CS270244B2 - 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 relates to a process for the preparation of the novel acyl derivatives of the following general formula (X) having valuable pharmacological properties.

New aoyldertvates of the general formula t have been found

wherein m is 0 _t X or 2

R ¹ represents hydrogen or acyl groups usable к acylabl Uaktamového antibiotic-type to 21 carbon atoms, a group of formula napřfidad

R ⁵ - CO -

CS 27o244 В2 in which

R represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms which is substituted by a cyano group,

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

R ¹ ^ ⁰ is alkyl having 1 to 8 carbon atoms and is optionally carboxy substituted alkyl group having 1-8 carbon atoms.

n has a value of 0.1. 2 or 3.

and in which further

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

R is hydrogen, alkyl of 1 to 8 carbon atoms, alkenyl of 2 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms. haloalkyl having 1 to 8 carbon atoms or haloalkyl.

Z is R ³⁰ -C or N, wherein

R @ ³ represents a hydrogen atom or a halogen atom, or

3o 31

R @ 1 and R @ 2 together represent a C3 -C5 alkylene group, a C2 -C4 alkylene mono group or a C1 -C2 alkyloxy group;

R represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms, or an optionally substituted 5- or 6-membered N-heterocyclic ring optionally containing an oxygen atom or an additional nitrogen atom,

R is hydrogen or halogen; or

33

R and R together represent an alkylene alkoxy group having from 1 to 4 carbon atoms, and

R represents a readily hydrolyzable protecting group useful in the chemistry of C— fas -porporins having up to 21 carbon atoms, such as a tert-butyl group, p-nitro. . benzyl or allyl.

as well as the salts of these compounds and the hydrates of the compounds of formula (U) or the hydrates of their salts.

Expression,. alkyl refers to straight and branched chain hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group. ethyl, n -propyl, iso -propyl, tert -butyl or the like.

The term "alkoxy" refers to straight or branched chain hydrocarbyl groups in which the alkyl moiety is as defined above. Examples which may be mentioned are methoxy, ethoxy, n-propoxy and the like.

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

The term "agg *" denotes an optionally substituted aromatic group * such as phenyl group * tolyl group * xylyl group * mesltyl group * cumyl group (isopropylphenyl group) * naphthyl group from below, wherein the aryl group may contain, for example, 1 to 3 suitable sub-substituents * As a halogen atom (for example fluorine * chlorine * bromine), hydroxyl group, etc. ·

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

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

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

The term ** substituted phenyl denotes a mono- or disubstituted phenyl group * wherein, for example, a halogen atom (e.g. chlorine * bromine * fluorine) * alkyl and 1 to 8 carbon atoms * amino groups * nitro or trifluoromethyl A groups are suitable substituents ·

** substituted alkyl ´ * means an alkyl group having 1 to 8 carbon atoms * which is optionally substituted by halogen (for example, chlorep, fluorine * bromine) * trifluoromethyl * amino * cyano, etc.

The term ** alkenyl group is. 2 to 6 carbon atoms denotes straight or branched chain hydrocarbon groups having an olefinic double bond and 2 to 8 carbon atoms * ie · the remainder of the compounds of the formula C ^ gn * in which n is 2 to 6 * such as allyl * vinyl group etc.

The term ** ar alkyl denotes a hydrocarbyl group and an aromatic and aliphatic structure * U · a hydrocarbon group * in which one hydrogen atom of an alkyl group having 1 to 8 carbon atoms is substituted by a monocyclic aryl group * for example phenyl group * tolyl group etc.

The term "5- or 6-membered heterocyclic ring" of 1 to 4 oxygen atoms of nitrogen and / or sulfur denotes, for example, the following groups and 6-membered nitrogen-containing heterocyclic rings. Such as pyridyl * plperidyl * plperidylnoscupine * N-oxidopyridyl * pyrimidyl * piperazinyl * pyrldazinylnyl * N-oxidopyridazinyl etc. • These are nitrogen containing heterocyclic rings * such as pyrrolidinyl * pyrazolyl * imldazolyl * thiazothyl * 1 * 2 * 3-thladoles 4-1Hadiazolyl * 1 * 3 * 4-thiadiazolyl * 1 * 2 * 3-oxadiazolyl * 1,2,4-oxadiazolyl * 1,3 * 3,4-oxadiazolyl * 1 * 2 * 5-oxadiazolyl *. 1 * 2 * 3-triazolyl * 1 * 2 * 4-triazolyl · 1H-tetrazotyl * 2H-tetrazotyl etc. ·

These heterocyclic rings may be further substituted with, for example, the following substituents alkyl alkyl having 1 to 8 carbon atoms, such as a methyl, ethyl, n-propyl, etc. alkoxy group having 1 to 8 carbon atoms. As methoxy * ethoxy etc., * halogen atom * As chlorine * bromine * etc · * haloalkyl of 1 to 8 carbon atoms * As trifluoroethyl group * trichloroethyl group etc. * amino group * mercapto group * hydroxy group * carbamoyl group or carboxes · kupina atd *

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

R ⁰ SR ³¹ may together be alkylene having 3-5 carbon atoms, * for example, the group "(CH ^ y * - _{(CH2) g} - or -CH (CH ₃₎ - (CH _{2) 2} -, and so on alkyl nmonooxys to fully with 2-4 carbon atoms, for example, * - (CH _{2) 2} -O-, - _(CH2) yO-, - (CH ^ -Onebo -CH (CH ₃₎ -CH ₂ -O-: or also C 1 -C 2 alkylenedioxy such as -O-CH ₂ -O-, -O- (CH ₂ ) ₂ -O- or -O-CH (CH ₃ ) -O-. gray condensed ring.

CS 27o244 B2

-О »сн _(сн з) -Сн _(сн з) -О- or the like, in this case preferably form a five- nsbo six membered fused ring.

_The term acyl group ** (proviso that both R ¹⁾ comprises an organic group, which matches are formed by removing a hydroxyl group from a carboxylic acid and which contains up to 21 carbon atoms. Examples of such acyl groups include those used to date to acylate α-lactam antibiotics, including 6-aminopenicanoic acid and derivatives thereof, as well as 7-aminocephalosulfonic acid and derivatives thereof, cf. for example, Cephalosporins and Penicillins, Verlag Fiynn, Academic Prese (1972) »Belgian patent 866 0З8, published 17.10. 1978, Belgian Patent No. 867,994, published December 11, 1978, U.S. Patent No. 4,152,432, published May 1, 1979, U.S. Patent No. 2,971,778, published July 27, 1978. 1976 and U.S. Pat. No. 4,173,199, published Aug. 23, 1976; 1379. These publications disclose the various acyl groups used in the present case. The following acyl groups further illustrate the term "acyl group ⁹ ", but do not limit it in any way. Examples of acyl groups include:

(a) an aliphatic group of the general formula

R ⁵ - CO in which

R

R represents a hydrogen atom or a C 1 -C 8 alkyl group which is substituted by a cyano t (to) carbocyclic aromatic group of the formulas

CH - c

COOH (c) a heteroaromatic group of the general formula

R ¹⁰¹ - ( ^CH ₂ ) _n " ^CO wherein n represents the number 0, 1, 2 or 3 a

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

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

б

Preferred heteroaromatic acyl groups are those groups in which R ¹⁰¹ represents a 2-amino-4-thiazolyl group or a 2-thlonyl group. (D) [1- (4-Substituted-2 ', 3-difluoro-1-plperaxinyl) carbonyl] aminojarylacetyl general group

in which

R ¹² ° represents an alkyl group having 1 to 8 carbon atoms *, for example 4- (C 1 -C 8 -alkyl * preferably ethyl or methyl) -2,3-Dloxo-1-plporazinylcarbonyl-D-phenylgtycyl t (e) (substenoxy) ) an arylacetyl group in general

R ¹³ ° -ONC-CO

wherein the aforementioned meaning is a

13o ·

R represents a carboxy-substituted alkyl group having from 1 to carbon atoms;

As examples of groups

R ¹³ ° .ON.C-CO the following groups may be mentioned with *

- (2-Aminothiazol-4-yl) -2-leopropoxyiminoacetyl *

2- (2-aminothlazol-4-yl) -2-methoxylminoacetyl *

2- (2-Aminothothiazol-4-yl) -2-hydroxylminoacetyl,

2-thienyl-2-methoxylminoacetyl group * *,

2-Thienyl-2-hydroxyiminoacetyl *

2-thienyl-2- (dichloroacotoxyl) -Noethyl group *

2- (2-aminothlazol-4-yl) -2-carboxymethoxyxyl) acetyl *

2- (2-aminothlazol-4-yl) -2- (carboxyisopropoxylmlno) -asyl group etc. ·

CS 27o244 B2

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

R ³¹ preferably represents an alkyl group having 1 to 8 carbon atoms, particularly preferably an ethyl group, or a halo gene having an alkyl group having 1 to 8 carbon atoms, in particular a fluoroethyl group or a cycloalkyl group having 3 to 7 carbon atoms, preferably a cyclopropyl group | R ³² preferably represents an alkyl group having 1 to 8 carbon atoms, in particular a methyl group * or a plperazinyl 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 ³³ preferably represents a hydrogen, chlorine or fluorine atom, in particular a hydrogen or fluorine atom;

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

CS 27o244 B2

CS 27o244 B2

X * 21

CS 27o244 B2

lo

CS 27o244 Q2

A preferred group of compounds of the invention are those of Formula 1b

(Ib). .

in which .

R ¹ has the abovementioned meaning,

R is an amino protecting group such as a trityl or chloroacetyl group, or preferably a hydrogen atom; and

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

COOH where

2223

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

2223

R and R are taken together with the carbon atom to which they are attached a 3- to 7-membered carbocyclic ring cyclobutyl ring or cyclopentyl ring. , ·

Particularly preferred are compounds of formula Xb wherein '

R stands for hydrogen atom a. ‘

R is methyl or formula

whereas

23 ·

R and R are hydrogen or methyl *

CS 27o244 B2

Groups

are preferably present in луп-íormŽ ie * in Z-form _T or as mixtures in which predominates • yn-form.

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

Compounds of formula Ц if they contain. a basic functional group. Like amino, for example, they also form addition salts and organic or inorganic acids. Examples of such acids include hydrohalides, for example hydrochlorides, hydrobromides, hydroiodides, as well as other salts and mineral acids, such as sulfates, nitrates, phosphates and the like, alkyl and monoaryisulfonates, such as ethanaulfonates, toluenesulfonates, benzenesulfonates and the like. and organic acids such as asates, tartrates, maleates, citrates, benzoates, aalicylates, ascorbates and the like.

The compounds of formula I, including their salts and e, may hydrate and may therefore be present in hydrated form. Hydration may occur during the manufacturing process or gradually as a result of the hygroscopic properties of the initially anhydrous product.

it consists in

The present invention provides a process for the preparation of novel acyl derivatives by reacting a compound of formula (P)

(II) wherein m, R ¹ , R ² are as defined above, and

Hal represents a halogen atom.

with a carboxylic acid salt of the general formula Ш

(III)

CS 27o244 132 in which

32 33

R, R and R have the above mentioned extract, and the obtained compound of formula 1 is optionally isolated in the form of a salt, a hydrate or a hydrate of a salt.

The reaction of the halide of formula (P) with a carboxylic acid salt of formula (Ш) according to the process of the invention is preferably carried out in a solvent which does not contain hydroxyl groups. Such as, for example, in dimethylformamide, methylene chloride or dimethyl dimethylacetamide. Suitable salts of the carboxylic acid are, for example, the sodium, potassium bisulfate, butylammonium or total sodium hyammonium salts. Hal in the compounds of general formula (P) has a halogen atom, in particular a bromine atom or an iodine atom. This reaction is preferably carried out at temperatures of about 0 ° C to about 80 ° C, in particular pH of room temperature.

The preparation of the salts and hydrates of the compounds of the formula I or the hydrates of these salts by the process 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. As in water or in an organic solvent. As in ethanol, methanol, acetone or similar solvents. The salt formation temperature is not critical and is generally about room temperature, but it can also be operated at a temperature slightly higher than the room temperature or a pH slightly lower than the room temperature, for example in the range of 0 ° C to + 80 ° 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 washed out of moist almospheres, for example at a pH of about + 10 ° C to + 40 ° C,

The following Reaction Scheme 1 illustrates the process for preparing the compounds of the invention:

S c h i n а *

(in)

CS 27o244 B2

2 32 32 33

The general symbols R, R, R, R, R, R and intermittent bonds have the meanings given above.

Depending on the choice of the protecting group of the ester group R and the halogen Hal, a compound of formula Vin is obtained with respect to the double bond in the entire ring of the 3- or Δ2-isomer of the compound of formula Vin. by subsequent reduction of this compound or separation of both components into the desired Δ 3-isomer ·

As is clear. The compounds of formula I, their salts and hydrates are important intermediates for the preparation of the pharmacologically active reaction products of the general formula Ia.

Clarification of Scheme I:

Па --- a * In

Compound of formula (IIa) It is a known compound or can be obtained in an analogous manner (cf., for example, U.S. Patent Nos. 4,440,899 and 4,266,449). This compound is reacted with a salt of the selected chlorolone of the formula.

VDI ---> Ia or Via

The protecting group of the ester group R of the compound of formula ШШ is then cleaved to give a carboxylic acid of formula Ia or a mixture of the carboxylic acid of formula Ia and Δ 3- (somer of the compound of formula Via).

The protecting groups of the ester group R are preferably those which are converted under mild conditions into a free carboxy group, for example tert-butyl, p-nitrobenzyl, benzhydryl, allyl, etc. ·

The protecting groups of the ester group are cleaved, for example, as follows: a p-nitrobenzyl group by hydrolysis in the presence of sodium sim pH from 0 ° C (or lower) to room temperature in a solvent. As in dimethylformamide (preferably aqueous dimethyiformamide): tert-butyl by reaction with trifluoroacetic acid in the presence of anlsol at a temperature of about 0 ° C to room temperature, with or without an additional solvent such as methylene chloride: allyl group by palladium catalysed transattylation. o) in the presence of sodium or potassium salt of 2-ethylcaproic acid (cf., for example, J · Org · Cham · 1982, 47, 587) ·

Via --- 5 »V

When the double bond isomerized to form the β-isomer, the compound of formula VIa thus obtained is oxidized.

By oxidizing the Δ2-isomer of formula VIa, this isomer is converted to the corresponding з-isomer of formula 1. This oxidation is carried out by the action of an organic or inorganic oxidizing agent. Various compounds which readily deliver oxygen are used as oxidizing agents. Such as organic peroxides, for example monosubstituted organic peroxides. Such as alkyl hydroperoxides and 1 to 4 carbon atoms and alkyl moieties or alkanoyl hydroperoxides. As tert-butyl hydroperoxide · permetic acid or paric acid Like 1 phenyisubstituted derivatives of these hydroperoxides. As a cumene hydroperoxide or per benzoic acid · The phenyl group The substituent may optionally contain other substituents, such as C 1 -C 4 alkyl or C 1 -C 4 alkoxy or also a halogen atom or a carboxy group, so that, for example, o 4-methylperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoic acid or o monoperphthalic acid · Various inorganic oxidizing agents can also be used as oxidizing agents and e. Such as hydrogen peroxide, ozone, permanganates such as potassium permanganate or sodium permanganate, hypochlorites. As sodium hypochlorite, potassium hypochlorite or ammonium hypochlorite, peroxymonosulphuric acid and peroxydisulphuric acid 3-chloro-benzoic acid is preferably used. The oxidation is preferably carried out in an inert solvent, for example an aprotic inert solvent. As in tetrahydrofuran, dloxane, methylene chloride, chloroform, ethyl acetate

CS 27o244 B2 or acetone, or in a protic solvent such as water, in a lower alkanol such as methanol or ethanol, or in a lower or optionally halogenated olocanecarboxylic acid such as formic acid, acetic acid or trifluoroacetic acid, reaction temperature ее ranges especially in the range of -2o ° C to + 5o ° C,

By using an equimolar amount of oxidizing agent or a slight excess in proportion to the starting material, it will in particular obtain the corresponding compound of formula (I). If the amount of oxidizing agent is increased to twice the stoichiometric ratio or even more,

In —....... = * Ια '

The compound of formula (V) thus obtained can be reduced to the final product of formula (10). This reduction can be carried out by a series of reactions, for example by treatment with nitric chloride in methylene chloride or trifluoroacetic anhydride in the presence of sodium iodide in acetone / methylene chloride. The temperature in these reactions is preferably about 0 to -20 ° C, especially 0 ° C.

Compounds of formula I with groups *

N - O - R ¹³ ° or N - O - R ²¹ .

11II

c-c (arov, supra) ее are preferably in the form of syn-forms. Such syn-forms can be obtained with the use of starting materials in which this syn-form is already present. If desired, the resulting syn / ant-form mixture of a compound of formula I can be separated in the usual manner into the corresponding syn- and ant-forms, for example, by crystallization or chromatographic methods using a suitable solvent or solvent mixture.

The compounds of formula I as well as the corresponding salts and / or hydrates of these compounds are anti-inflammatory, in particular bactericidally active. They may be used as a means of combating bacterial infections (including urinary tract and respiratory tract infections) in mammals such as dogs, cats, horses, etc. · As well as 1 in humans. These celosporins are active against a wide range of both gram-positive and 1 gram-positive bacteria.

The in vitro activity of the compounds according to the invention against a variety of Gram-positive and Gram-negative bacteria, expressed as the minimum inhalation concentration in mlc program / ml and determined using the dilution series (liquid) method, is as follows:

Compound A t hydrate [R- (6oc, 7 / b)] -3 - [[[(1-ethyl-1,4-dlhydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl)] carbonyl] oxymethyl] -6-oxo-7 - [(phenyloxymethyl) amino] -? - thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids;

Compound VI mono-sodium salt [(R, 3)] -3 · [[[(6-ethyl-5,8 "- <Hhydro-8-oxo-1,3,3-oxolo *] [4,0] (N-chloro-7-yl) carbonyl] oxy] ethyl] -8-oxo-7 - [(phenoxyacetyl) amino]. -5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

Compound C1. [6R- (6a, 7 &) (Z)] - [[(2-amino-4-thlazolyl) (methoxyxyl) acetyl] amino] -3 - [[[(1-ethyl-N- (11-hydroxy) -7-methyl] -4-methyl) -oxo-1,8-naphthyridin-3-yl) carbonyl-oxy] -methyl-8-oxo-5-thla-1-azablicyclo [4.2.0] oct-2-ene-2-carboxylic acid

CS 27o244 B2

Compound D: [6R- (6α, 76) (Z)] - [[(2-Amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3 - [[[(5-ethyl-5,8r-cyclohexyl) -8] sodium salt -axo-1,3-dioxolo [4,5-b] quinolin-7-ylcarbonyl] oxy] methyl] -8-oxo-5-tha-1-azabicyclo [4.2.0; -oct-2 -en-2-carboxylic acids. Compound E: (6R- (6a, 76) -3 - [[[[1-ethyl-6-fluoro-1,4-dihydro-7- (4-fluoro-1-piperazininyl) -4-oxoquinolin-3-yl] sodium] carbonyl] -oxy] -methyl-8-oxo-7 - [(phenoxyacetyl) -amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid Compound F t sodium salt of [6R- (6a, 7R)] - 3 - [[Q 5 -ethyl-5,8-dihydro-8-oxo-1,3-dioxolophase. chlorolin-7-yl) carbonyloxy] methyl] -8-oxo-7 - [(2-thienylationyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-yl en-2-carboxylic acids. Compound G: sodium salt of 6R- (61,7 / 5)] - 3 - [[[1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinoline] -3-yl] carbonyl] oxy] methyl 7-C (2-thlenylation-yl) -amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid acid. Compound H: [6R- (6α, 7β)] -3- [CCCl-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyl] oxy sodium methyl] -8-oxo-7-C (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid Compounds 1: C6R- (6cu76) (Z)] - R - [C (2-amino-4-thlazolyl) (methoxycarbonyl) amino] amino] -3 - [[CC 1-ethyl-6-fluoro-1] 4-Dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thla-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acids ·

Table

Minimum inhibitory concentration in vitro

microorganism

В

C

E

D

AND

E. coli 32 2 0.5 0.25 8 TO· pneunonioe A 16 1 0.5 0.25 2 E. cloacae 957oA 64 2 2 1 β E· cloacae 948-1 - 2 8 1 8 E. cloacae 2367-2 - 1 16 2 4 E. cloacae 7o99 16 0.5 8 0.5 2 E. cloacae 214 128 2 8 o, 5 8 P. vulgaris ATCC 638o 8 o, 5 o, 25 o, o63 4 P. mirabflis 19o 8 0.5 0.16 0.008 0.5 with. marcescens SM 16 1 1 0.5 4 P. Aeruginosa Stone 13o • 128 32 * 128 16 16 P. aeruginosa 5o3-56 128 64 128 32 32 WITH. aureus Smith - o, 25. 0.25 2 2 o, o63 with. aureus 95 4 8 4 2

CS 27o244 B2 continued table

minimum Inhibitory concentration of compounds (µg / nú) microorganism F G H AND E. cell 2 8 32 Г ^{1 1 -} - 0.0 K. penumonlae A 1 4 32 0.0 E. cloacae 907oA 2 8 32 2 E. cloacae 946-1 1 8 32 4 E. cloacae 2367-2 1 32 32 4 E. cloacae 7o99 0.6 2 2 2 E. cloacae 2 64 32 4 P. vulgarit ATCC 638o 0.0 4 32 0.0 P. mlrabllls 19o 0.0 4 0.0 о »оЭ 1 mercescene 8M 1 4 32 1 P. eeruglnosa Stone 12o 32 32 * 32 8 1 ', aaruginoes 0o3-06 04 / 64 04 / 32 S, aureus Smlth 0.20 o, 20 o, 20 0.20 S. and ureu · 96 4 · 4 0.0 0.0

To combat bacterial infection, the compound of the invention can be administered to a mammal at a daily dose of from about 5 to about 1000 mg / kg, preferably at a dose of from about 10 to about 100 mg / kg. Large types of applications which hitherto have no consideration of pH therapy of penicillin and phallosin are also applicable to the novel phallosin of the invention. Thus, the administration can be carried out, for example, by intravenous, intramuscular and enteral 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 a mixture 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, petrolatum, etc. ^ The pharmaceutical preparations may be present in solid form »for example in the form of tablets · dragees, suppositories» dripped or in liquid form, for example in the form of solutions, suspensions or emulsions. These preparations are optionally sterilized and optionally contain adjuvants, as preservatives »stabilizers, wetting agents, emulsifiers, osmotic-pressure-altering agents» anesthetics or buffers. These preparations may also contain other therapeutic agents. The carboxylic acids of formula I and their salts or hydrates are preferably suitable for parenteral administration and are preferably prepared in the form of lyols or dry powders for dilution by conventional means, such as water and isotonic sodium chloride solution, with auxiliary solvents. Like propylene glycol. Easily hydrolyzable esters of formula I are also suitable for enteral administration.

and.

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

ιη

CS 27o244 132

Example 1

6R- (6-methyl-4-nitro-phenyl) -methyl- [CC (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) -carbonyl] oxy (4-nitro-phenyl) -methyl ester methyl J-8-oxo-7- C (phenyloxy-aryl) amine o-5-tha-1-azabicyclo (4,2,0 J-okb-2- • n-2-carboxylic acid; and C2R- (2a, 6a, 7β) -3-CC- (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) (4-nitro-phenyl) -methyl ester (carbonyl) oxy] methyl] -8-oxo-7-r- (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-3-ene-2-carboxylic acid

A solution of 22.4 g (0.0-4 mol) of (4-nitro-phenyl) -methyl ester of C6R- (6 (X, 7fl)] - 3- (bromomethyl) -8-oxo-7 - [(phonoxyacetyl) amino] -5- thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids and 1.11 g (0.4 mol) of sodium 1-ethyl-1,4-dlhydro-7-methyl The 4-oxo-1,8-naphthyridine-3-carboxylic acid in 200 ml of absolute dimethylformamide was stirred for 0 hours under argon, then the solvent was evaporated under reduced vacuum and the solution of the residue in ethyl acetate was washed with aqueous sodium chloride solution. The organic liquor is purified by column chromatography on 800 g of neutral silica gel using ethyl acetate as the eluent (particle size 0.063 to 0% by weight) and the solvent is evaporated off under reduced pressure to a small volume. , 200 mm) · The respective tractions are combined and crystallized from ethyl acetate to give an additional portion of the reaction product · The isomer mixture obtained is used for the following reaction · Pure λЗ-ester is obtained by traction crystallization from ethyl acetate and Δ 2-ester is isolated by preparative chromatography on a layer of silica gel plates from the mother liquor ·

If

Data of both isomers:

I.

Δ 3-isomer 2j

IR spectrum (KBr technique) ζ * ·

34o5, 1785. 173β) 1697. 1637, 152o and 1348 cm ^-1 .]

Mass spectrum: 5 m / z 714 (M + H), 736 (M + H).

Δ 2-isomer:

IR spectrum (KBr technique):

356o, 348o, 3415, 178o, 1745, 1693, 162o, 152o cm ^1. '

AND

Mass spectrum:

m / z 713 (M &lt; + &gt;).

and

Example 2 [2R- (2a, 6cc, 7ft)] - 3 - [[C (1-ethyl-1,4-dlhydro-7-methyl-4-oxo-1,8-naphthyridin-3)] -yl) carbonyl] oxy] methyl-8-oxo-7 - ((phenoxyacetyl) amino-5-thia-1-azabicyclo [4.2.0] oct-3-enecarboxylic acid

To a solution of 6.11 g (0.088 mol) of a mixture of the two isomers of Example 1 in 45 ml of dimethylformamide, a solution of 2.8 g (0.16 mol) of hydrogen sulfide hydrate is added dropwise at -5 to -10 ° C. Sodium in 2 ml of water. After 35 minutes, the mixture is acidified to pH 3.5 by addition of 1N hydrochloric acid in water. The resin solidifies upon addition of 5 ml of ethyl acetate and 5 ml of ether. After filtration, washing with water and ether and drying at 5 ° C under reduced pressure over phosphorus pentoxide, the reaction product is obtained. Additional ether is added to the filtrate, leaving no additional precipitate, which is filtered off and dissolved in aq. Sodium bicarbonate solution, aqueous solution - washed with ethyl acetate and acidified to pH 3.5. The solution of the precipitated resin in methylene chloride was filtered, washed with water, dried over sodium sulfate and evaporated under reduced pressure. characteristics:

IR spectrum (KBr technique) t ·

342o, 33oo, 1773, 172o cm ^-1 .

Mass spectrum $ * m / z 579 (M + H).

Example 3

C (6R- (6R, 7R)) -3-CfC (1-Ethyl-1,4-dihydro-7-methyl-4-oxo-Ι, θ-naphthyridin-3-yl) carbonyl S-oxide oxy-methyl] -8-oxo-7-f (phonoxyacotyl) amino-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

To a suspension of 2.55 g (0.042 mol) of the reaction product of Example 2 in 6 ° C if methylene chloride was added dropwise with stirring at 0 ° C a solution of 0.96 g (85% purity, 0.48 mol) of m-chloroperbenzoic acid. in 10 ml of methylene chloride. The reaction mixture is stirred for 4 hours at 0 ° C and then filtered. The solid obtained is washed with methylene chloride and dried under reduced pressure. The reaction product thus obtained has the following properties t

IR (KBr): .delta.

336o, 1794, 1723, 1634, 1637, 1017 cm ^1st

Mass spectrum:

m / z 595 (M + H).

Example 4

[6R- (6a, 7R)] (1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyl] oxy] -methyl] -8 hydrate -oxo-7 - [(phenoxymethyl) amino] -5-4Ha-1-azabicyclo [4.2.0] oct-2-one-2-carboxylic acid.

* К solution of 1.64 (o, olo9 mol) of sodium iodide in ¹ ml of absolute acetone 4o and 2o ml of methylene chloride was added l »3O g (o, oo219 mol) the reaction product of Example 3 · The resulting slurry was cooled with stirring and when The temperature is adjusted to a temperature of 0 DEG C. and 1.75 ml (.alpha.24 mol) of trifluoroacetic anhydride is added thereto. After 3 minutes the pH is adjusted to 6 with aqueous sodium bicarbonate solution. 3.5 and a small insoluble portion was removed by filtration. The organic phase was washed with an aqueous sodium carbonate solution, dried over sodium sulfate and evaporated under reduced pressure. The residue was washed with ether, taken up in methylene chloride and the reaction product precipitated after addition of ether.

A mixture of 435 g (0.47 mmol) of the reaction product from Example 3 and 7 ml of absolute dimethylformamide was cooled to -12 ° C with stirring, and 0.1 ml (1.4 mmol) of sulfur trichloride was added thereto. After 7 minutes and additional 0.02 ml of phosphorous chloride are added. The mixture is stirred for 6.5 minutes and then a cold solution of 0.48 g (5.1 mmol) of sodium hydrogen carbonate in 7 ml of water is added. The precipitate obtained is filtered off, washed with water and dried under reduced pressure over phosphorus pentoxide to give a reaction product.

2о

CS 27-244 В2

The following characteristic data was obtained for the reaction product:

1C spectrum (KBr technique): ·

342o, 1785, 17o8, 16 2o cm ¹ ,

Mass spectrum:

m / z 579 (M + H).

Example 5

1,1-dl thyl thyle ster [6R- (64,76)] -3 - [[[(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline- 7-yl-carbonyl] oxy] methyl] -7-C (phenoxyacetyl) amino] -S-thia-1-azabicyclo [o] oct-2-ene-2-carboxylic acid

A solution of the sodium salt of _5-ethyl-5> 8 _r dihydro-8-oxo-l »3-dioxolo [4 _5-l .g] quinolines-7-carboxylic acid (1 mmol) in 12 mL of dlme thylform amide are stirred under an atmosphere nitrogen for 1 hour ·

1.5 g of molecular sieve (4 * ¹⁰ * ¹⁰ m), and then [6R- (6d, 76)] -3- (iodomethyl) -β-οχο-7- [(Hnoxyacetyl)] 1,1-dimethylethyl ester solution was added. amino] -5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (1 mmol) in 6 mL of absolute dimethylformamide and stirred for 5 hours. Evaporate to a residue with ethyl acetate or a mixture of ethyl acetate and methylene chloride, then wash the resulting solution with aqueous sodium bicarbonate solution and brine, dry with sodium sulfate and evaporate to dryness. fast chromium Biography using 8: 2 ethyl acetate / methylene chloride as eluant ·

Example 6

[6R- (64,76) (Z)] -3- [eta] (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) 1,1-dimethyl-ethyl ester carbonyl] oxy] methyl] -7- [η (methoxycarbonyl) - [2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -8-oxo-5-1N-α-1-acetyl-4,2-carboxamide; O] -Methoxycarboxylic acid

The title compound is obtained by repeating the reaction described in Example 5 and using 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid sodium salt and 1,1-dimethyl yle6R- (6d, 7ft) (z)] -3-iodo-thiyl-7 - [[(methoxyphenyl) -4- (triphenylmethyl) amino-4-thiazotyl] amino] amino] - 8-Oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid starting materials · The residue was purified by flash chromatography. using a 9: 1 mixture of ethyl acetate and methylene chloride as the solvent system.

.. Example?

[6R- (6,7-D) (Z)] -3- [eta] < 5 &gt; -ethyl- (5-ethyl-5, e-dihydro-8-oxo-1,3-dioxolo [1,5-g] quinoline) 1,1-dimethylethyl ester 7-yl) -carbonyl] oxy] methyl] -7- [E (methoxylmino) [2- (triphenylmethyl) amino-4-thlazolyl] acetyl] amino] -8-oxo-5-thla-1-azabicyclo [ 4.2,0] oct-2-ene-2-carboxylic acid

The title compound is obtained by repeating the reaction described in Example 5 using

5-Ethyl-5,8-dihydro-8-oxo-1,3-dloxolo [4,5-g] quinoline-7-carboxylic acid and [6R- (6 <χ, 7β) (z)], 1,1-dimethylethyl ester -3-Iodomethyl-7- [E (methoxyimino) -2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acids Starting materials The residue was purified by flash chromatography using a 9: 1 mixture of ethyl acetate and methylene chloride as the solvent system.

К H к I A d 8

6R- (6-oxo-76)] - 3-CCCC 1-ethyl-6-fluoro-1,4-dihydro-7- (4-fluorophenyl-plperazinyl) 4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacotyl) amino] -O-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The title compound is obtained by repeating the reaction of Example 6 using 1-ethyl-6-Quor-1,4 dihydro-, 7- (4- (aryl-1-plperazinyl) -4-oxo-3-chlorocarboxylic acid) and 1-ethyl-6-quoro-1,4-dihydro. [E] - (60.76)] -3-iodomethyl] -8-qq-7- [(phonoxyacyl) amino] -δ-needle-1-azabicyclo [4 * 2 * θ] oct-2-ene-1-dl-methyl-ethyl ester 2-carboxylic acids as starting materials · The residue is purified by the method · flash chromatography using a mixture of methylene chloride and methanol in a ratio of 2 ° t 1 as the solvent system.

Example 1 a d 9 '*

Sodium salt of [cis- (6 ', 7b)] -3 - [[[(S-ethyl-0', 6-dihydrol ', 8'> oxo-1 ', 3'-dioxolo [6']] quinolin-7-yl) carbonyl] oxy] methyl] -8-oxo-7- (phenoxyacetyl) amino] -6-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

To a solution of 3.0 g (4 * 02 mmol) of the reaction product of Example 5 in 18 ml of anlsol was added 1.6 ml of trifluoroacetic acid while stirring at room temperature. The reaction mixture was stirred for 4 hours and then evaporated to dryness under reduced pressure. · The residue is sieved in the form of an oil * which is dissolved in methylene chloride and water is added to the obtained solution. · The pH of the reaction solution is adjusted to pH 7 by addition of sodium bicarbonate · Stir the mixture for 2 minutes and then remove the aqueous phase. water and adjusting the pH to 7 * 0 with sodium bicarbonate with stirring twice repeated · The three aqueous extracts are combined and freeze-dried · The residue is purified by chromatography on a non-polar * stationary phase (reverse phase using 5% aqueous methanol as solvent) · After evaporation and freeze-drying, the title compound · ₉ is obtained

The compound obtained has the following properties i

IR spectrum (KBr) t

Ю4Ю, 1765, 1592, 1635, 1528 cm ^-1 .

Mass spectrum:

m / z 63 ° (M * H) * 602 (M * 4 Na).

Example lo

(6d * 7A) (z)] - 7- [[(2-Amino-4-thlasolyl) -4-methoxyimino] acyl] amino] -3 - [[E (1-ethyl-1,4-dihydro)] -7-methyl-4-oxo-1, aminopyridine-3 (1) carbonyl] oxy] methyl] -e-exo-O-thla-1-sablicyclo [4.2.0] oct-2-en-2- carboxylic acids

A suspension of 0.31 mmol of the reaction product of Example 6 in 0.66 ml of anlsol was cooled to 0 DEG C. under nitrogen and to the cooled suspension was added 3 * 3 ml of trifluoroacetic acid. The solution is kept at 0 ° C for 16 hours and then evaporated under reduced pressure at room temperature. After the addition of methylene chloride, evaporation under reduced pressure is repeated. The residue is triturated with ethyl acetate to give a solid, if possible, prior to conversion to sodium salt. If no solid is obtained, the residue is converted directly into sodium salt. the substance or oil obtained is dissolved in 9 ml of methylene chloride * and an aqueous solution of hydro22 is added dropwise to the solution thus prepared in methylene chloride at a temperature of 0 to 3 ° C.

CS 27o244 B2 sodium bicarbonate containing sufficient sodium bicarbonate to achieve 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 and a mixture of water and methanol with a methanol gradient (0-10% methanol, 20 minutes) as eluent. After evaporation and freeze-drying, the reaction product is obtained with the following characteristic values:

IR spectrum (KBr technique):

34o5, ЗЗоо »32oo, 1766, 1716, 1681. 1617, 1537 cm * ¹ .

. Example 11

[6R- (6α, 7β) (z)] - 7 - [(2-Amino-4-thiazolyl) (methoxymethyl) acetyl] amino] -3- (5-ethyl-5,8-dihydro- 6-oxo-1,3-dloxolo [4,5- g (quinolin-7-yl) carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acids

The title compound is obtained according to the procedure described in Example 1 but using the reaction product of Example 7.

The compound obtained has the following characteristic data 2

IR spectrum (KBr) t

34oo - 32oo »1767, 1715, 1685, 1635, 1616, 1533 cm * ¹ .

Mass spectrum:

m / z 679 (M + H), 7ol (M + Na). ’|

Example 12

[6R- (6d, 6R)] -3- [E-1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinoline-3] sodium salt -yl] carborryl] oxy] methyl] -7- (phenoxyacetyl) amino] -beta-5-thia-1-azabicyclo [4.2.0] oct-2-en2-carboxylic acid. .

Following the procedure described in Example 1 and using the reaction product of Example 8, the title compound having the following characteristics is obtained:

IR spectrum (KBr technique):

342o, 1768, 1668, 162o cm * ¹ . '

Mass spectrum:

m / z. 716 (M ⁺ H), 738 (M ⁺ H).

Example 13

C6R- (6tf, 76)] - 3 - [(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolof4,5-g] quinolin-7-yl) carbonyl] 1,1-dimethylethyl ester oxy] methyl-8-oxo-7-C (2-thlenylacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Using the procedure described in Example 5, but substituting 1,1-dimethylethyl ester (α, δ, δ)] - 3-

- (iodomethyl) -B-oxo-7-C (2-thlenylacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and 5-ethyl-5 Starting from 8-dlhydro-7-oxo-1,3-dloxolo [4,5-g] quinolin-7-yl) carboxylic acid, the title compound is obtained.

Example 14

[6R- (OD · 7ft)] -3-[[[[(5-ethyl-5,8-dlhydro-8-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl)] - sodium salt] carbonyl] oxy] methyl] -8-oxo-7-f (2-thlenylacetyl) amino] -5-thla-1-ozabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The title compound was obtained according to the procedure in Example 1 but using the reaction product of Example 13.

The compound obtained has the following characteristic data i

IR spectrum (KBr technique): ·

341o _in 1763, 1682 * 1632, 16o8 cm \

Mass spectrum:

m / z 62 ° (M + 1), 642 (M + 1).

Example 16

DLM ethyl 1.1- * «methyl. * T * r [6R- (6a, 7 &)] X- * thyi-6-Ouor _l-c-4-o dlbyds-7- (4-íormyi-l ~ r * PLP (Zyl) -4-oxoquinolin-3-yl] carbon-oxylmethyl-7-C (2-thienyl acyl) amino] -e-oxo-S-1H-1-aza-cyclo-. C4,2, O] oct-2-ene-2-carboxylic acid

Using the procedure described in Example 0, but using 1,1-dimethylethyl ester [6R- (α-70)] - 3- (iodomethyl) -α-α-7 · [(2-ethyleneacetyl) amino] -5-thla-1-one. —Azablicyclo [1,2.0] oct-2-ene-2-carboxylic acid and 1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-plperazinyl) sodium salt, 4-Oxo-3-> quinolinecarboxylic acid The title compound is obtained as starting material.

Example 16

[6R- (6,7)] - 3 - [(1-ethyl-6-fluoro-1,4-dlhydro-7- (4-methyl-1-piperazinyl)) -4-oxoquinolin-3-yl] sodium ] carbonyl] oxyJmethytJ-7-f (2 ' »thÍonyiacotyl) amÍno3-8-oxo-0-thia-l-azabicyclo £ 4 ₉ 2 ₉ O] oct-2-ene-2-carboxylic acid

Using the procedure described in Example 1, but using the reaction product of Example 15, to obtain the title compound *

The compound obtained has the following characteristic data:

IR (KBr): .delta. · ·

343o, 1765, 1716, 1662, 1623 cm ^-1 .

Mass spectrum:

m / z 70 (+ + H) * *.

Example 17

[6R- (6d, 73) (z)] -3-ECC-ethyl-6- (fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinoline) 1,1-dimethyl-ethyl ester 3-yl] carbonyl] oxy] methyl] -7- [(methoxyimino) C2- (triphenylmethyl) amino-4-4hlazolyl] acetyl] amino-8-oxo-5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

CS 27o244 B2

Using the procedure of Example 5, but employing 1,1-dl thyle thyle of the smear Q 6 R- (δ, 7) (z)] - 3- (iodomethyl) -7- [E (methoxycarbonyl) - [2- (triphenyl)] ethyl) amino-4-thlazolyl] acetyl] amino] -8-oxo-5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and sodium salt of 1-ethyl-6-fluoro 1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid starting material gives the title compound.

Example 16

[6R- (η 7 / J) (z)] -? - [[(2-amino-4-thiazolyl) (methoxy) amino] acetyl] amino] -3 - [[[[1-ethyl-6- fluoro-1,4-dihydro-7- (4-formyl-1-plperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2] , o] oct-2-ene-2-carboxylic acid

The title compound (ee) was obtained as described in Example 1 but using the reaction product of Example 17.

The compound obtained has the following characteristic data, 1 H spectrum (KBr technique):

342o, 1765, 1712, 1622 cm ^-1 . ·

Mass spectrum:

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

Example 19

[6R- (6d, 7D)] -3 - [[[[1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxo-ynyl] -in- 3-yl] carbonyl] oxy] methyl] -7-f (phenoxyalkyl) amino] -8-oxo-5-tha-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The title compound (ee) was obtained according to the procedure of Example 5, but using [6R- (6 (L, 7H)] -3- (iodomethyl) -8-oxo-7- [( Phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and 1-ethyl-6-fluoro-1,4-dlhydro-4-sodium sodium salt -oxo-7- (1-pyrrolldinyl) -3-chlorolinecarboxylic acid as starting materials ·

Example 2o

[6R- (6cc-7/5)] -3 - [[[[1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolldinyl) -4-oxoquinolin-3-yl]] - sodium salt carbonyl] oxy] methyl] -7 - [(phenoxyacetyl) amino] -8-oxo-5-thia-bicyclo [4.2 _t O] oct-2-ene-2-carboxylic acid.

The title compound is obtained by the procedure described in Example 1 but using the reaction product of Example 19.

The compound obtained has the following characteristic data:

IR (KBr) .delta

341o, 177o, 1695, 1628 cm ** ¹ .

Mass spectrum m / z 673 (M ⁺⁺ H), 695 (Μ ⁴ ♦ Na).

Example 21

[6Ρ- (όΛ, 7β) (z)] - 3-C [[C1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrololinyl) -4-oxoquinolin-3-yl] -ethyl-1,1-dimethylethyl ester 1,1-dimethylethyl ester ] carbonyl] oxy] methyl] -7- [f (methoxymethyl) -2- (triphenylmethyl) amino-4-thiazolyl] amino] amino] -e-oxo-5-thia-1-azabicyclo [4.2.0] O] oct-2-ene-2-carboxylic acid

Using the procedure described in Example B, but using [6R- (6c (.7 / 3)] - 3- (iodomethyl) -7 - [['(methoxyxyl) - [2- (triphenylmethyl) amino] 1,1-dimethylethyl ester] -4-thiazolyl] acetyl] amino] -e-oxo-5-lhia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and 1-ethyl-6-fluoro-1 sodium salt 4-dlhydro-4-oxo-7- (1-pyrrolldinyl) -3-quinolinecarboxylic acid Starting material, the title compound is obtained.

Example 1 a d 22

[R - (6d, 7 / J) (z) J -? - [['(2-Amino-4-thiazolyl) - (methoxyimido) acetyl] amino] -3 - [[S 1-ethyl-6] sodium salt -fluoro-1,4-dihydro-7- (1-pyrrolidininyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -O-oxo-5-thta-1-azabicyclo [4.2.0] okl-2-an-2-carboxylic acid

The haloacetic compound is obtained as described in Example 1, but using the reaction product of Example 21.

(such a compound has the following character!) · Determines the spectrum (KBr technique) i

3455, 343o, 1768, 1682, 163o cm ^-1 .

Mass spectrum: m / z 722 (M + 4 H). .

Example 23

[6R- (6d, R)] -3-CCCC 1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1,1-dimethylethoxy) carbonyl-1-pl-1,1-dimethyl-ethyl ester perazinyl] -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacyl) amino] -5-thla-1-azabicyclo [4.2.0] oct -2-ene-2-carboxylic acid

Using the procedure described in Example 0, but using 1,1-dimethylethyl ester [R- (6 (t, 7)) - 3-iodomethyl-6-o-7 - [(phenoxyacetyl) amino] -5-thla-1] —Azablicyclo [4.2.0] okl-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-7- [E- (1,1-dimethylathoxy) carbonyl] - 1-Piperazinyl] -4-oxo-3-quinolinecarboxylic acid Starting material, the title compound is obtained.

The compound obtained has the following characteristic spectrum (KBr technique)

342o, 1787, 173o, 1698. 151o cm ^-1 .

Mass Spectrum i>

m / x 822 (M + H).

Example 24

[6R- (6%, R)] -3 - [[[1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1,1-dimethylethoxy) carbonyl] -1-propenyl] 2-propenyl ester -piperazinyl] -4-exoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyalkyl) amino] -5-thia-1-azabicyclo [4.2.0] oct- 2-ene-2-carboxylic acids

Using the procedure described in Example 5, however, using [6R- (6a, 7/3)] -3-iodomethyl-8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [6R- (6a, 7/3)] - 4,2, o] oct-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dlhydro-7- [4- (1,1-dimethylethoxy) carbonyl-1-plperazinyl ] -4-oxo-3-chlorolinecarboxylic acid starting material, to give the title compound ·

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3415, 33oo. 1789, 1729, 1694, 1622 cm ^-1 .

Mass spectrum:

m / z 806 (M + H).

Example 25

2-propenyle ster 6R- (6 *, 7L)] -3 - [[[[1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1-propenoxy) carbonyl]] - 1-Plperazinyl] -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thla-1-azabicyclo [4.2.0] oct-2- en-2-carboxylic acids

Using the procedure described in Example 5, but using 2'-propenyl ester [6R- (6d, 76)] - 3-iodomethyl-8-oxo-7 - [(phenoxyacetyl) amino] -5-thla-1-azobicyclo [4.2.1.0 &lt; 2,7 &gt; , o] oct-2-en-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dlhydro-7- [4- (2-propenoxy) carbonyl-1-plperazinyl] -4- oxoquinoline-3-carboxylic acid starting material to give the title compound.

The compound obtained has the following characteristic data t

IR spectrum (KBr technique):

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

Mass spectrum:

m / z 79 ° (M ⁺ + H).

.. Example 26

[6R- (6T, 7 (J)] -3 - [[(5-methyl-5,8-dihydro-8-oxo-1,3-dloxolo [4,5-g] chloro) 2-propenyl] -ether -7-yl) carbonyl] oxy] n, thyl] -8-oxo-7 - [(thenoxyacyl) amino] -4-oxo-5-thla-1-azabicyclo [4.2.0] oct- 2-βη-2-carboxylic acids

Using the procedure of Example 5, but using the 2-pro foam tester [6R- (ode, 7A)] - 3-Iodomethyl-8-oxo-7 - [(phenoxyacetyl) amino] -5-thla-1-azablicyclo [4.2.1] 5-ethyl-5,8-dlhydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid, oct-2-ene-2-carboxylic acid and potassium salts compounds to give the title compound.

CS 27o244 B2

Example 27

Alternative synthesis of [6R- (6d, R)] -3 - [[[[(5-ethyl-5,0-dlhydro-1 H -oxo-1,3-dloxolo [4,5- g] chloroline] -7] sodium salt -yl) carbonyl] oxyimethyl] -α-oxo-7 - [(tooxycarbonyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-an-2-carboxylic acid acid

To a solution of the reaction product of Example 26 (337 mg), 0.1 ml of Irololphthalosil, 3.6 mg of palladium (II) acetate, 3.9 ml of ethyl acetate and 5.6 ml of methylene chloride were added dropwise with stirring over 15 minutes to 1.68 ml. 5M solution of sodium 2-ethylhexanoate in ethyl acetate. The mixture is then stirred for 30 minutes and 11 ml of acetone is added and stirring is continued for 1 minute; The reaction product is filtered off, washed with ether and air-dried. Purification by reverse-phase high performance liquid chromatography affords the title compound. The spectral data of this product are identical to the spectral data of the product prepared as in Example 9.

Example 28

R - (6α, 7β)] - 3 - [[[[1-Ethyl-6-Quor-1,4-dlhydro-7- (4-thromorpholinyl) -4-oxo-quinolin-3-yl] carbonyl] Oxymethyl) -8-oxo-6 - [(tonoxyacotyl) amino-5-thla-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- (4-thromorpholinyl) -3-quinolinecarboxylic acid sodium salt in 8 ml of dimethylformamide was stirred for 1 hour e. molecular sieve with a size of 4 · 10 * ¹⁰ m, after addition of 0.257 g of [6R- (6d | 7fl)] - 3- (iodomethyl) -8-oxo-7 - [(to noxyxysyl) amine 2-propenyl ester o] -5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 8 ml of dimethylformamide was stirred for 5 hours and then evaporated under reduced pressure. It is washed with aqueous sodium hydrogen carbonate solution and brine, dried over sodium sulphate and evaporated under reduced pressure. The residue is purified by preparative chromatography on a layer to give the allyiosulfate corresponding to the title compound as an intermediate.

To a solution of 63.5 mg of this allyl ester in 1.1 ml of methylene chloride and 75 ml of ethyl acetate was added 5.1 µl of triethylphosphite, 1 mg of palladium (II) o, 28 ml of a 0.2 M solution of nalrium-2-ethylhoxanoate in ethyl acetate. 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:

IR (K3r).

342o, 1768, 1695, 1622 cm "\

Mass spectrum:

m / x 7 ° (M * ♦ H), 727 (M * ♦ Na).

Example 1 a d 29

r.ofltiA .úl [ЛП- (f. », 7rt)] ~ .tliyt-A-il - i, <- · | Πty <t« · <»- * -« »м1I l- | iy1rul-1 ~ yi) [4-fluoro-1-yl] carbonyl] oxy] methyl] -Q-oxo-7 - [(6-oxoactyl) amino] -1H-1-yl-1-aaquicyclo [4.2.0.0 < 2,7 &gt; Oct-2- n-2-carboxylic acid

CS 27o244 B2

A solution of 0.845 g of potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1H-pyrrol-1-yl) -3-quinolinecarboxylic acid in 30 ml of methylformamide is stirred for 1 hour with molecular sieves. with a size of 4 &lt; -1 &gt; * ¹⁰ m. Then 1.54 g of [6R- (6 &apos;, 7/3) -3-iodomethyl-8-oxo-7 - [(phenoxyacetyl) amino] -5-phenoxyacetyl 2-propyl ester is added. -thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and then stirred for an additional 2.5 hours. The reaction mixture was then evaporated under reduced pressure, ethyl acetate was added to the residue, and the ethyl acetate solution was washed sequentially with aqueous sodium bicarbonate solution and brine. After drying over sodium sulfate and ethyl acetate, it is evaporated under reduced pressure and the residue is purified by flash chromatography to give the intermediate altyl ether corresponding to the title compound above.

A solution of 69 mg of this allyleateru in 1 ml of methylene chloride is treated with the addition of 3 mg of palladium acetate, 1 .mu.l triethylíosíitu, about 2 ml of a 5M solution natrlum 2-ethylhexanoate in ethyl асе acetate and _f 3 ml of ethyl acetate, After 3o minutes with stirring, the mixture was evaporated under reduced pressure. The residue was triturated with ether to give a solid. Purification by high performance liquid chromatography and reverse phase yields the title compound.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

342o, 1765, 1695, 162o cm ¹ .

Mass spectrum:

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

Example 3o

[6R- (6a, 76)] -3- [N 6 - (4-Fluorophenyl) -5,8-dihydro-8-oxo-1,3-dioxolo [5- g] quinolin-7-yl] carbonyl] sodium oxy-methyl-β-oxo-7 - [(phenoxyacetyl) amino] -5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

A solution of 0.1 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 for 1 hour. a molecular sieve having a particle size of 4 · 10 &^lt; -1 & gt ^; m. After adding 0.38 g of [6R- (6a, 76)] - 3-iodomethyl-8-oxo-7- (6-oxo-ethyl) -amine 2-propenyl ester 5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid was stirred for 5 hours, then evaporated under reduced pressure to the residue to add ethylation to melt. washed sequentially with aqueous sodium bicarbonate solution and brine. After drying over sodium sulfate, the ethyl acetate was evaporated under reduced pressure and the residue was purified by preparative layer chromatography to give the allyl ester corresponding to the title compound as an intermediate.

To a solution of .122 g of this allyleoler in 2.1 ml of methylene chloride and 1.5 ml of ethyl acetate, and 9.9 ml of triethyllithium, 1.94 mg of palladium acetate and 0.51 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate are added. The resulting mixture was stirred for 1 hour, diluted with acetone and evaporated under reduced pressure. The residue was triturated with ether to give a solid. Purification by reverse-phase high performance liquid chromatography affords the title compound.

The compound obtained has the following characteristic data t

IR spectrum (KBr technique):

342o, 1765, 1695, 1632 cm ¹ .

Mass spectrum:

m / z 696 (M + H), 718 (M + H).

P H k I a d 31

Sodium salt of [6R- (6 _«t 7A) (Z)] - 7 - [[(2-amino-4-thiazotyl) (methoxylmlno) acetyl] amino] -3 - [[[[l-ethyl-6-fluoro -1,4-dihydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thla-1-azabicyclo [4.2.0] oct-2 - »n-2-carboxylic acid

A solution of 0.374 with 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-thiomorpholinoyl) -3-quinolinecarboxylic acid potassium salt in 16 ml of DMF was stirred for 1 hour. molecular sieve (4 * lo * ^lo m), after addition of a solution of 1.7 g of 1,1-dimethylethyleotor [6R- (6a, 7fl)] - 3-iodomethyl-7 - [[(methoxyimino) - [(2 -triphenylmethyl) amino-4-thlazolyl] acetyl] amino] -8-oxo-5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 16 ml of dimethylformamide The reaction mixture was stirred for 5 hours. The mixture was evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed successively with aqueous sodium bicarbonate solution and brine. After drying over sodium sulphate, the ethyl acetate solution was evaporated under reduced pressure. The residue was purified by flash chromatography to give the title compound as an intermediate, which corresponds to the above-mentioned title compound. tert-butyl ester is dissolved in a mixture of 0.21 ml of anisole and 1.0 ml of trifluoroacetic acid and this solution is maintained at a temperature of 0 ° C for 16 hours. The mixture was evaporated under reduced pressure and the residue was dissolved in methylene chloride. The pH was adjusted to 7.5 by addition of water and sodium bicarbonate. The aqueous phase was freeze-dried. Purification of the residue by reverse phase high performance liquid chromatography gave the title compound. in title *

The compound obtained has the following characteristic data:

IR spectrum (KBr technique) t,

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

Mass spectrum: m / z 754 (M ⁺ 4 H).

Example Э2

Mono-sodium salt dihydrate [6R- (6c (, 7µ) (z)) - 7 - [[(2-amino-4-thlazolyl) (methoxyimino) acetyl] amino] -3 - [[[[6,8-difluoro] -l- (2-auorethyl) _t -L 4-dihydro-7 "" (4-methyl-l-piperazinyl) -4-oxo-3-chinoUnyl] carbonyl] oxy] methyl] -8-oxo-5-thia -1'-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

To a suspension of 5 g of 6,8-difluoro-1- (2-aoroethyl) -1,4-dihydro-7- (4-methyl-1-plperazinyl) -4-oxo-3-chlorolinecarboxylic acid potassium salt in 40 ml of dimethylformamide is added over 5 minutes, a solution of 1 g of 1,1-dimethylethyl ester [6R- (6d, 7 ')] -3- (iodomethyl) -7 - [[(methoxyimino) [2- (triphenylmethyl) amino] -4] is added. -> thiazolylacetyl] amino] -8-oxo-5-thila-1-alpha-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 4 ml of dimethylformamide * The reaction mixture is stirred for 2 hours and then evaporated in vacuo to a residue with ethyl acetate and aqueous sodium bicarbonate.

The organic phase was washed successively with aqueous sodium bicarbonate solution and brine, dried over magnesium sulphate and evaporated to give a brown foamy solid. Purification by flash chromatography on 50 g of silica gel (particle size 0.04-4.0 mm) using mixtures of methanol and chloroform (gradient 0 to 8% methanol), as intermediate, 1,1-dimethyl-methyl-ster, which corresponds to the above-mentioned title compound, is obtained.

A solution of 2.3 g of this 1,1-dl methylmethyl ester in 25 ml of methylene chloride is treated at 0 ° C with the addition of 2 ml of anisole, 0.2 ml of 1,2-ethanedithol 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. Ke

Зо

To the residue ee, add 5 ml cold ethyl acetate and then 25 ml ether, leaving a solid. Filtration, washing with ether and air-drying gives a brownish solid. This solid is dissolved in a loo ml of 1: 4 methanol / chloroform, and then under ice cooling, 100 ml of water and 35 ml of a 5% aqueous solution are added. sodium bicarbonate up to pH 7.8. The resin thus formed is dissolved in 1 ml of dimethylformamide and 20 ml of chloroform are added to the solution obtained, followed by the addition of water and aqueous sodium bicarbonate solution until the pH is adjusted to 7.8. Wash with chloroform and purify by reverse phase chromatography using a water / acetonitrile gradient as solvent. The fractions containing the reaction product are evaporated under reduced pressure and freeze-dried to give the title compound.

The compound obtained has the following characteristic data:

Mass Spectrum i m / x 787 (M + 4 H),

The following compounds can also be prepared according to the methods explained in the examples above:

[? - [? 4.7 / 5 (z)]] -7-CC (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino-3 - [[[E] -e thyl-6-fluoro -1,4-dihydro-7- (1-piperazinyl) -4-oxoquinolin-3-yl] carbortyljoxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -en-2-carboxylic acid

COOH

EN 27o244 B2 [or- (6 ", 76)] - 3 - [[[[lo _{ethyl-6-fluoro-f} 4-dihydro-4-oxo-7- (l-piperazinyl) quinolines chlnoiin-3- yl] carbonyl] oxyjmethyl] -O-oxo-7- (phenoxyacetyl) amino] -5-thla-1-azabicyclo [4.2.0] oct-2-one-2-carboxylic acid

COOH [6R- (1od, 7β)] -3-CCfC 6, 1'-difluoro-1- (2-fluoroethyl) -1,4-dlhydro-7- (4-methyl-1-piperazinyl) -4-oxoquinoline -3-.ylJ carbonyl oxy] methyl Khyla] -8-oxo-7 - [(phenoxyacetyl) afninoJ-5-thia-l-azabicyclo £ 4 _f 2 _f oJokt 2-.en-2-carboxylic acid

[6R- [7α, 7β (Z)]] -7- (2-amino-4-thiazolyl) (methoxyimino) asyl] amino] -3- (1-ethyl-6-dioxo) 4-Dihydro-7- (4-methyl-1-piperazinyl) -4-oxoindolin-3-ylcarbonyl] oxy] methyl-8-oxo-5-thia-1-azabicyclo [4.2.1.0 &lt; 2,7 > en-2-carboxylic acid

COOH o

CS 27o244 B2 [6R- (6o (1,7)) - 1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -3-oxo-7 - [(phenoxyacetyl) amino] -5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid A acid

(R, - (OD, 76)) -3-CCC (1-cyclopropyl-6-fluoro-1,4-dihydro-7- (1-piperazinyl) -4-oxoquinolta-3-yl] carbonyljoxy] methyl] -8- ОХО-7- C (phenoxyacyl) amino] -5-thia-1-azabicyclo (4.2.0) oct-2-ene-2-carboxylic acid

(R) - [(2S, 7β (z)]] - 7-QQ (2-amino-4-thiazolyl) (methoxyimino) aminoethyl] -3 - [[QC 1-cyclopropyl-6-fluoro-1,4-dihydro] -4-oxo-7- (1-piperazinyl) quinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5- [4H-1-azabicyclo [4.2.0] oct-2-ene- 2-carboxylic acid

COOH o

Св 370244

-7-t (cyanation «-yl) ttnHno] ^-3-6 TCCC i ^t) - ^{<dark-chloro-l- (2-AU} relhyL) -. L-4 dlhyclro-7- (4-m« Uiyl- L-plpsrazínyl) -4-oxochlnolÍn-3-yl karbonyljoxyjmelhylj-e-e-oxo-l-thia-C4 axablcyklo _t 2 oJoki βπ 2-2-carboxylic acid

COOH [or- (* ба 7β)] - 7- (řormylomino) -3 - _[[[[6-f 8 cUauor-l- (3-auoroUiyl) ^e M-dihydroe7e (4-molhyi-L-píperaxlnyl) - 4-oxoquinoline-3-yl] korbonyl] oxy] methyl] -8-охо 5-1Ыа-1-а «аЫсук1о £ _f 4.2] oct-2-ene-2-carboxylic acid

COOH [бк- (боч7Д)] -7- [ССС ⁴ - <^ У1-2 | 3-chloro-1-methyl-1-amino] phenylacetyl] amino-3-C 6-C6-dlfluoro-1- (2-fluoroethyl -l _l 4-dihydro-4-oxoquinoline-3-yl] karbonyljoxyjmethylj -8-oxo-5-thia-axabícyklo [oJokt 4.2 _{t-2-ene-2-carboxylic} acid

EN 27o244 6R B2-C6 <X, 7A (a)] J-7-ff 2-amino-4-thiazolyl) C [(l _r -l-carboxy-methyl) -ethoxy-3- imlnoJacetylJamlnoJ LLCC 6,8-difluoro 1- (2-Fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-ylcarbonyl-oxylmethyl-8-oxo-5-thia-1-azabicyclo [ 4,2-ioct-2-ene-2-carboxylic acid

(Z)] -7-CCC (2-Amino-4-thiazolyl) (methoxycarbonylamino) acetyl] -amino] -3- [C [[6,8-difluoro-1- (2-Fluoroethyl) -1,4-dihydro-7- (4-methyl-1-plperazinyl) -4-oxoquinolin-3-yl] carbonyl-oxy] methyl-8-oxo-5-thia-1-azabicyclo [4] 2,2-oct-2-ene-2-carboxylic acid

[6R- (6 *, 7O)] -3-LLCC 6,8-fluoro-1- (2-fluoroethyl) -1,4-dlhydro-7- (4-methyl-1-piperazinyl) -4-oxo quinolin-3-yl Carbonyl Joxy is thyl-8-oxo-7-C (phenylacetyl) amino-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

ch ₃

СОО.Ч o

[6Ρ- (6Α, 7β)] - 3- [CC _[6'-difluoro * 8 l- _(2-fluoro-r 4-dihydro-.7- (4-methyl-l-piperazinyl) -4-oxochlnolln -3-yl] carbonyl] oxy] methyl] -O-oxo-7α * [α-1-ethyleneacotyl) amino] -6-lhla-1-α-bicyclo [4.2.0] oct-8-ol-

ГоНмСбЛ | 7А (Z)] J-CC-7 (aa »iHno 4-lhlaeolyl) (melhoxylm4no) and <jetyiJamlnoJ 3- [£ C C 6 _t 8« dtauor «lw (4-nuoríenyl) -L _f 4 dihydro-7- (4-methyl-1piperalnyl) -4-oxoquinolin-3 * yl] carbonyl] oxy] methyl} -O-oxo-B * thia- »1-azabicyclo [4.2.1] octane -2-ene-2-carboxylic acid

[α- (6α, 7β)] -3 - [[[[6-fluoro-1- (4-fluorophenyl) -1,4-dlhydro-7- (4-methyl-1-piperazinyl) -4-oxoquinoline] - 3-yl] carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-a2abicyclo [4.2.0] oct-2-ene-2-carboxylic acid

COOH

CS 27o244 B2 [RR- (ба, 76)] -3 - [[[Q 9 -fluoro-3,7-dlhydro-3-methyl-lo- (4-methyl-1-piperazinyl) -7-oxo] -2H-pyrido [1,2,3-de] -1,4-benzoxazin-6-yl] carbonyl] oxy] methyl] -3-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.4.1.0 &lt; 2,7 &gt; 2, Oocok-2-ene-2-carboxylic acid

[6R- (6a, 7f, (z) J] -7 - [[(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3- [E [Q 9-fluoro-3,7-dlhydro] -3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2H-pyrido [1,2,3-de] -1,4-benzoxazin-6-yl] carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylic acid

[6R- (6a.7 / i)] - [[C 2 -carboxy-3 - [[[[6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (methyl- 1-piperazinyl) -4-oxo-quinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thla-1-azabicyclo [4.2.0] oct-2-en-7-yl] amino ] carbonyl] benzoic acid

EN 27o244 B2 [OR- [6A, 7A (Z)]] 7- (3-Amino-l-pyrrondlnyl) _{-6-chloro-l-cyclopropyl-6-fluoro-l-f} 4-dihydro-4-3 oxochinoiin -yl] carbonyljoxy] methyl] -7- [η (2-amino-4-thiazolyl) β (carboxymethoxy) iminoacetyl] amino] -8-oxo-5-thla-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acid

[? N-SA, 7? (Z)] J -3 - [[Q [7- (3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1'-dlhydro-4-oxoquinoline] -3-ylcarbonyl] oxy] methyl-7- [Q2-amino-4-thiazolyl] C (1-carboxy-1-methylelhoxy) amino] amino] amino] -8-oxo-5-tha-1-azabicyclo [4.2.0] , θ] oct-2-ene-2-carboxylic acid

[6R- [6cu7fl (2)] 2-3 - [[Q [7 ~ (3-amino-l-pyrrolidinyl) _{-8-chloro-l-cyclopropyl-6-fluoro-l} 4-dihydro-4-ox quinolin-3-yl] carbonyljoxy] methyl] -7 - [[(2-amino-4-thlazolyl) (methoxyiniino) acetyl] amino] 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-yl en-2-carboxylic acid

COOH

CS 27o244 B2

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

Example A

Preparation of dry ampoules for intramuscular administration:

Lyophilizate 1 g of monosodium salt (6R-6R, 7A (z))] - 7 - [[2-amino-4-thlazolyl (methoxyimino) acetyl] amino] -3- [eta] &lt; 6 &gt; 8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -β-οχο- 5-tha-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and filled into an ampoule. Sterile aqueous ampoule contains 10% propylene glycol. 2.5 ml of a 2% aqueous solution of hydrochloride _s -lidocaine are added to the thyophilisate prior to administration.

Claims (9)

1. A process for the preparation of novel acyl derivatives of the general formula I (I) in which m represents the number 0, 1 or 2, R ¹ represents a hydrogen atom or an acyl group useful for the acylation of antibiotics A-lactam type of up to 21 carbon atoms, for example a group of formulas CS 27o244 B2 R ⁵ - CO - COOH n ¹⁰¹ _ (CH ₂ ) _o - co R ¹³⁰ - O К ж c - what - in which R ^S represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms which is substituted by a cyano group; R ¹⁰¹ optionally represents an amino group substituted by a half-membered heterocyclic ring having 1 or 2 nitrogen and / or sulfur atoms, r ¹² ° represents an alkyl group having 1 to 8 carbon atoms, _R 13o · is an optionally substituted C 1 -C 8 -alkyl substituted carboxy group; n means 0, 1, 2 or 3 « and in which further R ² is hydrogen, an alkoxy radical containing 1 to 8 carbon atoms, amino, alkylthloskuplnu having 1-8 carbon atoms or alkanoylaminoskuplnu having 1 to 7 carbon atoms, _t 4о Is hydrogen, C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl or halo-phenyl, R 5 is C or N, wherein: R @ ³ denotes a hydrogen atom or a halogen atom, or R ⁰ and together represent alkyl new group with 3-5 carbon atoms alkylenmonooxyskupinu with 2-4 carbon atoms or alkylenedioxy в 1-2 carbon atoms, is hydrogen, halogen, alkyl having 1-8 carbon atoms or an optionally alkyl- a C 1 -C 8 group or a methyl group substituted by a five- or six-membered N-heter cyclic ring, optionally containing an oxygen atom or an additional carbon atom, means a hydrogen atom or a halogen atom; or 32 33 R and R together represent an alkylenedioxy group and 1 to 4 carbon atoms. R represents an easily hydrolyzable protecting group useful in the chemistry of phalos porins having up to 21 carbon atoms, such as a tert-butyl group, a p-nitrobenzyl group or an olyl group, as well as salts of these compounds and hydrates of the compounds of formula I or their salts, The process of claim 1, wherein the compound of formula (P) (II) in which 12, n, R, R and R are as defined above and Hal is a halogen atom, acts by a carboxylic acid salt of the general formula Ш (III), CS 27o244 B2 in which 31 32 33 R, R, R and Z are as defined above, and the compound obtained is optionally isolated in the form of a salt, a hydrate or a salt hydrate. 2. The method according to Article 16 of formula (I) O, R is hydrogen and 1, characterized in that corresponding starting materials are used II and III to give compounds of the general formula kterém in which m is a number of substituents having the meaning given in point 1, 2, characterized by. That the starting materials are used according to the method of (1) or (II) and (III), to give compounds of the formula (1) in which the 3o represents a group R -C, wherein R represents a hydrogen atom or a halogen atom, R ³¹ represents an alkyl group having 1 to 8 carbon atoms or a cycloalkyl carbon group, a haloalkyl group having 3 to 7 carbon atoms, R ³ 'represents an alkyl group or an alkyl group having from 1 to 6 atoms C 1 -C 8 -substituted by a carbon atom, a piperazine group R ³³ represents a hydrogen atom or a halogen atom. and other substituent (s) as defined in 1 or 2 4. compounds of general interest 3. The method of claim 3, wherein:. The corresponding compounds of formula 11 and Ш are used as starting materials to give compounds of the general formula kterém in which R @ ³ denotes hydrogen or fluorine, R ³¹ represents a group. ethyl, fluoroethyl or cyclopropyl R ³² represents a plperazinyl group or a 4-methylpiperazinyl group and R ³³ represents a hydrogen atom or a fluorine atom. and the other substituents have the meaning given in point 3 < 5. The method according to any one of Claims 1 to 4, characterized in that the corresponding compounds of the general formula II and Ш 2a are used as starting materials, to form compounds of the general formula t, in which: R ¹ represents 1,101 _R 13 denotes the group R ¹³ -ONC-CO-, R ^11c 2-amino-4- (1H-tolyl) and methyl or the general formula CS 27o244 B2 where R C - COOH, represents a hydrogen atom or a methyl group, represents a group R ³⁰ -C, where R ⁰ represents a hydrogen or halogen atom, an alkyl group в 1 to 8 carbon atoms, halogenoalkyl having 1 to 8 carbon atoms or cycloalkyl having 3 to 7 carbon atoms. R ³² a lower alkyl group having 1 to 8 carbon atoms, a piperazinyl group or an alkyl group having 1 to 8 carbon atoms substituted with a piperazinyl group; and R ³³ represents a hydrogen atom or a halogen atom. and other substituents have the meaning given in points 1 to 11, 6 < 5. A method according to claim 5, wherein the starting materials are the corresponding compounds of the formula II and Ш to give the compounds of the formula I in which: 7 « R ³ ° R ³¹ R ³² R ³³ means full. a hydrogen atom or a fluorine atom. ethyl, fluoroethyl or cyclo for methyl, 4-methylpiperazinyl or piperazin-1-yl and represents a hydrogen atom or a fluorine atom. The composition of claim 1, wherein the corresponding compounds of formula (P) and (III) are used as starting materials to form compounds of formula (I) in the form of (6-Ρ 6-β-6-β-β (ζ))]. amino-4-thiazolyl) (R ^^ - oxyimino) acetyiJamlno] -3- ££££ 6-R ^3, 8-R ³ °, R ^^ - l, 4-dihydro-7- (4-R [4- ⁽ 1-piperazinyl) -4-oxo-3-quinolinyl] carbonyljoxy] methyl] -8-oxo-5-tha-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, and the salts and hydrates thereof of these carboxylic acids and the salts in which: Method according to R ³³ a R @ 10 denotes a hydrogen atom or a halogen atom. R ³¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a 2-halogeno alkyl group having 1 to 8 carbon atoms. R ³⁴ represents a hydrogen atom or an alkyl group of 1 to 8 carbon atoms; R ²¹ represents a hydrogen atom, a C 1 -C 8 alkyl group or a group of the formula CS 27o244 B2 COOH in which 22 23 K and R are hydrogen or alkyl of 1 to 8 carbon atoms. 8. Process according to claim 7, characterized in that the starting materials used are corresponding compounds of formula П а Ш to give the compounds as defined in clause 7, wherein R ²¹ is methyl and the other substituents are as defined in stabbed 7th £ The method according to claim β, characterized in that the corresponding compounds of the general formula ti а Ш are used as starting materials to give the compounds defined in point 8, wherein R ³³ and R ³ are hydrogen or fluorine atoms, R ³¹ is ethyl or 2 -fluoroethyl and R ³⁴ is methyl and the other substituents are as defined in point 8. 1 °. Process according to claim 9, characterized ee that the starting materials used are corresponding compounds of formula II а Ш to give the compounds as defined in paragraph 9, wherein R ³³ and R ³ ° zna31 MenA fluoro and R is 2-fluorethyiovou group and other substituents have the meaning given in point 9. and The method according to clause β », characterized in that the corresponding compounds of the general formula II and Ш are used as starting materials and to give the compounds defined in point 8, wherein R is fluorine, R ³ is hydrogen, R ^{3 is} 2- fluoroethyl and R ³⁴ is methyl and the other substituents are as defined in point 8. ii ² · 8. The method of claim 8, wherein the starting materials used are the corresponding compounds of formulas II and III to give the compounds defined in point 8, wherein R @ ³³ is fluorine, R @ ^3e is hydrogen, R @ ³ is ethyl and R ³⁴ is methyl and other substituents have the meaning given in point 8. 13. 8. The method of claim 8, wherein the starting materials are the corresponding compounds of formula (11) and (III) and a compound of the formula (8), wherein R @ ³³ denotes a fluorine atom, R @ ³ denotes a 2-fluoroethyl group, R @ ^3. ° is hydrogen and R ³⁴ is methyl and the other substituents have the meaning given in point 8. ¹⁴ 14. A process according to any one of Claims 5 to 13, characterized in that ae used the corresponding compounds of the formulas II and III as starting materials to give the compounds defined in points 5 to 13 above. 13, in which groups of general formulas CS 27o244 B2 С N -О II с _R21 They are present in the syn-isomeric form or in the form of mixtures in which the syn-isomeric form predominates and the other substituents have the meaning given in One of points 5 to 13. 15 .. The method of claim 1, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to give compounds of formula (1) in the form of [6R- [6-a, 7-b] J-3-CCCC 6- R ³³ , EB ^3G , 1R ³¹ -1,4-dihydro-7- (4-R ³⁴ -1-piperazinyl) -4-oxo-3-quinolinylcarbonyl Joxymethyl] -8-oxo-7- [(phenoxy) amino-5-tha-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylic acids and salts and hydrates of these carboxylic acids and salts in which R @ ³³ and R @ ³ are31 hydrogen atoms or a halogen atom, R 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 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms and the other substituents have the meaning referred to in point 1. 16. 5. The process according to claim 15, wherein the corresponding starting materials are used 33 compounds of formula II and III to form the compounds defined in 15, wherein R and 3o31 R is hydrogen or fluorine, R is ethyl or 2-fluoroethyl and R is methyl and the other substituents are as defined in point 15. 17. ’ 16. The method of claim 16, wherein:. That corresponding starting materials are used 33 compounds of the formulas П and ΙΠ to form the compounds defined in point 16, wherein R and R ^ ⁰ are fluorine and R ^ ¹ is 2-fluoroethyl and the other substituents are as defined in point 16; 18. Process according to claim 15, characterized in that ·· starting materials used are corresponding compounds of formula П а III to give compounds as defined in paragraph 15, wherein R is fluorine, R ° is hydrogen, R @ ¹ is 2 fluoroethyl and R @ ⁴ is methyl and the other substituents are as defined in Note 15. 19 Dec Process according to claim 15, characterized in that the starting materials used are corresponding compounds of formula II а III to afford the compounds as defined in claim 15, wherein R ³³ is fluoro, R ^J is hydrogen, R ^J is ethyl, R ° is methyl and the other substituents have the meaning given in point 15. ²⁰ 20 May 15. A process according to claim 15, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to give the compounds defined in (15) wherein R is fluorine, R &lt; ¹ &gt; is 2-fluoroethyl, R &lt; and R ( ⁴⁾ is methyl and the other substituents are as defined in (15). 21 « A process according to claim 1, wherein the corresponding compounds of the formulas (I) and (III) are used as starting materials to give the compounds of the formula (1) in the form of £ККК £К £- 1- 6 6]] 7- 7-. -3- [C ^[R6-R33, e R ^3o, R ³¹ -l, 4-dihydro-7- (4-R ³⁴ -L-pip.razinyl) -4-oxo-3-chlnolinyl] carbonyl] oxy] methyl] -8-oxo-5-thla-1-azablicyclo [4.2.0] oct-2-ene-2-carboxylic acids and the salts and hydrates of these carboxylic acids and salts in which R and R are hydrogen or N-methyl. or a halogen atom, R represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or a 2-haloalkyl group having from 1 to 8 carbon atoms and R ³⁴ represents a hydrogen atom or an alkyl group having from 1 to 8 carbon atoms and the other substituents have as defined in point 1 '' 22 « The method of potentiating a compound of formula (II) and (III) to form compounds as defined in (21) wherein R and R ³ o is hydrogen or fluorine, R ³ⁱ is ethyl or 2-fluoroethyl group and R 34 is methyl and the other substituents are as defined in point 21. 23 «‘ The process according to claim 22, characterized in that corresponding starting materials are used 33 of a compound of formula (II) and (III) to form the compounds defined in point 22, wherein R a 3o 31 R is a fluorine atom and R is a 2-fluoroelyl group and the other substituents are as defined in 22 &quot; 24 « 2. The process of claim 2, wherein the starting materials used are the corresponding 33 of a compound of formula (II) and (III) to give the compounds defined in (21), wherein R is a fluorine atom, R ³¹ is a 2-fluoroethyl group, R ³ is hydrogen, 34 R represents a methyl group and the other substituents are as defined in 21 &quot; 25, The method according to claim 21, characterized in that corresponding starting materials are used 33 of a compound of formula II and III to form the compounds defined in 21, wherein R is fluorine, R ³ is hydrogen, R ³¹ is ethyl and R ³⁴ is methyl and the other substituents are as defined in 21 26. * A method according to clause 21, characterized in that the corresponding compounds of the general formula II are used as starting materials to give the compounds defined in clause 21 wherein R is fluorine, R ³¹ is 2-fluoroethyl, R ³ is atom hydrogen and R ³⁴ is methyl and the other substituents are as defined in 21. 27. ' A process according to claim 1, wherein the corresponding compounds of formula (P) and (IIIa) are used as starting materials to give compounds of formula (I) in the form of 6 6 R- 6a, 7A (Z)]]. (2-amino-4-thlazolyl) ^(R31 «» oxyimlno) асеtyljamino] -3- £ [[£ 6 -R ^33, 8 R ^3o, R ³¹ -l, 4-dihydro-7- (4-R ³ * -1-Plperazinyl) -4-oxo-3-chloroilnyl] carbonyl] oxymethyl-oxo-5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids and salts and hydrates of these carboxylic acids and salts thereof, in which R ³³ and R ³ ° are hydrogen or halogen, R ³¹ represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms or 2-halogenoalkyl having 1 to 8 carbon R ³⁴ represents a hydrogen atom or an alkyl group of from 1 to 8 carbon atoms, R ²¹ 4 6 CS 27 2244 B2 represents a group of the general formula - C - COOH * where 22 23 R and R are hydrogen or alkyl and 1 to 8 carbon atoms; 28. The method according to claim 27, characterized in that the corresponding starting materials are used 22 of a compound of formula (II) and (III) to form the compounds defined in (27) wherein R and 23 R is both methyl and the other substituents are as described in 27 &quot; 29. The method according to claim 28, characterized in that the corresponding starting materials are used 33 to give the compounds defined in point 28. wherein R and R 0 are hydrogen or fluorine. R is ethyl or 2-fluoroethyl and R is methyl and the other substituents are as described in point 28. 30. The method according to claim 29, wherein the corresponding starting material is used 33 of the compound of formula II а а to give the compounds defined in 29 * wherein R a R is fluorine and R is 2-fluoroethyl and the other substituents are as defined in 29 31. The method of Item 28 * wherein the corresponding compounds of formula II and III are used as starting materials to form the compounds defined in Item 28 * wherein R is fluorine * R ³ ° is hydrogen * R ³¹ is 2- and R ³⁴ is methyl and the other substituents are as defined in point 28. 32. 28. The method of claim 28 wherein. The compounds of formula (II) and (III) are used as starting materials to give the compounds defined in (28), wherein R ³³ is a fluorine atom. R @ ³ represents a hydrogen atom. R ³ ^. is ethyl and R ³⁴ is methyl and the other substituents are as defined in point 28. 33.. 28. The process of claim 28 wherein the corresponding compounds of formula (II) and (III) are used as starting materials to produce the compounds defined in (28) wherein R is fluorine. R &lt; ³ &gt; is 2-fluoroethyl. R &lt; ³ &gt; is hydrogen and R &lt; ^{34 &gt}; is methyl and the other substituents are as defined in 28. 34. 3. The method of claim 1, wherein:. The starting materials used are the corresponding compounds of the formulas II and III to give (4-nitrophenyl) methyl ester [6R- (6a, 7fl)] - 3 - [[E (1-ethyl-1,4r-dihydro-7)]]. -methyl-4-oxo-1,6-naphthyridin-3-ylcarbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] 27o244 B2 noj-5-thia-1-acetyl [4,2, θ] oct-2-ene-2-carboxylic acids, as well as the salts of this compound and hydrates of this compound or hydrates of its salts · 35. A method according to claim 1, characterized in that the corresponding compounds of the general formula 11 and 1П are used as starting materials to give 1,1-dl methylethyl tester [6R- (6a, 7/3)] -3 - [[[(5 5-Chloro-1,3-dloxolo [4,5-g] quinolin-7-yl) carbonyl] oxy] methyl-7- (phenoxyacetyl) amino] -5-thla-1-azabicyclo 4.2, oocok-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. 38. The method of claim 1, wherein the corresponding compounds of formula II are used as starting materials to form 1,1-dimethylethyl ester [6R- (order, 7/3) (2)] - 3 - [[[( 1-ethyl-1,4-dihydro-7-molyl-4-oxo-1,0-naphthyridin-3-yl) carbonyl] oxy] methyl] -7 - [[(methoxy 1mino)] [2- (tri) O-4-thlazolyl] -amethyl] ammonium-O-oxo-1-thla-1-azabicyclo [1,2.0] okl-2-ene-2-carboxylic acid, as well as salts thereof and hydrates of this compound, or hydrates of its salts. 37. A method according to claim 1, wherein the corresponding compounds of the formulas II and III are used as starting materials to give [6R- (6a, 7fl) (z) J-3 - [[[(5 ethyl-5,8-dihydro-e-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl) carbonyl] oxy] methyl] -7 - [[(melhoxyimino) 2- (triphenylmethyl)] amino-4-thlazolyl] acetyl] amino] -beta-δ-5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. As 1 salts of the compound and hydrates of the compound or hydrates of the salts thereof. 5. The method of claim 1, wherein:. The use of the corresponding compounds of formula (I) as starting materials is provided. a * ΙΠ to give 1,1-dimethylethyl thyroid [6R- (6d, 7j)] -3 - [[££ 1- ^] ethyl-6-fluoro-1,4-dihydro-7- (4- formyl-1-plperazinyl) -4-oxoquinolin-3-ylcarbonyloxy] methyl] -8-oxo-7- (phenoxyacyl) amino] -5-1H-1-azabicyclo [4.2.0] oct-2-en-2- carboxylic acids, such as 1 salts of this compound and hydrates of this compound or hydrates of its salts · 39. The method of claim 1, wherein the starting materials used are corresponding compounds of the formula P and ΙΙ to form 1,1-dimethylethyl ester [6R- (6o (76)] -3-Q [[(5-ethyl- 5 _l of e-dihydro-e-oxo-3-dloxolo [4,5-g] ehlnolln -? «yl) carbonyl] oxy] methyl-8-oxo -? - 2-thlenylacetyl) amlnoj 5-lhla- 1-azablicyclo [4.2.0] oct-2-ene-2-carboxylic acid as well as 1 salts thereof and hydrates thereof 40. The method according to claim 1, characterized in that the corresponding compounds of the general formula (I) are used as starting materials to give 1,1-dl thyl thyle of a [ω-(ω, 7/1)] - 3-methyl-1-ethyl -6-fluoro-1,4-dihydro-7- (4-formyl-1-plperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -7 - [(2-thlenylacetyl) amino] -8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid as well as salts of the compound and hydrates of this compound or hydrates of its salts. 41. The method of claim 1, wherein the starting materials used are the corresponding compounds of formulas II and III to give [6R- (6a, 7/3) (z) 1,1-dimethylethyl ester] - 3 - [[[[[ 1-ethyl-648 CS 27o244 B2-Fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3-ylcarbonyloxymethyl-7- (methoxyimino) C2- (triphenylmethyl) amino-4-thlazolyl-acetyl-amino-8-oxo-5-thia-1-azabicyclo [4.2.1] oct-2-ene 2-carboxylic acids as well as salts thereof and hydrates thereof, or hydrate salts thereof. 42. 2. The process of claim 1 wherein the corresponding compounds of formulas II and III are used as starting materials to give [6R- (6o (17A)] -3- [1,1-dimethyl-ethyl] 1,1-dimethyl-ethyl ester. 6-fluoro- 1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-ylcarbonyloxycarbonyl-7-Q (phenoxyacetyl) amino-8-oxo-5-thla-1-azabicyclo (η 4,2, as well as the salts of the compound and the hydrates of the compound or hydrates of the salts thereof. 5. The process of claim 1, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form .beta.-R- (6d, 7/3) (z) J-3- .beta.-ethyl-1,1-dimethylethyl ester. -6-fluoro-1,4-dihydro-7- (1-pyrrolinyl) -4-oxoquinolin-3-ylcarbonyloxymethyl-7- (N-methoxyimino) [2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino 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. 44. 2. The method of claim 1, wherein the starting compounds are the corresponding compounds of formula (II) and Ш to give [6R- (6a, 7 / S)] -3-ω-1-ethyl-6- 1,1-dimethylethyl ester. fluoro-1,4-dihydro-7- (4- (1,1-dimethylethoxy) carbonyl-1-piperazinyl-4-oxoquinolin-3-yl) carbonyl] oxy] methyl-8-oxo-7-Q (phenoxy) Amino-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid as the summer salt of the compound and the hydrates of the compound or hydrates thereof. 45. 2. The process of claim 1 wherein the corresponding compounds of formula (II) are used as starting materials to form 2-propenyl ester .beta.R- (6d, 7a). -1,4-dihydro-7- [4- (1-propenoxy) carbonyl-1-piperazinyl] -4-oxoquinolin-3-ylcarbonyloxy] methyl-8-oxo-7- (phenoxyacetyl) amino-5-thi-1-yl azabicyclo [4.2.0] octoct-2-ene-2-carboxylic acid as well as salts thereof and hydrates thereof, or hydrates thereof. 46. 6. The method of claim 1, wherein the starting materials are the corresponding compounds of formula II and III to form the allyl ester .beta.R @ 6 R @ - .beta. -fluoro-1,4-dihydro-7- (4-thromorpholinyl) -4-oxoquinolin-3-ylcarbonyloxycarbonyl-8-oxo-7- (phenoxy-aryl) amino-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acids, as well as salts thereof and hydrates thereof, or hydrates thereof. 47. 2. The process of claim 1 wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form the allyl ester Q6R- (6a, 7 / S) -3- (1-ethyl-6-fluoro-). 1,4-dihydro-4-oxo-7- (1H-pyrrol-1-yl) quinolin-3-yl] carbonyl} oxy} methyl-8-oxo-7- (phenoxyacetyl) amino] -5-1H-1-yl azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids, as well as salts thereof and hydrates thereof, or hydrates thereof. CS 27o244 132 48. 5. A process according to claim 1, wherein the starting materials are corresponding compounds of the formula (I) to form the allyl ester .beta.R @ 6 R- (6d, 7 (i)) - .beta.-5- (4-fluorophenyl) -5- and _{t-dihydro-8-oxo-l,} 3-dioxolo [4,6-g] quinolin-7-yl] carbonyl] oxy] methyl-8-ox o-7- £ (IE асе phenoxy acetyl) amino-5 - thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, as well as the salts thereof and the hydrates of this compound or the hydrates of their salts. 49 » A method according to claim 1, wherein the corresponding compounds of formula (II) and (III) are used as starting materials to form the tert-tributate tester (6R- (6d, 7A) (z)) - 7- (Q-2-amino-4-). thi azolyl) (methoxylmyl) amino] amino] -3- [eta] &lt; 1 &gt; -fluoro-1,4-dihydro-7- (4-thromophenyl) -4-oxoquinolin-3-yl carbonyl] oxy] methyl] -beta-5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid; the acid as well as the salts of this compound and the hydrates of the compound or the hydrates of its salts, i. ^: 5o · A method according to claim 1, wherein the corresponding compounds of formula (II) are used as starting materials to form .alpha., 6-dimethylethyl ester .delta. -amino-4-thiazolyl) (methoxylmlno) acetyl] amino] -3- [eta] &lt; 6 &gt; -beta-difluoro-1- (2-fluoroethyl) -1,4-dlhydro-7- (4-methyl- 1-Plperazinyl) -4-oxo-3-quinolinyl] carbonyl] oxy] methyl] -8-oxo-5-thiazolicyclo [4.2.0] oct-2-ene-2-carboxylic acid · As well as 1 salts of this compound and hydrates of this compound or hydrates of its salts ·