CS270247B2 - Method of cephalosporin's new salts 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 salts of cephalosporin of the following general formula I having valuable pharmacological properties.

New salts of cephalospprin of formula I have been found

wherein m is the number 0, 1 or 2,

R ¹ represents a hydrogen atom or an acyl group useful for acylating O-lectam type antibiotics of up to 21 carbon atoms, for example a group of formulas

R ⁵ - CO -

COOH

in which

R ⁵ represents a hydrogen atom or a C 1 -C 8 alkyl group substituted with a cyano group; R 11 represents an optionally substituted 5-membered heterocyclic ring having 1 or 2 nitrogen and / or sulfur atoms, 120 *

R represents an alkyl group having 1 to 8 carbon atoms and

Κ ¹³ θ represents an optionally substituted carboxy substituted alkyl group having 1 to Θ carbon atoms, and in which:

R is hydrogen, C1-C8alkoxy, amino, C1-C8alkylthio or C1-C7alkanoylamino, ^R31 is hydrogen, C1-C8alkyl , (C 2 -C 6) alkenyl, (C 3 -C 7) cycloalkyl, (C 1 -C 8) haloalkyl, or halo-phenyl,

Z is R ³⁰ -C or N, wherein *.

R < ³ > is hydrogen or halogen, or

R ( ³ ) and R ( ³ ) together are C 3 -C 5 alkylene, C 2 -C 4 alkylene monoxy or C 1 -C 2 alkylenedioxy,

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

3? 33

R @ 1 and R @ 2 together represent C1 -C4 alkylenedioxy and

M is a cation of a pharmaceutically acceptable base, as well as hydrates thereof. -. .

The term alkyl refers to straight and branched chain hydrocarbon groups having 1 to 8 carbon atoms, preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, tert-butyl or below.

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

CS 270247 02

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

The term aryl refers to an optionally substituted aromatic group such as a phenyl group, a tlyl group, a xylol group, a mesityl group, a cumyl group (isopropylphenyl group), a naphthyl group 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 C 1 -C 7 alkanoyl refers to a group of the general formula

R ²⁵ - CO in which *

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

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

The term "substituted phenyl" refers to a mono- or disubstituted phenyl group, with the substituent being a halogen atom (for example chlorine, bromine, fluorine), an alkyl group having 1 to 0 carbon atoms, an amino group, a nitro group or a trifluoromethyl group.

The term substituted alkyl means a C 1 -C 8 alkyl group optionally substituted by halogen (e.g. chlorine, fluorine, bromine), trifluoromethyl, amino, cyano, and the like.

The term "alkenyl having 2 to 6 carbon atoms" refers to straight or branched hydrocarbon hydrogen group with olefinic double bond and having 2 to 6 carbon atoms, i.e. the remainder of the compounds of the formula ^C _n H _2n j wherein n is 2-6, such as for example allyl, vinyl, etc.

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

The term five-, six- or seven-membered heterocyclic ring having from 1 to 4 oxygen atoms, du-. sulfur and / or sulfur denotes, for example, the following groups: six-membered, nitrogen-containing heterocyclic rings such as pyridyl, piperidyl, piperidino, N-oxidopyridyl, pyrimidyl, piperazinyl, pyridazinyl, N-oxidopyridazinyl, etc .; . _R five 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, ΙΗ-tetrazolyl, 2H-tetrazolyl and the like. heterocyclic ring radicals may be further substituted, for example, the following substituents: alkyl of 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, etc., alkoxy of 1 to 8 carbon atoms, such as a methoxy group, ethoxy group etc., a halogen atom, such as chlorine, bromine, etc. haloalkyl of 1 to 8 carbon atoms, such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxy, carbamoyl or carboxy, etc.

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

R ⁵⁰ and R ⁴¹ may together represent a C 3 -C 5 alkylene group, for example - (C 1-6) · * -, - (C 2-6), "(CH 2, or -CH (CH 3) - (CH 2) Or a (C 2 -C 4) alkylene monooxy group, for example - (CH ₂ ) ₂ '- (CH ₃ ) -O-, - (CH ₂ ) ₄ -O- or -CH (CH ₃ ) -CH 2 " O- or else C 1 -C 2 alkylenedioxy, such as -O-C 1-4 -O-, or -O-CH (CH 2 -O-), preferably forms a five- or six-membered fused ring.

33

R and R may together represent an alkylenedioxy group having 1 to 4 carbon atoms, such as for example the group -0 ·· 0Η ₂ -0-, -0- (CH _{2) 2} ^'0' -0- _(CH2) 3-O- , -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 five- or six-membered condensed ring is preferably formed.

The term acyl group (substituent R1) includes organic groups which are formed by removal of a hydroxyl group from a carboxylic acid and containing up to 21 carbon atoms. Examples of such acyl groups include those which have been used to date to synthesize β-lactam antibiotics, including 6-aminopenicillanic acid and derivatives thereof, as well as 7-aminocephalosporanic acid and derivatives thereof; cf. for example, Cephalosporins and. Penicillins, Verlag Flynn, Academic Press (1972), Belgian patent Θ66,038, published October 17, 1973, Belgian Patent No. 867,994, published December 11, 1978, US Patent No. 4,152,432, published May 1, 1979, U.S. Pat. U.S. Patent No. 3,971,778, published July 27, 1976, and U.S. Patent No. 4,173,199, published February 23, 1979. These publications disclose the various acyl groups used in the present case. The following acyl groups further illustrate the term acyl group, but do not limit it in any way. Examples of acyl groups include:

(a) an aliphatic group of the general formula

R ⁵ - C0 in which r ⁵ denotes a hydrogen atom of an alkyl group η 1 n? Β carbon atoms which is substituted with cyano;

(b) a carbocyclic aromatic group of formulas

COOH (c) a heteroaromatic group of the general formula

R ¹⁰¹ - (CH ₂ ) _n - CO CS 270247 82 where

n is 0, 1, 2 or 3; and ^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, pyrazinyl ring, thiazolyl ring, pyrimidinyl ring, and tetrazolyl ring.

Preferred heteroaromatic acyl groups are those in which R ¹⁰¹ is 2-amino-4-thiazolyl or 2-thienyl.

(d) [[(4-substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] arylacetyl group of formula

wherein _r 120 is C 1 -C 8 alkyl, for example 4- (C 1 -C 8 -alkyl, preferably ethyl or methyl) -2,3-dioxo-1-piperazinecarbonyl-D-phenylglycyl;

(e) an (subst. oximino) arylacetyl group of the formula

R ¹⁵⁰ -O -N * C-CO ^{1 R} 101

where r ¹⁰¹ . .. has the above meaning and * R ¹⁵⁰ . is optionally C1-C8alkyl substituted by carboxy.

As examples of _{R 10} groups

the following groups can be mentioned:

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

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

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

2-thienyl-2-methoxyiminoacetyl,

2-thienyl-2-hydroxyiminoacetyl,

2-thienyl-2- (dichloroethoxy) amino group,

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

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

R < ^{51 &gt}; is preferably alkyl of 1 to 8 carbon atoms, particularly preferably ethyl, or haloalkyl of 1 to 8 carbon atoms, in particular fluoroethyl, or cycloalkyl of 3 to 7 carbon atoms, preferably cyclopropyl;

R is preferably 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 azaquinolonyl substituent at the 3-position includes, in addition to

’Н

CS 270247 82

A preferred group of compounds of the invention are compounds of formula IB

(Ib) in which r! my meaning as above,

Π

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

R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or a group of the formula

I. '

- C COOH

AND

R ² 'where'

2223

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

R ²² and R ²³ together with the carbon atom to which they are attached represent a 3- to 7-membered carbocyclic ring, for example a cyclopropyl ring, an cyclobutyl ring or a cyclopsyntyl ring,

Particularly preferred are compounds of formula Ib, wherein:

2П

R is hydrogen and

R ²¹ is methyl or formula

R ²² R _ __ COQH 'wherein R • R ²² and R @ ² are hydrogen or methyl.

Groups

N - O - R ¹³⁰ β N - O - R ²¹ <1

- c -. c 14

CS 270247 92 are preferably present in the syn-form, i.e. in the Z-form, or in the form of mixtures, in the form of the Z-form. syn-form prevails.

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

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

The cephalosporin salts of the formula I can be hydrated and can 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. *

The object of the present invention is a process for the preparation of novel salts of valosporin of the general formula I, characterized in that the carboxylic acid of the general formula II

R ³³

R ³² (II),.

in which -------- . m, R, R, R, R and R are as defined above, reacted with at least an equimolar amount of a pharmaceutically acceptable base, and the salt obtained is optionally in the presence of water or atmospheric moisture isolated in the form of its hydrate.

The preparation of the salts of the formula I or the hydrates of the salts of the formula I by the process according to the invention can be carried out in a manner known per se, for example by reacting a carboxylic acid of the formula II with an equimolar amount of a base corresponding to the desired salt, conveniently in a solvent such as water, or in an organic solvent such as ethanol, methanol, acetone or the like. The salt formation temperature is not a critical condition 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. 0 ° 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 (i.e. the cephalosporin salt of formula I) may also be exposed to a humid atmosphere, for example at a temperature of from about + 10 ° C to + 40%.

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

2 32 32 33

The general symbols R, R, R, R, R, R, Z, Hal and the interrupted bonds have the meanings given above.

Depending on the choice of protecting group of the ester group R and the halogen Hal, the β- or β-isomer of the compound of formula VIII is obtained with respect to the double bond in the cephem ring. The resulting mixture of Δ> - / Δ 2-isomers can be purified as desired by preparing the sulfoxide of formula V followed by reduction of this compound or separation of the two items into the None 3-isomer.

Clarification of Scheme I:

Ila> VIII

CS 270247 82

The compound of formula Па is a known compound or can be obtained in an analogous manner (cf., for example, U.S. Patents 4,406,899 and 4,266,049). This compound is reacted with a salt of the selected quinolone of formula III, preferably in a solvent which does not contain hydroxyl groups, such as dimethylformamide, methylene chloride or N, N * -dimethylacetamide. Suitable carboxylic acid salts of the formula III are, for example, sodium, potassium, cesium, tert-butylammonium or tetramethylammonium salts. In the general formula (II), Hal represents a halogen atom, in particular a bromine or iodine atom. This reaction is preferably carried out at a temperature of about 0 to 80 ° C, especially at room temperature.

VIII -----------> la or Via

The protecting group of 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 this carboxylic acid of formula Ia with the β-isomer 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 carboxyl group, for example tert-butyl, p-nitrobenzyl, benzhydrol, allyl etc. The above-mentioned readily hydrolyzable esters can also be used. The ester protecting groups are cleaved, for example, as follows: a p-nitrobenzyl group by hydrolysis in the presence of sodium sulfide at a temperature of 0 ° C (or lower) to room temperature in a solvent such as dimethylformamide (preferably aqueous dimethylformamide); tert-butyl by reaction with trifluoroacetic acid in the presence of anisole at about 0 ° C to room temperature, with or without an additional solvent such as methylene chloride, an allyl group by palladium (0) catalysed transallylation in the presence of 2-ethylcaproic sodium or potassium salt acids (cf., for example, J. Org. Chem. 1982, 47, 587).

Via ----------> V

When the double bond isomerized to form the β-isomer, the compound of formula (VIa) thus obtained is oxidized. This oxidation is carried out by treatment with an organic or inorganic oxidizing agent. Various oxygen-releasing compounds such as organic peroxides, for example monosubstituted organic peroxides, such as C1-C4 alkyl hydroperoxides or alkanoyl hydroperoxides, such as tert-butyl hydroperoxide, permetic acid or peracetic acid, serve as oxidizing agents; as well as phenyl-substituted derivatives of these hydroperoxides, such as cumene hydroperoxide or perbenzoic acid. The phenyl group as a substituent may optionally contain further substituents, such as a C1-C4 alkyl group or a C1-C4 alkoxy group or else a halogen atom or a carboxyl group, so that it may be, for example, 4-methylperbenzoic acid, 4- methoxyperbenzoic 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, peroxymonosulfuric acid and peroxydisulfuric acid can also be used as oxidizing agents. Preferably 3-chloroperbenzoic acid is used. The oxidation is preferably carried out in an inert solvent such as an aprotic inert solvent such as tetrahydrofuran, dioxane, methylene chloride, chloroform, ethyl acetate or acetone, or in a protic solvent such as water, a lower alkanol such as methanol or ethanol, or a lower, optionally halogenated alkanecarboxylic acid, for example in formic acid, acetic acid or trifluoroacetic acid. The reaction temperature is in particular in the range of -20 ° C to + 50 ° C

In particular, the corresponding sulfoxide of formula V is obtained by using an equimolar amount of oxidizing agent, or with a slight excess relative to the starting material. When the amount of oxidizing agent is increased to twice the stoichiometric ratio or even more, the corresponding sulfone is formed.

In ------------ 5> la

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 (I) by, for example, phosphorus trichloride in dimethylformamide or trifluoroacetic anhydride in the presence of sodium iodide in acetone amethylene chloride. The temperature in this reaction is preferably at about 0 to -20 ° C, especially at 0 ° C. ·

Salts of formula I with groups

N - 0 - R ¹³⁰ N - 0 - R ²¹ 'or.

-C - - C -.

Such syn-forms can be obtained using starting materials in which the V-form is already present. If desired, the obtained syn / anti-forms of the compound of formula I can be separated in the usual manner into the corresponding syn- and anti-forms, for example by recrystallization or chromatographic methods using a suitable solvent or solvent mixture.

The salts of the formula I as well as the corresponding hydrates are antibiotic, in particular bactericidal, active agents. They can 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 humans. These salts of csfalosporins are effective against a broad spectrum of both gram-positive and gram-positive bacteria.

The in vitro activity of the compounds according to the invention against a wide range of Gram-positive and Gram-negative microorganisms, expressed as the minimum inhibitory congestion in micrograms / ml and observed using the dilution series (in liquid medium) is as follows:

Compound B * mono-sodium salt of [6R (6'C, 70)] -3- [E [(5-ethyl-5-8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline) -7-yl) carbonyljoxymethyl] -8-oxo-7 - [(phenoxyacstyl) amino] -5-th18-1-azabicyclo [4.2.0] oct-2-sn-2-carboxylic acid.

Compound C: tR- (E, C) 70 (23 - [[(2-amino-4-thiazolyl) (m-ethoxyimino) acyl] amino] -3 - [[[(1-ethyl-1,4- dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyloxy] methyl-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-sn- 2-carboxylic acids.

0 Compound: Sodium [6R (6X, 70) (Rev - [^ 2-amino-4-thiazolyl) (msthoxyrmino) acstyl] amino] -3 - _{[[[(5-ethyl-5-t} 8 dlhydro- 8-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl) carbonyl] oxy] * methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] ^e oct 2-ene-2-carboxylic ky'séliny.

Compound Et sodium [[R- (6 *, 70)] * 3- [Lt [1-ethyl-1 * fluoro-1,4] dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinoline] -3-yl] carbonyl] oxy-methyl] -3-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-zebaboylof4,2,01-oct-2-sn-2-carboxylic acid.

Compound F: [6R- (S, X., 70)] - 3 - [[N -ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline- 7-yl) carbonyl] oxy] methyl] -8-ΟΧΟ-7 - [(2-thienylacetyl) amino} -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid .

Compound Gt sodium salt of Q6R- (ε-7G) -1 * 3- [C [[1-ethyl-6-fluoro-1,4-dihydro-7- (4-isopropyl-1-piperazinyl) -4-oxoquinoline] -3-yl] carbonyl] oxy] methyl] -7 - [(2-thienylacetyl) amino] -8-oxo-5-thi-8-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid .

la

Compound H: [6R- (6'-X, 70)] - 3 - [[[[[1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinoline] -4-oxoquinoline] sodium] -3-yl] carbonyloxycarbonyl-8-oxo-7 - [(phenoxyacetyl) amino-5-thla-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

Compound I: sodium salt [6R- (6x, 70) (Z)} - 7 - [, C (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3- [t-Cl- ethyl- 6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyl] oxylmethyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

Table

Minimum in vitro inhibitory concentration (^ g / ml)

microorganism В C 0 E E. coli 2 0.5 0.25 8 K. pneumoniae A 1 0.5 0.25 2 E. cloacae 9570A 2 2 1 8 E. olneone 940-1 2 0 1 0 F. clnncnn 2367-2 1 16 2 4 E. cloacae 7099 0.5 8 0.5 2 E. cloocfIG 214 2 8 0.5 0 P. vulgnris ATCC 6300 0.5 0.25 0,063 4 P. mirabilis 0.5 0.16 0.008 0.5 S. marcescens SM 1 1 0.5 4 P. aeruginosa Stone 32 128 16 ¹⁶ P. aeruginosa 503-56 64 128 32 32 S. aureus Smith 0.25 2 2 0,063 S. aureus 4 8 4 2 continued table microorganism minimal inhibitory concentration of compounds ((µg / ml) F G H AND E. coli 2 0 32 0.5 K. pnmimoninň A 1 4 32 n, 5 E. cloacae 9570A 2 8 32 2 E. cloocoo 940-1 1 0 32 4 Г. cloncnn 2367-2 1 32 32 4 E. cloacae 7099 0.5 2 2 2 E. cloacae 2 64 32 4 P. vulgaris ATCC 6380 0.5 4 32 0.5 P. mirabilis 0.5 4 0.5 0,031 S. marcescens SM 1 4 32 1 P. aeruginosa Stone 32 32 32 8 P. aeruginosa 503-56 64 64 64 32 S. aureus Smith 0.25 0.25 0.25 0,25 ' S. aureus 4 4 0.5 0.5 To combat bacterial infection the compound according to invention apply to mammals in day- dose of about 5 to about 500 mg / kg conveniently at a dose of a you 10 to 100 mg / kg in particular in time · from about 10 to 55 mg / kg . All kinds of applications that yet come into consideration when te-

Penicillins and cephalosporins are also useful for the novel cephalosporins of the invention. Thus, administration can be effected, 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 the compounds or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral or parenteral administration, such as water, gelatin , 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 the form of solutions, suspensions or emulsions. These preparations are optionally sterilized and optionally contain adjuvants such 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, with 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 '1'

[6R- (6,77,71)] -3-Pht- (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3- (4-nitrophenyl) methyl ester) yl) carbonyl] oxy] methyl] -8-oxo-7- [phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and (4-nitrophenyl) ) [2R- (2x, 6,4,7Β)] - 3 - [[[(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyl] methyl ester] oxyjmethyl] -8-oxo-7 - [(phenoxyacetylamino) -5-thia-1-azabicyclo | 4,2,0] act-3-ene-2-carboxylic acid

A solution of 22.4 g (0.040 mol) of 6R- (60o, 70) | -3- (bromomethyl) -O-oxo-7- (phenoxyacetyl) amino | -5-thia- (4-nitrophenyl) methyl ester | 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and 10.1 g (0.040 mol) of 1-ethyl-1,4-dihydro-7-methyl-4-oxo-sodium salt of 1,8-naphthyridine-3-carboxylic acid in 200 ml of absolute dimethylformamide was stirred for 5 hours under argon. Then, the solvent was evaporated under reduced pressure. The ethyl acetate residue was washed with brine, decolorized with charcoal, dried over sodium sulfate and evaporated to a small volume under reduced pressure, whereupon the above reaction products crystallized. Excess lye was purified by column chromatography on 800 g of neutral silica gel using ethyl acetate as eluent (particle size 0.063-0.200 mm). Appropriate fractions were combined and crystallized from ethyl acetate to give an additional portion of the reaction product. The resulting mixture of isomers was used for the next reaction. The pure .beta.-ester is obtained by traction crystallization of 8 ethyl acetate and the .beta.-ester is isolated by preparative chromatography on a plate of silica gel plates from the mother liquor.

Dntn fire isomer:

Δ 3-isomer:

IR spectrum (KBr technique):

3405, 1785, 1735, 1697, 1637, 1520, and 1348 cm

Mass spectrum:

m / z 714 (M _{+ H) (736 (M ⁺ Na).}

Δ 2-isomer:

IR spectrum (KBr technique);

3560, 3480, 3415, 1780, 1745, 1693, 1620, 1520 cm &^lt; -1 ^&gt;.

Mass spectrum;

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

EXAMPLE 2 [2R- (2oL, 6E, 70)] - 3 - [(1-Ethyl-1,4-dihydro-7-methyl-4-oxo-1,1-naphthyl) -l- 3-yl) carbonyl]] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-3-enecarboxylic acid

To a solution of 6.11 g (0.00856 mol) of a mixture of the two isomers of Example 1 in 45 ml of dimethylformamide, a solution of 2.80 g (0.0116 mol) of sodium sulfide hydrate was added dropwise at -5 to -10 ° C. in 20 ml of water. After 35 minutes, the mixture was acidified to pH 3.5 by the addition of 1N hydrochloric acid in water to precipitate a resin. This resin solidified upon addition of 50 ml of ethyl acetate and 50 ml of ether. Filtration, washing with water and ether and drying at 50 ° C under reduced pressure over phosphorus pentoxide gave the reaction product. An additional amount of ether was added to the filtrate, leaving no additional precipitate, which was filtered off and dissolved in aqueous sodium bicarbonate. The aqueous solution was 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. An additional amount of a reaction product with a n-isomeric salt is obtained; . '

IR spectrum (KBr):

3420, 3300, 1773, 1720 cm ^-1 .

Mass spectrum;

m / z 579 (M ^& lt ^; + & gt ^; + H).

Example 3

S-oxide [(6R- (6R, 70)] - 3 - [[[(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl)] carbonyl] oxy] -methyl] -8-oxo-7 - [(phenoxyaoethyl) amino-5-thia-1-azabicyclo-1,4,2,01-oct-2-ene-2-carboxylic acid

To a suspension of 2.55 g (0.00442 mol) of the reaction product of Example 2 in 60 ml of methylene chloride, a solution of 0.986 g (85¾ pure, 0.00486 mol) of m-chloroperbenzoic acid in 15 ml of methylene chloride was added dropwise with stirring at 0 ° C. . The reaction mixture was stirred for 4 hours at 0 ° C and then filtered. The solid obtained was washed with methylene chloride and dried under reduced pressure. The reaction product thus obtained has the following characteristics:

IR spectrum (KBr technique):

3360, 1794, 1723, 1684, 1637, 1017 cm @ ^-1 .

Mass spectrum;

m / z 595 (M ^& lt ^; + & gt ^; + H).

Example 4

[6R- (6 < A, 70) -3 - [[[[(1-Ethyl-1,4-dihydro-7-methyl-4-oxo-l, B-naphthyridin-3-yl) carbonyl] oxy] hydrate - methyl] -B-oxo-7 - [(phenoxyacetyl) alpha] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

To a solution of sodium iodide (1.64 g, 0.0109 mol) in absolute acetone (40 ml) and methylene chloride (20 ml) was added the reaction product of Example 3 (1.30 g, 0.00.219 mol). 1.75 ml (0/0124 mol) of trifluoroacetic anhydride are added thereto at 0 ° C. After 30 minutes, the pH was adjusted to 6.0 with aqueous sodium bicarbonate. The pH was then adjusted to 3.5 by adding an aqueous 1N hydrochloric acid solution and a small insoluble portion was removed by filtration. The organic phase is washed with aqueous sodium sulphide solution, dried over sodium sulphate and evaporated.

reduced pressure. The residue is washed with ether, taken up in methylene chloride and the reaction product is added after addition of ether.

A mixture of 0.435 g (0.73 mmol) of the reaction product from Example 3 and 7 ml of absolute dimethyl formamide was cooled to -12 ° C with stirring and 0.128 ml (1.4 mmol) of phosphorus trichloride was added thereto. After 7 minutes, an additional 0.027 mL of phosphorus trichloride was added. The mixture was stirred for 6.5 minutes and then a cold solution of 0.428 g (5.1 mmol) of bicarbonate was added.

sodium 70 ml in water. The precipitate obtained is filtered off, washed with water and dried under reduced pressure over phosphorus pentoxide to give the reaction product. Another reaction product is precipitated from the filtrate.

The following characteristic data was obtained for the reaction product:

IR spectrum (KBr technique):

3420, 1785, 1708, 1620 cm ^{@ -1} .

Mass spectrum: m / z = 579 (M + + H).

This product can be converted in a manner analogous to that described in the following examples into a pharmaceutically acceptable salt.

Example 1 a d 5 '

[6R- (6R, 70)] - 3 - [[[(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinolin- 7-yl) carbonyl] oxy] methyl 11-7- (phenoxyacetyl) 8-amino] -5-thta-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylic acid

A solution of 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid sodium salt (1 mmol) in 12 mL of dimethylformamide was stirred under a nitrogen atmosphere for 1 hour with 1.5 g of molecular sieves (4.10 ~ ¹⁰ m) and then a solution of 1,1-dimethylenthylesteru [6R- (6 ^, 70) 1-3- (jodmethy1) -8-oxo-7- 1- (phenoxyacetyl) amino-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (1 mmol) * in 6 mL of absolute dimethylformamide and stirred for 5 hours. The mixture was then evaporated to dryness. The residue is taken up in ethyl acetate or a mixture of ethyl acetate and methylene chloride, the solution is then washed with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to dryness. The residue was purified by either preparative layer chromatography or flash chromatography using a 8: 2 mixture of ethyl acetate and methylene chloride as eluent.

Example 1 a d 6

[6R- (6X, 70) (Z)] - 3 - [[['(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3) -ethyl] -1-dimethyl-ethyl ester * yl) carbonyl] oxy] methyl] -7 - [[(methoxyimino) - [2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.1] O] oct-2-ene-2-carboxylic acid

The title compound is obtained by repeating the reaction described in Example 5 using 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid sodium salt and 1,1-dimethylethyl ester [6R- (6,71) (Z)] - 3-Iodomethyl-7- Q - [(methoxyimino) - [2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -? -? - 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 1 a d 7

1,1-dimethylethylbutyl] 6R- (6o <, 70) (Z)] - 3 - [[[(5-ethyl-5,8-dihydro-1 H -oxo-1,3-dloxolo [4,5- g]]) quinolin-7-yl) carbonyl] oxy] methyl] -7 - [[(methoxyimino) [6- (triphenylmethyl) amino-4-thiazolyl] nitro] oinino] -O-oxo-5-thia 1-azabicyclo |

The title compound is obtained by repeating the reaction described in Example 5 using 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid and 1,1 [6R- (6X, 70) (Z)] - 3-Iodomethyl-7 - [[(methoxylmino) [2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -8-oxo-5- dimethylethyl ester 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 8

[6R- (6X, 70)] - 3 - [[[[1-ethyl-6-fluoro-1,4] dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinoline] 1,1-dimethylethyl ester -3-yl] carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The title compound is obtained by repeating the reaction of Example 5 using 1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid and 1, [6R- (6R, 70)] - 3- [iodomethyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-α-bicyclo | * 4,2,0] - 1-dimethylethyl ester oct-2-ene-2-carboxylic acids as starting materials. The residue was purified by flash chromatography using a 20: 1 mixture of methylene chloride and methanol as the solvent system.

P t i k 1 and d 9

[6R- (6A, 70)] - 3 - [[[(5-ethyl-5,0-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl)] - sodium salt (carbonyl) oxy] -methyl] -8-chloro-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

To a solution of 3.00 g (4.52 mmol) of the reaction product of Example 5 in 15 ml of anisole was added, while stirring at room temperature, 10.6 ml of trifluoroacetic acid. The reaction mixture was stirred for hours and then evaporated to dryness under reduced pressure. The residue is obtained 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 was adjusted to pH 7.5 by addition of sodium bicarbonate. The mixture was stirred

CS 270247 02 minutes and then the aqueous phase is removed. Repeat the addition of water and adjust the pH to 7.5 with sodium bicarbonate with stirring. The three aqueous extracts were combined and freeze-dried. The residue was purified by chromatography on a non-polar, stationary phase (reverse phase C18) using 504 aqueous methanol as solvent. Evaporation and freeze-drying gave the title compound.

The compound obtained has the following properties:.

IR spectrum (KBr technique): ·

3410, 1765, 1692, 1635, 1528 cm ^-1 . '

Mass spectrum:

m / z 630 (M * H), 652 (M * H).

Example 10

C 6 R 6 - (6? 4, 70 ((Z)) - 7 - [[(2-amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -3 - [[[(1-ethyl-1) -] 4-Dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.01 oct-2] -en-2-carboxylic acids

A suspension of the reaction product of Example 6 (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 was kept at 0 ° C for 18 hours and then evaporated under reduced pressure at room temperature. After addition of methylene chloride, evaporation under reduced pressure was 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 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 4 methanol, 20 minutes) as eluent. After evaporation and freeze-drying, the reaction product is obtained with the following characteristic values:

IR spectrum (KBr technique):

3405, 3300, 3200, 1766, 1716, 1681, 1617, 1537 cm ^-1 .

Example 1 a d 11. '

[6R- (60o, 70) (Z)] - 7 - [[(2-amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -3 - [[[(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, 2,0] oct-2-ene-2-carboxylic acid

The title compound is obtained according to the procedure described in Example 10 but using the reaction product of Example 7.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

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

Mass spectrum:

m / z 679 (M _⁺ H) 70 i _{(M +} Na).

Example 12

[6R- (6x, 70)] - 3-Q [[[1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinoline-3-] sodium salt yl] carbonyl] oxy] methyl 1-7 - [(phenoxyacetyl) amino] -B-oxo-5-thia-1-azabicyclo | [4,2,0] oct-2-ene-2-carboxylic acid

Following the procedure described in Example 10 and using the reaction product of Example 8, the title compound having the following characteristics was obtained;

IR spectrum (KBr technique):

3420, 1768, 1668, 1620 cm ¹ .

Mass spectrum;

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

Example 13

[6R- (6R, 7O)] - 3 - [[[(5-ethyl-5,8-dihydro-β-oxo-1,3-dioxolo [4,5-g] quinoline], 1,1-dimethylethyl ester] -7-yl (-carbonyl] oxy] methyl] -8-oxo-7- (2-thienylacetyl) amino-5-thia-1-azabicyclo [4.2.0] oct-2-en-2 -carboxylic acids

Using the procedure described in Example 5, but using [6R- (6oC, 713)] -3- (iodomethyl) -B-oxo-7- (2-thienylacetyl) amino] -5-thia-1, 1-dimethylethyl ester -azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and 5-ethyl-5, B-dihydro-7-oxo-1,3-dloxolo [4,5-g] quinolin-7- yl) carboxylic acid starting materials to give the title compound.

Example 1 a d 14

[6R- (6X, 70)] - 3 - [[[(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxo [4,5-g] quinolin-7-yl)] - sodium salt (carbonyl] oxy] -methyl] -8-oxo-7 - [(2-thienylacetyl) amino] -5-thla-1-azabicyclo [4.2.0] oct-2-beta-2-carboxylic acid ^:

The title compound is obtained as described in Example 10, but using reaction product 2 of Example 13.

The compound obtained has the following characteristic data.

IR spectra (KBr technique).

-3410, 1763, 1682, 1632, 160B cm ^-1 .

Mass Spectrum :.

m / z 620 (M @ ⁺ + H), 642 (M @ ⁺ + Na).

Example 15

[6R- (6 < 70 &gt;, 70)] - 3 - [[[[1-ethyl-6-fluoro-1,4-dlhydro-7- (4-formyl-1-piperazinyl) -4] -ethyl] -4,4-dimethyl-ethyl ester -4-dimethylethyl ester -oxochlnoli-3-yl [carbonyl] oxylmethyl] -7 - [(2-thienylacetyl) amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Using the procedure described in Example 5, but using [6R- (6 < 70 &gt;) - 3- (iodomethyl) -8-oxo-7 - [(2-thienylacetyl) amino] -5-thia] 1,1-dimethylethyl ester -1-azabicyclo [4.2.0] oct-2-ene-2EN 270247 02

carboxylic acids and sodium salts of 1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxo-3-quinoline-carboxylic acid starting materials to give the title compound. title.

Example 1 a d 16

[6R- (6c, 73)] - 3 - [[t [1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3-yl)] - sodium salt carbonyl] oxy] methyl] -7 - [(2-thienylacetyl) amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

Following the procedure described in Example 10 but using the reaction product of Example 15, the title compound was obtained. *

The compound obtained has the following characteristic data:>

IR spectrum (KBr technique):

3430, 1765, 1715, 1662, 1623 cm ^-1 .

Mass spectrum:

m / z 706 (b + H).

Example 17 ·

[6R- (6,78) (Z) -1,3- [1 [[1-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl)] - 1,1-dimethylethyl ester -4-oxoquinolin-3-yl] carbonyl] oxyjmethyl] -7 - [[(methoxyimino) [2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid

Using the procedure of Example 5 but substituting [6R- (6e <, 70) (Z)] - 3- (iodomethyl) -7 - [[(methoxyimino) -] 2- (triphenylmethyl) amino-4, 1,1-dimethylethyl ester. -thiazolyl] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and sodium salt of 1-ethyl-6-fluoro-1,

Starting from 4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxo-3-quinolinecarboxylic acid, the title compound is obtained.

Example 18

[6R- (6K, 70) (Z)] - 7 - [[(2-Amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -3 - [[[1-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

The title compound was obtained as described in Example 10 but using the reaction product of Example 17.

The compound obtained has the following characteristic data:

IR spectrum (K8r technique):

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

Mass spectrum:

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

Example 1 a d 19

[6R- (6 < 6 &gt;, 70)] -3-[[[[[1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] -4-oxoquinolin-3-yl] ethyl ester yl] carbonyl] oxy] methyl] -7 - [(phenoxyacetyl) amino] -5-thio-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The title compound is obtained by the procedure of Example 5 but using

1.1- dimethylethyl ester [6R- (6 <70) J-3- (iodomethyl) -8-oxo-7- [(phenoxyacetyl) amino] _{-5-thia-azabicyklof4>} 2 (i] "oct-2 -en-2-carboxylic acid and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-pyrrolidinyl) -3-quinolinecarboxylic acid sodium salt as starting materials.

Example 20

[6R- (6,70)] - 3 '' [[[[1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl]] - carbonyl] oxy] methyl] -7 - [(phenoxyacetyl) amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

The title compound was obtained as described in Example 10 but using the reaction product of Example 19.

The compound obtained has the following characteristic data:

IR spectrum (KOr technique):

3410, 1770, 1695, 1628 cm ^-1 .

Mass spectrum:

m / z 673 (M @ ⁺ + H), 695 (M @ + + Na).

Example 21

[6R- (6X, 70) (Z)] - 3 - [[1-Ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinoline-3] -1-dimethylethyl ester -yl] carbonyl] oxy] methyl] -7 - [[(methoxyimino)] 2- (triphenylmethyl) amino-4-thiazolyl] acetyl] amino] -> 8-oxo-5-thia-1-azabicyclo [4] , 2,0] oct-2-ene-2-carboxylic acids

Using the procedure described in Example 5, but using [6R- (6e, 70)] -3- (iodomethyl) -7-f [(methoxyimino) - [2- (triphenylmethyl) amino] -4,1-dimethylethyl ester, 1,1-dimethylethyl ester -4 1-methyl-6-fluoro-1,4-thiazolyl] acetyl] amino-5-thin-1-azabicyclo [4.2.0] oct-2-an-2-carboxylic acid of dihydro-4-oxo-7- (1-pyrrolidinyl) -3-quinolinecarboxylic acid as starting material to give the title compound. ·,

Example 22

[6R- (6R, 70) (Z) 1-7 - [[(2-Amino-4-thiazolyl) - (methoxyimino) acetyl] amino] -3-m-ethyl-6-fluoro-1, sodium salt 4-Dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -0-oxo-5-thia-1-azabicyclo [4.2.0] oct 2-ene-2-carboxylic acids

The title compound was obtained as described in Example 10 but using the reaction product of Example 21.

The compound obtained has the following characteristic data:

IC spectrum (KBr technique): ··

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

Mass Spectrum: m / z 722 (M @ + + H).

Example 1 a d 23.

[6R- (6X, 70)] - 3 - [[[[1-Ethyl-6-fluoro-1,4-dihydro-7-] 4- (1,1-dimethylethoxy) carbonyl-], 1,1-dimethylethyl ester 1-piperazinyl] -4-oxoquinolin-3-yl] carbonyl] oxy] -methyl | -8-oxo-7-yl-phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2 -en-2-carboxylic acids

Using the procedure described in Example 5, but using [6R- (6 < K, 70)] - 3-iodomethyl-8-O-OP-7 - [(phenoxyacetyl) amino] -S-thia-1-azabicyclophyl-1,1-dimethylethyl ester , 2,0] oct-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1,1-dimethylethoxy) carbonyl-1- piperazinyl *] - 4-oxo-3-quinolinecarboxylic acid starting material to give the title compound. *

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3420, 1787, 1730, 1698, 1510 cm ^-1 .

Mass Spectrum: A / Z 822 (M ⁺ H).

Example 24

[6R- (6? A, 7Q)] - 3 - [[1-ethyl-6-fluoro-1,4-dihydro-7-] 4- (1,1-dimethylethoxy) -cacbonyl-1- [2-propenyl ester] piperazinyl [-4-oxo-pyridin-3-yl] carbonyl] oxy] methyl] -8-oxo-7- (phenoxyacetylamino) -5-thia-1-azabicyclo [4.2.0] oct-2-en-2- carboxylic acids

Using the procedure described in Example 5, but using [6R- (6,7,7,7)] -3-iodo-methyl-8-oxo-7 - {(phenoxyasyl) amino] -5-thia-1-azabicyclo 2-propenyl ester £ 4,2, (£ | oct-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-7- [4- (1,1-dimethylethoxy) carbonyl-1- piperazinyl] -4-oxo-3-quinolinecarboxylic acid starting material to give the title compound.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3415, 3300, 1789, 1729, 1694, 1622 cm ^-1 .

Mass spectrum:

i- of 806 (Μ * + H).

CS 270247 02

Example 25

[6R- (6x, 7fl)] -3- [tert-ethyl-6-fluoro-1,4-dlhydro-7-] 4- (1-propenoxy) carbonyl-1-piperazinyl] -4-propenyl ester -oxoquinolin-3-yl] carbonyl] oxy] methyl-8-oxo-7- (phenoxyacetyl) amino | -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid acid

Using the procedure described in Example 5, but using [6R- (6α, 7B) -1-3-iodomethyl-8-oxo-7-t- (phenoxyacetyl) amino] -5-thia-1-azabicyclo [2R] - 2, c} oct-2-ene-2-carboxylic acid and potassium salt of 1-ethyl-6-fluoro-1,4-dihydro-7- [4- (2-propenoxy) carbonyl-1-piperazinyl] - Starting from 4-oxoquinoline-3-carboxylic acid, the title compound is obtained.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

3410, 1709, 1725, 1699, 1622 cm ¹ .

Mass spectrum:

m / z 790 (M ^& lt ^; + & gt ^; + H).

Example 26

[6R- (6 < 70 &gt;) 70-Propenyl ester [3- ( _b- C (5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolol-4,5-g) -quinolin-7)] -y1) carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-en-2- carboxylic acids

Using the procedure of Example 5 but substituting [6R- (6χ, 70)] - 3-iodomethyl-β-oxo-7- (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.1] 2-propenyl ester, O] oct-2-ene-2-carboxylic acid and 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo-4,5-g] quinoline-7-carboxylic acid potassium salt as starting material compounds to give the title compound.

Example 27

Alternative synthesis of [6R- (6R, 70)] - 3 - [[(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo) 4,5-g] quinoline- sodium salt 7-yl) carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

To a solution of 337 mg of reaction product 2 of Example 26, 0.03 ml of triethylphosphite, 5.6 mg of palladium acetate, 3.9 ml of ethyl acetate and 5.6 ml of methylene chloride were added dropwise over 15 minutes with stirring 1.68 ml 0. Of a 5M solution of sodium 2-ethylhexanoate in ethyl acetate. The mixture is then stirred for 30 minutes and acetone (11 ml) is added and stirring is continued for 10 minutes. The reaction product was filtered off, washed with ether and air dried. Purification by C ₁₀ 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 according to Example 9.

Example 28

[6R- (6X, 70)] - 3 - [[E1-ethyl-6-fluoro-1,4-dihydro-7- (4-thiomorpholinyl), -4-oxoquinolin-3-yl] sodium] -carbonyl] oxy] methyl 11-8-0X0-6- (phenoxyacetyl) amino-5-thia-1-azabicyclo _(of 4,2,2) oct

-2-ene-2-carboxylic acid

A solution of 0.187 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (4-thiomorpholinyl) -3-quinolinecarboxylic acid sodium salt in 8 ml of dimethylformamide is stirred for 1 hour and the molecular sieve is sized. 4. lCT ^ m. After addition of 0.257 g of 2-propenyl ester .beta.- (6- (70)) -3- (iodomethyl) -8-oxo-7 - [(phenoxyacetyl) aminol-5-thia-1-azabicyclo | The ene-2-carboxylic acid in 8 ml of DMF was stirred for 5 hours and then evaporated under reduced pressure. The solution of the residue in ethyl acetate was washed successively with aqueous sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated under reduced pressure. 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 63.5 mg of this allyl ester in 1.1 ml of methylene chloride and 0.75 ml of ethyl acetate was added 5.1 µl of triethylphosphite, 1 mg of palladium acetate and 0.28 ml of a 0.5Й solution of sodium 2-ethylhexanoate in ethyl acetate. The mixture is stirred for 1 hour, then 2 ml of acetone are added and then evaporated to dryness 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:

IR spectrum (KBr technique):

5420, 1768, 1695, 1622 cm ^-1 .

Mass spectrum:

m / z 705 (? * + H), 72? (M + + Na).

Example 29

[6R- (60o, 70)] - [[(1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1H-pyrrol-1-yl) quinolin-3-) sodium salt yl] -carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

A solution of 0.845 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1H-pyrrol-1-yl) -3-quinolinecarboxylic acid potassium salt in 30 ml of methylformamide was stirred for 1 hour. molecular sieve with size 4. 10 ” ¹⁰ . Then 1.54 g of [6R- (6,6,7,9)] - 3-iodomethyl-8-oxo-7- (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.1] 2-propenyl ester [4,2] Of (1Q) oct-2-ene-2-carboxylic acid and then stirred for a further 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 successively with aqueous sodium bicarbonate solution and brine. After drying over sodium sulfate, the ethyl acetate is evaporated under reduced pressure and the residue is purified by flash chromatography to give the intermediate allyl ester corresponding to the title compound above.

A solution of 69 mg of this allyl ester in 1 ml of methylene chloride was added with the addition of 0.3 mg of palladium acetate, l (triethylphosphite, 0.2 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate and 0.3 ml of ethyl acetate). After stirring the mixture was evaporated under reduced pressure and the residue was triturated with ether to give a solid After purification by reverse-phase high performance liquid chromatography, the title compound was obtained.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

5420, 1765, 1695, 1620 cm ^-1 .

Mass spectrum:

m / z 669 (M * 4b), 691 (M @ + _{+ Na)}

CS 270247 02

Example 30

R - (6e &gt; 70) - 3 - [[5- (4-fluorophenyl) -5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline] sodium salt -7-γ-J-carbonyljoxyjmethyl-8-oxo-7- (1-phenoxyacetyl) amino-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

A solution of 0.183 g of 5- (4-fluorophenyl) -5,8-dihydro-8-oxo-1,3-dioxolo [4,5-g] quinoline-7-carboxylic acid potassium salt in 0 ml of dimethylformamide was stirred for 1 hour with molecular sieves having a particle size of 4, 10 .mu.m. After adding 0.308 g of 6R- (6 < X, 70) -3-iodomethyl-8-oxo-7 - [(phenoxyacetyl) aminol-5-thia-1-azabicyclo [4.2.0] oct-2-propenyl ester. The ene-2-carboxylic acids were stirred for 5 hours, then evaporated under reduced pressure and ethyl acetate was added to the residue. The mixture was then washed successively 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 intermediate allyl ester corresponding to the title compound.

To a solution of 0.122 g of this allyl ester in 2.1 ml of methylene chloride and 1.5 ml of ethyl acetate were added 9.9 µl of triethylphosphite, 1.94 mg of palladium acetate and 0.51 ml of a 0.5 M solution of sodium -2-ethylhexanoate in ethyl acetate. The resulting mixture was stirred for 1 hour, diluted with acetone and evaporated under reduced pressure. The residue is triturated from therem to give a solid. Purification by reverse-phase high performance liquid chromatography affords the title compound.

The compound obtained has the following characteristic data:

IR spectrum (KBr technique):

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

Mass spectrum:

m / z 696 (M + + H), 718. (M ⁺ + Na).

Example 31

T6R- (6 <A, 70) (Z)] - 7- [X (2-Amino-4-thiazolyl) - (methoxyxyl) acetyl] amino] -3- [N-ethyl-6-fluoro-1, 6-fluoro-1] sodium, 4-Dihydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-yl] carbonyl-oxylmethyl-8-oxo-5-thla-1-azabicyclo [4.2.2] oct-2-en-2- carboxylic acids

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 ml of dimethylformamide was stirred with 1.5 g of molecular sieve for 1 hour. (4.10 “1θΓη). After addition of a solution of 1.07 g of [6R- (6X, 70)] - 3-iodomethyl-7- [β (methoxyimino) -1- (2-triphenylmethyl) amino-4-thiazolyl] amino 1-8-oxo-5-thla-1-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 16 ml of dimethylformamide was stirred for 5 hours. The mixture was evaporated under reduced pressure, the residue was taken up in ethyl acetate, and the mixture thus obtained was washed successively with aqueous sodium bicarbonate solution and brine. After drying over sodium sulfate, the ethyl acetate solution was evaporated under reduced pressure. The residue was purified by flash chromatography to give the intermediate tert-butyl ester corresponding to the title compound above.

0.103 g of tertbutyl ester was dissolved in 0.21 ml of anisole and 1.06 ml of trifluoroacetic acid and the solution is kept for 18 hours at 0 DEG C. The mixture ^D was evaporated under reduced pressure and the residue dissolved in methylene chloride. The pH was adjusted to 7.5 by addition of water and sodium bicarbonate. The aqueous phase is freeze-dried.

Purification of the residue by reverse phase high performance liquid chromatography affords the title compound.

The compound obtained has the following characteristic data:

IR (KBr).

3410, 176B, 1715, 1652, 1622 cm ^1st '

Mass spectrum:

m / z 754 (M + H). ·:

Example 1 a d 32.

Monosodium salt dihydrate [6R- (6S, 7B) (Z)] -7-Q [(2-amino-4-thiazolyl) (methoxylmino) acetyl] jamino} -3 - [[[[6,8-difluoro] -1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-3-quinolinyl carbonyl] oxylmethyll-8-oxo-5-thia- 1-azabicyclo [4.2. d] 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 g of [6R- (6,4,70)] -3- (iodomethyl) -7- [E ((methoxyimino)] 2- (triphenylmethyl) -aminol-4- (1,1-dinethylethyl) ester 1,1 g is added over 5 minutes. thiazolylacetyl] amino-3-β-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid in 40 ml of dimethylformamide The reaction mixture is stirred for 2 hours and then evaporated to a residue. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate.

The organic phase was washed successively with aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated to give a brown foamy solid. Purification by flash chromatography on 500 g of sillkagel (particle size 0.04-0.08 mm) using a mixture of methanol and chloroform (gradient 0 to 84 methanol) afforded 1,1-dimethylethyl ester as the title compound as above. compound.

_ч solution of 2.30 g of 1,1-dimethylethyl ester in 25 ml of methylene chloride at 0 DEG 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. After evaporation, methylene chloride is added to the residue and the evaporation is 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 54 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 solution 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 chromatography (C18) using a water / acetonitrile gradient as solvent. Fractions containing the reaction product were evaporated under reduced pressure and freeze-dried to give the title compound.

The compound obtained has the following characteristic data:

j Mass spectrum:

m / z 787 (M &lt; + &gt;)

H).

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

[6R- [6,6,7 (Z)]] - 7R- (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -3 - [[[[1-ethyl-6-phenyl] -1,4-dihydro-7- (1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -0-oxo-5-thia-1-aza bicyclo [4.2.0] oct-2-ene-2-carboxylic acid

[6R- (60o, 70)] - 3 - [[[[1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl) quinolin-quinolin-3-yl] carbonyl]] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

[6R- (6,44,70)] -3- {N, 8-difluoro-1- (2-fluoroethyl) -1,4-dlhydro-7- (4-methyl-1-piperazinyl) -4-oxoquinoline -3-yl [carbonyl] oxy] methyl] -8-oxo-7- [phenoxyacetyl) amino] -5-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

P

Q 6 R -> 7G (Z)]] - 7 [[, (2-Amino-4-thiazolyl) (methoxy-imino) acetyl] amino] -3 - [[[[1-ethyl-6-fluoro-1,4] dihydro-7- (4-methyl-1-plperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] | methyl] -8-oxo-5-thia-i-azabicyclo [4.2] oct-2-ene-2-carboxylic acid ₂ п н

COO1

N - (6- (4,70)) - 3- [1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinoline-3] -yl | carbanyloxy] methyl] -ZH-5-oxo-7-phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylic acid

R - (6 <4.70)] - 3 - [[[1-Cyclopropyl-6-fluoro-1,4-dihydro-7- (1-piperazinyl) -4-oxoquinolin-3-yl}] carbonyljoxy methyl] -8-oxo-7 - [(phenoxyacetyl) amino} -5-thla-1-azabicyclo [14.2.0] oct-2-en-2-one lily bouquet

[6R- [6,6- (Z)]] -7-L (2-amino-4-thiazolyl) (methoxyimino) acetyl) amino] -3- [L-cyclopropyl-6-fluoro-1,4- dihydro-4-oxo-7- (1-piperazinyl) quinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [2.2.1] oct-2-en-3 -carboxylic acid

6R- (6 < 70 &gt;)] - 7 - [(cyanacetyl) aBino] -3 - [[[[6,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4 &lt; 6 &gt; (methyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo | [4,2,0] oct-2-ene-2-carboxylic acid

COOH [6R (6'X, 70)] - 7- (formylamino) -3- (6-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1) -piperazinyl) -4-dioxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-

QóR- (6 <X 7G)] - 7- _[> [[Q4-ethyl-2,3-dioxo-1-piperazinyl) carbonyl ljamiho] phenyl acetate cheapness] amino] -3 H • »8-Difluoro-1 - (2-fluoroethyl) -1,4-dihydro-4-oxoquinolin-3-yl [carbonyl] oxy] methyl] -8-

к [6R- [λ X, 70 (2)]] -7- (η 2 -amino-4-thlazolyl) [[(1-carboxy-1-methyl) -ethoxy [imino] atyl Spring no} £ -3 - [[η 6,8,8-difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinoline-3-yl] carbonyl oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

[6R- (6 *, 70 (Z)] 1- 7- 2-amino-4-thiazole) (carboxymethoxy) imino] -asyl] amino] -3- [Ц [6,8-difluoro-1- (2-Fluoroethyl) -1,4-dlhydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-yl]] carbonyl] oxy] methyl] -8-oxo-5-thia-1 -azabicyclo (4,2,0 '] oct-2-en-2-carboxylic acid

COOH

CS 270246 B2.

16R- (6X, 70) -1,3-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4- oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7- (phenylacetyl) amino] -5-thia-1-azabicyclo

[6R- (6 "/ 70)] - 3- [[C _[6> B-difluoro-l- (2-fluore.thyl-l, 4-dihydro-7 .- (4-methyl-piperazinyl (4-Oxoquinolin-3-yl) carbonyl] oxylmethyl] -B-oxo-7- [2-thienylacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene -2-carboxylic acid

[6R- [6Z, 70 (Z)]] - 7- [[(2-amino-4-thiazoles) (methoxyimino) acetyl] amino] -3 - [[[L, 6,8-difluoro-1- ((4 -fluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-5-thia-1 azabicyclo [4 _t 2.0] oct-2-ene-2-carboxylic acid

COOH

O

CS 270247 £ 2 6 6 R- (6 <A, 70)] - 3 [[f 6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7- (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0} oct-2-en-2 -carboxylic acid

COOH

[6R- (6 ', 70')] - 3- [E-9-fluoro-3,7-dihydro-3-methyl-10- (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 [4,2,10] oct-2-ene-2-carboxylic acid

[6R- [λ < 4.70 (Z)]] - 7- [(2-amino-4-thiazolyl) (methoxyimino) acetyl] amino} -3- [[5-fluoro-3,7-dihydro- 3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-2H-pyrido] 1,2,3-del-1,4-benzoxazin-6-yl] carbonyl] oxy] methyl] -8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

[6R- (6C, 70)] - [2- [8-Difluoro-1- (2-fluoroethyl) -1,4-dihydro-7-] - [2,3-d] -cyclohexan-3-one (4-Methyl-1-piperazinyl) -4-oxo-quinolin-3-ylcarbonyl] oxy] methyl] -O-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene -7-yl] amino (1-carbonyl) benzoic acid

ΌΗ

O [6R- [6u, 70 (Z)]] - 3 - [[[7- (3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro] -4-oxoquinolin-3-yl] carbonyl] axy] methyl] -7- [[(2-amino-4-thiazole) [(carboxyphethoxy) amino] acetyl] amino] -8-oxo-5-thla- 1-azabicyclo [4.2, d] oct-2-ene-2-carboxylic acid

[6R- (1 ', 7D (2))] - 3- [t [[7- (3-amino-1-pyrrolidinyl) -8-chloro-1-cyclopropyl-6-fluoro-1,4-dlhydde] trans-4-oxoquinolin-3-yl] carbonyljoxy] methyl] -7- [C2-amino-4-thiazolyl] [(1-carboxy-1-methylethoxy) imino] acetyllamino] -8-oxo-5-thia-; 1-aabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

[RR- Х, 70 (Z)]] - 3 - [[[[7-O-amino-1-pyrrolidinyl] -8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-] oxoquinolin-3-yl] carbonyl] oxy] methyl} -7- [C (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino] -8-oxo-5-thia-1-azabicyclo ~ 4.2, θ] Oct-2-ene-2-carboxylic acid

The following cephalosporin example discloses forms of pharmaceutical compositions of the invention that contain derivatives of aden.

Preparation of dry ampoules for intramuecular application

1 g of the monosodium salt of 6R- (6¼, 70 (ZJ-7- [12-amino-4-thiezolyl (methoxyimino) eethyl) amino] -3- [UX 6,8-difluoro-1-] - is prepared in a conventional manner. (2-Fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -Boxo-5-thia-1- Azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and filled into an ampoule The sterile aqueous ampoule contains 10¾ propylene glycol and 2.5 ml of a 24% aqueous lidocyanine hydrochloride solution is added to the lyophilisate.

Claims (48)

A process for the preparation of the novel cephalosporin salts of the general formula I R ³¹ (I), stands for 0, 1 or 2, R ¹ represents a hydrogen atom or an acyl group useful for acylating β-lactam-type antibiotics of up to 21 carbon atoms, for example a group of formulas ". r ⁵ -co- CHCOI COOH R ¹⁰¹ - (CH ₂ ) _n - CO _B 120 C C - CO - in which R ⁵ represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms * which is substituted by a cyano group * '101 represents an optionally substituted 5-membered heterocyclic ring having 1 or 2 nitrogen atoms or β sulfur atoms * * '120 is C1-C8alkyl; '130 represents optionally C1-C8alkyl-substituted carboxy; and in which further 2 ' R represents a carbon atom * an alkoxy group having 1 to 8 carbon atoms * an amino group * an alkylthio group having 1 to 8 carbon atoms or an alkanoylamino group having 1 to 7 carbon atoms * R ( ¹⁾ is hydrogen * alkyl of 1 to 8 carbon atoms * alkenyl of 2 to 6 carbon atoms * cycloalkyl of 3 to 7 carbon atoms to * haloalkyl of 1 to 8 carbon atoms or halophenyl group *. Z is R ^C or N, wherein. represents a hydrogen atom or a halogen atom, or r ⁵⁰ and represents a common C 3 -C 5 alkylene group, an C 2 -C 4 alkylene mono-mono group. or C 1 -C 2 alkylenedioxy, R ³² 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 alkyl group having a fully substituted five- or six-membered N-heterocyclic ring; . if it contains an oxygen atom or an additional nitrogen atom, R ( ³³⁾ is hydrogen or halogen or _{R (} 32) and R ( ³³⁾ together are (C1 -C4) alkylenedioxy, a cation of the pharmaceutically acceptable base * and of the hydrates of the salts of the formula I * characterized in that the carboxylic acid of the formula II (Π) in which M, R, R, Z, R, R and R are as defined above, act with at least an equimolar amount of a pharmaceutically acceptable base, and optionally recover the salt obtained in the form of a salt hydrate in the presence of water or atmospheric moisture. 2. A process according to claim 1, wherein the corresponding compounds of formula (II) are used as starting materials to give compounds of formula (I) wherein m is 0 and R is hydrogen and the other substituents are as defined in 1. 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of formula (II) are used as starting materials to give compounds of formula (I) in which: of represents a group R 1 -C, whereas - R <10> denotes: hydrogen or halogen R ³¹ is C1-C8alkyl, haloalkyl; C 1 -C 8 or C 3 -C 7 cycloalkyl, R ³² 'к is C1-C6alkyl, piperazinyl or C2-C8alkyl substituted by piperazinyl; . _R 33 represents a hydrogen atom or a halogen atom, and others the substituents have the meaning given in 1 or 2. 4. The process of claim 3, wherein the corresponding compounds of formula (II) are used as starting materials to form compounds of formula (I) in which: R ³⁰ represents a hydrogen atom or a fluorine atom, R ³¹ represents ethyl, fluoroethyl or cyclopropyl, represents a piperazinyl or 4-methylpiperazinyl group and represents a hydrogen atom or a fluorine atom, and the other substituents have the meaning given in point 3. Process according to one of Claims 1 to 4, characterized in that the corresponding compounds of the formula (II) are used as starting materials to give compounds of the formula (I) in which R ¹ is R ¹⁵ -O-N = C-CO-, L · ¹ R ¹⁰¹ represents a 2-amino-4-thiazolyl group a R ¹⁰³ represents a methyl group or a group of the general formula R ² * ' AND C-COOH Where ² 22 23 R and R are hydrogen or methyl, 1 represents a group R ³⁰ -C where R ^{32 33 * * * 37} represents a hydrogen atom or a halogen atom, R (1) is (C1-C8) alkyl, (C1-C8) haloalkyl or (C3-C7) cycloalkyl, R is C 1 -C 8 alkyl, piperazinyl or C 1 -C 8 alkyl substituted with piperazinyl; and R ³³ . . represents a hydrogen atom or a halogen atom, and the other substituents are as defined in any one of items 1 to 4. 6. The process of claim 5, wherein the corresponding compounds of formula (II) are used as starting materials to produce the compounds of formula (5) in which: R ³⁰ represents a hydrogen atom or a fluorine atom, R ³¹ represents ethyl, fluoroethyl or cyclopropyl, R is methyl, 4-methylpiperazinyl or piperazinyl and R ³³ represents a hydrogen atom or a fluorine atom. 7. A process according to claim 1, wherein the corresponding compounds of the formula II are used as starting materials to give the compounds of the formula in the form of salts of [6R- (6k, U) (Z)] -7- [L (2)]. amino-4-thiazolyl) (R ²ⁱ oxyimino) acetyllaminol-3- [JJJi -R ^33, 8 -R ^30, R ³¹ -L 4-dhydr-7- (4-R ³⁴ -L-piperazinyl) - 4-oxo-3-quinolinyl] carbonyl-oxymethyl-8-oxo-5-thia-1-aza-bicyclo-4,2,0-oct-2-ene-2-carboxylic acids and hydrates of these salts in which R ³³ and R ³⁰ 31 represents a hydrogen atom or a halogen atom, R represents a hydrogen atom, an alkyl group having from 1 to 3 carbon atoms; 8 carbon atoms or 2-haloalkyl of 1 to 8 carbon atoms, R ³⁴ is hydrogen or alkyl and 1 to 8 carbon atoms and R ²¹ is hydrogen, alkyl of 1 to 8 carbon atoms or a group of the formula, R ²² . - C - COOH R ²³ in which 22 23 R and R are hydrogen or C 1 -C 8 alkyl. 8. Process according to claim 7, characterized in that the corresponding starting material is used 21. to form the compounds defined in item 7, wherein R is methyl and the other substituents are as defined in item 7. 9. A process according to claim 8, wherein the corresponding compounds of formula (II) are used as starting materials to give the compounds defined in point 8, wherein ^R33 and ^R30 are hydrogen or fluorine atoms, ^R31 is ethyl or 2-; and R &lt; ^{34 &gt}; is methyl and the other substituents have the meaning given in paragraph 8 above. 10. The process of claim 9, wherein the corresponding compounds of formula (II) are used as starting materials to give the compounds of formula (9), wherein ^R33 and ^R30 are fluoro and R is 2-fluoroethyl and the other substituents are as defined above. referred to in point 9. . 11. The method pocile claim 8, characterized in that as a starting material uses a corresponding compound of formula II to give the compounds as defined in item 8, wherein R ³³ is fluoro, R ³⁰ is hydrogen, R ³¹ represents 2-fluoroethyl and R ³⁴ represents a methyl group and the other substituents have the meaning given in point 8. ¹² 12. The method according to claim 8, characterized in that as a starting material uses a corresponding compound of formula II to give the compounds as defined in item 8, wherein R ³³ known to the fluorine atom, R ³⁰ is hydrogen, R ³¹ is ethyl and R ³⁴ represents a methyl group and the other substituents have the meaning given in point 8. 13. The method of claim 8, wherein the fact that as starting materials using a corresponding compound of formula II to give the compounds as defined in item 8, wherein R ³³ known to the fluorine atom, R ³¹ represents a 2-fluoroethyl group, R ³⁰ represents hydrogen hydrogen and R ³⁴ represents a methyl group and the other substituents have the meaning given in point 8. Process according to one of Claims 5 to 13, characterized in that the corresponding compounds of the general formula (II) are used as starting materials to give the compounds defined in points 5 to 13, in which the groups of the general formulas: N - O - R ¹³⁰ N - O - R ²¹ IIII - C - β - C - ‘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 items 5 to 13. 15. The method according to claim 1, characterized in that as a starting material uses a corresponding compound of formula II to give compounds of formula I in salt form Q6R- (6a, 70)] - 3-LX £ |> -R ³ \ 8-R ^30, 1 R ³¹ -1, 4-dihydro-7- (4-R ³⁴ piperazinyl) -4-oxo-3-quinolinyl]. carbonyljoxy] methyl] -8-oxo-7- (phenoxyacetyl) amino] -5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids and hydrates of these salts, in which: and are hydrogen or halogen, R ³ represents a hydrogen atom, an alkyl group having 1-8 carbon atoms or a '· 34 2-haloalkyl of 1 to 8 carbon atoms and R is hydrogen or alkyl of 1 to 8 carbon atoms and the other substituents are as defined in 1. 16. The process of claim 15, wherein the starting material is a corresponding compound of formula (II) to form the compounds defined in point 15, wherein ^R33 _and ^R30 are hydrogen or fluorine, ^R31 is ethyl or 2; -fluoroethyl and R ³⁴ is methyl and the other substituents are as defined in point 15. 17. The process of claim 16, wherein the corresponding compounds of formula (II) are used as starting materials to produce the compounds defined in (16), wherein R @ ³³ and R @ ³⁰ are fluoro and R @ ³ is 2-fluoroethyl. and the other substituents have the meaning given in point 16.. 18. A process according to claim 15, wherein the starting material is a corresponding compound of formula (II) to give the compounds defined in point 15, wherein R @ ³³ is fluorine, R @ ³ is hydrogen, R @ ³ is hydrogen. and R ³⁴ represents a methyl group and the other substituents are as defined in point 15. 19. The method claimed in claim 15 * characterized in that it is used as a starting material corresponding compounds obecn.ého formula II to give the compounds as defined in paragraph 15, wherein R ³³ is fluoro, R ³⁰ is hydrogen, R ³¹ is ethyl and R ³⁴ represents a methyl group and the other substituents have the meanings given in 15. 20. The method according to claim 15, characterized in that it is used as a starting material corresponding compounds of formula II to give the compounds as defined in paragraph 15, wherein R ³³ is fluoro, R ³¹ is 2-fluoroethyl group, R ³⁰ represents hydrogen and R ³⁴ represents a methyl group and the other substituents are as defined in point 15. 62 21. A process according to claim 1, wherein the corresponding compounds of formula (II) are used as starting materials to give the compounds of formula (I) in the form of [6R- (6X, 70)] - 7- (formylamino) -? - [ U.L.-R ³³ , O-R ³⁰ , 1R ³¹ -1,4-dihydro-7- (4-R ³⁴ -1-piperazinyl) -4-oxo-3-quinolinyl] carbonyl] oxy] methyl] - 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acids and hydrates of these salts, in which R ³³ and R ³⁰ are hydrogen or halogen, R ³¹ is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 2-haloalkyl and R ³⁴ represents hydrogen or C 1 -C 8 alkyl and the other substituents are as defined in 1. 22. The method according to item 21, characterized in that as a starting material uses a corresponding compound of formula II to give the compounds as defined in paragraph 21, wherein R ³³ and R ³⁰ are ethyl or 2-fluoroethyl and R ³⁴ represents a methyl group and the other substituents are as defined in 21. 23. The method according to item 22, characterized in that as a starting material uses a corresponding compound of formula II to give the compounds as defined in paragraph 22, wherein R @ ³³ and R @ ³ represents fluorine and R @ ³ represents 2-fluoroethyl and the other substituents have the meaning given in point 22. 24. The method according to item 21, characterized in that as a starting material uses a corresponding compound of formula II to give the compounds as defined in paragraph 21, wherein R ³³ is fluoro, R ³⁰ is hydrogen, R ³¹ represents 2-fluoroethyl and R ³⁴ is methyl and the other substituents are as defined in 21. 25. The method of clause 21, wherein it is used as a starting material corresponding compounds of formula II to give the compounds as defined in paragraph 21, wherein R ³³ is fluoro, R ³⁰ is hydrogen, R ³¹ is ethyl and R ³⁴ is methyl and the other substituents are as defined in 21. 26. The method according to item 21, characterized in that as a starting material uses a corresponding compound of formula II to give the compounds as defined in paragraph 21, wherein R ³³ is fluoro, R ³¹ is 2-fluoroethyl group, R @ ³ represents a hydrogen and R &lt; ^{34 &gt}; is methyl and the other substituents are as defined in 21. 27. The process of claim 1 wherein the corresponding compounds of formula (II) are used as starting materials to form compounds of formula (I) in the form of salts of &lt; 6 &gt; R- (6x, 70) (Z)] -7- amino-4-thiazolyl) (R ²¹ oxyimino) acetyl] amino] -3 - ^[[[[6-33 R 8 R ^30, 1 R ³¹ -1, 4-dihydro-7- (4- R ³⁴ -1-piperazinyl) -4-oxo-3-quinolinylcarbonyl] oxy] methyl] -8-oxo-5-thiazabicyclo [4.2.0} oct-2-ene-2-carboxylic acids and hydrates of these salts in which R ³³ and R ³⁰ represent a hydrogen atom or a halogen atom, R ³¹ represents a hydrogen atom, an alkyl group of C 1 -C 8 or 2-haloalkyl C 1 -C 4, R is hydrogen or C 1 -C 8 alkyl, R is the formula R ²² - CR ²³ COCH CS 270247 82 where 22 23 R and R are hydrogen or an alkyl group of 1 to 8 carbon atoms. 28. The method of claim 27, further characterized by the ae ae used as starting material corresponding compounds obeoného pattern II to give compounds of the stab 27, where R ²² and R ²³ are each methyl and the other substituents have the meaning as defined in the 27th 29. The method of claim 28, wherein the compound of formula (II) is used as the preferred material to form the compounds of formula (28) wherein R @ 1 and R @ 2 are hydrogen or fluorine, R @ ³¹ is ethyl or 2; -fluoroethyl and R ^ is methyl and the other substituents have the meaning given in point 28. 30. The process of claim 29, wherein the corresponding compounds of formula (II) are used as starting materials to give the compounds defined in (29), wherein R @ 1 and R @ ³⁰ are fluoro and R @ 2 is 2-fluoroethyl and the others. the substituents are as defined in 29 · _w 31st a method according to Claim 28, further characterized by the fact that as the vinyl acetate copolymers ee substance used corresponding compounds of the specimen II, to give compounds as defined in item ⁴ 28 wherein R represents a fluorine atom, R ³⁰ represents a hydrogen atom, R ¹ represents 2- and R ³⁴ is methyl and the other substituents are as defined in point 28. 32. The method of clause 28, wherein the compound of formula (II) is used as the preferred material to form compounds as defined in clause 28 wherein R @ ³ is fluorine, R @ 4 is hydrogen, R @ ¹ is ethyl. and R 1 represents a methyl group and the other substituents have the meanings defined in point 26 &apos; 33. The method of clause 28, wherein the corresponding compounds of formula II are used as starting materials to form the compounds defined in clause 28, wherein R R is fluorine, R ^ is 2-fluoroethyl, hydrogen, and R R. znamená represents a methyl group and the other substituents have the meaning given in point 26. 34. The process of claim 1, wherein the compound of formula (II) is used as the preferred material to produce [6R- (6x, 7fl)] - 3-U [(5-ethyl-5,8-dihydro) sodium salt. -8-oxo-1,3-dioxolo [4,5-g] quinolin-7-yl) carbonyl] oxy] methyl] -8-oxo-7 - [(phenoxyacetyl) amino] -5-thia-1-azabicyclol-4 1,1-d] oct-2-ene-2-carboxylic acid. 35. The method of claim 1, wherein the corresponding compound of formula II is used as the starting material to form the [6R- (6x, 7B) (Z)] J-7 - [[(2-amino-4) -odium] aodium salt. -Ъ -thiazolyl) (methoxyimino) acetyl] amino] -3- [t [(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridin-3-yl) carbonyl] oxy] mothyll -8-oxo-5-thi-8-l-azabicyclo-4,2,01-oct-2-ene-2-carboxylic acid | 36. The method of claim 1, wherein the corresponding compound of formula II is used as the preferred material to form the sodium salt of [6R- (6A, 70) (Z)] - [[(2-amino-4-)]. thia201yl) (methoxyimino) acetyl] amino] -3-m (5-8-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo- [4,5-0] quinolin-7-yl) carbonyl] oxy methyl] -8-oxo-5-thie-1-azabioylclo [4.2.1] oct-2-ene-2-carboxylic acid. AND 37. The process of claim 1, wherein the corresponding compound of formula (II) is used as the starting material to form [6R- (6X, 70)] - 3- [E, 6-ethyl-6-fluoro- 1,4 'dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl-8-oxo-7- [henoxyacetyl) amino] -5-thia-1-azabicyclo [ 4,2,0] oct-2-ene-2-carboxylic acid. 38. The process of claim 1, wherein the corresponding compound of formula II is used as the starting material to form the sodium salt of Q6R- (6 & lt _; 17 & gt _; O)] - 3 - {[E (5-ethyl-5.8) -dihydro-8-oxo-1,3-dioxolo [4,5- g] quinolin-7-yl) carbonyl] oxy] methyl] -7- (2-thienylacetyl) amino) -8-oxo-5-thia -1-azabicyclo [4.2.2] oct-2-ene-2-carboxylic acid. 39. The process of claim 1, wherein the corresponding compound of formula (II) is used as the starting material to form the sodium salt of 6R- (6A, 70)] - 3 - [[[[1-ethyl-6-fluoro] - 1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3-yl) carbonyl] oxy] methyl] -7- (2-thienyl-acetyl) amino] -8- oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. , 40. The process of claim 1, wherein the corresponding compound of formula II is used as the starting material to form the sodium salt of [6R- (6x, 7B)] - 3- [fL-1-ethyl-6-fluoro-1]. 4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7- (phenoxyasyl) amino] -5-thia-1-azabicyclo [b], 2,0-oct-2-ene-2-carboxylic acid. 41. The process of claim 1, wherein the corresponding compound of formula (II) is used as the starting material to form the sodium salt of [6R- (6X, 70) (Z)] -7-Q- (2-amino-4-). thlazolyl) methoxyimino) acetyl] amino] -3- [1-ethyl-6-fluoro-1,4-dihydro-7- (1-pyrrolidinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] - 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. 42. The process of claim 1, wherein the corresponding compound of formula (II) is used as the starting material to form the sodium salt of [alpha] - (6X, 7fl) (Z)] - 7-Qf (2-amino-4-thiazolyl). (methoxyimino (acetyl) -amino] -3- [1,1'-ethyl-6-fluoro-1,4-dihydro-7- (4-formyl-1-piperazinyl) -4-oxoquinolin-3-yl] carbonyl oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid ^: 43. The process of claim 1, wherein the corresponding compound of formula II is used as the starting material to form the sodium salt of [$ R- (6X, 70) *] - 3-ethyl-6- fluoro-1,4-dihydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-yl] carbonyl] oxy] methyl] -8-oxo-7-phenoxyacetyl) amino] -5-thia-1-azabicyclo- , 2,0] oct-2-ene-2-carboxylic acid. 44. The process of claim 1, wherein the corresponding compound of formula (II) is used as the starting material to form the sodium salt of &lt; 6 &gt; R- (6x, 7B) -3- (1-ethyl-6-fluoro-1). 4-Dihydro-4-oxo-7- (1H-pyrrol-1-yl) quinolin-3-yl] carbonyl] oxy] methyl-8-oxo-7- [1 (phenoxyacetyl) amino] -5- thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. 45. The process of claim 1, wherein the corresponding compound of formula (II) is used as the starting material to form the sodium salt of < 6 &gt; R- (6 &lt; 70 &gt;) -3- [4- (4-fluorophenyl)]. -5,8-dihydro-8-oxo-1,3-dioxolo] 4,5-g] quinolin-7-yl] carbonyl] oxy] methyl-8-oxo-7- * ie: phenoxyacetyl) amino] -5 -thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. ; 46. The process of claim 1, wherein the corresponding compound of formula II is used as the starting material to form the sodium salt of &lt; 6 &gt; R- (6 &apos;, 7B) (Z)] -7- [E (2-amino)]. -4-thiazolyl) (methoxyimino) acetyl] amino] -3- [[1-ethyl-6-fluoro-1,4-dihydro-7- (4-thiomorpholinyl) -4-oxoquinolin-3-yl] carbonyl [oxy] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.1] oct-2-ene-2-carboxylic acid. CS 270247 82 47. The method of claim 1, wherein the corresponding compound of formula II is used as the starting material to form the sodium salt dihydrate [6R- (6 < 70 > amino-4-thiazolyl (methoxyimino) acetyl) amino} -3-? - difluoro-1- (2-fluoroethyl) -1,4-dihydro-7- (4-methyl-1-piperazinyl) -4- oxo-3-quinolinyl] carbonyl} oxy] methyl] -B-oxo-5-thia-1-azabicyclo [2.0.0] oct-2-ene-2-carboxylic acid. acid. . 48. The method of claim 1, wherein the corresponding compounds of formula (II) are used as starting materials to form the compounds of formula (I) as defined in any one of items 1 to 33, wherein M is sodium and the other substituents are as defined in from points 1 to 33.