BG60385B2 - Antibacterial cephalosporin compounds - Google Patents

Abstract

Antibacterial cephalosporins are used as a medicinal form. They have broad antimicrobial activity and have a formula in which r1 denotes an antibiotically active quinoline, r2 is hydrogen, lower alkoxy, amino, lower alkylthio or amido radical, r3 is hydrogen or an acyl group and m has a value of 0, 1 or 2. The invention relates and to the readily hydrolyzable esters and salts of the compounds, to their hydrates or their esters or salts. 45 claims

Description

This application is a continuation-in-part of a related pending application with serial number 07/068092, filed on June 29, 1987, now abandoned, which is a continuation-in-part of an application with serial number 881555, filed on July 3, 1986, now abandoned.

The invention relates to antibacterial compounds of formula

d S n n RjN—(— O N O Z| Ch / \ / CHj с и soon about In which R, means quinolone or aza-

a quinolone group; R 1 represents hydrogen, lower alkoxy, amino, lower alkylthio or amido radical; R ₃ represents hydrogen or an acyl group; m has the value 0, 1 or 2, with M preferably being 0, and to readily hydrolyzable esters or salts of these compounds and hydrates of the compounds of formula 1 or their esters or salts.

The terms "lower alkyl" or "alkyl" as used herein refer to both straight-chain and branched-chain saturated hydrocarbon groups containing from 1 to 8, preferably up to 4, carbon atoms, for example methyl, ethyl, propyl, isopropyl, tert-butyl and the like.

The term "lower alkoxy" as used herein refers to a straight-chain or branched-chain oxycarbon group in which the "alkyl" portion has the meanings indicated. Such radicals include, for example, methoxy, ethoxy, propoxy, and the like.

The term “halogen” refers to the four elements, i.e. chlorine, bromine, iodine or fluorine, unless otherwise stated.

The term "acyl" as used in connection with R ₃ in the specification means and includes all organic radicals derived from an organic acid (i.e., a carboxylic acid) by removal of the hydroxyl group. Although the group R ₃ can represent many acyl radicals, certain acyl radicals are preferred.

Representative acyl groups are those already used for acylation of β-lactam antibiotics, including 6-aminopenicillinic acid and derivatives and 7-aminocephalosporanic acid and derivatives, and are described in the literature: Cephalosporins and Penicillins, edited by Flynn, Academic Press (1972), Belgian Patent 866,038, published October 17, 1978, Belgian Patent 867,994, published December 11, 1978, U.S. Patent No. 4,152,432, issued March 1, 1979, U.S. Patent 3,971,778, issued July 27, 1976, and U.S. Patent 4,173,199, issued October 23, 1979. These references, describing various acyl groups, are incorporated by reference into the specification. The following list of acyl groups illustrates the term "acyl", without limiting it.

Representative acyl groups are:

(a) Aliphatic groups with the formula

O

II

R ⁵ — C — in which R ⁵ represents alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, cyclohexadienyl or alkyl or alkenyl substituted with one or more halogen atoms, cyano, nitro, amino, mercapto, alkylthio or cyanomethylthio groups.

(b) Carbocyclic aromatic groups with formulas

g'

R’

R*

O AND O— CHj—C—

R’ 15 SOj- M*

(R ^w is preferably an amino group, a hydroxyl group, a carboxyl group or a sulfosol).

Other acyl groups suitable for the purposes of the present invention are the following: -sulfonylacetyl -hydroxylsulfonyloxyphenylacetyl -sulfamoylphenylacetyl -(phenoxycarbonyl)phenylacetyl -(p-toluyloxycarbonyl)phenylacetyl -formyloxyphenylacetyl -carboxyphenylacetyl -formylaminophenylacetyl -benzyloxycarbonylphenylacetyl and 2-(Ν,N-dimethylsulfamoyl)-2-phenylacetyl

2-bromo-2-thienylacetyl, etc.

(c) A heteroaromatic group of formula

0 0 20 I ¹⁰¹ - (CH ₂ ) _a - CI ¹⁰¹ - CH - C -, 0 0 I ¹⁰¹ - 0 - CH ₂ - C -, I ¹⁰¹ - S - CHg - C - SOj- M* 0 0 25 or jioi _ · _ - _ _R130

which η has the value 0, 1, 2 or 3;

R' and R' and R' each independently represent hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl containing from 1 to 4 carbon atoms, alkoxy containing from 1 to 4 carbon atoms, or an aminomethylene radical and

R" denotes the groups amino, acylamino, hydroxyl, carboxyl salt, protected carboxyl group, such as benzyloxycarbonyl, formyloxy or azido group.

Preferred carbocyclic aromatic acyl groups include those of the following formula:

wherein η is 0, 1, 2 or 3; R ⁹⁰ is as defined above and R ¹⁰¹ is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms (preferably 1 or 2) of nitrogen, oxygen or sulfur atoms. Examples of such heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl and tetrazolyl. Exemplary substituents are halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl containing 1 to 4 carbon atoms, or alkoxy containing 1 to 4 carbon atoms.

Preferred heteroaromatic acyl groups are those groups of the above formulae in which ^R'01 represents 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyridin-2-yl, 2-amino-1,3,4-thiadiazol-5-yl, 2-thienyl, 2-furanyl, 4-pyridinyl or 2,6-dichloro-4-pyridinyl.

(e) //4-substituted-2,3-dioxo-1-piperazinyl)carbonyl/amino/-substituted acetyl groups of formula ^{0 0} Y*“\ ^{and z} _11β —C—CH—NH—C—Ν N— R ²⁰

wherein R ¹¹¹ represents an alkyl, hydroxyalkyl or aromatic group (including carbocyclic aromatic groups) such as those of the formula

wherein R ⁶ , R ⁷ and R' have the meanings described and heteroaromatic groups as included in the definitions for R ¹⁰¹ ;

R ¹²⁰ represents alkyl, substituted alkyl (wherein the alkyl group is substituted by one or more halogen atoms, cyano, nitro, amino or mercapto groups), for example 4-lower alkyl (preferably ethyl or methyl)-2,3-dioxo-

1-piperazinecarbonyl-O-phenylglycyl.

(e) (substituted oxyimino) substituted acetyl groups of formula and

-C-C«H-0 - R ¹³ ®

I _R IO!

in which R ¹⁰¹ has the meanings indicated, and R ¹³⁰ represents hydrogen, lower alkyl and C _3-7 cycloalkyl or substituted lower alkyl (wherein the alkyl group is substituted with 1 or more halogen, cyano, nitro, amino, mercapto, lower alkylthio, aromatic group (as defined for R ^HI ) carboxyl group (including salts thereof), amido, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy)phosphinyl, di-lower alkoxy-phosphinyl, carboxyl lower alkyl or carboxyl-3-7-cycloalkyl.

Examples of

O

I 1zo

-С-c = NOR ¹ 101 R groups are:

2-(2-chloroacetamidothiazol-4-yl)-2-(p-nitrobenzyloxycarbonyl/-methoxyimino/acetyl;

2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetyl;

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-furyl-2-methoxyiminoacetyl;

2-(4-hydroxyphenyl)-2-methoxyiminoacetyl;

2-phenyl-2-methoxy-iminoacetyl;

2-phenyl-2-hydroxyiminoacetyl;

2-thienyl-2-hydroxyiminoacetyl;

2-phenyl-2-(dichloroacetyloxyimino)acetyl;

2-/4-(γ-D-glutamyloxy)phenyl/-2-hydroxyiminoacetyl;

2-(4-(3-amino-3-carboxypropoxy)phenyl)-2-hydroxyiminoacetyl;

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

2-(5-chloro-2-aminothiazol-4-yl)-2-methoxyiminoacetyl;

2-(tert-butoxycarbonyl)isopropoxyimino/-2-(2-sulfonaminothiazol-4-yl)acetyl;

2-(2-tert.butoxycarbonyl)isopropoxyimino/-2-(2-triphenyl-methylamino-thiazole-

4-yl)acetyl;

2-(2-chloroacetamidothiazol-4-yl)-2-isopropoxyiminoacetyl;

2-Methoxyimino-2-(2-sulfoaminothiazol-4-yl)acetyl;2-(2-aminothiazol-4-yl)-2-carboxymethoxyimino/acetyl;

2-(2-(2-Mesylaminothiazol-4-yl)-2-isopropoxyiminoacetyl;

2-(2-imino-3-mesyl-4-thiazolin-4-yl) 2-isopropoxyiminoacetyl;

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

(f) (Acylamino) substituted acetyl groups of the formula phenylmethyleneamino or 2-furylmethyleneamino. As used herein the quinolonyl or azaquinolonyl substituent R ¹ includes among others compounds of the formulae ο ο

II I U0

-C-CH-NH-C-R >111

R in which R ¹¹¹ has the meanings specified above and

R ^uo means

(wherein R ⁶ , R ⁷ , R* and η have the meanings described) hydrogen, lower alkyl, substituted lower alkyl, amino, alkylamino, (cyanoalkyl)amino or acylamino group.

Preferred (acylamino) are substituted acetal groups of the above formula, in which R ¹⁴⁰ represents an amino or acylamino group. Also preferred are those groups in which R ¹⁴⁰ represents phenyl or 2-thienyl.

(d) ///3.substituted-2-oxo-1-imidazolidinyl/carbonyl/aminoAsubstituted acetyl groups of formula

O cn ₂ —cn ₂ in which R ¹ " has the meanings indicated above, and R ^1J means hydrogen, alkylsulfonyl, arylmethyleneamino (Te-N=CHR ^H1 , where R ¹ " has the meanings indicated).

O I 16 -CR (wherein R ¹⁶ represents hydrogen, alkyl or halogen substituted alkyl), an aromatic group (as defined for R ¹ above), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen atoms, cyano, nitro, amino or mercapto groups).

Preferred ///3-substituted-2-oxo-1-imidazolidinyl/carbonyl/amino/substituted acetyl groups of the above formula are those in which R ¹ represents phenyl or 2-thienyl. Also preferred are those groups in which R ¹⁵ represents hydrogen, methylsulfonyl,

the

F

The

The

The term “aryl” is a substituted or unsubstituted aromatic radical such as phenyl, toluyl, xylyl, mesityl, (cumenyl) naphthyl and others, where the aryl group may have from 1 to 3 suitable substituents such as halogen (fluoro, chloro, bromo, etc.), hydroxy group and others.

The term “lower alkanoyl” or “alkanoyl” refers to a group of the formula:

R -CI 25 in which R ²⁵ represents a (C _{6 -C} 10 ) lower alkanecarboxylic acid, for example acetyl, formyl, propionyl, butyryl and the like.

The term "substituted phenyl" refers to phenyl mono- or di-substituted with halogen (chlorine, bromine, fluorine, etc.), lower alkyl, amino, nitro or trifluoromethyl.

The term “substituted alkyl” refers to a “lower alkyl” group substituted, for example, with halogen (chlorine, fluorine, bromine, etc.), trifluoromethyl, amino, cyano, etc.

The term “lower alkenyl” refers to straight-chain or branched-chain hydrocarbon groups containing one olefinic double bond, containing from 2 to 6 carbon atoms, i.e. radicals of compounds of formula C _n K _2n , where η has a value from 2 to 6, for example alkyl, vinyl, etc.

The term "aralkyl" refers to a hydrocarbon group having an aromatic and aliphatic structure, i.e. a hydrocarbon group in which a hydrogen atom of a lower alkyl group is replaced by a monocyclic aryl group, for example phenyl, toluyl, etc.

The expression 5- or 6-membered heterocyclic radical containing from 1 to 3 heteroatoms selected from oxygen, nitrogen and sulfur means the following groups: pyridyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, Noxy-pyridazinyl, etc., and a 5-membered nitrogen-containing heteroring is for example pyrazolyl, imidazolyl, thiazolyl, 1,2,3-thiadiazolyl,

1,2,4-thiadiazalyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, etc. Each of these heterocycles may be further substituted with other substituents. As substituents, there may be mentioned, for example, lower alkyl groups such as methyl, ethyl, propyl, etc., lower alkoxy groups such as methoxy, ethoxy, etc., halogen such as chlorine, bromine, etc., alkyl substituted with halogen such as trifluoromethyl, trichloroethyl, aminomethyl, ethylaminomethyl, etc., amino, mercapto, hydroxyl, carbamoyl or carboxyl groups, etc.

The term "cycloalkyl" refers to a 3-6 membered saturated carbon ring, for example, cyclopropyl, cyclobutyl, cyclohexyl, and the like. 20

By readily hydrolyzable esters of the compounds of formula 1 are meant compounds of formula 1 in which the carboxyl group (i.e. the 2-carboxyl group) is/are in the form of a readily hydrolyzable ester group or groups. Such esters, which may be of the usual type, are, for example, lower alkanoyloxyalkyl esters, for example acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl esters, lower alkoxycarbonyloxyalkyl esters, such as methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1-isopropoxycarbonyloxyethyl esters, lactonyl esters, such as phthalidyl and thiophthalidyl esters, lower alkoxy-35 methyl esters, such as methoxymethyl ester and lower alkanoylaminomethyl esters, for example acetamidomethyl ester. Other esters such as benzyl and cyanomethyl esters can also be used. 40

Examples of salts of the compounds of formula 1 are alkali metal salts, for example sodium and potassium salt, ammonium salt, alkaline earth metal salts such as calcium salt, salts with organic bases such as salts with amines (salts with 45 N-ethyl-piperidine, procaine, dibenzylamine,

Ν,Ν’-dibenzylethylenediamine, alkylamino or dialkylamines) as well as salts with amino acids, for example those with arginine or lysine. 50

The compounds of formula 1, when containing an alkaline functional group such as

A preferred class of amino group formula also forms addition salts with organic or inorganic acids. For example, such salts are the hydrohalides (hydrochlorides, hydrobromides and hydroiodides) and with other mineral acids such as sulfates, nitrates, phosphates and the like, alkyl sulfonates and monoarylsulfonates such as ethanesulfonates, toluenesulfonates, benzenesulfonates and the like, and also other organic acid salts such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

The compounds of formula 1, as well as their salts and readily hydrolyzable esters, may be hydrates. Hydration may occur during their preparation or may occur gradually as a result of the hygroscopic properties of the initially anhydrous product.

compounds are with

COOH ° in which R ¹ has the meanings indicated above, R ^ represents hydrogen or an amino-protecting group such as trityl or chloroacetyl, R ^ represents hydrogen, lower alkyl or a group of the formula *22 —C—COOH I *2.<

wherein R ₂₂ and R _M represent hydrogen or lower alkyl or R ₂₂ and R^ together with the carbon atom to which they are attached form a 37 carbon ring, for example cyclopropyl, cyclobutyl or cyclopentyl. Compounds of formula II are preferred in which R _M represents hydrogen, R ₂₁ represents methyl or a group of the formula

T" —S—UN

I *2J in which R ₂₂ and Rjj represent hydrogen or nor ₂₁

RjoNH

methyl.

The nor ₂₁ group is preferred.

II

to be in the syn-form, i.e. the Z-form. It is preferable that R ¹ be of the formula

in which Z means »30

C or nitrogen, R ₃₀ represents hydrogen or halogen; R ₃₁ represents hydrogen, lower alkyl, lower alkenyl, C _3-7 cycloalkyl, halogen lower alkyl or mono, di and tri-halophenyl; and R ₃₁ taken together represent a lower alkylene mono-oxy group having 2-4 carbon atoms or a lower alkylene dioxy group containing 1-2 carbon atoms;

R ₃₁ represents hydrogen, halogen, lower alkyl, a 5- or 6-membered heterocyclic ring containing from 1 to 3 heteroatoms such as oxygen, nitrogen and sulfur, which may be substituted; R ₃₃ represents hydrogen and halogen and

R ₃₁ and R ₃₃ taken together represent a C _1-12 lower alkylene dioxy group.

In a preferred embodiment, Z represents »30

-wherein R _M represents hydrogen, chlorine and fluorine, preferably hydrogen or fluorine; R ₃₁ represents higher alkyl, preferably methyl or piperizinyl, which may be substituted at the 4-nitrogen atom by a lower alkyl group, preferably methyl, and R _J3 represents hydrogen or chlorine or fluorine, more preferably hydrogen or fluorine, most preferably fluorine.

R» *32

I Rji

in which R ₂₀ , R ₂₁ , Z, R ₃₁ , R ₃₂ and R ₃₃ have the meanings indicated.

The compounds of formula 1 and their salts, esters and hydrates can be used as agents for combating bacterial infections (including urinary tract and respiratory infections) in mammalian species, e.g. dogs, cats, horses, etc., and in humans. Cephalosporins exhibit activity against a broad spectrum of gram-negative and gram-positive bacteria. 45

The in vitro activity of the compounds of the invention is measured by the minimum concentration that inhibits microorganisms in ml using the Agarwell diffusion method or the broth method 50 by dilution against various gram-positive and gram-negative organisms as follows:

compound A: /6R-(6a, 7β)/-3-///(1t ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-yl)carbonyl/oxy/methyl/-8-oxo-7/ (phenoxyacetyl)amino/-5-thia-1 -azabicyclo/4,2.0/oct-2-ene-2-carboxylic acid, hydrate;

Compound B: /6R-(6a,7β)/-3-///(5ethyl-5,8-dihydro-8-oxy-1,3-dioxo/4,5-g/xHnolin-7-yl)carbonyl/oxy/methyl/-8-oxo-7-/ (phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, monosodium salt;

Compound C: /6R-(6a, 7β) (Z)/-7-//(2amino-4-thiazolyl) (methoxyimino)acetyl/ amino/-3-///(1 -ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-yl)carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2ene-2-carboxylic acid, sodium salt;

Compound D: /6R-(6a, 7β)(Z)/-7-//2amino-4-thiazolyl) (methoxyimino)acetyl/amino/-3-/// (5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo/4,5-£/quinolin-7-yl)carbonyl/methyl/-

8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, sodium salt;

compound E: /6R-(6a, 7β)/-3-////Ιοτιυι-ό-ίίνιγορ-Ι^-ΑΗΧΗΑρο^-^-φορΜίιζι-Ι-ΠΗperazine)-4-oxo-quinolin-3-yl/-carbonyl/oxy/methyl-8-oxo-7-/ (phenoxyacetyl)amino/-

5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt;

Compound D: /6R-(6a,7β)/-3-//(-5ethyl-5,8-dihydro-8-oxo-1,3-dioxolo/4,5^/quinolin-7-yl)carbonyl/oxy/methyl/-8-oxo7-/(2-thienylacetyl)amino/-5-thia-1-azabicyclo-/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt;

compound C: /6R-(6a,7β)/-3-////1ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)-4-oxoquinolin-3-yl/-carbonyl/oxy/methyl/-7-(2-thienylacetyl)amino/-55thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt;

compound F: /6R-(6a, 7β)/-3-////1ethyl-6-fluoro-1,4-dihydro-7- (I-pyrrolidinyl)-

4-oxo-quinolin-3-yl/carbonyl/oxy/methyl/— 10 8-oxo-7-(phenoxyacetyl)amino)-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt;

Compound G: /6R-(6a, 7β)(Ζ)/-7-//(2amino-4-thiazolyl) (methoxyimino)acetyl/amino/-3-////1-ethyl-6-fluoro-1,4-dihydro-7-(1pyrrolidinyl) -4-oxoquinolin-3-yl/-carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt.

In vitro minimum yeast concentration (μg/ml) by the broth method, enteric dilution

Compounds

. culture A B C D E F O H 1 £ colt 41 32 2 0.5 0.25 8 2 8 32 0.5 K. pneumoniae A 16 1 0.5 0.25 2 1 4 32 0.5 £ cloacae 957OA 64 2 2 1 8 2 8 32 2 £ cloacae 948· 1 — 2 8 1 8 1 8 32 4 £ cloacae 2367-2 — 1 16 2 4 1 32 32 4 £ cloacae 7099 16 0.5 8 0.3 2 0.5 2 2 2 £ cloacae 214 128 2 8 0.3 8 2 64 32 4 Λ eulgaris ATCC 6310 8 0.5 0.25 0.063 4 0.5 4 32 0.5 P. mtrabilis 190 8 0.5 0.16 0.008 0.3 0.3 4 0.5 0.031 i martescens SM 16 1 1 0.3 4 1 4 32 1 Λ aeruginosa Slone 130 128 32 128 16 16 32 32 32 8 L. aeruginosa 503-36 128 64 128 32 32 64 64 64 32 £ aureus Smith 0.23 0.25 2 2 0.063 0.23 0.25 0.25 0.25 S. aureus 93 — 4 8 4 2 4 4 0.5 0.5

For combating bacterial infections in mammals, the compound of the invention may be administered to the organism in need thereof in an amount of from 5 to 500 mg/kg per day, preferably from 10 to 100, most preferably from 10 to 55 mg/kg per day.

All the routes of administration previously used for penicillins and cephalosporins at the site of infection can also be used with the new group of dual-acting cephalosporins of the invention. Such routes of administration include intravenous or intramuscular injection or internal administration by suppository.

The following reaction schemes illustrate the methods and intermediates used in the preparation of the novel compounds of formula 1.

In the following schemes, when there is a substituent that may be affected in the reaction, it should be protected using well-known protecting groups. For example, amino groups can be protected with easily removable protecting groups used in peptide chemistry. For example, an alkoxycarbonyl group such as tert-butoxycarbonyl, etc., a substituted alkoxycarbonyl group such as trichloroethoxycarbonyl, etc., a substituted alkylcarbonyl, such as monochloromethylcarbonyl, or a substituted aralkyloxycarbonyl group such as p-nitrobenzyloxycarbonyl.

A preferred protecting group is tert-butyloxycarbonyl (t-BOC).

As ester protecting groups, an ester form can be used which is easily converted to a free carboxyl group under mild conditions. Examples of ester protecting groups are, for example, tert-butyl, p-nitrobenzyl, benzhydryl, allyl and the like. The following reaction schemes show novel methods and intermediates in the preparation of a compound according to claim 1:

Scheme I

where RpR ₂ and R _} have the indicated meanings.

In the above reaction scheme, depending on the ester protecting group chosen and the halogen used, the double bond in the cephem ring can be Δ3 or Δ2 with respect to the sulfur atom due to isomerization. The mixed product can, if necessary, be purified to obtain only the desired isomer by preparing the sulfoxide (IX) and subsequent reduction of this compound, or purified by separating the two isomers.

Scheme I

VI-VII

The compound of formula VI, which is known or can be prepared analogously (e.g. US 4406899 and US 4266049), is reacted with the salt of the selected quinolone. The reaction is carried out in a non-hydroxyl solvent such as dimethylformamide, methylene chloride or N,N-dimethylacetamide. Other non-hydroxyl solvents can also be used. Suitable salts of the quinolone acid are, for example, sodium, potassium, cesium, tetrabutylammonium or tetramethylammonium. Hal represents halogen, preferably bromine or iodine. The reaction is carried out at about 0°C to 80°C, preferably at room temperature.

VII-VIII or X

The compound of formula VII is then deprotected using agents compatible with the ester protecting group used. For example, the following reagents and their corresponding compatible esters are used: paranitrobenzyl—removed by hydrolysis in the presence of sodium sulfide at or below 0° C. to room temperature in a solvent such as dimethylformamide (aqueous); tert-butyl ester—removed by reaction with trifluoroacetic acid in the presence of anisole at about 0° C. to room temperature with or without a solvent such as methylene chloride; or allyl esters—removed by palladium(0) catalyzed transallylation reaction in the presence of sodium or potassium salt of 2ethylhexanoic acid, see J. Org. Chem., 1982, 47, 587.

VIII-IX

If isomerization of the double bond occurs, the compound of formula VIII is then oxidized with a peracid such as metachloroperbenzoene in a solvent, for example methylene chloride, the reaction taking place at a temperature of from -20° to 40°C, preferably around 0°C.

1X-I

The compound of formula IX is then reduced to the desired final product I using one of a variety of reactions. For example, treatment with phosphorus trichloride in dimethylformamide or with trifluoroacetic anhydride in the presence of sodium iodide in acetone/methylene chloride. The temperature for carrying out both reactions is from 0°C to 20°C, preferably about 0°C.

Example 1. A mixture of /6R-(6a, 7β)/-3-/// (1 -ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-yl)carbonyl/oxy/methyl/-8-oxo7-/(phenoxyacetyl) amino/-5-thia-1 -azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester and /2R-(2a, 6α, 7β)-3-///(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-yl) carbonyl/oxy/methyl/-8-oxo-7-/(phenoxyacetyl) amino/-5-thia-1 -azabicyclo/4.2.0/oct-3-ene-2-carboxylic acid (4-nitrophenyl) methyl ester

A solution of 22.4 g (0.040 mol) of [6R-(6a,7β)]-3-(bromomethyl)-8-oxo-7-(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid (4-nitrophenyl) methyl ester and 10.1 g (0.040 mol) of 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-carboxylic acid sodium salt in 200 ml of dry dimethylformamide was stirred under argon for 5 hours. The solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate and washed with saturated brine, decolorized with activated carbon, dried over sodium sulfate and concentrated to a small volume under reduced pressure. The title products crystallized out. The mother liquor was purified by column chromatography on 800 g of neutral silica gel (0.063 - 0.200 mm, 70-230 mesh ASTM), using ethyl acetate as eluent. The appropriate fractions were collected and crystallized from ethyl acetate to obtain additional amounts of the final products. The mixture of isomers was used for the next reaction. Pure Δ3 isomer was obtained by fractional crystallization from ethyl acetate, and

The Δ2 isomer was isolated by preparative thin layer chromatography of the mother liquor on Merck plates (Silica gel 60 F-254). The physical properties of the two isomers are as follows:

AZ-isomer: IR (KVg) 3405, 1785, 1735, 1697, 1637, 1520, 1348 cm ¹ ; mass spectrum m/z 714 (M*+H), 736 (M ⁺ +Na);

A2-isomer: IR (KVg) 3560, 3480, 3415, 1780, 1745, 1693, 1620, 1520 cm ¹ , mass spectrum m/z 713 (M ⁺ ).

Example 2. [2R-(2a, 6α, 7β)-3-[(1ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-yl)carbonyl]oxy[methyl]-8-oxo-7-(phenoxyacetyl)-amino]-5-thia-1-azabicyclo[4.2.0]oct-3-ene-carboxylic acid

A solution of 2.80 g (0.0116 mol) of sodium sulfide hydrate in 20 ml of water was added dropwise to a solution of 6.11 g (0.00856 mol) of the mixture of the two isomers of Example 1 in 45 ml of dimethylformamide at a temperature of -5° to -10° C. After 35 minutes the mixture was acidified to pH

3.5 by adding 1 L hydrochloric acid, whereupon a gummy product precipitated. After addition of 50 ml ethyl acetate and 50 ml ether the product solidified. It was filtered, washed with water and ether and dried at 50°C under vacuum over P ₂ O ₃ to give the final product. Upon addition of more ether to the filtrate, an additional amount of precipitate was obtained, which was filtered off and dissolved in aqueous sodium bicarbonate. The aqueous solution was washed with ethyl acetate and then acidified to pH 3.5. The solution of the precipitated gummy product in methylene chloride was filtered, washed with water, dried over sodium sulfate and concentrated under reduced pressure to give an additional amount of the final product: IR (KBr) 3420, 3300, 1773, 1720 cm 2 ; mass spectrum m/z 579 (ΝΓ+Η).

Example 3. /(6R-(6a, 7β)/-3-///(1-ethyl-

1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-Zyl)carbonyl/oxy/methyl/-8-oxo-7-/ (phenoxyacetyl)-amino-5-thia-1 -azabicyclo/4.2.0/oct2-ene-2-carboxylic acid S-oxide

A solution of 0.986 g (85% pure, 0.00486 mol) of m-chloroperbenzoic acid in 15 ml of methylene chloride was added dropwise with stirring to a suspension of 2.55 g (0.00442 mol) of the final product of Example 2 in 60 ml of methylene chloride at 0°C. The mixture was stirred for 4 hours at 0° and filtered. The solid phase was washed with methylene chloride and dried under reduced pressure to give the final product: IR (KBr) 3360, 1794, 1684, 1637, 1017 cm ^-1 ; mass spectrum m/z 595 (NΓ+H).

Example 4. /6R-(6a,7β)/-3-///(1-ethyl-

1,4-Dihydro-7-methyl-4-oxo-1, 8-naphthhydrin3-yl)carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)-amino/-5-thia-1-azabicyclo/ 4.2.0/oct-2-ene-2-carboxylic acid, hydrate

To a solution of 1.64 g (0.0109 mol) of sodium iodide in 40 ml of dry acetone and 20 ml of methylene chloride was added 1.30 g (0.00219 mol) of the final product of Example 3. The suspension was cooled with stirring and 1.75 ml (0.0124 mol) of trifluoroacetic anhydride was added at 0°C. After 30 minutes, aqueous sodium bicarbonate was added to pH 6.0. 1 N hydrochloric acid was added to pH 3.5 and the small undissolved portion was filtered off and removed. The organic phase was washed with aqueous sodium sulfite, dried over sodium sulfate and concentrated under reduced pressure. The residue was washed with ether and reprecipitated with methylene chloride by addition of ether. Thus the final product was obtained.

Alternatively, a mixture of 0.435 g (0.73 M mol) of the final product according to Example 3 and 7 ml of dry dimethylformamide are stirred and cooled to -12° and 0.128 ml (1.4 M mol) of phosphorus trichloride is added. After 7 minutes, another 0.027 ml of phosphorus trichloride is added. The mixture is stirred for 6.5 minutes. A cold solution of 0.428 g (5.1 M mol) of sodium bicarbonate in 70 ml of water is added. The precipitate is filtered off, washed with water, dried under reduced pressure over diphosphorus pentoxide and the final product is obtained. A second precipitate is separated from the filtrate, which also represents the final product: IR (KBr) 3420, 1785, 1708, 1620 cm ^-1 , mass spectrum m / z 579 (M ⁺ +H).

Example 5. /6R-(6a,7β)/-3-///(5-ethyl-

5,8-dihydro-8-oxo-1,8-dioxolo-[4,5-q/xHHOlon-7-yl]carbonyl/oxy/methyl/-7-/(phenoxyacetyl)-amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester

A solution (1 mmol) of 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-c]quinoline-7-carboxylic acid, sodium salt in 12 ml of dimethylformamide was dried by stirring under nitrogen with 1.50 g of 4A molecular sieves for 1 hour and then mixed with a solution of [6R-(6a,7P)]-3-(iodomethyl)-8-oxo-7-(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester in 6 ml of dry dimethylformamide and stirred for 5 hours. The mixture was concentrated to dryness. The residue was dissolved in ethyl acetate or ethyl acetate/methylene chloride, washed with aqueous sodium bicarbonate and saturated sodium chloride, dried over sodium sulfate and concentrated to dryness. The residue was purified either by preparative thin layer chromatography or by flash chromatography using an 8:2 mixture of ethyl acetate and methylene chloride as eluent.

Example 6. /6R-(6a, 7β)(Z)/-3-///(1ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-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 acid, 1,1-dimethylethyl ester

The reaction of Example 5 was repeated, using as reagents 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-carboxylic acid sodium salt and /6R-(6a, 7β)(Ζ)/-3iodomethyl-7-/ /(methoxyimino/2-(triphenylmethyl)amino-4-thiazolyl/acetyl/amino/-8-oxo-

5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester.

The residue in this example was purified by flash chromatography using 9:1 ethyl acetate/methylene chloride as eluent.

Example 7. /6R-(6a, 7β)(Z)/-3-///(5ethyl-5,8-dihydro-8-oxo-1,3-dioxolo-/4,5-h/quinolin-7-yl)carbonyl/oxo/methyl/-7-// (methoxy-imino) -/2-(triphenylmethyl)amino-4-thiazolyl/acetyl/amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester

The procedure is as in Example 5, using as starting materials 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-c]quinoline-7-carboxylic acid sodium salt and [6R-(6a,7β)(Ζ)]-3-iodomethyl-7-[(methoxyimino)[2(triphenylmethyl)amino-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylic acid 1,1-dimethylethyl ester. In this example, the residue is purified by flash chromatography, using a 9:1 mixture of ethyl acetate/methylene chloride as eluent.

Example 8./6R-(6a,7β)/-3-(////1-ethylb-fluoro-1,4-dihydro-7-(-4-formyl-1-piperazinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/-8-oxo-7-/ (phenoxyacetyl)amino/5-thia-

1-Azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester

The procedure is as in example 5, using 1-ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)- as starting materials.

4-oxo-quinoline-carboxylic acid, monosodium salt and /6R-(6a, 7β)/-3-(iodomethyl)-8-oxo-7-(phenoxyacetyl)-5-thia-1-azabicyclo-/4.2.0/oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester. The residue was purified by flash chromatography, eluting with a 20:1 methylene chloride/methanol mixture.

Example 9. /6R-(6a,7β)-3-///(5-ethyl-

5,8-dihydro-8-oxo-1,3-dioxolo[4,5-q/-quinolin-7-yl)carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)-amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

A solution of 3.00 g (4.52 mmol) of the final product of Example 5 in 15 ml of anisole was stirred at room temperature while 10.6 ml of trifluoroacetic acid was added. The mixture was stirred for 4 hours and concentrated under reduced pressure to dryness. The residual oil was dissolved in methylene chloride and water was added. Sufficient sodium bicarbonate was added to pH 7.5. The mixture was stirred for 20 minutes and then the aqueous phase was removed. The addition of water and sufficient sodium bicarbonate to pH

7.5 with stirring was repeated twice more. The three aqueous extracts were combined and freeze-dried. The residue was purified by _C1g reversed phase chromatography on a Waters Prep 500A using 50% aqueous methanol. After evaporation and freeze-drying the title compound was obtained: IR (KBr) 3410, 1765, 1635, 1528 cm ^-1 ; mass spectrum m/z 630 (M ⁺ +H), 652 (M*+Na).

Example 10. /6R-(6a,7β)(Ζ)/-7-//2-amino-4-thiazolyl)(methoxyimino)acetyl/-amino/-3-///(1-ethyl-1,4-dihydro-7-methyl-4-oxo-

1,8-naphthhydrin-3-yl)-carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo-/4.2.0/oct-2-ene-215

carbonic acid, sodium salt

A suspension of 0.31 mmol of the final product of Example 6 in 0.66 ml of anisole was cooled to 0°C under nitrogen and 3.3 ml of trifluoroacetic acid were added. The resulting solution was kept at 0°C for 18 hours and then concentrated under reduced pressure at room temperature. Methylene chloride was added and evaporated again under reduced pressure. The residue was then triturated with ethyl acetate to give a solid, preferably before conversion to the sodium salt. If conversion to a solid was not possible, the sodium salt was obtained. In each case, the solid or oil was dissolved in 9 ml of methylene chloride and added dropwise at 0 to 3°C to 9 ml of aqueous sodium bicarbonate solution to maintain a final pH of 7.2-7.4. Freeze-dry and the resulting residue was purified by Waters Analytical HPIC system using a Whatman M9 ODS-2 reversed phase column and eluted with a water-methanol gradient (0-100% methanol, 20 minutes). After evaporation and freeze-drying, the final product was obtained and had the following data: IR (KBr) 3405, 3300, 3200, 1766, 1716, 1681, 1617, 1537 cm· ¹ .

Example 11. /6R-(6a,7β) (Z)/-7-//(2amino-4-thiazolyl) (methoxyimino)acetyl/- 30 amino/-3-/// (5-ethyl-5,8-dihydro-8-oxo-1,3dioxolo/4,5-ia/quinolin-7-yl)carbonyl/oxy/methyl/-8-oxo-5-thia-1 -azabicyclo-/4,2,0/-oct-

2-ene-2-carboxylic acid, sodium salt

Working as described in Example 10, but using the final product from product 7, the title compound was obtained: IR (CrCl) 3400-3200, 1767, 1715, 1685, 1635, 1616, 1533 cm ^-1 ; mass spectrum m/z 679 (NH-H), 701 (MH-Na). 40

Example 12. /6R-(6a, 7β) /-3-//// 1-ethyl-

6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/-7-(phenoxyacetyl)amino/-8-oxo-5-thia-

1-Azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

Working according to the method of Example 10 and using the final product of Example 8, the title compound was obtained: IR (KBr) 3420, 1768, 1668, 1620 cm ^-1 , mass spectrum 50 m/z 716 (MH-H), 738 (MH-Na).

Example 13. /6R-(6a, 7β)/-3-/// (5-ethyl-

5.8- Dihydro-8-oxo-1,3-dioxolo[4,5-c]quinolin-7-yl)carbonyl/oxy/methyl/-8-oxo-7-(2-thienylacetyl)amino/-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester

By working according to the method described in Example 5, but using as reagents [6R-(6a,7P)]-3-(iodomethyl)-8-oxo-7-(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid 1,1-dimethylethyl ester and 5-ethyl-5,8-dihydro-7-oxo-1,3-dioxolo[4,5-c]quinolin-7-yl)carboxylic acid, sodium salt, the title compound was obtained.

Example 14. /6R-(6a,7P)/-3-///(5-ethyl-

5.8-dihydro-8-oxo-1,3-dioxolo[4,5-c]-quinolin-7-yl)carbonyl/oxy/methyl/-8-oxo-7-(2-thienylacetyl)-amino/-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt

Working as in Example 10, but with the final product from Example 13, the title compound is obtained: IR (KBr) 3410, 1763, 1682, 1632, 1608 cm ¹ ; mass spectrum m/z 620 (MH-H), 642 (MH-Na.

Example 15. /6R-(6a,7β)-3-////-ethyl-

6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/ -7-(2-thienylacetyl)amino/-8-oxo-5thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester

By following the method of Example 5, but using the reagents /6Κ-(6α,7β)/3-(iodomethyl)-8-oxo-7-(2-thienylacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester and 1-ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)-4-oxo-quinoline-carboxylic acid, sodium salt, the title compound is obtained.

Example 16. /6R-(6a, 7β)/-3-////1ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/-7-(2-thienylacetyl)amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

The procedure described in Example 10 was followed, but the final product from Example 15 was used, yielding the title compound: IR (CH2): 3430, 1765, 1715, 1662, 1623 cm; mass spectrum m/z 706 (MH-H).

Example 17. /6R-(6a, 7β) (Z)-3-////l16 ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/-7-//(methoxyimino)/2-(triphenylmethyl) amino-4-thiazolyl/acetyl/-amino/-8-5thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 1,1 -dimethylethyl ester

The procedure is as described in Example 5, but using the reagents /6R-(6a, 7β) (Ζ)/-3-(iodomethyl)-7-// (methoxyimino)-/2(triphenylmethyl)amino-4-thiazolyl/acetyl/amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-

2-ene-2-carboxylic acid, 1,1-dimethylethyl ester and 1-ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)-4-oxo-quinoline-carboxylic acid, sodium salt, afforded the title compound.

Example 18. /6R-(6a, 7β) (Z) /-7-//(2amino-4-thiazolyl) (methoxyimino) acetyl/amino/-3-//// 1-ethyl-6-fluoro-1,4-dihydro-7(4-formyl-1 -piperazinyl) -4-oxo-quinoline-Zyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1 -azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

The procedure is as in Example 10, but using the final product from Example 17, the final title compound is obtained: IR (KBr) 3420, 1765, 1712, 1622 cm ^-1 ; mass spectrum m/z 764 (NH+H).

Example 19. /6R-(6a, 7β)/-3-////1-ethylb-fluoro-1,4-dihydro-7-(1-pyrrolidinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/-7-/(phenoxyacetyl)amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester

The procedure is as in Example 5, but using the reagents /6R-(6a, 7β)/-3-(iodomethyl)-8-oxo-7-(phenoxyacetyl)-amino/-amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, dimethylethyl ester and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinyl)-3-quinolinecarboxylic acid, sodium salt, to obtain the title compound.

Example 20. /6R-(6a,7p)/-3-////1-ethyl-

6-fluoro-1,4-dihydro-7-(1-pyrrolidinyl)-4-oxo-quinolin-yl/oxy/methyl/-7-(phenoxyacetyl)amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

Working according to the method of Example 10, but using the final product of Example 19, the title compound was obtained with the following data: IR (KH2) 3410, 1770,

1695, 1628 &<’; mass spectrum m/z 673 (M*+H),

695 (M++Na).

Example 21. /6R-(6a,7β)/(Ζ)-3-////1ethyl-6-fluoro-1,4-dihydro-7-(1-pyrrolidinyl)-

4-oxo-quinolin-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 acid,

1,1-dimethylethyl ester

The procedure described in Example 2 was followed using the reagents (6R-(6a, 7β)/3-(iodomethyl)-7-(methoxyimino)/2-(triphenylmethyl)amino/-4-thiazolyl/acetyl/amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2carboxylic acid, 1,1-dimethylethyl ester and 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-pyrrolidinoxyl)-3-quinolinecarboxylic acid, sodium salt, to obtain the title compound.

Example 22. /6R-(6α,7β)(Ζ)/-7-(2-amino-4-thiazolyl)methoxyimino)acetyl/amino/3-////1-ethyl-6-fluoro-1,4-dihydro-7-(1-pyrrolidinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct2-ene-2-carboxylic acid, sodium salt

Following the method of Example 10, but using the final product of Example 21, the title compound was obtained: IR (CrCl) 3455, 3430, 1768, 1682, 1630 cm'; mass spectrum m/z 722 (M+H).

Example 23. /6R-(6a,7β)/-3-////1-ethylb-fluoro-1,4-dihydro-7-/4-(1,1-dimethylethoxy)carbonyl-1-piperazinyl/-4-oxo-quinolinyl/carbonyl/oxy/methyl/-8-oxo-7-/(phenoxyacetyl)amino/-thia-1 -azabicyclo/5.2.0/oct-

2-ene-2-carboxylic acid, 1,1-dimethylethyl ester

Working according to example 5, but using the reagents /6R-(6a, 7β) /-

3-iodomethyl-8-oxo-7-((phenoxyacetyl)-amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester and 1-ethyl-6-fluoro-1,4-dihydro-7-(4-(1,1-dimethylenoxy)carbonyl-1-piperazinyl)-4-oxo-quinoline-carboxylic acid, potassium salt, gave the title compound: IR 3420, 1787, 1730, 1698, 1510 cm'; mass spectrum m/z 822 (ΝΓ+Η).

Example 24. /6R-(6a,7β)/-3-////1-ethyl-

6-fluoro-1,4-dihydro-7-[4-(1,1-dimethylethoxy)carbonyl-1-piperazinyl]-4-oxo-quinolinyl]carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 2-propenyl ester

The procedure described in Example 5 was followed, but using the reagents (6R-(6a,7p)-3-iodomethyl-8-oxo-7-(phenoxyacetyl)-amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 2-propenyl ester and 1-ethyl-bfluoro-1,4-dihydro-7-(1,1-dimethylethoxy)carbonyl-1-piperazinyl)-4-oxo-quinoline-carboxylic acid, tin salt, to give the title compound: IR 3415, 3300, 1789, 1729, 1694, 1622 cm'; mass spectrum m/z 806 (M ⁺ +H).

Example 25. /6R-(6a, 7β)/-3-////1-ethylb-fluoro-1,4-dihydro-7-4-(1-propenoxy)carbonyl-1-piperazinyl/-4-oxo-quinolin-yl/carbonyl/oxo/methyl/-8-oxo-7-(phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2ene-2-carboxylic acid, 2-propenyl ester

By working according to the method of Example 5, but using peakTHBHTe/6R-(6a,7β)/3-iodomethyl-8-oxo-7-(phenoxyacetyl)-amino-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 2-propenyl ester and 1-ethyl-2fluoro[1,4-dihydro-7-(4-(2-propenoxy)carbonyl-1-piperazinyl)-4-oxo-quinoline-3-carboxylic acid, sodium salt, the title compound was obtained: IR (KBr) 3410, 1789, 1725, 1699, 1622 cm ^-1 ; mass spectrum m/z (M ⁺⁺ H).

Example 26. /6R-(6a, 7β) /-3-///(5-ethyl-

5,8-dihydro-8-oxo-1,3-dioxolo[4,5-c]-quinolin-7-yl)carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)amino/-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 2-propenyl ester

The procedure is as in Example 5, using reagents (6R-(6a, 7β))-3-iodomethyl-8-oxo-7-(phenoxyacetyl)-amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 2-propenyl ester and 5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-o]quinoline-7-carboxylic acid, sodium salt, to obtain the title compound.

Alternative synthesis of /6R-(6α, 7β)/ -3-/// (5-ethyl-5,8-dihydro-8-oxo-7-/ (phenoxyacetyl) amino/-5-thia-1-azabicyclo/4.2.0/ oct-2-ene-2-carboxylic acid, sodium salt.

To a solution of the final product of Example 26 (337 mg), 0.03 ml of triethylphosphite, 5.6 mg of methylene chloride, 1.68 ml of a 0.5 molar solution of sodium 2-ethylhexanoate in ethyl acetate was added dropwise over a period of minutes while stirring. The mixture was stirred for 30 minutes, 11 ml of acetone was added and stirring was continued for another 10 minutes. The product was filtered off, washed with ether and air-dried. After purification by reverse phase high performance liquid chromatography with C ₁₍ , the title compound was obtained. This product was identical in its spectral properties to the product obtained according to Example 9.

Example 28. /6R-(6a, 7β)/-3-////1ethyl-6-fluoro-1,4-dihydro-7-(4-thiomorpholinyl)-4-oxo-quinolin-yl/carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)amino/-5thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

A solution of 0.187 g of 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-thiomorpholinyl)-3-quinoline-carboxylic acid, potassium salt in 8 ml of dimethylformamide was stirred with 4A molecular sieves for one hour. Then a solution of 0.257 g of /6R-(6a,7β)-3(iodomethyl)-8-oxo-7-(phenoxyacetyl)amino)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, propenyl ester in 8 ml of dimethylformamide was added and the mixture was stirred for 5 hours. The mixture was concentrated under reduced pressure. The residue in ethyl acetate was washed with aqueous sodium bicarbonate and aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography to give the intermediate allyl ester.

To a solution of 63.5 mg of allyl ester in

To 1.1 ml of methylene chloride and 0.75 ml of ethyl acetate were added 5.1 µl of triethyl phosphate, 1 mg of palladium (II) acetate and 0.28 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate. The mixture was stirred for one hour and then 2 ml of acetone was added and concentrated to dryness under reduced pressure. The residue was triturated with ether to give a solid. Purification by reverse phase high performance liquid chromatography gave the title compound: IR (KBr) 3420, 1768, 1695, 1622 cm ¹ ; mass spectrum m/z 705 (M*+H), 727 (M*+Na).

Example 29. /6R-(6a, 7β)/-3-///(1-βπυι-

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

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 dimethylformamide was stirred for one hour with 4A molecular sieves. 1.54 g of /6R-(6a,7β)/3-iodomethyl-8-oxo-7-(phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, 2-propenyl ester was added and the mixture was stirred for 2.5 hours. The mixture was concentrated under reduced pressure. Ethyl acetate was added and the mixture was washed with aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over sodium sulfate, the ethyl acetate was evaporated under reduced pressure and the residue was purified by flash chromatography to give the intermediate allyl ester.

To a solution of 69 mg of allyl ester in 1 ml of metal chloride were added 0.3 mg of palladium (II) acetate, 1 µl of triethyl phosphite, 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 for 30 min, the mixture was concentrated under reduced pressure. Trituration of the residue with ether gave a solid. Purification by reverse phase high performance liquid chromatography gave the title compound: IR (KBr) 3420, 1765, 1620 cm ¹ ; mass spectrum μ/ζ 669 (M ⁺ +H), 691 (M++Na).

Example 30. /6R-(6a, 7β) /-3-////5-(4fluorophenyl)-5,8-dihydro-8-oxo-1,3-dioxolo/4,5-c/quinolin-7-yl/carbonyl/oxy/methyl/ -8-oxo-7-/ (phenoxyacetyl) amino/-5-thia-1 azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

Solution of 0.183 g of 5-(4-fluorophenyl)-

5,8-Dihydro-8-oxo-1,3-dioxolo/4,5-q/quinoline-7-carboxylic acid, potassium salt, in 8 ml of dimethylformamide was stirred for one hour with 4A molecular sieves. A solution of 0.308 g of /6R-(6a,7β) /-3-iodomethyl-8-oxo-7-/ (phenoxyacetyl) amino/-5-thia-1-azabicyclo/4.2.0/oct-2ene-2-carboxylic acid, 2-propenyl ester was added and the mixture was stirred for 5 hours. The mixture was concentrated under reduced pressure and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium carbonate solution and saturated brine. After drying over sodium sulfate, the ethyl acetate was evaporated under reduced pressure and the residue was purified by thin layer chromatography to give 0.129 g of the intermediate allyl ester.

To a solution of 0.122 g of allyl ester in

To 2.1 ml of methylene chloride and 1.5 ml of ethyl acetate were added 9.9 µl of triethyl phosphate, 1.94 mg of palladium(II) acetate and 0.51 ml of a 0.5 M solution of sodium 2-ethylhexanoate in ethyl acetate. The mixture was stirred for one hour, diluted with acetone and concentrated under reduced pressure. The residue was triturated with ether to give 0.128 g of a solid. After purification by high performance chromatography the title compound was obtained (28.6 mg): IR (KBr) 3420, 1765, 1695, 1632 cm ¹ ; mass spectrum μ/ζ 696 (M*+H), 718 (M ⁺ +Na).

Example 31. /6r-(6a, 7β)(Ζ)/-7-//(2amino-4-thiazolyl) (methoxyimino)acetyl-/ amino/-3-////1-ethal-6-fluoro-1,4-dihydro-7(4-thiomorpholinyl) -4-oxo-quinolin-yl/carbonyl/oxy/methyl/-8-oxo-5-thia-1 -azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt

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 for 1 hour with 1.5 g of 4A molecular sieves. A solution of 1.07 g of [6R-(6a,7β)]-3-iodomethyl-7-(methoxyimino)-(2-triphenylmethyl)amino-4-thiazolyl]acetylamino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid 1,1-dimethylethyl ester in 16 ml of dimethylformamide was added and the mixture was stirred for 5 hours. The mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and saturated aqueous sodium chloride. After drying over sodium sulfate, the ethyl acetate solution was concentrated under reduced pressure. The residue was purified by flash chromatography to give 0.365 g of the intermediate tert. butyl ester.

The tert-butyl ester was dissolved (0.103 g) in a mixture of 0.21 ml of anisole and 1.06 ml of trifluoroacetic acid and kept at 0°C for 18 hours. The mixture was concentrated under reduced pressure and the residue was dissolved in methylene chloride. Water and sodium bicarbonate were added to pH 7.5. The aqueous phase was freeze-dried. The title compound was obtained after purification by reverse phase high performance liquid chromatography: IR (KBr) 3410, 1768, 1715, 1682, 1622 cm ^-1 ; mass spectrum m/z 754 (M+H).

Example 32. /6R-(6a, 7β) (Z)//-7-//(2amino-4-thiazolyl-(methoxyimino)acetyl/amino/-3-////6,8-difluoro-1-(2-fluoroethyl)-1,4dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3quinolinyl/carbonyl/oxy/methyl/-8-oxo-5thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, monosodium salt dihydrate

Solution of 10 g of /6R-(6a,7)/-3-(iodomethyl)-7-/ / (methoxyimino) /2-(triphenylmethyl)amino/-4-thiazolylacetyl/amino/-8-oxo-

5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 1,1-dimethylethyl ester in 40 ml of dimethylformamide was added to a suspension of 5 g of 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinoline-carboxylic acid, potassium salt, in 40 ml of dimethylformamide over 5 minutes. The mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with aqueous sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate and concentrated to give 16.8 g of a brown porous product. Purification by flash chromatography on 500 g of silica gel (230-400 mesh) using a methanol-chloroform solution (gradient from 0 to 8% methanol) gave 5.42 g of the intermediate ester.

To a solution of 2.30 g of intermediate in 25 ml of methylene chloride at 0°C were added 2 ml of anisole, 0.2 ml of 1,2-ethanediol and 25 ml of trifluoroacetic acid. The mixture was stirred at 0°C for 3.5 hours and then concentrated under reduced pressure at 0°C. Methylene chloride was added to the residue and the evaporation was repeated. To the residue was added 5 ml of cold ethyl acetate followed by 25 ml of ether and a solid precipitate was obtained. After filtration, the precipitate was washed with ether and air dried. 3.1 g of solid product were obtained, which was dissolved in 100 ml of 1:4 methanol-chloroform under ice-cooling. 100 ml of water and 35 ml of 5% aqueous sodium bicarbonate solution were added, while the pH was adjusted to 7.8. This operation gave a gummy product which was dissolved in 10 ml of dimethylformamide. 20 ml of chloroform were added, followed by water and aqueous sodium bicarbonate to pH 7.8. The combined aqueous extracts containing the product were washed with chloroform and purified by reverse phase chromatography on C _| b using a water-acetonitrile gradient. The appropriate fractions were concentrated under reduced pressure and lyophilized to give 0.65 g of the title compound: mass spectrum m/z 787 (ΝΓ+Η).

By following the working method from the examples, the following compounds can be obtained:

/6R-/ (6α, 7β (Z)//-7-//(2-amino-4-thiazolyl) (methoxyimino) acetyl/amino/-3-//// 1 -ethyl-6-fluoro-1,4-dihydro-7-(1 -piperazinyl)-3-quinolinyl/carbonyl/oxy/methyl /-8oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2carboxylic acid

/6R-(6α,7β)/-3-////1 -ethyl-6-fluoro-

1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid

/6R-(6α, 7β) 1-3-1 ///6,8-difluoro-1 -(2fluoroethyl) -1,4-dihydro-7- (4-methyl-1 -piperazinyl)-4-oxo-3-quinoline/carbonyl/oxy/ ethyl/-8- oxo-7-/ (phenoxyacetyl) amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid

/6R-/6a, 7β (Z)/-7-//(2-amino-4-thiazolyl) (methoxyimino) acetyl/amino/-3-1 /// 1 -ethyl-fluoro-1,4-dihydro-7-(4-methyl-1 -piperazinyl)-4-oxo-3-quinolinyl /-carbonyl/oxy/methyl/ -8-oxo-5-thia-1 -azabicyclo/4.2.0/ oct-2-ene-2-carboxylic acid /6R-(6ot, 7β) /-7-(formylamino)-3-////

6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/ 5 4.2.0/oct-2-ene-2-carboxylic acid /6R-(6a, 7β)/-3-////1 -ethyl-6-fluoro-

1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl(carbonyl)oxy(7-phenoxyacetyl)amino)-5-thia-(azabicyclo)4.2.0(oct-

2-enecarboxylic acid

/6R-(6α, 7β)/-7-//// (4-ethyl-2,3-dioxo-1 -piperazinyl) carbonyl/ amino/phenylacetyl/amino/-3-////6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1 -azabicyclo/ 4.2.0/oct-2-ene-2-carboxylic acid /6R-(6a, 7 )/-3-////1-cyclopropyl-6fluoro-1,4-dihydro-7-(1 -piperazinyl) -4-oxo- 20

3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-7/ (phenoxyacetyl) amino/-5-thia-1-azabicyclo/ 4.2.0/oct-2-ene-2-carboxylic acid

F

/6R-/6a, 7β (Z)//-7-//(2-amino-4-thi-azolyl)methoxyimine/acetyl/-amino/-3-//// 1 -cyclopropyl-6-fluoro-1,4-oxo-7- (1 -piperazinyl)-3-quinolinyl/carbonyl/oxy/methyl/-8oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2carboxylic acid 35

/6R-(6α, 7β)/-7-/ (cyanoacetyl) amino3-////6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3quinolinyl/carbonyl/oxy/methyl/-8-oxo-5- 45thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid k

/6R-/6a, 7β (Z)//-7-//(2-amino-4-thiazolyl) //1 -carboxy-1 -methyl) -ethoxy/imino/ acetyl/amino/-3-////6,8-difluoro-1-(2-fluoroethyl) -1,4-dihydro-7-(4-methyl-1 -piperazinyl) -4-oxo-3-quinolinyl/carbonyl/ oxy/methyl/-8-oxo-5-thia-1 -azabicyclo/4.2.0/oct-2ene-2-carboxylic acid

F

COOK o /6R-/6a, 7β (Z)//-7-///(2-amino-4-thiazolyl) (carboxymethoxy)imino/acetyl/amino/ -3-////6,8-difluoro-1 - (2-fluoroethyl) -1,4dihydro-7- (4-methyl-1 -piperazinyl) -4-oxo-3quinolinyl/carbonyl/oxy/methyl/-8-oxo-5thia-1 -azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid

3-methyl-10-(4-methyl-1-piperazinyl)-7-oxo-2H-pyrido/1,2,3-ben/-1,4-benzoxazin-6yl/carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid /6R-(6α, 7β)/-3-////6,8-difluoro-1-(2fluoromethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-7-(phenylacetyl)amino/-5-thia-

1-Azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid

F

/6R-(6α,7β)/-3-////6,8-difluoro-1-(2fluoroethyl-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/-carbonyl/oxy/ 15 methyl/-8-oxo-7-(2-thienylacetyl)amino/-5thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid

/6R-/6a, 7β (Z)//-7-///(2-amino-4-thiazolyl)methoxyimino/acetyl/-amino/-3-////

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/-

8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2carboxylic acid

K

H,N—ζ

D /6R-/6a, 7β (Z)//-7-//(2-amino-4-thiazolyl) (methoxyimino) acetyl/amino/-3-////

6,8-difluoro-1-(4-fluorophenyl)-1,4-dihydro-7(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabi-30cyclo/4.2.0/oct-2-ene-2-carboxylic acid /6R-(6a,7β)/- ///2-carboxy-3-////

6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7(4-methyl-1-piperazinyl-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/ 4.2.0/oct-2-en-7-yl/amino/carbonyl/ benzolacetic acid

/6R-(6a, 7β))/-3-////6-fluoro-1-(4fluorophenyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/ methyl/-8-oxo-7-(phenoxyacetyl)amino/-5thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid /6R/6a, 7β (Ζ)//-3-////7-(3-amino-1pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-7-// (2-amino-4-thiazolyl) (carboxymethoxy)imino/acetyl/amino/-8-oxo-5-thia-1 -azabicyclo/4.2.0/oct-2-ene-2carboxylic acid

/6R-/6O, 7β (d)//-3-////7-(3-amino-1pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-7-//(2-amino-4-thiazolyl)/(1carboxy-1-methyleneoxy)imino/acetyl/amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2ene-2-carboxylic acid

in which Z represents /6R-/(6a,7β(Z)//-3-////7-(3-amino1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinyl/carbonyl/methyl/-7-//(2-amino-4-thiazolyl)(methoxyimino)acetyl/amino/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid

Claims (8)

1 η —C—CH—NH- -C—Ν Ν— R ¹⁵ cn ₂ —cn ₂ in which R ¹¹¹ represents a heteroaromatic radical as described, R ¹⁵ represents hydrogen, alkylsulfonyl, -N-CH-R ¹¹¹ (wherein R ¹¹¹ has the indicated meanings), I 16 -CR (wherein R ¹⁶ represents hydrogen, lower alkyl or halogen substituted lower alkyl), an aromatic group (as defined for R ¹¹¹ above), lower alkyl or substituted lower alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups). 34. A compound according to claim 24, wherein R ₃₃ and R ₃₀ are fluorine, R ₃₁ is 2-fluoroethyl, which represents the compound /6R-/6a,7β(Ζ)//-7-!/2-amino-4-thiazolyl) (methoxyimino)acetyl/amino/-3-////6,8-difluoro1 - (2-fluoroethyl) -1,4-dihydro-7-(4-methyl-1 -piperazinyl) -4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 35. A compound according to claim 24, wherein R ₃₃ is fluorine, R _M is hydrogen, R _3] is 2-fluoroethyl and R ₃₄ is methyl, which represents the compound /6R-(6a,7β (Ζ)//-7-// 2-amino-4-thiazolyl) (methoxyimino)acetyl/ amino/-3-/ ///6-fluoro-1 - (2-fluoroethyl) -1,4-dihydro-7-(4-methyl-1 -piperazinyl) -4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 36. A compound according to claim 24, wherein R ₃₃ is fluorine, R _M is hydrogen, R j is ethyl and R ₂₄ is methyl, which represents the compound /6R-/(6α, 7β (Z)//-7-// 2-amino-4-thiazolyl) methoxyimino) acetyl/amino/-3-////6-fluoro-1-ethyl-1,4-dihydro-7-(4methyl-1 -piperazinyl) -4-oxo-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1 -azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 37. A compound according to claim 27, wherein R1 and _R30 are fluorine and _R31 is 2-fluoroethyl, which is the compound /6R-/6a,7β//-3-////6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)amino/-5-thia1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 38. A compound according to claim 26, wherein R ₃₃ is fluorine, R _M is hydrogen, R ₃₁ is 2-fluoroethyl and R ₃₄ is methyl, which represents the compound /6R-/6-a,7-β //-3-////6-fluoro-1 - (2-fluoroethyl) -1,4-dihydro-7-(4-methyl-1 piperazinyl) -4-oxo-3-quinolinyl) carbonyl/ oxy/methyl/-8-oxo-7-(phenoxyacetyl) amino/ -5-thia-1 -azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 39. A compound according to claim 26, wherein _{R is} fluorine, R is hydrogen, _R is ethyl and _R is methyl, which represents the compound [6R-/6-a,7-β//3-////6-fluoro-1-ethyl-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxy-(7-phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 40. A compound according to claim 29, wherein _R33 and R4 are fluorine and R4 is 2-fluoroethyl, which represents /6R-/ 1 SOj-M* in which η has the value 0, 1, 2 or 3; R ⁶ , R ⁷ and R' denote hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms or an aminomethyl radical and R'° denotes amino: hydroxide, carboxyl salt, protected carboxyl or azido group; (c) a heterocyclic group of the formula o R ^,0, -(CH ₂ )«-C- o R ¹⁰¹ —O—CH ₂ —C— o O , _H1 and N R ¹⁰¹ —CH—C— R ¹⁰¹ —S—CH ₂ —C— R« O H O II or R1OI_C_C- in which η has the value 0, 1, 2 or 3; R ⁹⁰ has the indicated meanings and R ¹⁰¹ represents an unsubstituted or substituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms, independently of each other representing nitrogen, oxygen or sulfur, the remainder of the ring atoms being carbon, the heterocyclic ring may optionally be substituted with halogen, hydroxide, nitro, amino, cyano, trifluoromethyl, alkyl containing 1 to 4 carbon atoms, alkoxy containing 1 to 4 carbon atoms, halogenated alkyl, carbamoyl or carboxyl groups. (d) (4-substituted-2,3-dioxo-1-piperazinyl)carbonyl/amino substituted acetyl group of formula in which R ¹ ” represents lower alkyl, hydroxy lower alkyl or an aromatic group of formula in which R ⁶ , R' and R' have the indicated meanings or represent a heteroaromatic radical as given for R ¹⁰¹ , and R ¹¹⁰ represents lower alkyl or substituted lower alkyl (wherein the alkyl group is substituted by one or more halogen, cyano, nitro, amino or mercapto groups); (e) (Substituted oxyimino) substituted acetyl group of formula O And —with—C««N—o— R·» R'0> wherein R ¹⁰¹ is a heteroaromatic radical as defined above, and R ¹³⁰ represents hydrogen, lower alkyl, C3-7 cycloalkyl or substituted lower alkyl, wherein the alkyl group is substituted by one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio, aromatic group (as defined under R ¹ '*), carboxyl (including salts thereof), amido, lower alkoxycarbonyl, phenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl or dinialkoxyphosphinyl, carboxyl lower alkyl or carboxyl-C3-7 cycloalkyl; (0 (Acylamino) substituted acetyl group with formula R'>« in which R ¹ has the indicated meanings and R ¹⁴⁰ means and'g' . | _k »· X is (CH)-o(wherein ^R , ^R , R and η are as defined), hydrogen, lower alkyl, substituted lower alkyl, amino, lower alkylamino, (cyanolower alkyl)amino or arylamino and (g) a 3-substituted-2-oxo-1-imidazolidinylcarbonylamino substituted acetyl group of formula O O O N C 1. Compound with formula *30 C or N, R _M represents hydrogen, chlorine, bromine or fluorine, R ₃₁ represents hydrogen, lower alkyl, lower alkenyl, C _3-7 cycloalkyl, chlorine, bromine or fluorolower alkyl or chloro-, bromo- or fluorophenyl, R _M and R ₃₁ taken together represent lower alkylene with 3 to 5 carbon atoms, lower alkylene mono-oxy group containing 2 to 4 carbon atoms or lower alkylene dioxy group having 1-2 carbon atoms, R ₃₂ represents hydrogen, chlorine, bromine, fluorine, lower alkyl or 5- or 6-membered heterocyclic containing one to three heteroatoms such as oxygen, sulfur and nitrogen, the remaining atoms in the ring are carbon, the ring may be optionally substituted with at least one substituent such as lower alkyl, lower alkoxy, halogen, alkyl substituted with halogen, aminomethyl, ethylaminomethyl, amino, mercapto, hydroxyl, carbamoyl and carboxyl; R ₃₂ represents hydrogen, chlorine, bromine or fluorine and R ₃₂ and R ₃₃ taken together represent a C ₁₄ lower alkylene dioxy group. 2-chloro-, 2-bromo- or 2-fluoro-lower alkyl and R ₁₄ is hydrogen or lower alkyl. 27. A compound according to claim 25, wherein _R33 and _R41 are hydrogen or fluorine, _R31 is ethyl or 2-fluoroethyl and R42 is methyl. 28. A compound according to claim 1 of formula /6R-/6-a,7-β //-7-(formylamino)- 2-ene-2-carboxylic acid, monosodium salt. 16. A compound according to claim 1 of formula (6R-(6a, 7β)(Ζ)/-//(Ζ)-7-3ΜΗΗ0-4thiazolyl) (methoxyimino)acetyl/amino/-3-// / (1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthhydrin-3-yl)carbonyl/oxy/methyl/-8-oxo- 2. A compound according to claim 1, wherein m is zero and _R2 is hydrogen. 3- [6- _R33-8 - _R3O -1- _R31-1,4 -dihydro-7-(4-R4-1 piperazinyl)-4-oxo-3-quinolinylcarbonyloxymethyl-8-oxo-5-thia-1-azabicyclo4.2.0oct-2-ene-2-carboxylic acid and its pharmaceutically acceptable salts, wherein _R33 and _R34 are hydrogen, chlorine, bromine or fluorine, _R31 is hydrogen, lower alkyl or 2-chloro-, 2-bromo- or 2-fluoro-lower alkyl and _R34 is hydrogen or lower alkyl. 29. A compound according to claim 27, wherein R ₁₃ and R ₁₄ are hydrogen or fluorine, R ₁₅ is ethyl or 2-fluoroethyl and R 16 is methyl. 30. A compound according to claim 1, wherein R ₂₂ and R _m are methyl. 31. A compound according to claim 29, wherein _R33 and _R34 are hydrogen or fluorine, _R31 is ethyl or 2-fluoroethyl and R35 is methyl. 32. A compound according to claim 1 of formula /6R-/6-a,7-β (Ζ)//-7-//(2-amino- 3. A compound according to claim 2, wherein R1 is wherein R2 is hydrogen, chlorine, bromine or fluorine, _R31 is lower alkyl, chloro-, bromine- or fluoro-lower alkyl or _C3-7 cycloalkyl; _R12 is lower alkyl, piperazinyl or lower alkylpiperazinyl and _R13 is hydrogen, chlorine, bromine or fluorine. 4-oxo-3-quinolinyl/-carbonyl/oxy/methyl/- 4-thiazolyl) ^ ₂₁ oximino)acetyl/amino/-3-/ ///6-R ₃₃ -8- _RM -1 -R ₃₁ -1,4-dihydro-7-(4-R _J4 -1 piperazinyl) -4-oxo-3-quinolinyl / carbonyl / oxy/methyl/-8-oxo-5-thia-1 -azabicyclo/ 4.2.0/oct-2-ene-2-carboxylic acid and its pharmaceutically acceptable salts, in which R ₃₃ and R j ₀ denote hydrogen, chlorine, bromine or fluorine, R ₃₁ is hydrogen, lower alkyl or chloro-, bromo- or fluorolower alkyl, R ₃₄ denotes hydrogen or lower alkyl and R ₂₁ is the group Rjj I —s—soon Rd in which R ₂₃ and R ₂₂ represent hydrogen or lower alkyl. 33. A compound of formula 1, wherein the acyl group represents (a) an aliphatic group of formula O 4-Oxoquinolin-3-yl/carbonyl/oxy/methyl/-7/ (2-thienylacetyl) amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt. 21. A compound according to claim 1 with the formula /6R-(6a, 7β)/-3-////1-ethyl-6-fluoro-1,4-dihydro-7-(1-pyrrolidinyl)-4-oxo-quinolin-3-yl/carbonyl/oxy/methyl/-8-oxo-7-(phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt. 22. A compound according to claim 1 of formula /6R-(6a,7β) (Z)/-7-//(2-amino-4-thiazolyl) (methoxyimino)acetyl/amino/-3-//// 1 -ethyl-6-fluoro-1,4-dihydro-7-(1 -pyrrolidinyl)-4-oxy-quinolin-3-yl/carbonyl/methyl/- 8-Oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, sodium salt. 23. A compound according to claim 3 of formula (6R-/6a,7β(Ζ)//-7-//2-amino-4-thiazolyl) ( _12| oximinoo)acetyl/amino/-3-/////6-Rjj-SR^-1-R ₃₁ -1,4-dihydro-7-(4-R _J4 -1-piperazinyl)-4-oxo-3-quinolinyl)-carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid and pharmaceutically acceptable salts, esters and hydrates thereof, in which R ₂₁ represents hydrogen, lower alkyl or a group of formula Τ ²¹ —s—soon Rm in which each of R ₂₂ and R ₂₃ represents hydrogen or lower alkyl, R 1 represents hydrogen or halogen; R ₂₄ is hydrogen, lower alkyl, lower alkenyl, C _3-7 cycloalkyl or ₂ -halogeno-lower alkyl; R ₃₃ is hydrogen or halogen and R ₃₄ represents hydrogen or lower alkyl. 24. A compound according to claim 23, wherein _R2 is methyl. 25. A compound according to claim 24, wherein R ₃₃ and R ₃₀ represent hydrogen or fluorine, R ₃₁ represents ethyl or 2-fluoroethyl and R ₃₄ represents methyl. 26. A compound according to claim 1 of formula /6R-/6-a,7-β //-3-/////6-^-8-^1 -R ₃₁ -1,4-dihydro-7-(4-R^-1-piperazinyl)-4oxo-3-quinolinyl/carbonyl/oxy/methyl/-8oxo-7-(phenoxyacetyl)amino/-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid and pharmaceutically acceptable salts thereof, wherein R ₃₃ and R ₃₀ are hydrogen, chlorine, bromine and fluorine, R 31 is hydrogen, lower alkyl or 4-oxo-quinolin-3-yl/carbonyl/oxy/methyl/- 8-Oxo-7-[(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt. 19. A compound according to claim 1 with the formula [6R-(6a,7β)]-3-[(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-h]quinolin-7-yl]carbonyl]oxy]methyl [-8-oxo-7-(2-thienylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt. 20. A compound according to claim 1 of formula (6R-(6a,7β))-3-////l-ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)- 4. A compound according to claim 3, wherein Z is *30 C in which R represents a quinolinyl or azaquinolinyl group, which may be unsubstituted or substituted; R ₂ represents hydrogen, lower alkoxy, amino, lower alkylthio or amido; Rj is an acyl group derived from a carboxylic acid and has a value of 0, 1, 2 or a readily hydrolyzable ester or salt of the compound, or a hydrate of the compound, ester or salt. 5 1 R-C in which R ⁵ represents lower alkyl, lower cycloalkyl, lower alkoxy, lower alkenyl, lower cycloalkenyl, cyclohexadienyl or lower alkyl or lower alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio or cyanomethylthio groups. (b) a carbocyclic aromatic group representing Xz+sz’ · 7-0—chi—с- 5-Thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt. 17. A compound according to claim 1 with the formula [6R-(6a,7β) (Z)///(2)/-7-amino-4-thiazolyl) (methoxyimino)acetyl/amino/-3-///(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo/4,5^/quinolin-7yl)carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid, sodium salt. 18. A compound according to claim 1 of formula /6R-(6a,7β)-/-3-////1-ethyl-6-fluoro-1,4-dihydro-7-(4-formyl-1-piperazinyl)- 5. A compound according to claim 4, wherein R ₁₁ represents hydrogen or fluorine, R ₃₁ represents ethyl, fluoroethyl or cyclopropyl, R ₃₂ represents piperazinyl or 4-methylpiperazinyl and R ₃₃ represents hydrogen or fluorine. 6-α,7-β//-7-(formylamino)-3-////6,8-difluoro-1 - (2-fluoroethyl) -1,4-dihydro-7- (4-methyl1 -piperazinyl) -4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 41. A compound according to claim 28, wherein R ₃₃ is fluorine, R _M is hydrogen, R ₃₁ is 2-fluoroethyl and R _M is methyl, which represents the compound /6R-/6-α,7-β//-7-(formylamino)-3-////6fluoro-1 - (2-fluoroethyl) -1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 42. A compound according to claim 28, wherein R ₃₃ is fluorine, R ₃₄ is hydrogen, R ₃₁ is ethyl and R 35 is methyl, which represents the compound /6R-/6-O,7-β//-7-(formylamino)-3-/ / / /6-fluoro-1-ethyl-1,4-dihydro- 6. A compound according to claim 1, wherein the acyl group is a carbocyclic aromatic group of the formula wherein R ⁹⁰ represents amino, acylamino, hydroxyl, carboxyl salt, benzyloxycarbonyl, formyloxy or azido group; R ⁶ , R ⁷ and R* may be hydrogen, halogen, hydroxyl, nitro, amino, cyano, trifluoromethyl, C _1-4 alkyl, C _1-4 alkoxy or aminomethyl. 7-(4-Methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 44. A compound according to claim 30, wherein R ₃₃ is fluorine, R ₃₀ is hydrogen, R ₃₁ is 2-fluoroethyl and R ₃₄ is methyl, which represents the compound /6R-/6-a,7-β (Z)//-7-// (2-amino-4-thiazolyl)/(1-carboxy-1-methylethoxy)imino/acetyl/amino/-3-///6-fluoro1 - (2-fluoroethyl) -1,4-dihydro-7-(4-methyl-1 piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1 -azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 10 45. A compound according to claim 30, wherein R ₃₃ is fluorine, R ₃₀ is hydrogen, R ₃₁ is ethyl and R ₃₄ is methyl, which represents the compound /6R-/6-a, 7-β (Ζ) //-7-// (2-amino-4-thiazolyl)/(1-carboxy-1-methylethoxy)imino/acetyl/amino/-3-////6-fluoro-1ethyl-1,4-dihydro-7-(4-methyl-1-piperazinyl)- 7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinyl/carbonyl/oxy/methyl/-8-oxo-5-thia-1-azabicyclo/4.2.0/oct-2-ene-2-carboxylic acid. 43. A compound according to claim 31, wherein R ₃₃ and R ₄₀ are fluorine and R ₃₎ is 2-fluoroethyl, which represents the compound /6R-/6-a,7-β (Z) //-7-//2-amino-4-thiazolyl) I (1-carboxy-1-methylethoxy)imino/acetyl/amino/-3-///6,8-difluoroethyl) -1,4-dihydro- 7. A compound according to claim 6, wherein R', ^R7 , R' are hydrogen and ^R90 represents hydrogen or a hydroxy group. 8. A compound according to claim 1, wherein the acyl group is a group of the formula O II 130 — C—C = N —O —R I ιοί R in which R ¹⁰¹ represents an unsubstituted or substituted 5, 6 or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms, independently selected from the group consisting of nitrogen, oxygen and sulfur, the remainder of the ring being carbon atoms, wherein the heterocyclic ring is substituted with halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, C, alkyl or C1-4 alkoxy and R ¹³⁰ represents hydrogen, lower alkyl, C3-7 cycloalkyl and substituted lower alkyl, wherein the lower alkyl is substituted with one or more halogen, cyano, nitro, amino, mercapto, lower alkylthio, carboxylic (including salts thereof), amido, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl, dinialkoxyphosphinyl, carboxy-lower alkyl or carboxyl-3,7-cycloalkyl. 9. A compound according to claim 1, wherein the acyl group Rj has the formula wherein R ₂₀ represents hydrogen or an amino protecting group, R ₂₁ represents hydrogen, lower alkyl or a group of formula -c-sone I in which R ₂₂ and R ₂₃ represent hydrogen, lower alkyl or together with the carbon atom to which they are attached form a 3-7 membered carbon ring. 10. A compound according to claim 9, wherein _R20 represents hydrogen, R1 represents methyl or —C—COOH. I *13 in which R ₂₂ and R _m represent hydrogen or methyl. 11. A compound according to claim 1 having the formula ϊ°* ^! · With NM N I ^I « I «JI in which R ₂₁ represents hydrogen, lower alkyl or a group of formula —C—COOH I *13 in which R ₂₂ and Rjj represent hydrogen or lower alkyl or R ₂₂ and R _n taken together with the carbon atom to which they are attached form a 3 to 7 membered carbon ring, Z represents *30 C or N; R _M is hydrogen or halogen; R _3I is hydrogen, lower alkyl, lower alkenyl, C _3-7 cycloalkyl, halogen lower alkyl, or mono-, di- or tri-halophenyl; _m and R jp when taken together form a lower alkylene containing 3 to 5 carbon atoms, a lower alkylene mono-oxy group containing 2 to 4 carbon atoms or a lower alkylene dioxy group containing 1 to 2 carbon atoms, R ₃₂ represents hydrogen, halogen, lower alkyl, a 5- or 6-membered heterocyclic ring containing one or two heteroatoms selected from oxygen, sulfur or nitrogen, the remainder of the ring atoms being carbon, R ₃₃ represents hydrogen or halogen and R _3J and R ₃₃ taken together form a C] ₄ lower alkylene dioxy group. 12. A compound according to claim 11, wherein R ₂₎ represents methyl or a group of formula —c—sone I in which R ₂₂ and R _m represent hydrogen or methyl, Z represents »30 c wherein R ₃₀ is hydrogen or halogen, R ₃₁ represents lower alkyl, halogen-lower alkyl or C _3-7 cycloalkyl, R ₁₂ represents lower alkyl, piperazinyl or lower alkylpiperazinyl and R ₃₃ represents hydrogen or halogen. 13. A compound according to claim 12, wherein R30 represents hydrogen or fluorine, _R31 represents ethyl, fluoroethyl or cyclopropyl, _R31 represents methyl, 4-methylpiperazinyl or piperazinyl and _R33 is hydrogen or fluorine. 14. A compound according to claim 1, of formula [6R-(6a,7β)]-3-[(1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphhydrin-3-yl)carbonyl]oxy]methyl]-8-oxo-7-(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, hydrate. 15. A compound according to claim 1 of formula (6R-(6a,7β))-3-[(5-ethyl-5,8-dihydro-8-oxo-1,3-dioxolo[4,5-c]quinolin-7yl)carbonyl]oxy[methyl]-8-oxo-7-(phenoxyacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid.