solution is washed successively with an aqueous solution. sodium bicarbonate and sodium chloride solution · After drying with sodium sulphate, ethyl acetate is evaporated under reduced pressure and the residue is purified by flash chromatography to give the intermediate allyl ester corresponding to the title compound above ·

A solution of 69 mg of this allyl ester in 1 ml of ethylene chloride was mixed with the addition of 0.3 mg of palladium acetate, 1 µl of triethylphosphite, 0.2 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate and 0.3 ml of ethyl acetate. the mixture was evaporated under reduced pressure · The residue was triturated with ether to give a solid · Purification by reverse-phase high performance liquid chromatography gave the title compound ·

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3420, 1765, 1695, 1620 cm ^-1 .

Finished spectrum:

m / z 669 (M + + H), 691 (M + 4 Na).

Example 26

Sodium salt of [6R- (6d, 7O)] -3- [f- [5- (4-fluorophenyl) -5,8-dihydro-8-oxo-1,3-dioxolo E ⁴ » ⁵ ” 92 quinoline -7-yl-carbonyl-3-oxymethyl-8-oxo-7- (phenoxyacetyl) amino-5-thia-1-esabicyclo [4.2.1] oct-2-ene-2-carboxylic acid

A solution of 0.183 g of 5- (4-fluorophenyl) -5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid potassium salt in 8 ml of dimethylformamide was stirred with a molecular sieve for 1 hour. having a particle size of 4 · 10 ”^ · m · After the addition of 0.308 g of [6R- (6CO, 70)] -3-iodomethyl-8-oxo-7- [(phenoxyacetyl) amino] -5-thia-1-2-propenyl ester -azabicyclo [4.2.02 oct-2-ene-2-carboxylic acid was stirred for 5 hours, then evaporated under reduced pressure and ethyl acetate was added to the residue. The mixture was then washed sequentially with aqueous sodium bicarbonate solution and chloride solution After drying over sodium sulfate, the ethyl acetate is evaporated under reduced pressure and the residue is purified by preparative layer chromatography to give the intermediate allyl ester corresponding to the title compound.

CS 270 227 B2

To a solution of »122 g of this allyl ether in 2 1 1 ml of methylene chloride and 1.5 ml of ethyl acetate and add 9 9 9 µl of triethyl phosphite 1,9 1.94 mg of palladium ootane and 0.51 ml of a 0 5 5M solution of sodium 2-ethylhexanoate in ethylene The mixture is stirred for 1 hour »diluted with acetone and evaporated under reduced pressure» The residue is triturated with ether »to give a solid · After purification by reverse-phase high performance liquid chromatography, the title compound is obtained ·

The compound obtained has the following characteristic data:

spectrum (KBr technique):

3420, 1765, 1695, 1632 cm ^-1 .

Mass spectrum:

m / z 696 (M * tH) »718 (M * 4 Na) ·

Example 27

Sodium salt E 6R- (6 4) → 7 [b) (Z) -7-LC (2-amino-1H-thiazolyl- (methoxyimino) acetyl-3-amino) -3- [? 6-fluoro-1,4-dlhydto-744-thlomorpholinyl) -4-oxoquinolin-3-yl-3-carbonyloxy-3-methyl-8-oxo-5-thia-1-asabioyl-4-carboxylic acid

A solution of 0.14 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7R- (4-thiomorpholinyl) -3-quinolinecarboxylic acid potassium salt in 16 ml of dimethylformamide was stirred for 1 hour with 1.5 g. molecular sieves (4 · 10 ~ ¹⁰ m) · After addition of 1 × 07 gl · 1-dlmethylethylBtera Q6R- (6d> 7 β) -3-iodomethyl-7-CE (methoxylBine J - [(2-triphonylmethyl)) amino-4-thiazelyl-acetyl-amino-4-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 16 ml of dimethylformamide was stirred for 16 hours 5 hours · the mixture was evaporated under reduced pressure »residue is taken up in ethyl acetate« n _f whereupon the mixture thus obtained was successively washed with aqueous sodium bicarbonate and brine · drying over sodium sulfate seethylaoetátový solution was evaporated under reduced pressure »the residue was purified by flash chromatography, whereupon t-butyl ester corresponding to the above compound is obtained as an intermediate Woman in name ·

0.103 g of this tert-butyl ester are dissolved in a mixture of 0 »21 ml of anisole and 06 ml of trifluoroacetic acid and kept for 18 hours at 0 DEG C. The mixture is evaporated under reduced pressure and the residue is dissolved in methylene chloride · The pH is adjusted to 7 by addition of water and sodium bicarbonate · 5 · The aqueous phase is freeze-dried · After purification of the residue by high-performance reverse-phase liquid chromatography, the title compound is obtained ·

The compound obtained has the following characteristic data:

spectrum (KBr):

34Ю, 1768, 1715 * 1682, 1622 св “ ¹ .

Weight center:

m / z 754 (M * + H)

Example 28

Monosodium salt dihydrate C 6 H- (6?, 7β) (Z) -7-CC (2-amino-4-thiazolyl) (methoxyxino) aminoethyl 1 amino] -3 - [[[[6,8] difluoro-1] - (2-Fluoroethyl) -1,4-dihydro-7- (4-methyl-1-plperazinyl) -4-oxo-3-quinolinyl 3-carbonyl-13-oxy] methyl] -O-o-5-thla-1-azabicyclo 4,2,0-oct-2-ene-2-carboxylic acid

To a suspension of 6,8-6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydroc7- (4-ethyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid potassium salt in 40 ml of dimethylformamide A solution of 10 g of 1,1-dimethylethyl estrole (6R- 16SC, 7R) -3- (iodoethyl) -7- (1-methoxyimino) [2-) triphenylmethyl) amino-4-carboxylic acid is added over 5 minutes. 1-thiazolyl-ethyl-3-amino-3-ω-5-thia-1-azabicyclo-4,2,0-3-oct-2-ene-2-carboxylic acid in 40 ml of dimethylfoxmamide. The reaction mixture was stirred

The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution.

The organic phase was washed successively with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give a brown solid, purified by flash chromatography on 500 g of silica gel (size 0 * 04 to 0 * 08 mm). using methanol-chloroform (with a gradient of 0 to 8% methanol) gave the intermediate 1,1-dimethylethyl ether * which corresponds to the above-mentioned title compound *.

A solution of 2 * 30 g of this 1,1-dimethylethyloether in 25 ml of methylene chloride is treated at 0 DEG with the addition of 2 ml of anisole, 0 * 2 ml of 1,2-ethanedithiol and 25 ml of trifluoroacetic acid. at 0 * 0 and then evaporated at 0 ° 0 under reduced pressure. Methylene chloride is added to the evaporation residue and the evaporation is repeated * 5 ml of cold ethyl acetate and then 25 ml of ether are added to the residue * solids precipitate * After filtration * washed with ether and air dried to give a brownish solid * This solid the substance is dissolved in 100 ml of a 1: 4 methanol / chloroform mixture and 100 ml of water and 35 ml of a 5% aqueous sodium bicarbonate solution are then added to ice cooling until the pH is adjusted to 7 * 8 * * dissolved in 10 ml of dimethylformamide and 20 ml of chloroform were added thereto, followed by water and aqueous sodium bicarbonate solution to adjust the pH to 7 * 8 * The combined aqueous extracts * containing the reaction product were washed with chloroform and purified by chromatography with a reverse phase using a water / acetonitrile gradient as solvent * Fractions containing the reaction product * are evaporated vacuum and freeze-dried * to give the title compound *

The compound obtained has the following characteristic data

Mass spectra:

m / s 787 (Μ * + H)

The following compounds can also be prepared according to the methods described above in the examples above: [6R-E6 #, 7β (Z)]] -7R-C (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino2 ? 3-CCC £ l? Et? ethyl-4-fluoro-1,4 _- dihydro-7R (1-plperazinyl) -4-oxoquinoline-3-arylcarbonyloxy-methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-ene-2-eno-4-carboxylic acid; 2-carboxylic acid

COOH 6 R - (6 C, 7 P) -3-R - [1- [1-ethyl-6-fluoro-1,4-dihydro-4-hydroxy-7- (1-piperazinyl) quinoline] -quinolin-3-yl] carbonyl} oxylmethyl -8-oxe * 7α- (phenoxyacetyl) amino] -5rthia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

COOH o

CS 270 227 B2

C6R- (6d, 70) -3-LLr [6,8-difluoro-1- (2-fluoroethyl) 71,4-ilhydro-7- (4-ethyl-1-piperazinyl) -4-oxoquinoline-3 -yl] carbonyl-oxy-3-methyl-8-oxo-7R- (phenoxyaoethyl) amino-5-thia-1-azablicyclo-E4,2,0-oct-2-ene-2-carboxylic acid

C 6 R-Q 6 4}, 70 (Z)]] - 7- [(2-Amino-4-thiazolyl) (methoxyinine) acetyl] amino-3'C 'ethyl-6-fluoro-1,4'-lihydTO -7- (4-ethyl-17-pyrazinyl) -4-oxoquinolin-7-ylcarbonyloxycarbonyl-8-oxo-5-thia-1-ezabioylclo-4,2,0-oct-2-ene-2-carboxylic acid

E 6 R- (6,7,7) J-37 C-1-ethyl-4-fluoro-1,4-dihydro-4-ethyl-1-piperazinyl-4-oxoquinolin-3-yloxycarbonyloxy-methyl -7-C (phenoxyaoethyl) amino-5-thia-1-azabicyclo-

E 6R- (6 ®, 70) J-3 - [[[[1-cyclopropyl-6-fluoro-1,4-dihydropyrrole] -4- (1-piperazinyl) -470Xoquinolin-3-yl] carbonyl] Jozy 3methyl 3 -в-охо-7; L (phenoxyacetyl) amino-5-thia-1-azabloyclo-4,2,0ipkb-2-ene-2-carboxylic acid

. С ООН 0

L6R-C 6 <C, 7β (Z)]] -7R1- (2-amino-4-thiazolyl) (methoxyimino) acetyl] amyl-1-oxo-1,4-diaminophen-1,4 хот-т (ре oxyр1 oxy oxy oxy oxy oxy oxy oxy]] oxy oxy] oxy] oxy oxy] oxy oxy oxy] oxy oxy] oxy oxy]]]]]]]]]]]]]]]] oxy] oxy] oxy]] oxy] oxy]] oxy] oxy oxy] oxy oxy] oxy] oxy] oxy] oxy] oxy oxy oxy] oxy oxy oxy oxy oxy oxy oxy oxy oxy oxy] oxy] oxy oxy] oxy]]]] oxy] oxy oxy oxy oxy] oxy] oxy oxy oxy] oxy] oxy]] oxy]] oxy oxy oxy oxy oxy] oxy]]]]]

2б

CS 270 227 В2

С 6R- (6tf> 7 β) 3 7-C (cyanoacetyl) and «lnoJ ГЕ -3-C [6 _t 8-difluoro-l- (2-fluoroethyl) rl> 4-dihydro? 7- (4-Methyl-1-piperazinyl) -4-oxoquinolin-3-yl-3-carbonyloxy-methyl-β-ω-5-thla-1-azabicyclo C 4 * 2.0 □ oct-2-en-2- carbonyl acid

. ^ »3

Г6R (6 <r, β 7) 1-7- (foxwylamino) -3rC £ C [E, ± Sd flaor-l- (2-fluoroethyl) -l, _4-T dihydro-7- (4s «· et hyl- 1-piperazinyl) -4-oxo-quinolin-3-ylcarbonyl] oxy] methyl 3-e-oxo-5-thialeesabioyl ** C 4,2,0 oct-2-ene-2-carboxylic acid

COOH

C6R- (6?, 7?) 1-7-CCCC 4-ethyl-2,3-diethoxy-1-piperazinyl) carbonyl-amino-phenylaethyl-amino-3REC [[5.8] difluoro-1- (2-fluorophore)] Ethyl-1,4-dihydro-4-oxoquinoline-3-ylcarbonyl-oxylmethyl-8-oxo-5,4-aza-bicyclo [4.2.1] oct-2- <n-2-carboxylic acid

C6R-E6a7 β (Ζ) 33-7- [β-2-amino-4-thiazolyl] Ef (1-carboxy-1-methyl) ethoxyxyl] acetyl] amino] -3 - [[[[6, θ-difluoro-1]] -) 2-Fluoroethyl-1,1'-dihydro-7- (4-ethyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl-8-oxo-5-thla-1- azabicycloC 4,2.03 oct-2-ene-2-carboxylic acid

CS 270 227 B2

j

6 6 R- [6a, 7A (Z)] 3-7-CD CD (2-amino-4-thiazolyl) (carboxymethoxy) amino-2-acetyl-amino-3-yl L 6-C 6,8-difluoro-1- (2) (fluoroethyl) -1,4-lihydro-7- (4-methyl-1-piperaziayl) -4,4-oxoquinoline;

6R- (6C, 7B)] -3-CC-6,8-Difluoro-17 (2-fluoroethyl) -1,4-dihydro-17 '(4-methyl-1-piperazinyl) -4- oxoquinolin-3-yl-3-carbonyl] methyl-8-oxo-7- (phenylacetyl) amino] -5-thia-1-azabicyclo C 4.2.0 J oct-2-ene-2-carboxylic acid

£ 6R- (6 Λ, 713) J-3- £ £ CC 6, 8-difluoro-l- (. ^{<^^.} Trifluoroethyl-l, 4-dihydro-7- (4r ^'e' methyl-piperazinyl (4-Oxoquinoline-3-ylcarbonyl) oxy] methyl (8-oxo-7 (2-thienylacetyl) amino) -5-thiazaboyoyl-4,2,01-oct-2-an-2-carboxylic acid

COOH

Г6R-t6 <£ _f 7 beta (Z) I [-7 - [[(2-aBxlno thiaeolyl * 4) (methoxyimiiio) acetyl3 -amino J -3- CC [6,8-C difluoro-l- (4-fluorophenyl ) 71 _t 4-dihydro-7- (4-aethyl «l-piperazinyl) -4? 3řyl oxoquinoline-3 · 13 carbonyl oxy methyl 3 -8-oxo-5-thia-4,2,03 Gzabioyklo C -oct-2-ene-2-carboxylic acid

COOH

O

270 227 B2

6 6R- (6 £, 70) -3-CtC [67-Fluoro-1- (4-fluorophenyl) -1,4-dihydro-7 H (4-ethyl-1-piperaninyl) -4-oxoquinoline-3- 9] carbonyl] oxy] methyl] -ЮОООхх-f (phonoxyacetyl) amino □ -5-thiazaboyoyl-4,2,2-oct-2-yne-2-carboxylic acid Г

E6R- (6X-, 70)] -3 - [[CE9-Fluoro-3,7-dihydro-35-methyl-10- (4-ethyl-1-piperazinyl) -7-hydroxy] -2H-pyridin-1,2,3-de] [1,4] benzoxaine-4 (1) carbonyl] ozyl methyl] -3-oxo-7-carboxylic acid; C (phenoxyaoethyl) eminol-5-thia-1-azabioyl-C4,2,0] oct-2-ene-2-carboxylic acid

C6R- [6®, 70 (Z) T] -7-CC (2-amino-4-thiazolyl) (methoxyxino) acetyl] amino] - p - [[[[9; fluoro-3,7-dihydro-3-ene) ethyl] -10; (4-Methylyl-piperazinyl) -7H-oxo-2H-pyrido [1,2,3-de]; 1,4-benzoxazin-6-yl] carbonyl] oxy] methyl-8-oxo-5-thi-1-azababicyclo C 4,2,0 J oct- 2-ene-2-carboxylic acid

C6R- (6d, 70)] - [C] -SCH 2-carboxy-3-CCCC6,8-difluoxo-1- (2-fluoroethyl) yl, 4-dihydrol-7y (4-methyl-1-piperazinyl) -4yoxoquinoline [3-yl] carbonyl-1J oxy] methyl] -S-oxo-hexthia-1-azabicyclo [4.2.0] oct-2-en-7-yl] amino] carbonyl] benzoic acid

ЮН

о

CS 270 227 B2

C-C 6 R 6d _t 7β (Z)] J -ЗтСЕСС 7- (3-amino-l-pyrrolidinyl) -β-chloro-l-cyclopropyl-6-fluoro-l, 4-dihydro-4-oxoquinoline-3-yl] Carbonyloxyoxymethyl] -7-CC (2-amino-4-thiazolyl) -8-carboxy-methoxy) imino-13-amino-8-oxo-5-thia-1-azabioyllo E 4,2,03 oct-2-en-2 -carboxylic acid

C6R -C 6 H, 7β (Z) -3-CC CLLC7- (3-amino-l-pyrrolidinyl) -e-chlor-lTcyklopropyl-6-fluoro-4-dihydro-l _t 4rOxochinolin-3-yl carbonyl oxy methyl 11 □ -7- (2-Amino-4-thiazolyl) E (1-carboxy-1-methyl-ethoxy) amino-3-ethyl-amino-8'-oxo-5-thia-1-azabioyklo Q 4,2, 0 3 oct2-ene-2-carboxylic acid

[6R, 7B (Z)]] 3r [E - [7 - [(3-amino-1-pyrrolidinyl) -e-chloro] -1-cyclopropyl-6-fluoro-4-dihydro-4-hydroxy-quinoline-3-ylcarbonyl] oxy] methyl] -7rEC (2 (amino-4-thiazolyl) (methoxyimino) acetyl] amino 3-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

containing deri ^

The following example illustrates the foxes of the pharmaceutical compositions of the invention of cephalosporin.

Example A

Preparation of euohýoh ampoules for intramuscular administration:

Lyophilisate 1 g of mono-sodium salt of C6Rr (6C, 7β (Z) J-7-CE-2-amino-4-thiazolyl) methoxyimino) -acetyl-3-amino-3-methyl-6,8-difluoro-1- (2-fluoroethyl) ) -l, 4-dihydro-7 -. (4 "-ethyl-piperazinyl) -4roxochinolin ^e-3-yl] carbonyl] oxy] methyl] -8-70x0-5-thia-azabioyklo L 4» 2 , O3 oct-2-ene * 2-carboxylic acid and filled into ampoule · Sterile aqueous ampoule contains 10% propylene glycol · 2.5 ml of 2% aqueous lidocaine hydrochloride solution are added to lyophilisate ·

Claims (51)

SCOPE Í В Z U A process for the preparation of novel aoyl derivatives of the general formula I (I) in which m represents the number 0, 1 or 2, R ¹ represents hydrogen or acyl groups usable к aoylaoi antibiotics (i-type lactate sponding to 21 carbon atoms, for example a pattern where CS 270 227 B2 represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms which is substituted by cyano 8 to full, optionally amino substituted by a fully substituted five-membered heterooyl caustic with 1 or 2 nitrogen atoms and / or sulfur atoms, R ¹²⁰ represents an alkyl group having 1-8 carbon atoms, Ar ^ O _represents carboxy and optionally substituted alkyl of 1 to β. N is 0, 1, 2 or 3, and in which n is 0 R is hydrogen, C 1 -C 8 alkoxy, amino, C 1 -C 8 alkylthio or C 1 -C 7 alkanoylamino means C 1 -C 8 alkyl, C 2 -C 6 alkenyl carbon, C3-C7cycloalkyl, C1-C8haloalkyl or halogenphenyl, Z represents a nitrogen atom or group, wherein R (10) is hydrogen or halogen, or R ^ ° and R ^ together represent an alkylene group of ee of 3 to 5 carbon atoms, an alkylene monooxy group of ee of 2 to 4 carbon atoms, or an alkylenedioxy group of 1 to 2 carbon atoms. means a hydrogen atom »a halogen atom» an alkyl group of 1 to 8 carbon atoms, or optionally an alkyl group of 1 to 8 carbon atoms or a formally substituted five- or six-membered N-heterocyclic ring which optionally contains an oxygen atom or an additional nitrogen atom » a hydrogen atom or a halogen atom or together represent a C1 -C4 alkylenedioxy group, as well as salts of these compounds and hydrates of the compounds of formula (I) or hydrates of their salts, characterized in that the compounds of formula (IV) are Rf NH COOR in which 32 »ш» R ¹ »R ² » R · ⁵¹ »r32 _and r33 as defined above and (IV) R CS 270 227 B2 means an ester protecting group that is useful in cephalosporin chemistry and which is cleavable under mild conditions, for example, a target, butyl, p-nitrobenzyl or allyl group, cleaves the ester protecting group R, preferably p-nitrobenzyl, by hydrolysis in the presence of sodium sulfide, a tert-butyl group by reaction with 0 trifluoroacetic acid in the presence of anisole or a palladium catalyzed allyl transallylalo group in the presence of a sodium or potassium salt of 2-ethylcaproic acid to give the carboxylic acid of formula I; , hydrate or salt hydrate · 2. Method according to claim 1, characterized in that as starting material use ^ yawns pattern corresponding compound of IV to give compounds obeoného formula I in which m is 0 and R ² is hydrogen and the other substituents are as defined in point 1 * 3. A process according to claim 1 or 2, wherein the corresponding compounds of formula (IV) are used as starting materials to give compounds of formula (I) in which: Z represents a group R,-C, wherein it represents a hydrogen atom or a halogen atom, R ^ represents an alkyl group having from 1 to 8 carbon atoms, a haloalkyl group having from 1 to 8 carbon atoms or a cycloalkyl group having from 3 to 7 carbon atoms,. R ² is C 1 -C 6 alkyl, piperazinyl or C 1 -C 8 alkyl substituted piperazinyl; and R @ 1 represents a hydrogen atom or a halogen atom, and the other substituents have the meanings given in 1 or 2; 4. A process according to claim 3, wherein the corresponding compounds of formula (IV) are used as starting materials to give compounds of formula (I) in which: R <10> is hydrogen or fluorine, & R represents an ethyl group, or a group fluorethylovpu oyklo for pollen group ¹ R ² is piperazinyl or 4-methylpiperazinyl and a R (3) is hydrogen or fluorine, and the other substituents are as defined in (3) 5. A process according to any one of claims 1 to 4, wherein the corresponding compounds of formula (IV) are used as starting materials to produce compounds of formula (I) in which: R @ ¹ represents a group of the formula _R @ ₁ represents an amino-4-thiazolyl group and represents a methyl group or a group of the general formula ## STR4 ## -C, where hydrogen or halogen, is alkyl. and C 1 -C 8, haloalkyl, C 1 -C 8 or C 3 -C 7 cycloalkyl »means C 1 -C 8 alkyl» piperazinyl or C 1 -C 8 alkyl substituted piperazinyl ε stands for hydrogen atom or halogen atom »and other substituents have the meaning given in the nectar of 1 and 4 · 6. A process according to claim 5, wherein the corresponding compounds of formula (IV) are used as starting materials, in which the compounds of formula (5) are those in which the hydrogen atom or the fluorine atom are ethyl, fluoroethyl or cyclopropyl. represents a methyl group, an N-methylpiperazinyl group or a piperazinyl group and represents a hydrogen atom or a fluorine atom; 7. A process according to claim 1, wherein the corresponding compound of formula 17 is used as the starting material to form compounds of formula I in the form of C6R- (6eC, 7β) (Z)] -7-ΓΕ (2-amine) -thiazolyl) (R 4 -cryimino) acetyl] amino] -3-β - [[6 'R 8,8-R 8'] 1 R 4 '-1,4-dihydro-7' (4 '-1-piperazinyl) -4'-oxo -3-quizollnylcarbonyloxycarbonyl-8-oxo-5-thia-1-ezabicyclo-4'-oxo-1'-oxo-2'-en-2-carboxyl acids and their salts and hydrates thereof carboxylic acids and hydrates of salts in which R ^ and R ^ ° represent a hydrogen atom or a halogen atom; Jp ¹ represents a hydrogen atom, an alkyl skipime having from 1 to 8 carbon atoms or a 2-dialkyl alkyl group of from 1 to 8 carbon atoms , R ^ represents a hydrogen atom or an alkyl group of β 1 to 8 carbon atoms а means a hydrogen atom »an alkyl group of 1 to 8 carbon atoms or a group of the general formula CS 270 227 B2 in which R @ ²² and R @ ² are hydrogen or alkyl having 1 to 8 carbon atoms, · A process according to claim 7, wherein the starting material is a corresponding compound of formula IV to form the compounds defined in point 7, wherein R ²¹ is methyl and the other substituents are as defined in point 7 9. A process according to claim 8, wherein the corresponding compounds of formula (IV) are used as starting materials to form the compounds defined in point 8, wherein R @ ¹ and R @ 2 are hydrogen or fluorine atoms; or a 2-fluoroethyl group and R 6 represents a methyl group and the other substituents are as defined in point 8; 10. A process according to claim 9, wherein the corresponding compounds of formula (IV) are used as starting materials to give the compounds defined in (9), wherein R R and R ^ ° are fluoro and R ^ ¹ is 2-fluoroethyl and the others the substituents have the meaning given in point 9, 11. A process according to claim 8, wherein the corresponding compounds of formula IV are used as starting materials to give the compounds defined in point 8, wherein R6 is fluorine, R6 is hydrogen, R6 is 2- and R 6 represents methyl and the other substituents have the meaning given in point 8> 12. A process according to claim 8, wherein the corresponding compounds of formula (IV) are used as starting materials to give the compounds defined in point (8), wherein R @ 1 is fluorine, R @ 4 is hydrogen, R @ 4 is ethyl; _brand names methyl radical substituents are as defined in paragraph 8 « 13. A process according to claim 8, wherein the corresponding compounds of formula (IV) are used as starting materials to form the compounds defined in point 8, wherein R @ 1 is fluorine, lpi is 2-fluoroethyl, R @ 4 is atom. hydrogen and R ^ represents a methyl group and the other substituents are as defined in point 8; Process according to any one of Claims 5 to 13, characterized in that the corresponding compounds of the general formula IV are used as starting materials to give the compounds defined in points 5 to 13 in which the groups of the general formulas - - 0 - R ¹³ ° N - 0 - R ²¹ - are present in the syn-isomeric form or in the form of mixtures in which the syn-isomeric form predominates, and the other substituents are as defined in one of items 5 to 13 · The method of claim 1, wherein the corresponding compounds of formula (IV) are used as starting materials to form compounds of formula (I) in the form of C 6 R- (6 d>, 7 p) J -З-ССССб-R ³³ , 8 -R ^30, 14i ³¹ -l, 4-dihydro-7- (4-R ³⁴ piperazinyl) -4-oxo-3rchinolinyl] carbonyl oxy 1-8-oxo-74 £ phenoxyacetyl) amino-l- -5rthia azabicyclo L '4,2,0 J-oct-2-ene-2-carboxylic acids and their salts and hydrates of these carboxylic acids and salt hydrates in which R 1, R 2 and R 3 are hydrogen or halogen; ^ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a 2-haloalkyl group having 1 to 8 carbon atoms and R R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms and the other substituents have the meaning given in point 1; CS 270 227 B2 16 · The process according to claim 15, characterized in that as starting material is used a corresponding compound of the specimen IV to give the compounds as defined in paragraph 15, wherein R 3 _{and R} 30 ₌ J ^ is hydrogen or fluoro, LPI is ethyl or 2-fluoroethyl and R R represents methyl and the other substituents are as defined in point 15; 17. A process according to claim 16, wherein the corresponding compounds of formula (IV) are used as starting materials to produce the compounds defined in (16), wherein R @ 1 and R @ 2 are fluorine and R @ 2 is 2-fluoroethyl. and the other substituents have the meaning given in point 16 * 18 * Process according to claim 15 * characterized in that as the starting materials are the corresponding compounds of the specimen IV give compounds definovanýoh in paragraph 15, wherein R 3 represents a fluorine atom, R ° is hydrogen * R · ^ ¹ represents 2-fluoroethyl and R 1 is methyl and the other substituents are as defined in 15 Dec 19 * The method of clause 151 wherein the corresponding compounds of formula (IV) are used as starting materials to form the compounds defined in clause 15 * wherein R 3 is fluorine * is hydrogen * is ethyl and r34 is methyl and other substituents have the meaning given in point 15 * 20 * The method of clause 15, wherein the corresponding compounds of general formula IV are used as starting materials to form the compounds defined in clause 15 * wherein R ^ 3 represents a fluorine atom * R ^ ¹ represents a 2-fluoroethyl group * R ^ ° represents a hydrogen atom and R ^ represents a methyl group and the other substituents are as defined in point 15; 21. The process of claim 1 wherein the corresponding compounds of formula (IV) are used as starting materials to produce compounds of formula (I) in the form of L 6R- (6X * 7β) 3-7-formyl-amino) -3 - Е С 6-R 6-R * 8-R ° * l R--1-4-dihydro-7- (4-R--1-piperazinyl) -4-oxo-3-quinolinyl] carbonyl] oxylmethyl-8-oxo- 5-thia-1-azabicyclo-E4,2 * O] oct-2-ene-2-carboxylic acids and salts and hydrates of these carboxylic acids and salt hydrates * in which R1 and R2 are hydrogen or halogen * R1 = ¹ R @ 1 represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms or a 2-haloalkyl group having from 1 to 8 carbon atoms and R @ 1 represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms; 22 · method according to claim 21 * characterized in that * the 00 as a starting material using a corresponding compound obeoného pattern IV give compounds definovanýoh in paragraph 21 * wherein R ^ _and R ° are hydrogen or fluorine; R ¹ is ethyl or 2-fluoroethyl and R 6 represents methyl and the other substituents are as defined in 21 · The method according to item 22, characterized in that the corresponding compounds of the general formula IV are used as starting materials and that all of the compounds defined in item 22 are used, Wherein r 'a represents a fluorine atom and R ^p represents a 2-fluoroethyl group and the other substituents have the meaning given in 22 * A process according to claim 21, wherein the corresponding compounds of formula (IV) are used as starting materials to form the compounds defined in claim 21, wherein R is hydrogen; R is hydrogen; R is 2-fluoroethyl; ^ is methyl and the other substituents are as defined in 21 · The method according to item 21 *, characterized in that the corresponding compounds of the general formula IV are used as starting materials to give the compounds defined in item 21 * in which R is O, R is O, ethyl and Ρ is methyl. the group and other substituents are as defined in 21. Oh 08 270 227 В2 26. The method of claim 21, wherein ee uses the corresponding compounds of formula (IV) to give the compounds defined in claim 21, wherein R is fluorine, R is 2-fluoroethyl, θ is hydrogen, and r34 is methyl and other e-substituents are as defined in 21 * 27 · The method of clause 1, wherein the starting material used is an answer? yielding compounds of formula (IV) to give compounds of formula (I) in the form of 6 6 R-1R-R, 4-dihydro-77 (4-B * 1-piporazinyl) -4-oxo-3- (4-quinolinyl) carbonyl} oxy3 methyl-8-oxo-5-carboxylic acid; thia-1-azabicyclo C4,2,0 J oct-2-ene-2-carboxylic acids and their salts and hydrates of these carboxylic acids and salt hydrates in which R @ 1 and R @ 2 are hydrogen or halogen; R vod is hydrogen, alkyl of 1 to 8 carbon atoms or 2-haloalkyl and 1 to 8 carbon atoms, R ^ is hydrogen or alkyl of 1 to 8 carbon atoms, R ²¹ is a group of the formula 0 - COOH where R ²² and R ²³ represent a hydrogen atom or an alkyl group having 1 to 8 carbon atoms; The method of clause 27, wherein the starting materials are the corresponding compounds of formula IV to give the compounds defined in clause 27, wherein R ²² and R ² are both methyl and the other substituents are as defined in clause 27. · The method according to clause 28, wherein the starting material is a corresponding compound of formula (IV) to form the compounds defined in clause 28, wherein R _and R 30 are hydrogen or fluorine, R ¹ is ethyl or 2-fluoro a thylovene group and R 1 represents a methyl group, and the other e-substituents are as defined in point 28; The method of item 29, wherein the starting materials used are the resistance of each compound of formula (IV) to the formation of the compounds defined in item 29, wherein R 1 and R 2 are fluorine and indicate a 2-fluorophenyl group. and other eubstituents have the meaning defined by ▼ point 2f> The method of clause 28, wherein the compound of formula (IV) is used as the preferred material to form the compounds defined in clause 28, wherein R 1 is fluorine, R 2 is hydrogen, R 2 is 2-fluoroethyl and R ^ is methyl and the other substituents are as defined in point 28. 32. The method of claim 28 wherein the compound of formula (IV) is used to produce the compounds as defined in claim 28 wherein R @ 1 is fluorine, R @ 2 is ethyl, and R @ 3 is methyl. and other eubstituents have the meaning given in point 28 · The method of clause 28, wherein ee uses the corresponding compounds of formula (XV) as starting materials to produce the compounds defined in clause 28, wherein: R represents fluorine, R represents 2-fluoroethyl ekupinu, R is hydrogen and R ³⁴ is methyl and the other eubstituenty are as defined in point 28. 08 270 227 В2 34 The method according to claim 1, characterized in that it is approx. A compound of formula (IV) is used as starting material to form C6R- (6cC, 7β) β-LLL (1-ethyl-1,4-dihydro-7-ethyl-4-oxo-1,6) naphthyridin-37-yl) carbonyl (methyl) -870x0-7; [(phenoxyaoethyl) araino] -5-thia-1-azabicycloC4 * 2,0-oct-2-ene-2-carboxylic acid and salts thereof and hydrates thereof, or hydrates thereof. 35 · The method according to the above, characterized in that an answer is used as starting material? Further compounds of general formula IV and culprit C 6 R- (6 ° C → 7 β) 3 "3" CCC (5-methyl-5,8-dihydro-8-oxo-1,3-dioxolo E4,5-g)? оЫпо11пр7 $ У1 carbamoyl] oxy] -methyl] -7R- (phenoxyacetyl) -amino-5-thia-1-azabloyclo [4.2.2] oct-2-ene-2-carboxylic acid, as well as the salts thereof and hydrates thereof or hydrates of their salts, 36. The process of claim 1, wherein the starting material is a corresponding compound of formula IV to form [6- (6-β-7β) (Z)] -7- (2-amino-4-thiazolyl). () - (methoxyiminoacetyl-amino) -3-ГЦ (1-ethyl-1,4-dihydro-7,7-ethyl-4-oxo-1,8-thiophthyridin-3-yl) carbonyl] oxo-ethyl-β-οχο-5 -thia-1-azabioyl-4,2,0] oct-2-ene-2-carboxylic acid, as well as the salts of this compound and the hydrates of this compound or the hydrate of its salts; 37 · The method of clause 1, wherein 00 denotes that 00 uses the answer as a preferred substance? other compounds of the IV series are combined with [to- (W, 7β) (Z)] - 7-CC (2-emino-4-thiasolyl) (methoxyimino) acetyl] amino] -3 * CCC (5-ethyl-5) , 8-dihydro-8-oxo-1,3-dioxolo [4,5,8] quinolin-7-yl) carbonyl] oxy] methyl] * 8-oxo-5-thla * 1 'sabloyclo C4,2,0]] oct-2-ene-2-carboxylic acid as well as salts thereof and hydrates thereof, or hydrates thereof, 38. The method of claim 1, wherein the preferred compound is a compound of the general formula IV to form tot- (6 Λ, 7 β) -3-CCC [1-ethyl - <> -. fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl-8-oxo-7α (phonoxyaoethyl) amino] -5-thio -l-azabioyl-4,2,03-oct-2-one-2-carboxylic acid, as well as the salts of this compound and the hydrates of the compound; 39 · The method of clause 1, wherein said ee is used as a higher substance in said reaction. yielding compounds of both IV and IV with the formula (β-α (β, 7β)] * 3? L (C? 5-ethyl-5,8-dlhydre-eoxo-1,3 * dioxole? 4,5-g) quinolin-7 -yl) carbonyl] exyl-ethyl-7 - [(2-thionylaethyl) amino-8-oxo-5-thia-1-ozabioyl-C4,2,0] oct-2-one-2-carbaxylic acid, and salts thereof and hydrates of this compound or hydrates of its salts; 40 · The method according to clause 1, wherein the answer is as a starting material? give compounds of the formula IV to give C? (G? O, 70)? -3 - [[[1-ethyl-6-fluoro-1,4-dihydro-7 '] (4'-phonayl-1'-piperazinyl) (4-Oxoquinolin-3-yl) carbonyl] oxy] methyl] -7C (2-thionylaethyl) aninole-6-oxo-5-thia-1-azabioylc 4,2,0] oct-2-one-2-carboxylic acid the acid as well as the salts of the compound and the hydrates of the compound and, if appropriate, the hydrates of its salts; 41. The process of claim 1, wherein the preferred compounds are the corresponding compounds of formula IV to form C1-C6-ethyl-1-fluoro-1-methyl-1-ethyl-1-fluoro-1,4-diol. dihydro-4'-pyrrolidines-D-ethoxy-4'-oxo-4'-carbonyl] oxyjmethyl] -8-oxe-7- (phenoxyacetyl) amino] -5-thla-1-azabloyclo C4,2,0 3 oct-2-one-2 carboxylic acids and salts thereof and hydrates thereof, or hydrates thereof; 42. The process of claim 1 wherein the preferred compound is a compound of formula IV to form C (6, O, 7β) (Z) -7C (2-emino-4-thiazolyl). ) (mothoxydmino) acetylj amino]? 3? ЕГСС lTethyl - ^? fluor? l, 4 ^<i 41hydro-7?) l? pyrrolidinyl) -4-охооЫпо11п-Здг1] 1 carbonyl] oxy] methyl] -8? «» The 5-thiazol-azaboyl-C4, 2, OD, oct-2-ene-2-carboxylic acids, as well as the salts of the compound and the hydrates of the compound or hydrates thereof. 43 · The method according to clause 1, characterized in that he uses the answer as a substance discharge? give compounds of formula (IV) to give L? - (6,7β) - (Z) -7- (2-amino-> 4-thiazolyl) - (methoxyimino) acetyl] amino] -3-CCC 1-ethyl? Fluoro-1,4-dihydro-7- (4-formyl-1-piperazine) CS 270 227 82 zinyl) -4-oxoquinolin-3-yl] carbonyl-oxy] -methyl] -8-oxo-5-thia-1-azabicyclo-4,2,0-oct-2-ene-2-carboxylic acid, as well as the salts of the compound and the hydrates of the compound or the hydrates of the salts thereof · A process according to claim 1, wherein the starting material is the corresponding compound of formula (IV) to give 6R- (6,7,7) -1,3-ethyl-6-fluoro- 1,4-Hydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-ylcarbonyloxycarbonyl-8-oxo-7- (phenoxyacetyl) amino-5-thia-1-azabicyclo [4.2.0] oct -2-ene-2-carboxylic acids, as well as the salts of this compound and the hydrates of this compound or the hydrates of its salts · The method of claim 1, wherein the corresponding compound of formula (IV) is used as the starting material to form C 6 R- (6cG, 7β)] -3- [E (1-ethyl-6-fluoro-1)]. 4-dihydro-4-oxo-7- (1H-pyrrol-1-yl) quinolin-3-ylcarbonyl-oxyjmethyl-8-oxo-7- (phenoxyacetyl) amino-5-thia-1-azabicyclo-4,2, 0J-oct-2-ene-2-carboxylic acid, as well as the salts of this compound and the hydrates of this compound or the hydrates of its salts · 46. The method of claim 1, wherein the corresponding compounds of formula (IV) are used as starting materials to give 66R- (6cG, 7β)] -3- [[5- (4-fluorophenyl) -5], 8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl] carbonyl] oxy] methyl-8-oxo-7- (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.2] oct- 2-en-2-carboxylic acids, as well as the salts of the compound and the hydrates of the compound or the hydrates of their salts; Process according to claim 1, characterized in that the corresponding compounds of the general formula (IV) are used as starting materials to give? 6R- (6,7β) (Z)? - (2-amino-4-thiazolyl) (methoxyimino) (Acetyl) amino] -3- [1-ethyl-6-fluoro-1,4-dihydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-yl] carbonyl} oxy} methyl} -8-oxo 5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, as well as the salts thereof and the hydrates thereof, or the hydrates of their salts; The method of claim 1, wherein the corresponding compounds of formula (IV) are used as starting materials to give 6 6 R- (6 £ 7β) (Z)] -7- £ (2-amino-4- thiazolyl (methoxyimino) acetyl] amino] -3-CCL 6,8-difluoro-1- (2-fluoro-ethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo 3-quinolinyl] carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, as well as salts thereof and hydrates thereof, or hydrates thereof · Process according to claim 1, characterized in that the corresponding compounds of the general formula (IV) are used as starting materials to give? 6R- (6,7,7)) (Z) J -3-? - (3-Amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -7- [E (2-amino-4) -thiazolyl) [(carboxymethoxy) imino] acetylamino] -8-oxo-5-thiazabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, and salts thereof and hydrates thereof, or hydrates thereof salts · The method of claim 1, wherein the corresponding compound of formula (IV) is used as the starting material to form a compound of formula (IV) to form a compound of formula (IV). -amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-quinolin-3-yl] carbonyl} oxy} methyl 3-7- [E (2-amino-4) thiazolyl) - C (carboxy-l-methylethoxy) iminoj -acetyUaminoj -8-oxo-5-thia-azabicyclo C ⁴ · ^{2 »0]} oct-2-ene-2-carboxylic acid and salts thereof the compound and the hydrates of this compound or the hydrates of its salts · 51. The method of claim 1, wherein the corresponding compound of formula (IV) is used as the starting material to form β 6 R- (6 d 3, 7β) (Z) J -3-ЕСГС 7- (3-amino-1- pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinolin-3-yl] carbonyloxy] methyl] -7-C (2-amino-4-thiazolyl) (methoxyimino) acetyl amino] -8-oxo-5-thia-1-azabicyclo-C4,2,0-oct-2-ene-2-carboxylic acid, as well as the salts thereof and hydrates thereof, or hydrates thereof