CS270246B2 - Method of new acyl derivatives production - Google Patents

Abstract

3-Quinolonyl carbonyloxymethyl - cephalosporin derivs. of formula (I), their easily hydrolysed esters and salts, opt. as hydrates, are new: m = O-2; R1 = H or acyl; R2 = H, lower alkoxy, NH2, lower alkylthio or low alkanoylamino; R31 = H, lower alkyl (opt. halo substd.), lower alkenyl, 3-7C cycloalkyl or halophenyl; Z = R30C or N; R30 = H or halo, or R30 and R31 together form 3-5C alkylene, 2-4C alkyleneoxy or 1-2C alkylenedioxy; R32 = H, halo, lower alkyl or opt. substd. 5 0r 6-membered heterocycle with 1-3 O, N and/or S; R33 = H or halo, or R32 and R33 together form 1-4C alkylene dioxy.

Description

The present invention also relates to a process for the preparation of the novel acyl derivatives of the following general formula (I) which possesses valuable pharmacological properties.

New acyl derivatives of the formula I have been found

Ý ··.

wherein (j) m is 0, 1 or 2,

R represents a hydrogen atom, an alkoxy group having 1 to β carbon atoms, an amino group, an alkylthio group having 1 to 8 carbon atoms or an alkanoylamino group having from 1 to 7 carbon atoms,

R ^ represents a hydrogen atom, an alkyl group having from 1 to 8 carbon atoms, an alkenyl group having from 2 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 carbon atoms, a haloalkyl group having a β1i! 8 carbon atoms or a halophenyl group,

Z represents a CΒ-C-C group or a nitrogen atom, wherein

R (10) is hydrogen or halogen, or _and L (1) is together C3 -C5 alkylene, C2 -C4 alkylene monoo or C1 -C2 alkylenedioxy,

R ² represents a hydrogen atom, a halogen atom, a C 1 -C 8 alkyl group or an C 1 -C 8 alkyl group or a formyl substituted 5- or 6-membered N-heterocyclic ring optionally containing an oxygen atom or an additional nitrogen atom,.

R ( ³⁾ is hydrogen or halogen;

· R ² * _and R 33 together are alkylenedioxy _Zn amenajl я 1 to 4 carbon atoms, and

R ¹⁰² represents an amino-substituted 5-, 6- or 7-membered heterocyclic ring having 1, 2, 3 or 4 nitrogen, oxygen and / or sulfur atoms; and

R ^ ° represents a hydrogen atom, a C в-C alky alkyl group, a C až-C cyk cycloalkyl group, a C až-C kar carboxycycloalkyl group or a C až-C alky alkyl group which is substituted one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, mercapto, alkylthio β 1 to 8 carbon atoms, an aromatic group of the formula

CS 270 246 B2

where * 7 β

R, R 'а й ° are hydrogen »halogen» hydroxy »nitro» amino »cyano, trifluoromethyl» C1-4 alkyl »C1-4 alkoxy or aminomethyl» carboxy »carboxy in the form of salts »alkanoylamino of 1 to 7 carbon atoms» alkoxycarbonyl of 2 to 9 carbon atoms »phenylmethoxycarbonyl» diphenylmethoxycarbonyl »hydroxy (alkoxy) foefinyl of 1 to 8 carbon atoms in the alkoxy part» dihydroxyphosphinyl group »hydroxy (phenylmethoxy) foefines and / or di (alkoxy) phosphinyl group having from 1 to β carbon atoms in the alkoxy moieties, as well as the ester-hydrolysable esters and salts thereof and the hydrates of the compounds of the formula I, optionally the hydrates of their salts.

The term alkyl group of 1 to 8 carbon atoms refers to a straight or branched chain hydrocarbon group β of 1 to 8 carbon atoms »preferably in 1 to 4 carbon atoms» such as methyl group »ethyl group» n-propyl group, isopropyl group »target · Butyl group or below ·

The term C 1 -C 8 alkoxy refers to straight or branched chain hydrocarbon oxy groups in which the alkyl group is as defined above. Examples which may be mentioned are methoxy, ethoxy, n-propoxy and the like.

The term halogen includes chloro »bromo» iodo or fluoro unless otherwise specified.

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

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

R ^P5 - CO in which.

R @ 25 denotes a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms.

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

Substituted phenyl refers to a mono- or disubstituted phenyl group, with the substituents being a halogen atom (for example chlorine, bromine, fluorine), an alkyl group having 1 to 8 carbon atoms, an amino group, a nitro group or a trifluoromethyl group.

CS 270 246 B2

The term "substituted alkyl" means an alkyl group of 1 to 8 carbon atoms optionally substituted by halogen (for example chlorine, fluorine, bromine), trifluoromethyl, amino, cyano, and the like.

The term alkenyl group of 2-6 carbon atoms ”denotes straight or branched hydrocarbon groups by an olefinic double bond and 2-6 carbon atoms, i.e. the remainder of the compounds of the formula С _ц Н _2п , in which n is 2-6, such as allyl, vinyl, etc. *

The term "aralkyl" denotes a hydrocarbon group and an aromatic and aliphatic structure, ie a hydrocarbon group in which one hydrogen of an alkyl group having 1 to 6 carbon atoms is substituted by a monocyclic aryl group such as a phenyl group, a tolyl group etc. ·

The term "5-, 6- or 7-membered heterocyclic ring of 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 pyrrolidinyl, pyrazolyl, imidazolyl, 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-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl and the like. heterocyclic rings may be further substituted, taking into account, for example, the following sub-states: alkyl of 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, etc., alkoxy of 1 to 8 carbon atoms, such as methoxy, a halogen atom such as chlorine, bromine, etc., a C 1 -C 8 haloalkyl group such as a trifluoromethyl group, a trichloroethyl group, etc., an amino group, a methoxy group, a hydroxy group, a carbamoyl group or a carboxy group, etc.

The term "C 3 -C 7 cycloalkyl" refers to a 3- to 7-membered saturated carbocyclic radical, for example cyclopropyl, cyclobutyl, cyclohexyl, etc.

_And R ^ ⁰ ^ _{оо ои} together be alkylene having 3-5 carbon atoms, e.g., - (CH ^) ^ -, - (CH ^) ^ -, or -CH (CH?) - (CH _{2) 2} - or else C 2 -C 4 alkylene monooxy, for example - (C 8 ₂ ) ₂ -O-, - (CH ₂ ) ₃ -O-, - (CH ₂ ) 4 -O- or -CH (CH 2) - CH ₂ -O-; or also alkylenedioxy having 1 to 2 carbon atoms, such as -O-CH ₂ -O-, -O- (CH ₂ ) ₂ -O- or -O-CH (CH 2) -O-. Preferably they form a 5- or 6-membered fused ring.

R32 and R33 may together represent an alkylenedioxy group having 1 to 4 carbon atoms such as -O-CH-O-, -O- (CH _2)? -O-, -О- (СН _? ) ₃ ~ 0-, -O- (CH ₂ ) ₄ -O-, -O-CH (CH ₃ ) -O-, -O-CH (CH ₃ ) -CH (CH ₃ ) -O- or similar groups. In this case, a 5 or 6-membered condensed ring is preferably formed. ·

As examples of groups

R ¹³⁰ -O-N = C-CO 1102

The following groups may be mentioned in CS 270 246 B2:

2- (2-aminothiazol-4-yl) -2-isopropoxyiminoacetyl

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

2- (2-aminothiazol-4-yl) -2-hydroxyiminoacetyl-N- [4- (3-amino-3-carboxypropoxy) phenyl] -2-hydroxyiminoacetyl, N- (5-chloro-2-aminothiazole-) 4-yl) -2-methoxythioacetyl,

2- (2-aminothiazol-4-yl) -2- (carboxyaethoxyimino) acetyl,

2- (R-imino-3-mesyl-4-thiazolin-4-yl) -2-isopropoxyiminoacetyl,

2- (2-aminothiazol-4-yl) -2- (carboxyisopropoxyimino) acetyl, etc. ·

In the preferred position of the 3-position of the quinolonyl or aza-quinolonyl substituents in the 3-position, Z represents a group R ^ ° -C in which R ^ ° represents a hydrogen atom, a chlorine or fluorine atom, preferably hydrogen or fluorine; particularly preferably ethyl or haloalkyl of 1 to 8 carbon atoms, in particular fluoroethyl, or cycloalkyl of 3 to 7 carbon atoms, preferably cyclopropyl;

r32 preferably denotes an alkyl group having 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 is preferably hydrogen, chlorine or fluorine, in particular hydrogen or fluorine, in particular fluorine;

The quinolonyl or optionally quinolonyl substituent at the 3-position includes, but is not limited to, the following formulas:

AND

CS 270 246 B2

О

о

CS 270 246 B2

CS 270 246 B2

CHO

CS? 70 246 B2

CS 270 246 B2

CS 270 246 B2

CS 270 246 B2

CS 270 246 В?

CS 270 246 B2

CS 270 246 B2

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

(Ib) wherein

R ¹ has the abovementioned meaning and

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

R ²²

AND

- c - COOH hr

wherein _R 22 _and D 23 represent a hydrogen atom or a C 1 -C 8 alkyl group or _R 22 _{and R} 22 together represent in the carbon atom to which they are attached a 3- to 7-membered carbocyclic ring, for example a cyclopropyl ring, cyclobutyl ring or cyclopentyl ring.

Particularly preferred are compounds of formula Ib in which

R ²⁰ represents a hydrogen atom and R ²¹ represents a methyl group or a group of formula R ²² | - C - COOH 1 rZJ wherein R ²² and R ²³ are hydrogen or methyl N - 0 я Groups - R ¹³⁰ and N - 0 - R ²¹ H -0- -C-

CS 270 246 B2 are preferably present in the syn-form, i.e. in the Z-form or in the form of mixtures in which the syn-form predominates ·

Easily hydrolyzable esters of the compounds of formula (I) are understood to be those compounds of formula (I) in which the carboxy group (s) are present in the form of a readily hydrolyzable ester group. Examples of such esters which may be of the conventional type include acetoxyethyl ester and 1-pivaloyloxyethyl ester; alkoxycarbonyloxyalkyl esters such as methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-iopropoxycarbonyloxyethyl; lactonyl esters such as phthalidylester and thiophthalidylester; alkoxymethyl such as methoxymethyl and alkanoylamino · ethyl, například.асеtamidomethylester · _f

However, other esters such as benzyl ester and cyanomethyl ester are also useful. The alkyl moieties and alkoxy moieties in the above moieties contain 1 to 8 carbon atoms.

Examples of salts of the compounds of formula 1 include alkali metal salts 8 such as sodium and potassium salts, ammonium salts; alkaline earth metal salts such as calcium salt; salts with organic bases such as salts of amines, for example salts with N-ethylpiperidine, procaine, dibenzylamine, N, K * -dibenzylethylenediamine, alkylamines or dialkylamines, as well as salts with amino acids such as salts with arginine or lysine.

Compounds of formula I which contain an amino group also form addition salts in organic or inorganic acids. Examples of such acids include hydrohalides such as hydrochlorides, hydrobromides, hydroiodides, as well as other salts with 8 mineral acids such as sulfates, nitrates, phosphates and the like; alkyl and monoarylsulfonates such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like; and also other salts with organic acids such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula I, including their salts, may hydrate and may therefore be present in a hydrated form · Hydration 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 new acyl derivatives of formula I, which comprises cleaving the protecting group in the substituent R aDinoskupiny ^one-compound of formula VII

(VII)

CS 270 246 B2 in which m, ^R? »R ^32, _and R ^ O h _oa .jí _{ora e} defined above, and

R ¹⁰³ is as defined for R ¹⁰² , wherein the aminoeubetituent is present in the protected state, or the salt ester 61 of such a compound, and the obtained compound is optionally isolated in the form of a salt, the hydrate thereof in the form of a salt hydrate.

As examples of formula residues

R ¹³⁰ - 0 - N »C - CO - ¹⁰³ can be mentioned:

2 - [(2-chloroacetamidothiazol-4-yl)] - 2 - [(p-nitrobenzyloxycarbonyl) methoxyiminotacetyl *

2- (2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetyl * - (5-chloro-2-chloroacetamidothiazol-4-yl) -2-methoxyiminoacetyl *

2- [2- (tert-butoxycarbonyl) isopropoxyimino-3- (2-sulfoaminothiazol-4-yl) acetyl *

2- [2- (tert-butoxycarbonyl) iopropoxyimino] -2- (2-triphenylmethylaminothiazol-4-yl) acetyl * 2- (2-chloroacetamidothiazol-4-yl) -2-isopropoxyiminoacetyl * 2-methoxyimino-2- (2 -sulfoaminothiazol-4-yl) acetyl *

2- (2-mesylaminothiazol-4-yl) -2-isopropoxyiminoacetyl

Cleavage of the amino protecting group in the substituent of the compound of formula VII by the process of the invention leads to the corresponding compounds of formula I with a free amino group. Possible amino-protecting groups are those * used in peptide chemistry * for example alkoxycarbonyl groups * such as tert-butoxycarbonyl groups etc. * substituted alkoxycarbonyl groups such as trichloroethoxycarbonyl groups etc. * substituted aralkoxycarbonyl groups * for example p-nitrobenzyloxy groups * a trityl group or a benzhydryl group or a haloalkanoyl group * such as a chloroacetyl group * a bromoacetyl group * an iodoacetyl group or a trifluoroacetyl group.

Preferred amino protecting groups are tert-butoxycarbonyl (t-BOC) and trityl.

Amino-protecting groups are removable, for example, by acid hydrolysis (for example, a tert-butoxycarbonyl or trityl group) or also by hydrolysis under basic conditions (for example, trifluoroethyl). Chloro- * bromo- and iodoacetyl groups can be cleaved by thiourea ·

Protective groups cleavable by acid hydrolysis are preferably removed by means of a lower alkanecarboxylic acid which may optionally be halogenated. In particular, formic acid or trifluoroacetic acid is used. The working temperature * is generally room temperature * although slightly elevated or slightly lower temperatures than room temperature may be used, for example temperatures ranging from about 0 ° C to * 40 ° C · The alkali-cleavable protecting groups are hydrolyzed by generally dilute aqueous hydroxide at a temperature of 0 ° C to 30 ° C. The chloroacetyl group, the bromoacetyl group and the iodoacetyl group, which groups are used as protecting groups, can be cleaved by treatment with thiourea in acidic neutral or alkaline conditions at a temperature between 0 ° C and 30 ° C.

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 1 with an equimolar amount of the desired base suitably in a solvent such as water or an organic solvent such as ethanol. methanol, acetone or similar solvents · The salt formation temperature is not critical and is generally about room temperature, but can also be operated at a temperature slightly above room temperature or at a temperature slightly below room temperature, e.g. ° C to * 50 ° C.

Hydrates are usually produced 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 a hydrate, the wholly 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 of about + 10 ° C to +40 ° C.

The following Reaction Scheme X illustrates a process for preparing compounds of the invention:

(III)

CS 270 246 B2

The general symbols R @ ¹ , R @ ² , R @ ³¹ , R @ ³² , R @ ³³ , R, Z, Hal and the intermittent versions have the meanings indicated above.

Depending on the choice of protecting group of the ester group R and the halogen Hal, the α- or N -isomer of the compound of formula VIII is obtained with respect to the double bond in the cephem ring. The resulting mixture of the β-N-isomers can be purified, if desired, by producing a sulfoxide of formula V followed by reduction of the compound or separation of the two components into no β-isomer.

Clarification of Scheme I:

II and ---> VIII

The compound of formula (IIa) is a known compound or can be obtained in an analogous manner (eg, U.S. Pat. Nos. 4,406,699 and 4,266,049). This compound is reacted with a salt of the allowed quinolone of formula III, preferably in a solvent which does not contain hydroxyl groups such as dimethylformamide, methylene chloride or N, N'-dimethylaoatamide. Suitable salts of the carboxylic acid of the formula III are, for example, sodium, potassium, oesic, tert-butylammonium or tetramethylammonium salts. The symbol Hal in the formula II represents a halogen atom, in particular bromine or iodine. especially at room temperature.

VIII ----> Ia or Via

The ester group R of the compound of formula VIII is then cleaved to give the carboxylic acid of formula Ia or a mixture of the carboxylic acid of formula Ia in the α-isomer of the compound of formula VIa.

Protecting groups of the ester group R are preferably those which convert under mild conditions into a free carboxyl group, for example, a target, a butyl group, a p-nitrobenzyl group, a benzhydryl group, an allyl group, etc. For example, the protecting groups of the ester group are cleaved as follows: a p-nitrobenzyl group by hydrolysis in the presence of sodium sulfide at 0 ° C (or lower) to room temperature in a solvent such as dimethylformamide (preferably aqueous dimethylformamide); a 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 methylene chloride; allyl group by palladium (O) catalysed transallation with the presence of sodium or potassium salt of 2-ethylcaproic acid (cf., for example, J · Org · Chem. 1962 · ££, 587) ·

Via ---- * V ·

When the double bond isomerized to form the A3-isomers, the compound of formula VIa thus oxidized is oxidized by the action of an organic or inorganic oxidizing agent. Various oxygen-releasing compounds such as organic peroxides, e.g. monosubstituted, are used as oxidizing agents.

Organic peroxides »such as alkyl hydroperoxides containing from 1 to 4 carbon atoms in the alkyl moiety or alkanoyl hydroperoxides» such as tert-butyl hydroperoxide »permetic acid or peracetic acid; as well as phenyl-substituted derivatives of these hydroperoxides, such as cumene hydroperoxide or perbenzoic acid. The phenyl group as the eubetituent may optionally contain other substituents, such as, for example, a C1-C4 alkyl group or a C1-C4 alkoxy group, or a halogen atom or a carboxyl group, so that, for example, it may be 4-methylperbenzoic acid. 3-chloroperbenzoic acid or monoperphthalic acid. Various inorganic oxidizing agents »such as hydrogen peroxide» ozone »permanganates» such as potassium permanganate or sodium permanganate »hypochlorites» such as sodium hypochlorite »potassium hypochlorite or ammonium hypochlorite» peroxymonosulphuric acid and peroxisulphuric acid can also be used as oxidizing agents.

Preference is given to using 3-chloroperbenzoic acid. The oxidation is preferably carried out in an inert solvent, for example in an aprotic inert solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform, ethyl acetate or acetone, or in a solvent such as water, lower alkanol. »For example in methanol or ethanol» or in a lower »optionally halogenated alkanecarboxylic acid» for example in formic acid »acetic acid or trifluoroacetic acid. The reaction temperature is preferably in the range from -20 ° C to * 50 ° C.

By using an equimolar amount of oxidizing agent »or a slight excess in proportion to the starting material, the corresponding sulfoxide V is obtained in particular. If the amount of oxidizing agent is increased to twice the stoichiometric ratio or even more», the corresponding sulfone is formed.

In ---- * Ia.

The compound of formula (V) thus obtained is itself a reaction product of formula (I). However, it can be reduced to the final product of formula (Ia), for example by treatment with phosphorus trichloride in dimethylformamide or trifluoroacetic anhydride in the presence of sodium iodide in acetone / methylene chloride. The temperature of this reaction is preferably at about 0 to -20 ° C, especially at 0 ° C.

Compounds of formula I with groups

NOR ¹³⁰ NOR ²¹

I · II

- C - or - C (γгоу. Above) ee preferably occur in the form of syn-forms. Such syhforms can be obtained using starting materials in which this syn-form is already present. If desired, the resulting syn / anti-forms of the compound of formula I can be separated in the usual manner into the corresponding syn- and anti-forms by, for example, recrystallization or chromatographic methods using a suitable solvent or solvent mixture.

The compounds of the formula I as well as the corresponding hydrates or esters of these compounds and esters are particularly antibacterially active. They can be used as a means to treat bacterial infections (including urinary tract and respiratory tract infections) in mammals, such as dogs, cats, horses, etc., and humans. These cephalosporins are effective against a wide range of both gram-negative and gram-positive bacteria.

CS 270 246 B2

The in vitro activity of the compounds of the invention against a variety of? Gram-positive and gram-negative micro-organisms, expressed as the minimum inhibitory concentration in microgram / ml and ascertained using the maturation series (liquid) method, is as follows:

Compound C: sodium [6R- (6,7,7 / 3) (Z)] - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3-f [[1-ethyl-1,4] -dihydro-7-methyl-4-oxo-1,5-naphthyridin-3-yl) carbonyl] oxy] -methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -? - carboxylic acids.

Compound D: [6R- (6,7,7) (Z) J-f (2-amino-4-thiazolyl) (methoxyifflino) acetyl] amino] -3- [[[(5-ethyl- 5,8-dihydro-8-oxo-1,3-dioxolo [4,5-gquinolin-7-yl] carbonyl-oxo-methyl] -8-oxo-5-thi-1-azabicyclo [4.2.1.0 < 2,7 &gt; o-Oct-2-ene-2-carboxylic acid ·

Compound I: 6R- (6d (, 7/3) (Z)) - 7-ff (2-amino-4-thiazolyl) (methoxyimino) acetyl ylamino-3-f [f [1-ethyl-6] sodium salt fluoro-l, 4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinoline-3 -vinyl] carbonyl] oxy] methyl J-8-oxo-5-thia-1-azabicyclo [4.2 _f o oct-2-ene-2-carboxylic acid.

Table

Minimum in vitro inhibitory concentration (/ Ug / ml)

microorganism C D AND E. coli 0.25 0.5 K. pneumonis A 0.5 0.25 0.5 E. cloacae 957OA 2 1 2 E. cloacae 948-1 8 1 4 E. cloacae 2367-2 16 2 4 E. cloacae 7099 8 0.5 2 E, cloacae 214 8 0.5 4 P. vulgaris ATCC 6380 0.25 0,063 0.5 P. mirabilis 0.16 0.008 0,031 S. marcescens SM 1 0.5 1 P. seruginosa Stone 128 16 8 P. aeruginosa 503-56 128 32 32 S. aureus Smith 2 2 0.25 S. aureus 8 4 0.5

To combat bacterial infection, 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. All types of applications that are currently contemplated in the treatment of penicillins and cephalosporins are also applicable to the novel cephalosporins of the invention. Thus, administration can be accomplished, for example, by intravenous, intramuscular, and enteral administration.

CS 270 246 В?

The compounds of the invention may also be used as medicaments, for example in the form of pharmaceutical preparations containing these 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, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, vaseline, etc. · The pharmaceutical preparations may be present in solid form, for example in the form of tablets · dragees · suppositories · capsules or in liquid form, for example in in the form of solutions, suspensions or emulsions. These preparations are optionally sterilized and optionally contain adjuvants · as preservatives · stabilizers · wetting agents, emulsifiers, salts for varying the osmotic pressure, anesthetics or buffers. These preparations may also contain other therapeutically valuable substances. The carboxylic acids of the formula I and their salts or hydrates are preferably suitable for parenteral administration and are preferably prepared in the form of lyophilisates or dry powders for dilution by conventional means such as water and isotonic sodium chloride solution, co-solvents such as propylene glycol. Easily hydrolyzable esters of formula I are also suitable for enteral administration.

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

Example 1

[6R- (64,7 R)] - 3 - [[[(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5- g] quinolin-7-yl) carbonyl] oxy] methyl] -7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

A solution of 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolof4,5-g] quinoline-7-carboxylic acid sodium salt (1 mmol) in 12 µl dimethylformamide was stirred under nitrogen for 1 hour. in 1.5 g of molecular sieve (4 µm), and then a solution of [6R- (6 (7,7)) - 3- (iodomethyl) -8-oxo-7 - [(phenoxyacetyl) 1,1-dimethylene ethyl ester solution is added Amino-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (1 mmol in 6 ml of absolute dimethylformamide) was stirred for 5 hours and then evaporated to dryness. The residue is taken up in ethyl acetate or a mixture of ethyl acetate and methylene chloride, and then the solution is washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to dryness, and the residue is purified by preparative layer chromatography or flash chromatography using 8: 2 ethyl acetate / methylene chloride.

Example 2

[N - (6,7,7) (Z)] - 3 - [[[(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3)] - 1,1-dimethylethyl ester -yl) carbonyl] oxyjmethyl] -7 - [[(methoxyimino) - [6- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0.0 &lt; 2,7 &gt; oct-2-ene-2-carboxylic acid

CS 270 246 B2

The title compound 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 1,1-dimethylethyl ester R- (6α, 7M (Z)) -3-iodomethyl-7H- (methoxyimino) - [2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino-8-oxo-5-thia-1-azabicyclo [4.2.1] octane The residue is purified by flash chromatography using a 9: 1 mixture of ethyl acetate and methylene chloride as the solvent system.

Example 3

6R- (6Z, 7/3 (Z)) -3- [(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g) quinoline] 1,1-dimethylethyl ester -7-yl) carbonyl] oxy] methyl] -7- [E (methoxyimino) [2- (triphenylmethylamino-4-thiazolyl) acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acids

The title compound ae is obtained by repeating the reaction described in Example 1 using 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid and

[6R- (6,7,7 / 5) (Z)] -3-iodomethyl-7-f (methoxyimino) -4- (triphenylmethyl) amino-4-thiazolyl] acetyl} amino-8-oxo-5-thia-1-dimethyl-ethyl ester -azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid starting materials. The residue is purified by flash chromatography using a 9: 1 mixture of ethyl acetate and methylene chloride as solvent ⁴ system.

Example 4

1R- (6,7,7/2) (Z)] - 7-f [(2-amino-4-thiazolyl) - (methoxyimino) acetyl] amino-3 - [[L (1 - thiyl) - 1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyloxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acids

A suspension of the reaction product of Example 2 (0.31 mmol) in anisole (0.66 ml) was cooled to 0 ° C under nitrogen and 3.3 ml of trifluoroacetic acid was added to the cooled suspension. The solution thus obtained is kept at 0 ° C for 18 hours and then the flask is evaporated under reduced pressure at room temperature. After 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. If no solid is to be obtained, the residue is converted directly into the sodium salt.

In both cases, the solid or oil obtained is dissolved in 9 ml of methylene chloride, then an aqueous solution of sodium bicarbonate containing sufficient sodium bicarbonate is added dropwise to the solution thus obtained in methylene chloride at 0 to 3 ° C. reached a final pH of 7.2 to 7.4. The aqueous phase was freeze-dried and then purified by high-performance liquid chromatography using a reverse phase column using a mixture of water and methanol with a methanol gradient (0 to 100% methanol, 20 minutes) as eluent.

CS 270 246 B2

After evaporation and drying of the precipitates, the reaction product is obtained with the following characteristic values:

IR (KBr): .delta.

3405 »3300» 3200 »1766» 1716 »1681» 1617 »1537 cm” ¹ .

Example 5

(6R- (6L, 7R) (Z)] - 7 - [[(2-Amino-4-thiazolyl) - (methoxy-amino) acetyl] amino] -3 - [[[(5 -ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinolin * 7-yl) carbonyl, 1-oxymethyl] -8-oxo-5-thia-1-azabicyclo [4 &gt; 2 &gt; Ooct-2-ene-2-carboxylic acid

The title compound is obtained according to the procedure »described in Example 4» but using the reaction product of Example 3 »

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3400-300, 1767, 1715, 1685, 1635, 1616, 1533 cm ^-1 .

Mass spectrum: m / z 679 (M ^{+ +} H) _t 701 (M + + Na).

EXAMPLE 6 11.1-Dimethylethyl ether [6R- (6 < 7 &gt; H) (Z)] - 3 - [[[1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl)]] -1-piperazinyl) -4-oxoquinolin-3-ylcarbonyl] oxymethyl-7-1 - [(methoxyimino) N - (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -8-oxo-5 * thia -1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids

Using the procedure of Example 1, but using 1 ', 1-dimethylethyl ester .beta .- (6? 7/6) (Z) - (iodomethyl) -7-? (Ae thoxyimino) -? - (triphenylme) ethyl) amino-4-thio-1-azabicyclo [4.2.0.0] oct-2-ene-2-carboxylic acid and 1-ethyl sodium salts 6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid starting material gave the title compound.

• * Example 7

Sodium salt [, 6R (6 R, 7/3) (Z)] - 7-E [(2-amino-4-thiazolyl) - (methoxyimino) acetylJamino.J 3- [LL ¹ £ ^"e ethyl- _6-fluoro-1 4-dihydro-7- (4-formyl-l-piperazinyl) -4-oxoquinoline-3-yl] carbonyl 1] oxy] methyl thylJ-8-oxo-5-thia-l-azabicyclo [ 4- (2-10) oct-2-ene-2-carboxylic acid

CS 270 246 B2

The title compound is obtained as described in Example 4 _t but using the reaction product of Example 6th

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3420, 1765 »1712, 1622 cm” ¹ .

Mass spectrum:

m / z 764 (M &lt; + &gt; + H).

Example S-l l _t dimethylethyleeter [6R- (6a _t 7/5) (Z)] - 3- [fl [l-ethyl-6-fluoro-l * 4-dihydro-7- (l-pyrrolidinyl) -4 oxoquinolin-3-yl] carbonyl] oxy.] methyl 7-7 - [[(methoxyimino)]. 2- (triphenylmethyl) amino-4-thiazolyl] acetyl-amino-8-oxo-5-thia-1-azabicyclo [4 * 2 * oct-2-ene-2-carboxylic acid

Using the procedure described in Example 1 * but using 1 * 1-dimethylethyl ester β- (6,6 * 7/3) -3- (iodomethyl-7 - [[(methoxyimino) - [N - (triphenylmethyl) amino]] - 4-thiazolyl-acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.1.0] oct-2-ene-2-carboxylic acid and sodium salt of 1-ethyl-6-fluoro-1,4-dihydro-4- oxo-7- (1-pyrrolidinyl) -3-quinolinecarboxylic acid starting material * yields the title compound ·

Example 9

66R- (6,77ZW (Z) J-7- [1- (2-Amino-4-thiaablyl) - (methoxyimino) acetyl] amino) -3- (11-H) -ethyl-6-fluoro-1,4-dihydro-sodium -7- (l-pyrrolidinyl) -4-oxoquinoline-3-yl-karbonylJoxy7methyl] -8-oxo-5-thia-l-azabicyclo [4 _t 2 * 0] oct-2-ene-2-carboxylic acid

The title compound is obtained as described in Example 4 _t but using the reaction product of Example eighth

The compound obtained has the following characteristic data:.

IR spectrum (KBr technique):

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

Mass spectrum:

m / x 722 (M ^& lt ^; + & gt ^; + H).

CS 270 246 В?

? 5

Example 10

Sodium salt of [6R- (6,4,7 / 3) (Z)] J-7 - [[(2-amino-4-thiazolyl) - (methoxyiciino) amino] -3] - [[[11-ethyl-6]] -fluoro-1 * 4-dihydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-yl] carbonyloxy] methyl] -8-oxo-5-thia-1-azabicyclo [4 * 2 * o] oct -2-ene-2-carboxylic acid

A solution of 0 * 374 g of 1-ethyl-6-fluoro-1,4 * dihydro-4-oxo-7- (4-thiomorpholinyl) -3-quinolinecarboxylic acid potassium salt in 16 µl of dimethylformamide is stirred for 1 hour in 1.5 g. molecular sieves (4 · 10 -4 ° m) · After adding a solution of 1 * 07 gl * 1-dimethylethyl ester [6R- (6o * 7E)] -3-iodomethyl-7- (L-methoxyiino) - [(2- triphenylmethyl) amino-4-thiazolyl] acetyl] amino.] - 8-Oxo-5-thia-1-azabicyclo [4 * 2 * O] oct-2-ene-2-carboxylic acid in 16 ml of methyl methyl forms the reaction mixture is stirred for 5 hours · The mixture is evaporated under reduced pressure * the residue is taken up in ethyl acetate * and then the mixture is washed successively with aqueous sodium bicarbonate solution and brine. After drying over sodium sulfate, the ethyl acetate solution is evaporated under reduced pressure. flash chromatography *, then the intermediate t-butyl ester * corresponding to the above-mentioned compound * is obtained as the intermediate ·

Dissolve 0 * 103 g of this tert-butyl ester in a mixture of 0 * 21 ml of anisole and 1 * 06 ml of trifluoroacetic acid and hold this solution at 0 ° C for 18 hours. The mixture is concentrated under reduced pressure and the residue dissolved in methylene chloride. The pH is adjusted to 7 * 5 by addition of water and sodium bicarbonate. The aqueous phase is freeze-dried. After purification of the residue by reverse phase high performance liquid chromatography, the title compound is obtained. ·

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3410, 1768, 1715, 1682, 1622 cm ^-1 .

Mass spectrum:

m / z 754 (M + H) ·

Example 11

Monosodium salt dihydrate [6R- (6GO * 7/4) (Z)] J-7 - [(R-amino-4-thiazolyl) (methoxyimino) acetyl] amino-3-LLi 6,8-difluoro-1- (2- Fluoroethyl) -1 * 4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinyl] carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4 *] 2 * θ] oct-2-ene-2-carboxylic acid

To a suspension of 5 g of 6 * 8-difluoro-1- (2-fluoroethyl) -1 * 4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid potassium salt in 40 ml of dimethylformamide a solution of 10 gl * 1-dimethylethyl ester [6R- (6,4 * 7/3)] - 3- (iodomethyl) -7 - [[(methoxyimino) [2- (triphenylmethyl) amino] -4] is added over 5 minutes -thiazolylacetyl] amino-8-oxo-5-thia-1-azabicyclo [4 * 2 * o] oct-2-ene-2-carboxylic acid in 40 ml of dimethylformamide. The reaction mixture was stirred for 2 hours and then evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution.

CS 270 246 B2

The organic phase was washed successively with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give a brown, pan-like solid. Purification by flash chromatography on 500 g of silica gel (particle size 0.04-0.08 mm) using a mixture of methanol and chloroform (gradient 0 to 8% methanol) gave the intermediate 1,1-dimethylethyl ester as described above. the title compound.

A solution of 2.30 g of this 1,1-dimethylethyl ester in 25 ml of methylene chloride was treated at 0 ° C with the addition of 2 ml of anisole, 0.2 ml of 1,2-ethanedithiol and 25 ml of trifluoroacetic acid. The mixture was stirred at 0 ° C for 3.5 hours and then evaporated at 0 ° C under reduced pressure. Methylene chloride was added to the evaporation residue and the evaporation was repeated. 5 ml of cold ethyl acetate were added to the residue, followed by 25 ml of ether, whereupon a solid formed. Filtration, washing with ether and air-drying gave a brownish solid. This solid was dissolved in 100 mL of 1: 4 methanol: chloroform and then 100 mL of water and 35 mL of 5% aqueous sodium bicarbonate were added under ice-cooling until the pH was adjusted to 7.8. The resin thus formed is dissolved in 10 ml of dimethylformamide and 20 ml of chloroform are added to the obtained solution, followed by water and aqueous sodium bicarbonate until the pH is adjusted to 7.8. The combined aqueous extracts containing the reaction product were washed with chloroform and purified by reverse phase C18 chromatography using a water / acetonitrile gradient as solvent.

The fractions containing the reaction product were evaporated under reduced pressure and dried as illustrated to give the title compound.

The compound obtained has the following characteristic data:

Mass spectrum:

m / s 787 (M + H).

According to the methods explained in the above examples, the following compounds can be produced:

CS 270 246 B2

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CS 270 246 B2

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CS 270 246 B2

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CS 270 246 B2 [6R- [6α, 7β (Ζ)]] - 3-C [[7- (3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl]

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CS 270 246 В?

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CS 270 246 B2

The following example illustrates forms of pharmaceutical compositions containing the cephalosporin derivatives of the invention.

Example 1 a d A

Preparation of dry ampoules for in-tram sculptor application:

1 g of the monosodium salt of [6R- (6,7,7,4) - (Z) -1] -7-L [2-amino-4-thiazolyl (methoxyitino) acetyl] amino] -3- [[ C6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-ylcarbonyl] oxy] methyl-1- 8- oxo-5-thia-l-azabicyclo _[4.2> Ojokt-2-ene * 2-carboxylic acid and filled into ampoules · sterile water ampoule contains 10 & propylene · Before application ее к lyophilisate is treated with 2.5 ml of 2% aqueous lidocaine hydrochloride solution.

Claims (31)

A process for the preparation of novel acyl derivatives of the general formula I in which m is 0, 1 or 2, p R is hydrogen, C 1 -C, alkoxy, amino, C 1 -C 8 alkylthio or C 1 -C 7 alkanoylamino, C 1 -C 8 alkyl, C 2 -C 6 alkenyl carbon atoms, C 3 -C 7 cycloalkyl, C 1 -C 8 haloalkyl or halophenyl, Z represents a group R 1 -C or a nitrogen atom wherein it represents a hydrogen atom or a halogen atom, or R ^ O and LPI _2n amenají together are alkylene having 3-5 carbon atoms alkylenmonooxyskupinu with 2-4 carbon atoms or alkylendiox.yekupinu в 1-2 carbon atoms, R3? represents a hydrogen atom, a halogen atom, a C 1 -C 8 alkyl group or an C 1 -C 8 alkyl group or an optionally substituted 5- or 6-membered N-heterocyclic ring optionally containing an oxygen atom or an additional nitrogen atom, r33 represents a hydrogen atom or a halogen atom or r3? and R 6 together represent an alkylenedioxy group having from 1 to 4 carbon atoms, and R ^10? represents an amino-substituted 5-, 6- or 7-membered heterocyclic ring having 1, 2, 3 or 4 atoms of due, oxygen and / or sulfur, and R (10) is hydrogen, (C1-C8) alkyl, (C3-C7) cycloalkyl, (C3-C7) carboxy-cycloalkyl, or (C1-C8) alkyl which is substituted one or more substituents selected from the group consisting of halogen, cyano, nitro, amino, mercapto, alkylthio of 1 to 8 carbon atoms, aromatic group of formula EN í> 70 246 B2 where й 7 Я R, R 'and R are hydrogen, halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or tri-methyl, carboxy, carboxy in the form of salts, C 1 -C 7 alkanoylamino, C 2 -C 9 alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, C 1 -C 8 hydroxy (alkoxy) phosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) a phosphinyl group and / or a di (alkoxy) phosphinyl group having from 1 to 6 carbon atoms in the alkoxy moieties, as well as pharmaceutically acceptable readily hydrolyzable esters and salts of these compounds and hydrates of the compounds of formula I, or hydrates of their salts, the amino protecting group in R &lt; ¹⁰ &gt; of formula Vil · R ³¹ (VII) in which m, R ^? , R ^1, R ?, R33 and ^R1 ^ ⁰ are as defined above, and Ί 07 * 10? R ^J is as defined for R, but the amino substituent is present in the protected state, or an ester or salt of such a compound, and the compound obtained is optionally isolated in the form of a pharmaceutically acceptable salt ester, hydrate or salt hydrate. СВ 270 246 В2 2. Method according to claim 1, characterized ее that is used as starting material corresponding compounds of formula VII or a salt or ester of such compound 2a give compounds of formula I where m is 0, R ² is hydrogen and the other substituents have the meaning given in point 1. 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the general formula (VII) or an ester or a salt of such a compound are used as starting materials, in which: Z represents a group R ^ °C, wherein R (10) is hydrogen or halogen, R ( ¹⁾ represents an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms, R is C 1 -C 6 alkyl, piperazinyl or C 1 -C 8 alkyl substituted piperazinyl and r 33 is hydrogen or halogen, and the other substituents are as defined in 1 or 2; 4. A process according to claim 3 wherein the starting material is a corresponding compound of formula (VII) or an ester or salt of such compound to form compounds of formula (I) wherein r @ 3 is hydrogen or fluorine, R ¹ represents ethyl, fluoroethyl or cyclopropyl, ^R3? means a piperazinyl group or a 4-methylpiperazinyl group and ГрЗ means a hydrogen atom or a fluorine atom, and the other substituents are as defined in point 3; 5. Method according to one of claims 1 to 4, characterized in that as a starting material uses a corresponding compound of formula VII, or ester or salt thereof of such compounds to give compounds of formula I wherein r13O_ _O- ^ _SCR 1O2_ _C 0_ _2namen and an acyl group of formula NORWAY ²¹ CS 270 246 B2 in which R ^{? 0} R @ ¹ represents a hydrogen atom or an amino protecting group and represents a hydrogen atom, an alkyl group of 1 to 8 carbon atoms or a group of the formula: - C - COOH l _{- 3} where · 99 91 » R 1 and R 2 represent hydrogen, an alkyl group having 1 to 8 carbon atoms or together with the carbon atom to which they are attached a 3- to 7-membered carbocyclic ring, and the other substituents are as defined in any one of items 1 to 4 · 6. The process of claim 5, wherein the corresponding starting material is a corresponding compound of formula (VII) or an ester or salt thereof, to form the compounds defined in (5), wherein:. R is hydrogen and R is methyl or formula AND - C - COOH where R ²² and R ² are hydrogen or methyl, and the other substituents are as defined in point 5; Ί. 2. The method of claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form compounds of formula (I). COOH R ³¹ CS 270 246 B2 in which. R is as defined in point 5 a Z, R ^ ¹ , R ^ _and r33 are as defined in 1. Process according to one of Claims 1 to 7, characterized in that ee uses the corresponding compounds of the general formula (VII) or the ether or salt of such a compound as the starting material, to give compounds of the general formula (I) in which: R 'is methyl or f - C - COOH '23 where 22 23 R and R are each hydrogen or methyl ₉ Z represents a group R 1 -C, where R (10) is hydrogen or halogen, R ¹ represents an alkyl group having 1 to 8 carbon atoms, a haloalkyl group having 1 to 8 carbon atoms or a cycloalkyl group having 3 to 7 carbon atoms ₉ ^J R 8 is an alkyl group 1-8 carbon atoms, piperazinyl or alkyl having 1-8 carbon atoms substituted piperazinyl group, and R33 is hydrogen or halogen and the other substituents are as defined in any of claims 1 to 7 9. A process according to claim 8, wherein the starting material is a corresponding compound of formula (VII) or an ester or salt thereof, to give compounds of formula (8) in which: R 6 represents a hydrogen atom or a fluorine atom, R @ ¹ represents an ethyl group, a fluoroethyl group or a cyclopropyl group; is methyl, 4-methylpiperazinyl or piperazinyl and r 33 is hydrogen or fluoro. 10. A process according to claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form compounds of formula (6R-) (6a, 7ZO (Z) J-7-). (2-amino-4-thiazolyl) - ^{(R 1} -oxi.mino) acetyl] atiiino] -3-r [i (6-R ^33, B-8 ^{30 31} R -l, 4-dihydro-7 - (4-R ³⁴ piperazinyl) -4-oxo-3-carbonyl chinolinylJ] oxyjmethylj-8-oxo-5-thia-azabicyklof4, '0] CS 270 246 B2 -oct-2-ene-2-carboxylic acids and their salts and hydrates of these carboxylic acids and salt hydrates in which R ³³ and R ³ are hydrogen or halogen, R ³¹ is hydrogen, alkyl group 0 to 8 C ^-Cogen-Cogen-haloalkyl, R ³ ^ is hydrogen or C 21-C až alkyl, and R is hydrogen, C až-C alky alkyl or C obecného-C nebo alkyl; . R ^?? ' AND - C - COOH i ²³ , in which R? ³ _{and znanena} it _and the atom or an alkyl group having 1 to 8 carbon atoms. 11. A process according to claim 10, wherein the corresponding starting material is a corresponding compound of the formula (VII) or an ester or salt of such a compound. 21 'to form the compounds defined in 10, wherein R is methyl and the other substituents are as defined in 10. 12. The method of claim 11, characterized in that as a starting material uses a corresponding compound of formula VII or a salt or ester of such compound to give the compounds defined in item 11, wherein R ³³ and R ³⁰ are hydrogen atoms or fluorine, ^{R33 ,} is ethyl or 2-fluoroethyl and R @ ³ is methyl and the other eubstituenty are as defined in 11 above. 13. A process according to claim 12, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to produce the compounds defined in (12), wherein ^R33 and ^R30 are fluorine and ^R31 is 2- the fluoroethyl group and the other e-substituents have the meaning given in point 12. 14. The process of claim 11, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form the compounds defined in (11), wherein R &lt; ³³ &gt; is fluorine, R &lt; ³⁰ &gt; ³³ represents a 2-fluoroethyl group and R ³ represents a methyl group and the other substituents have the meaning given in 11. 15. The method of claim 11, wherein the ee that is used as starting material corresponding compounds of formula VII or an ester or salt of such a compound to give the compounds defined in item 11, wherein R ³³ is fluoro, R ³⁰ is hydrogen, R ³¹ is ethyl and R &lt; ³ &gt; is methyl and the other substituents are as defined in 11. CS 270 246 B2 16. The method of claim 11 * characterized in that * is used as starting material corresponding compounds of formula VII or a salt or ester of such compound 2a give the compounds defined in item 11 wherein _2namen * $ F * R represents a 2-fluoroethyl * R ( ³⁰⁾ is hydrogen and R ( ³⁴⁾ is methyl and the other substituents are as defined in (11) above. Process according to one of Claims 1 to 16 *, characterized in that the corresponding compound of the general formula (VII) or an ester or salt of such a compound is used as the starting material to give the compounds defined in items 1 to 16 * in which groups of the general formulas N - 0 - R ¹³⁰ and N - 0 - R ³¹ n H - c - - c are present in the syn-isomeric form or in the form of mixtures * in which the synisomeric form * prevails and the other substituents have the meaning given in one of items 1 to 1 16. 18. The process of claim 1 wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form compounds of formula (I) in the form of R6- (6rf * 76) (Z) J-7-. [1- (2-Amino-4-thiazolyl) (R ²¹ -oxyimino) acetyl] amino] -3- [[[L 6 -R 4 '] 8-R 4' -1 '4-dihydro-7- (4-R) ^34- l-piperazinyl) -4-oxo-3-quinolinylcarbonyljoxyjmethyl] -8-oxo-5-thia-1-azabicyclo [4.1.0] oct-2-ene-2-carboxylic acids and their salts and hydrates of these carboxylic acids and salts * in which R @ ¹ and R @ 2 are hydrogen or halogen * R @ ¹ is hydrogen * alkyl of 1 to 8 carbon atoms or 2 _T haloalkyl of 1 to 8 carbon atoms * R ^ ⁴ means is hydrogen or alkyl в 1-8 carbon atoms, R * ² ^ represents a group of formula COOH wherein and R ² is hydrogen or C 1 -C 8 alkyl. 19. The method of claim 18, wherein the compound of formula (VII) or an ester or salt thereof is used as the starting material to form the compounds defined in (18), wherein R ²² and R ²³ are both methyl and the others. the substituents have the meaning given in point 18. CS 270 246 B2 20. The process of claim 19, wherein ee uses the corresponding compounds of formula (VII) or an ester or salt thereof to form the compounds defined in (19), wherein Jp3 _and r30 are hydrogen or fluorine, lpi is ethyl or 2-fluoroethyl and R &lt; ^{4 &gt}; is methyl and the other sub-substituents are as defined in 19 * 21. The method of claim 20, characterized ве that is used as starting material corresponding compounds of formula VII or an ester or salt of such a compound to give the compounds defined in item 20, JP3 _{and R} 30 are fluorine and R @ ¹ represents · The 2-fluoroethyl group and the other substituents have the meaning of defino-. bathtubs in point 20. · 22. The method according to item 19, characterized in that as starting substance used corresponding compound of formula VII or ester or salt thereof such compounds to give the compounds as defined in paragraph 19, wherein JP3 is fluorine, R @ ⁰ is hydrogen, R R 1 represents a 2-fluoroethyl group and R ⁴ represents a methyl group and the other subetituents are as defined in point 19. ? 3. 19. The method of claim 19, wherein the starting material is a corresponding compound of formula (VII) or an ester or salt thereof, to form the compounds defined in (19), wherein R @ 1 is fluorine, R @ 2 is hydrogen, R @ 2 R ¹ is ethyl and R ⁴ is methyl and the other substituents are as defined in point 19. 24. The process of claim 19, wherein the starting material is a corresponding compound of formula (VII) or an ester or salt thereof, to form the compounds defined in (19), wherein R @ 1 is fluorine, R @ 1 is? fluoroethyl, R is hydrogen and R ⁴ is methyl and the other subetituenty are as defined in point 19. ' 25. The process of claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form [6H- (6, z, 7) (7)] - 7 - [[ (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3-LLL (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyl] oxyjmethyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, and salts thereof and hydrates thereof, or hydrates thereof. 26. The process of claim 1, wherein the starting material is a corresponding compound of formula (Vit) or an ester or salt of such compound to form [6R- (6,6,7 / 4) (Z)] -7- L- (R-amino-4-thiazolyl) (methoxyimino) acetyl-amino-3 - [[f- CS 370 246 B2 - (5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5- g] quinolin-7-yl) carbonyl] oxy] methyl] -8-oxo-5-thia 1-azabicyclo [4.1.0] oct-2-ene-2-carboxylic acid, as well as the salts of the compound and the hydrates of this compound or the hydrates of their salts. 27. The process of claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form [6R- (6Z, 7 / O (Z)] -7 - [(. 3-LLLL-1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyloxy-3-methyl-2-amino-4-thiazolyl) (methoxyimino) acetyl 1-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, as well as the salts thereof and hydrates thereof, or hydrates thereof. ' 28. The method of claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form [6R- (6,7,7/5) (Z)] -7-. 1L (2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino-3 - [[[N-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4] oxoquinolin-3-ylcarbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, and salts thereof and hydrates thereof, or hydrates thereof salts. 29. The method of claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form [6R- (6o6.7 / S) (Z)] -7- Ш 2- amino-4-thiazolyl) (methoxyimino) acetyl-amino] -3- (1,1'-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 salts thereof and hydrates thereof, or hydrates thereof 30. A process according to claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to produce &lt; 6 &gt; R- (6OT, 7 / i) (Z) J-7 - [[(2 (amino-4-thiazolyl) (methoxyimino) acetyl] amino-3- - [, [[6,8-difluoro-1- (2-fluoroethyl) -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 of their salts. 31. The process of claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form [6R- (6οό, 7β) (Z)] -3 - [[17] - ( 3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinolin-3-yl] carbonyloxy] methyl] -7- [[2-amino- 4-thiazolyl-8 (carboxymethoxy) -amino] acetyl] amino-8-oxo-5-thial-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid as well as eol of this compound and of hydrates of this compound, or of hydrates of their salts · CS 270 246 B2 32. A process according to claim 1, wherein the corresponding compound of formula (VII) or an ester or salt thereof is used as the starting material to form Β 6Β- (6 ^ 7β) (ΖΠ-3- £ Πΐ7- (3-amino). -l-pyrrolidinyl) _{-8-chloro-l-cyclopropyl-6-fluoro-1-t} 4-dihydro-4-oxoquinoline-3-yl carbonyl ljoxyjme methyl] -7- £ t (2-amino-4-thiazolyl) N - (1-carboxy-1-methylethoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, and salts thereof and hydrates thereof or hydrates thereof. 33. The process of claim 1, wherein the starting material is a corresponding compound of formula (VII) or an ester or salt of such compound to form [6R- (6a, 7/3) (Z)] -3 - [[ [E 7- (3-Aaino-1-pyrrolidininyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -7-7 [(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -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. .