MC2000A1 - ACYL DERIVATIVES - Google Patents

Description

1

10

15

20

30

The present invention relates to acylated derivatives of cephalosporins, processes for their preparation and medicinal products containing them.

More specifically, the invention relates to acylated derivatives corresponding to the formula [?]™

r2 h 1

r33

r32

1

in which m is zero, 1, or 2, R is a hydrogen or an acyl group; R is a hydrogen, a lower alkoxy, or an alkylthio

"31

lower or a lower alkanoylamino; R is a hydrogen, a lower alkyl, a lower alkenyl, a cycloalkyl, a lower haloalkyl, a phenyl, or a mono-, di-, or trihalophenyl; Z is R₁-C or a nitrogen; R₂ is a hydrogen or a halogen, or R and R, taken together, represent a C₁-C₂ alkylene group, a C₁-C₂ alkylene monooxy group, or a group

32

alkylenedioxy en; R is a hydrogen, a halogen, a lower alkyl, or an optionally substituted 5- or 6-membered heterocycle containing one, two, or three oxygen, nitrogen, and/or sulfur atoms; and R is a hydrogen or a halogen, or R and 25 o

R, taken together, represent a C^-C^ alkylenedioxy group, and the easily hydrolyzable esters or salts of these compounds and the hydrates of the compounds of formula I or their esters or salts.

In formula I above, m is preferably 0.

As understood in this description, the term "lower alkyl" or "alkyl" refers to straight or branched saturated hydrocarbon groups having 1 to 8, and preferably 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl,

isopropyl, tert-butyl and similar.

As used here, the term "lower alkoxy" or "alkoxy" refers to straight or branched hydrocarbonoxy groups of which

35

°*

The "alkyl" portion is a lower alkyl group as previously described. Examples include methoxy, ethoxy, n-propoxy, and the like.

The term "halogen" as used here represents the four forms, i.e., chloro, bromo, iodo or fluoro, unless otherwise indicated.

The term "aryl" refers to a substituted or unsubstituted aromatic fragment, such as phenyl, tolyl, xylyl, mesityl, cumenyl, naphthyl and the like, where said aryl group may have one to three suitable substituents, such as halogen (like fluoro, chloro, bromo), hydroxy and the like.

The term "lower alkanoyl" or "alkanoyl" used here refers to a formula fragment

R25-CO-

c in which R is a hydrogen or an alkyl group in Cg. Examples of such groups are acetyl, formyl, propionyl, n-butyryl and similar.

The term "substituted phenyl" refers to a phenyl that is mono- or di-substituted with a halogen (such as chloro, bromo, fluoro), lower alkyl, amino, nitro, or trifluoromethyl.

The term "substituted alkyl" refers to a lower alkyl fragment substituted, for example by halogen (such as chloro, fluoro, bromo), trifluoromethyl, amino, cyano, etc.

The term "lower alkenyl" or "alkenyl" refers to a straight or branched hydrocarbon group that contains an olefinic double bond having 2 to 6 carbon atoms, such as the radical of compounds of formula CnH2n in which n is from 2 to 6 such as allyl, vinyl, etc.

The term "aralkyl" refers to a hydrocarbon group having an aromatic structure and an aliphatic structure, that is, a hydrocarbon group in which a hydrogen atom of a lower alkyl is replaced by a monocyclic aryl group such as phenyl, tolyl, etc.

The expression "heterocycle with 5, 6 or 7 links containing 1 to 4 oxygen, nitrogen and/or sulfur atoms" represents, for example

3

a 6-membered nitrogen heterocycle, such as pyridyl, piperidyl, piperidino, N-oxydopyridyl, pyrimidyl, piperazinyl, pyridazinyl, N-oxydopyridazinyl, etc., a 5-membered nitrogen heterocycle, such as pyrrolidinyl, pyrazolyl, imidazolyl, thiazolyl, 5-1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl, etc., and others. Each of these heterocycles can, moreover, be substituted and, as substituents, 10 we can mention for example lower alkyls such as methyl, ethyl, n-propyl, etc., lower alkoxys, such as methoxy, ethoxy, etc., halogens, such as chlorine, bromine, etc., halogen-substituted lower alkyls, such as trifluoromethyl, trichloroethyl, etc., an amino, a mercapto, a hydroxy, a 15 carbamoyl or a carboxy, etc.

The term "lower cycloalkyl" or "cycloalkyl" refers to a saturated carbocyclic fragment with 3 to 7 links, such as cyclopropyl, cyclobutyl, cyclohexyl, etc.

OA Ol

R and RJ together can represent a "20 C3~0g alkylene" such as -(CH2)3-, -(CH2)4-, -(CH2)5~ or -CH(CH3)-(CH2)2-; or also a "C2-C^ monooxy alkylene" such as -(CH2)2-0-, -(0112)3-0-, -(CH2)4-0- or -CH(CH3)-CH2-0-; or alternatively a "C^-C2 alkylenedioxy" such as -0-CH2-0-, -0-(CH2)2-0- or -0-CH(CH3)-0-. A condensed ring of 5 or 6 members is preferably formed. R and R together can represent a "C^-C4 alkylenedioxy" such as -0-CH2-0-, -0-(CH2)2-0-,

-o-(ch2)3-o-, -o-(ch2)4-o-, -o-ch(ch3)-o-, -o-ch(ch3)-ch(ch3)-o- or similar. A condensed ring of 5 or 6 links is preferably formed.

1

3Q The term "acyl", as used here in relation to R,

This term designates and includes all organic radicals derived from an organic acid (i.e., a carboxylic acid) by the removal of the hydroxyl group. Although the R* group can be any of the many acylated radicals, certain acylated groups are preferred.

Examples of acyl groups are acyl groups that

°t(

4

have been used in the past to acylate p-lactam family antibiotics, including 6-aminopenicillanic acid and its derivatives and 7-aminocephalosporanic acid and its derivatives;

See, for example, Cephalosporins and Penicillins, edited by Flynn, 5. Academic Press (1972), Belgian patent 866,038 issued October 17, 1978, Belgian patent 867,994 issued December 11, 1978, US patent 4,152,432 issued May 1, 1979, US patent 3,971,778 issued July 27, 1976, and US patent 4,173,199 issued October 23, 1979. Portions of these references describing various acyl groups are incorporated here for reference. The following list of acyl groups is provided to better illustrate the term "acyl"; it should not be considered as limiting this term. Examples of acyl groups are:

(a) Aliphatic groups of formula 15 R5-CO-

in which R5 is a lower alkyl, a C3-C7 cycloalkyl, a lower alkoxy, a lower alkenyl, a C3-C7 cycloalkenyl, or a cyclohexadienyl; or a lower alkyl or lower alkenyl substituted with one or more halogeno, cyano, nitro, amino, mercapto groups

lower alkylthio or cyanomethylthio.

(b) Carbocyclic aromatic groups conforming to one of the following formulas

25

(ch2)n-c-

30

35

5

30

ch2—0—(t-

10

^3~*-ch2j.

15

20

r'

25

r'

y^xlcJc-

\=j s03~ m +

35

w-

io ~ m +

6

10

15

fi 7 8

where n is 0, 1, 2, or 3; R, R, and R are each independently a hydrogen, a halogen, a hydroxyl, a nitro, an amino, a cyano, a trifluoromethyl, an alkyl of 1 to 4 carbon atoms, an alkoxy of 1 to 4 carbon atoms, or a

Qfl is aminomethyl; and R™ is an amino, acylammo, hydroxy, carboxy salt, protected carboxy such as a benzyloxycarbonyl, formyloxy or azido; and M is a cation.

Preferred carbocyclic aromatic acylated groups include those corresponding to the formulas c3~ ch2-^-

•<q>—och2-ï-

20

30

_A-?£rc-

35

QA

(R is preferably an amino group, a hydroxy group, a carboxy salt, or a sulfo salt).

Examples of other suitable acylated groups in the invention are suifophenylacetyl,

hydroxysulfonyloxyphenylacetyl,

suifamoylphenylacetyl,

(phenoxycarbonyl)phenylacetyl, (p-tolyloxycarbonyl)phenylacetyl,

formyloxyphenylacetyl,

carboxyphenylacetyl,

formylaminophenylacetyl,

benzyloxycarbonylphenylacetyl, 2-(N,N-dimethylsulfamoyl)-2-phenylacetyl, 2-bromo-2-thienylacetyl, etc.

(c) Heteroaromatic groups corresponding to the formulas

101

r -(ch2)n-co-

101 r -ch-co-

r101-o-ch2-co-r101-s-ch2-co-

101 r -co-co-

QA

where n is 0, 1, 2 or 3; R is as defined above; and R"®-®^ is a 5, 6 or 7 substituted or unsubstituted heterocycle containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen and/or sulfur atoms.

8

Examples of heterocycles are thienyl, furyl, pyrrolyl,

pyridyl, pyrazinyl, thiazolyl, pyrimidinyl, and tetrazolyl. Examples of substituents are halogeno, hydroxy, nitro, amino,

cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms.

Preferred heteroaromatic acylated groups include

1 01

the groups corresponding to the above formulas in which R^ is a 2-amino-4-thiazolyl, a 2-amino-5-halogeno-4-thiazolyl, a 4-aminopyridine-2-yl, a 2-amino-1,3,4-thiadiazole-5-yl, a 2-thienyl, a 2-furyl, a 4-pyridyl or a 2,6-dichloro-4-pyridyl.

(d) [[(4-substituted-2,3-dioxo-l-piperazinyl)carbonyl] aminojarylacetyl groups corresponding to the formula d120 m

R —^ !—CO—NH—CH—CO—

r111

"O 111

in which R is a lower alkyl, a lower hydroxyalkyl, or an aromatic group (including carbocyclic aromatics) such as those corresponding to the formula

,.7

,6

fi 7 fi in which R , R and R are as previously defined; or

1 01 1 90

a heterocycle corresponding to the definition of R; and R is a lower alkyl or a substituted lower alkyl (the lower alkyl group being substituted by one or more halogeno, cyano, nitro, amino and/or mercapto groups), such as a lower 4-alkyl (preferably ethyl or methyl)-2,3-dioxo-l-piperazinecarbonyl-D-phenylglycyl.

(e) (Oxyimino-substituted)arylacetyl groups corresponding to the formula

r130-o-n=c-co-I

r101

101,130

in which R is as defined above and R is a hydrogen, a lower alkyl, a C.j-C7 cycloalkyl, a C3-C7 carboxycycloalkyl, or a substituted lower alkyl

(whose lower alkyl group is substituted by one or more halogeno, cyano, nitro, amino, mercapto substituents,

lower alkylthio, aromatic group (as defined above 111

for R), carboxy (including the corresponding salts), lower alkanoylamino, lower alkoxycarbonyl, phenyl methoxycarbonyl, diphenyl methoxycarbonyl, lower hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenyl-

methoxy)phosphinyl or di-(lower alkoxy)phosphinyl).

130

Examples of the group r -0-n=c-c0- are

I

r101

2-[(chloroacetamidothiazole-4-yl)]-2-[(p-nitrobenzyloxycarbonyl) methoxyimino]acetyl, 2-(2-chloroacetamidothiazole-4-yl)-2-methoxyiminoacetyl, 2-(2-aminothiazole-4-yl)-2-isopropoxyiminoacetyl, 2-(2-aminothiazole-4-yl)-2-methoxyiminoacetyl, 2-(2-aminothiazole-4-yl)-2-hydroxyiminoacetyl, 2-thienyl-2-methoxyiminoacetyl, 2-furyl-2-methoxyiminoacetyl, 2-(4-hydroxyphenyl)-2-methoxyiminoacetyl, 2-phenyl-2-methoxyiminoacetyl, 2-phenyl-2-hydroxyiminoacetyl, 2-thienyl-2-hydroxyiminoacetyl, 2-thienyl-2-(dichloroacetyloxyimino)acetyl, 2-[4-(r-D-glutamyl-oxy)phenyl]-2-hydroxyiminoacetyl, 2-[4-(3-amino-3-carboxy-propoxy)phenyl-2-hydroxyiminoacetyl, 2-(5-chloro-2-chloro-acetamidothiazole-4-yl)-2-methoxyiminoacetyl, 2-(5-chloro-2-amino-thiazole-4-yl)-2-methoxyiminoacetyl, 2-[2-tert-butoxy-carbonyl)isopropoxyimino]-2-(2-sulfoaminothiazole-4-yl)acetyl, 2—[2—(tert-butoxycarbonyl)isopropoxyimino]-2-(2-triphenylmethyl-aminothiazol-4-yl)acetyl, 2-(2-chloroacetamidothiazol-4-yl)-2-isopropoxyiminoacetyl, 2-methoxyimino-2-(2-sulfoamino-

10

10

15

30

thiazole-4-yl)acetyl, 2-(2-aminothiazole-4-yl)-2-(carboxy-methoxyimino)acetyl, 2-(2-mesylaminothiazole-4-yl)-2-iso-propoxyiminoacetyl, 2-(2-imino-3-mesyl-4-thiazoline-4-yl)-2-isopropoxyiminoacetyl, 2-(2-aminothiazole~4-yl)-2-(carboxyiso-propoxyimino)acetyl, etc.

(f) (Acylamino)arylacetyl groups corresponding to the formula r140-co-nh-ch-co-

I

r111

111,140

in which R is as defined above and R is r6

7 -

r8

/r 7 o

(in which R, R, R and n are as previously defined),

a hydrogen, a lower alkyl, a substituted lower alkyl, an amino, a lower alkylamino, a (cyanoalkyl)

20 amino or an acylamino.

Preferred (acylamino)arylacetyl groups conforming to the above formula include those in which R*^® is an amino or a

111

acylamino. Groups in which R is a phenyl or a 2-thienyl are also preferred.

25 (g) Groups of [[[3-substituted-2-oxo-l-imidazolidinyl]carbonyl]amino]arylacetyl corresponding to the formula

O II

r15—j^^n—co—nh—ch—co—

35

I i111

ch-sj—gh_ r

1 1 *1 1 C

in which R is as defined above and R is a hydrogen, a lower alkylsulfonyl, an arylmethylenamino (i.e., -N^CHR^"®- where R11-®- is as defined above), R16C0- (where R1^ is a hydrogen, a lower alkyl, or a halogen-substituted lower alkyl), an aromatic group

C

11

111

(as defined for R above), a lower alkyl or a substituted lower alkyl (where the lower alkyl group is substituted by one or more halogeno, cyano, nitro,

amino and/or mercapto).

The groups [[[3-substituted-2-oxo-l-imidazolidinyljcarbonyl]

amino]arylacetyl preferred, meeting the above formula

111

include those in which R is a phenyl or a 2-thienyl.

1 S

We also prefer groups in which R is a hydrogen, a methylsulfonyl, a phenylmethylenamino or a 2-furylmethylenamino.

In a preferred embodiment of the substitute

30 30

quinolonyl or azaquinolonyl of position 3, Z is R-C where R

is a hydrogen, a chlorine or a fluorine, most preferably a hydrogen or a fluorine;

31

R is preferably a lower alkyl, more preferably an ethyl or lower haloalkyl, most preferably a C3-C7 fluoroethyl or cycloalkyl, most preferably a cyclopropyl;

R^2 is preferably a lower alkyl, most preferably a methyl or a piperazinyl which can be substituted on the nitrogen atom of position 4 by a lower alkyl group, most preferably a methyl;

r33 is preferably hydrogen, chlorine or fluorine, most preferably hydrogen or fluorine and even more preferably fluorine.

As understood here, the quinolonyl or azaquinolonyl substituents of position 3 include, among others, the groups corresponding to the formulas

12

10

15

20

t1

k

25

30

35

ch

3 •

t

13

10

15

k Qh cho

20

25

nch-

30

nhch

35

15

10

15

20

25

0—c(ch3)

30

35

,och2cci3

16

17

A preferred category of compounds consists of those with the formula r2onh'

21

nh-

- nor"- h 9 e;

c &.

1.20

in which R is as above, R is an ammo- group

10 protective agent, such as trityl or chloroacetyl, or preferably a

91

hydrogen, R is a hydrogen, a lower alkyl group, or a group of formula r22

I

15 -c-cooh i

r23

22 23

in which R and R are chosen from the group consisting of a hydrogen and a lower alkyl, or R and R23, taken together with the carbon atom to which they are attached,

form a carbocyclic ring with 3 to 7 members, such as cyclopropyl, cyclobutyl, or cyclopentyl. We prefer all

20

particularly compounds of formula Ib in which R

21

25 is a hydrogen and R is a methyl group or a group with the formula r22

I

-c-cooh

I

30 r23

00 0"i , ,

in which R and R are chosen from the group consisting of a hydrogen and a methyl.

N-O-R-130 N-O-R21 H H

35 Preferably the groups -C- and -C- are under

18

the syn form, that is to say the Z form or mixtures in which the syn form predominates.

Readily hydrolyzable esters of formula I compounds are understood to be compounds of formula I in which the carboxy group(s) (i.e., the 2-carboxy group and any other carboxy group present) is/are present as readily hydrolyzable ester groups. Examples of such esters, which can be of the classical type, include lower alkanoyloxyalkyl esters (such as 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 alkoxymethyl esters (such as methoxymethyl ester), and lower alkanoylaminomethyl esters (such as acetamidomethyl ester). Other esters (such as benzyl and cyanomethyl esters) may also be used.

Examples of salts of compounds of formula I are alkali metal salts, such as sodium and potassium salt, ammonium salt, alkaline earth metal salts, such as calcium salt, salts formed with organic bases, such as amine salts (e.g. salts formed with N-ethylpiperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkylamines) as well as salts formed with amino acids, such as, for example, salts formed with arginine or lysine.

Compounds of formula I, when they contain a basic functional group, such as an amine, also form salts with organic or mineral acids. Examples of such salts are halides (such as hydrochlorides, hydrobromides, and iodines) as well as other salts of mineral acids.

such as sulfates, nitrates, phosphates and the like, alkylsulfonates and monoarylsulfonates, such as ethanesulfonates, toluenesulfonates, benzenesulfonates and

19

similar and also other salts of organic acids, such as acetates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates and the like.

Compounds of formula I, as well as their salts or their 5. easily hydrolyzable esters, can be hydrated.

Hydration can be carried out during the manufacturing operation or can occur gradually due to the hygroscopic nature of a product that is initially anhydrous.

The aforementioned acylated derivatives are manufactured according to the present invention by a process which includes

(a) for the preparation of a readily hydrolyzable ester of a carboxylic acid of formula I, the reaction of a compound of formula

[°3m

2 ♦

R H- T

15 IAîh—S 11

20

CH2 Hal

COOR'

1 2

in which m, R and R are as above, Hal is a halogen and R' is the remainder of a readily hydrolyzable ester, with a salt of a carbothioic acid of formula

25 III

•51 11 T-J

in which R, R and R are as above,

30 or

(b) for the preparation of a carboxylic acid of formula i, the conversion of an ester of formula

35

of

20

10

15

20

25

30

35

r2 h

[Oî

t m

Oh'

0^

7-

coor ch2.sco- —:

iv i 2 31 32 33 in which m, R, R, R, R and R are as above and

R is an ester protecting group,

in the carboxylic acid of formula I, or

(c) for the manufacture of a compound of formula I, in which m is zero, the reduction of a compound of formula

1 9 31 3? 33

in which R, R, R, R and R are as above,

Or

(d) for the manufacture of a compound of formula I, in which m is 1 or 2, or of an ester or salt thereof, the oxidation of a compound of formula

;ch2sco-

cooh vi in which R1, R2, R31, R32 and R33 are as above and the dotted lines indicate the presence of a double bond A2 or

9i

21

U3,

or of an ester or a salt thereof, or

(e) for the manufacture of a compound of formula I, wherein R1 contains an amino substituent, or an ester or salt thereof, the cleavage of the amino-protecting group of the substituent R of formula

10

of a compound

10

15

20

25

30

35

r10nh

•chjs co-

VII

9 31 19

in which m, R, R, R and R are as above and 1 o

R is an acyl group containing a protected amino group, or an ester or salt thereof, or

(f) for the preparation of a readily hydrolyzable ester of a compound of formula I, the corresponding esterification of a carboxylic acid of formula I, or

(g) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts, the conversion of a compound of formula I into a salt or hydrate or into a hydrate of said salt.

The reaction of compounds II with the salts of compounds III according to embodiment (a) is preferably carried out in a non-hydroxyl solvent, such as dimethylformamide, methylene chloride, or N,N'-dimethylacetamide. Other non-hydroxyl solvents may also be used. Suitable salts of quinolonic acid include, for example, sodium, potassium, cesium, tetrabutylammonium, or tetramethylammonium salts. Hal is a halogen, preferably bromine or iodine. The reaction is preferably carried out between 0°C and 80°C, preferably near room temperature.

The deprotection of esters IV according to embodiment (b) is carried out using agents compatible with the group

22

ester protectant used. As ester protecting groups R, an ester form that can be readily converted to a free carboxyl group under moderate conditions can be used; the ester protecting group being, for example, tert-butyl, p-nitrobenzyl, 5-benzhydryl, allyl, etc. The remnants of the readily hydrolyzable esters mentioned above as end products can also be used. For example, the following reacting compounds and their corresponding compatible esters are used: p-nitrobenzyl removed by hydrolysis in the presence of sodium sulfide between near or below 0°C and room temperature, in a solvent such as (aqueous) dimethylformamide; tert-butyl removed by reaction with trifluoroacetic acid in the presence of anisole between near or below 0°C and room temperature, with or without a co-solvent such as methylene chloride; or allyl eliminated by a palladium (O) catalyzed transallylation reaction in the presence of the sodium or potassium salt of 2-ethylhexanoic acid, see for example J. Org. Chem. 1982, 47, 587.

The reduction of sulfoxides V according to embodiment 20(c) is carried out by one of several reactions, for example, treatment with phosphorus dichloride in dimethylformamide or trifluoroacetic anhydride in the presence of sodium iodide in an acetone/methylene chloride mixture. Both of the above reactions can be carried out between approximately 25°C and -20°C, preferably at approximately 0°C.

The oxidation of compounds VI according to embodiment (d) isomerizes any isomer A2 of formula VI to the corresponding isomer A3 of formula I, where n is 1 or 2. The oxidation is carried out by treatment with an organic or mineral oxidizing agent. Various compounds that readily produce oxygen can be used as oxidizing agents. For example, organic peroxides, such as monosubstituted organic peroxides (like C₅-C₅ alkyl or alkanoyl hydroperoxides such as tert-butyl hydroperoxide), performic acid, and peracetic acid, as well as phenyl-substituted derivatives of these.

ôf■

23

Hydroperoxides, such as cumene hydroperoxide and perbenzoic acid. The phenyl substituent may, if desired, also bear a lower group (such as a C1-C4 alkyl or alkoxy group), a halogen atom, or a carboxy group (e.g., 4-methylperbenzoic acid, 4-methoxyperbenzoic acid, 3-chloroperbenzoic acid, and monoperphthalic acid). Various mineral oxidizing agents may also be used; for example, hydrogen peroxide, ozone, permanganates, such as potassium or sodium permanganate, hypochlorites, such as sodium, potassium, or ammonium hypochlorite, peroxymonosulfuric acid, and peroxydisulfuric acid. 3-chloroperbenzoic acid is preferred. Oxidation is advantageously carried out in an inert solvent, for example, an aprotic inert solvent such as tetra-15 hydrofuran, dioxane, methylene chloride, chloroform, ethyl acetate, or acetone, or in a protic solvent such as water, a lower alkane (like methanol or ethanol), or a lower alkanecarboxylic acid, which may be halogenated (for example, formic acid, acetic acid, or 20-trifluoroacetic acid). Oxidation is generally carried out at a temperature in the range of -20°C to +50°C.

When the oxidizing agent is used in equimolar quantities or in slight excess relative to the starting material, the corresponding tallow oxide is mainly obtained, 25 that is to say a compound of formula I in which m is 1.

When the amount of oxidizing agent is increased to twice the stoichiometric ratio or more, the corresponding sulfone is obtained, that is, a compound of formula I in which m is 2. It is also possible to obtain the sulfone from the corresponding tallow oxide 30 by treatment with an equimolar or greater amount of the oxidizing agent. The operating conditions are essentially the same as in the manufacture of tallow oxides.

Cleavage of the amino-protective group in the R1® substituent of a compound VII according to the procedure (e) provides the 35 corresponding compounds of formula I bearing a free amino group.

24

Appropriate amino-protecting groups are those used in peptide chemistry, such as an alkoxycarbonyl group, like tert-butoxycarbonyl, etc., a substituted alkoxycarbonyl group, like trichloroethoxycarbonyl, etc., a 5-substituted aralkyloxycarbonyl group, like p-nitrobenzyloxycarbonyl, an aralkyl group, such as trityl or benzhydryl, or a haloalcanoyl group, such as chloroacetyl, bromoacetyl, iodoacetyl, or trifluoroacetyl.

The preferred protecting groups are tert-butoxycarbonyl (tert-BOC) and trityl.

10 Amino-protecting groups can be cleaved by acid hydrolysis (e.g., in the case of the tert-butoxycarbonyl or trityl group) or by basic hydrolysis (e.g., in the case of the trifluoroacetyl group). Chloroacetyl, bromoacetyl, and iodoacetyl groups are cleaved by 15 treatment with thiourea.

Amino-protecting groups that are cleavable by acid hydrolysis are preferably removed using a lower alkanecarboxylic acid, which may be halogenated. In particular, formic acid or trifluoracetic acid are used. Acid hydrolysis is generally carried out at room temperature, although it can be performed at slightly higher or lower temperatures (e.g., in the range of approximately 0°C to +40°C). Protecting groups that are cleavable under basic conditions are generally hydrolyzed with dilute aqueous caustic alkali between 0°C and 30°C. Chloroacetyl, bromoacetyl, and iodoacetyl protecting groups can be cleaved with thiourea in acidic, neutral, or alkaline media between approximately 0°C and 30°C.

To prepare a readily hydrolyzable ester of carboxylic acids of formula I, according to the procedure (f) of the process provided by the present invention, a carboxylic acid of formula I is preferably reacted with a corresponding halide, preferably an iodide, containing the desired ester group. The reaction can be accelerated with the aid of a base, such as an alkali metal hydroxide, an alkali metal carbonate, or an organic amine.

4

25

such as triethylamine. Esterification is preferably carried out in an inert organic solvent, such as dimethylacetate, hexamethylphosphorotriamide, dimethyl sulfoxide, or, in particular, dimethylformamide. The reaction is preferably carried out at a temperature in the range of approximately 0°C to 40°C.

The preparation of salts and hydrates of compounds of formula I, or of hydrates of said salts, according to embodiment (g) of the process of the present invention, can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I with an equivalent amount of the desired base, appropriately in a solvent such as water, or an organic solvent (such as ethanol, methanol, acetone, or the like). The temperature at which the salt formation is carried out has no strict limitation. Salt formation is generally carried out at room temperature, but it can be carried out at a temperature slightly above or below room temperature, for example, in the range of 0°C to +50°C.

The preparation of hydrates is generally carried out automatically during the preparation operation or results from the hygroscopic properties of an initially anhydrous product. For the controlled preparation of a hydrate, a completely or partially anhydrous carboxylic acid of formula I or a salt thereof can be exposed to a humid atmosphere (e.g., between approximately +10°C and +40°C).

Reaction scheme I illustrates an example of the process for obtaining products according to the invention:

30

35

1?

26

SCHEMA I

R1, R2, R31, R32, R33, R, Z and the dotted lines are all as defined above and X is a cation.

SCHEMA I

The carboxylic acid form of the corresponding quinolone is activated by treatment with a 2-fluoro-l-methyl salt

27

Pyridinium. Exposure of the activated acid to triphenylmethyl mercaptan and 4-dimethylaminopyridine yields the thioester of formula

Pl^CSCO

3

10

15

20

25

30

in which R31, R32, R33 and Z are as above and Ph is a phenyl.

The compound of formula IX is treated with an aqueous acid, preferably hydrochloric acid, and then neutralized with a base, preferably potassium hydroxide, to obtain the thioic acid salt of formula

31

and Z are as above and X is

35

in which R is a cation.

Ha -» VIII

The compound of formula Ia, which is known or prepared in a manner analogous to that described, for example, in US patent no. 4,406,899 and US patent no. 4,266,049, is reacted with the salt of the chosen quinolone, i.e., a compound of formula X. The reaction is carried out as described above for possible process (a). Depending on the protecting ester group chosen and the halogen used, the double bond of the cepheme ring of the reaction product of formula VIII can be A3 or A2 relative to the sulfur atom as a result of isomerization.

VIII -» the and Via

The compound of formula VIII is then deprotected, as described

28

above for possible process (b), to obtain a carboxylic acid of formula la or a mixture thereof with the isomer A2 of formula Via.

Via -♦ V

If isomerization of the double bond occurs, the compound of formula Via is then oxidized as described for possible process (d), i.e. with a peracid, such as meta-chloroperbenzoic acid, in a solvent, such as methylene chloride, at a reaction temperature of about -20°C to 40°C, preferably about 0°C.

V -» the

The compound of formula V is itself an end product corresponding to formula I. However, it can be reduced to an end product a, as described for possible process (c).

Compounds with the formula containing the groups

N-O-RX30 N-O-R21

It's 11

Or

-c- "c-

(see above) preferably exist in syn forms. These syn forms can be obtained by using starting materials containing this group preformed in the syn form. Alternatively, a syn/anti mixture obtained can be separated into the corresponding syn and anti forms in the usual way, for example by recrystallization, or by chromatographic processes using a suitable solvent or solvent mixture.

The compounds of formula I, their salts, and the corresponding hydrates and esters can be used as agents to combat bacterial infections (including urinary tract infections and respiratory tract infections) in mammals such as dogs, cats, horses, etc., and humans. These cephalosporins have antibacterial activity and are effective against a broad range of Gram-negative and Gram-positive bacteria.

The in vitro activity of the compounds of the present invention

29

measured by the minimum inhibitory concentration in ytg/ml, according to the broth dilution method against various Gram-positive and Gram-negative microorganisms, can be represented as follows:

The in vitro activity of the monosodium salt of [6R-[6a,7J3(Z)]]-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[6,8-difluoro-l-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolyl]carbonylthio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is as follows:

Escherichia coli 257 COD

dc2

Pseudomonas aeruginosa 56 Staphylococcus aureus Smith Streptococcus pneumoniae 6301

a) MIC in (jtg/ml b) ED50 in mg/kg cmia de50b

0.0625 <2

0.125 < 0.0157

64

243

<0.0157

To combat bacterial infections in mammals, a compound of the invention can be administered to a mammal that requires it in an amount of about 5 mg/kg per day to about 500 mg/kg per day, preferably about 10 mg/kg per day to 100 mg/kg per day, most preferably about 10 mg/kg per day to about 55 mg/kg per day.

30

All routes of administration previously used to deliver penicillins and cephalosporins to the site of infection are also considered with the new family of dual-action cephalosporins of the invention. These routes of administration include intravenous, intramuscular, and enteric administration.

The cephalosporin derivatives provided by the present invention can be used as medicinal products: for example, in the form of pharmaceutical preparations containing them in combination with a compatible pharmaceutical vehicle. This vehicle can be an inert organic or mineral vehicle suitable for enteric or parenteral administration, such as, for example, water, gelatin, acacia gum, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petrolatum, etc. The pharmaceutical preparations can be presented in solid form (such as tablets, coated tablets, suppositories, or capsules) or in liquid form (such as solutions, suspensions, or emulsions). The pharmaceutical preparations can be sterilized and/or can contain excipients, such as preservatives, stabilizers, wetting or emulsifying agents, salts for modifying osmotic pressure, anesthetics, or buffers. Pharmaceutical preparations may also contain other substances with therapeutic activity. Carboxylic acids of formula I, as well as their salts and hydrates, are particularly well suited for parenteral administration and, for this purpose, are preferably presented as lyophilized or dry powders intended to be diluted with ordinary reagents, such as water or an isotonic sodium chloride solution, as well as dissolving agents, such as propylene glycol. Readily hydrolyzable esters of formula I are also suitable for enteric administration.

The following examples illustrate the invention without limiting it.

Example 1

A suspension of 21.25 g (0.075 mol) of 2-fluoro-l-methylpyridinium p-toluenesulfonate in 300 ml of anhydrous dichloromethane is cooled to between -15 and -10°C in a salt ice bath and stirred under argon. To this mixture, 22.16 g (0.06 mol) of 6,8-difluoro-l-(2-fluoroethyl)-l,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolinecarboxylic acid and 7.32 g (0.06 mol) of 4-dimethylaminopyridine are slowly added at -10°C. The yellow reaction mixture is stirred at -10°C for 30 minutes, then treated with 16.6 g (0.06 mol) of triphenylmethyl mercaptan and 7.32 g (0.06 mol) of 4-dimethylaminopyridine at -20°C. The mixture is slowly equilibrated at 23°C and stirred for 16 hours. It is diluted with approximately 1.0 L of CHgCl₂. The solvent concentration under reduced pressure yields 45 g of a yellow oil, which is purified twice by flash chromatography on 100 g of silica gel by eluting with 20% acetone in CH₂Cl₂. The fractions containing the desired product are combined and concentrated under vacuum to obtain the semi-hydrated S-triphenylmethyl ester of 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolinecarbothioic acid.

Example 2

6.1 g (9.6 mmol) of the semihydrated S-triphenylmethyl ester of 6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazihyl)-4-oxo-3-quinolinecarbothioic acid and 8 mL of 6 N aqueous HCl are stirred in 30 mL of tetrahydrofuran at 23°C under argon for 16 hours. The mixture is concentrated at 3°C and then reconstituted in 50 mL of water and 50 mL of CHCl₂. The mixture is treated with approximately 55 mL of a 1.0 N aqueous KOH solution at a pH of approximately 11. Extracts are made with two 50 mL portions of CHCl₂. The combined extracts in CHCl₂ are then re-extracted with two 50 mL portions of water. The organic extracts (MgSO₄) are dried and concentrated to obtain 2.57 g of a foam which thin-layer chromatography reveals to be primarily the starting thioester. The combined aqueous phases are passed through a C₁g (100 g) reversed-phase chromatography column and eluted with a

32

A gradient of 3% to 20% acetonitrile in water is used. The fractions containing the desired product are combined and concentrated under vacuum to remove the acetonitrile. The aqueous solution is lyophilized to obtain the hydrated potassium salt of 6,8-difluoro-1-(2-5-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-0x0-3-quinolinecarbothioic acid as a yellow solid.

Example 3

A mixture of 1.8 g (4.07 mmol) of the hydrated potassium salt of 6,8-difluoro-1-(2-10 fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3- is shaken at 23°C under argon.

quinolinoline carbothioic acid and 2.0 g of propylene oxide in 20 ml of anhydrous dimethylformamide. To this mixture is added 3.69 g (4.5 mmol) of tert-butyl ester of [6R-[6a,7|3(Z)]]-7-[[[[(methoxyimino)-2-(triphenylmethyl)amino]-4-thiazolyl]acetyl] 15 amino]-3-(iodomethyl)-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-

The carboxylic acid is added to 25 mL of anhydrous CH₂Cl₂ and stirring is continued for 36 minutes under argon. The reaction mixture is resuspended in 100 mL of ethyl acetate and washed with one 100 mL portion of water and two 100 mL portions of salt water. The 20 aqueous wash liquids are re-extracted with two 100 mL portions of ethyl acetate. The organic extracts are combined, dried (MgSO₄), and filtered. The solvent is concentrated under reduced pressure to obtain 4.1 g of crude product, which is subjected to flash chromatography on 125 g of silica gel. Elution with 2% to 4% CH₃OH in 25 mL of CH₂Cl₃ yields fractions 6 to 13 containing the desired product. Dry evaporation of the solvent under reduced pressure yields a yellow-brown solid: the 1,1-dimethylethyl ester of [6R-[6a,7|3(Z) ] ]-3-[ [ [ [6,8-dif luoro-1- (2-f luoroethyl) -1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolyl]carbonyl]thio]methyl]-30 7-[[[[(methoxyimino)-2-triphenylmethyl)amino]-4-thiazolyl]acetyl]amino]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Example 4

The solution is cooled to 0°C and treated with 20 mL of cold trifluoroacetic acid with 1.9 g (2.2 mmol) of the 35 1,1-dimethylethyl ester of [6R-[6a,7|3(Z) ]]-3-[[[[6,8-

°h

33

difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolyl carbonyl thiomethyl 7-(methoxyimino)-2-(triphenylmethyl)amino-4-thiazolyl acetyl amino-8-oxo-5-thiazolyl azabicyclo-4,2,0-2-ene-2-carboxylic acid, 2 mL of anisole, and 0.1 mL of 1,2-ethanedithiol in 20 mL of CH2Cl2. The reaction mixture is maintained at -20°C for 17 hours, then evaporated in a rotary evaporator at approximately 4°C under reduced pressure. The residue is resuspended in 10 mL of CH2Cl2 and 100 mL of ether is rapidly added. The precipitate is collected and thoroughly washed with ether to obtain 2.03 g of solid. This material is dissolved in 20 mL of a 1:1 acetonitrile/water mixture and treated with a 5% aqueous NaHCO₃ solution. During this process, 5 mL of dimethylformamide is added to dissolve the gummy material. Bicarbonate solution is added until the pH reaches 9.0. The aqueous solution is then chromatographed on a reversed-phase chromatography column (C₅g absorbing) and eluted with 5% to 60% acetonitrile in water. Fractions 11 to 16 (eluted with 20% to 25% CH3CN/H2O) are combined, concentrated under vacuum, and then lyophilized to obtain the product in the form of a white powder: monosodium trihydrate salt of [6R-[6ct,7|3(Z) ]]-7-[[ (2-amino-4-thiazolyl) (methoxyimino) acetyl] amino]-3-[[[[6,8-difluoro-1-(2-fluoroethyl)-l,4-dihydro-7-(4-methyl-l-piperazinyl) -4-oxo-3-quinolyl]carbonyl]thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

Following the procedures shown in the examples, the following compounds are prepared:

acid [6R-(6a,7(i) ]-3-[[[[6,8-difluoro-l-(2-fluoroethyl) -1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolyllcarbonyl] thio]methyl]-8-oxo-7-[(phenoxyacetyl)amino]-5-thia-l-azabicyclo [4.2.0]oct-2-ene-2-carboxylic,

acid [6R-[6a,7|3(Z)jj-7-[[[(2-amino-4-thiazolyl)methoxy-iminojacetyljaminoj-3-[[[[l-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolyljcarbonyljthiojmethylj-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic,

acid [6R-(6a,7|3) j-7-[(cyanoacetyl)amino]-3-[[[[6,8-

34

difluoro-1-(2-fluoroethyl)-l,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolyl carbonyl thiomethyl-8-oxo-5-thia-l-azabicyclo [4.2.0 joct-2-ene-2-carboxylic,

acid [6R-(6a,7p)]-7-[[[[(4-ethyl-2,3-dioxo-l-piperazinyl) 5 carbonyljaminojphenylacetyljaminoj-3-[[[[6,8-difluoro-1-(2-fluoroethyl) -1 ,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolylj carbonyl]thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0joct-2-ene-2-carboxylic,

acid [6R-[6a, 7|3(Z) ]]-8-[[ (2-amino-4-thiazolyl) —[[ (1— 10 carboxy-l-methyl)ethoxyjiminojacetyljaminoj-3-[[[[6,8-difluoro-1-(2-fluoroethyl)-l,4-dihydro-7-(4-methyl-l-piperazinyl)-4-0x0-3-quinolyljcarbonyl]thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0] oct-2-ene~2-carboxylic,

acid [6R-[6a,7|3(Z) ] j—7—[[[(2-amino-4-thiazolyl) (carboxy 15 methoxy)iminojacetyljaminoj—3—[[[[6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolyljcarbonylj thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0joct-2-ene-2-carboxylic,

acid [6R-[6a,7(3(Z) j j—7—[[[ (2-amino-4-thiazolyl) 20 methoxyiminojacetyljaminoj—3—[[[[9-fluoro-3,7-dihydro-3-methyl-10-(4-methyl-l-piperazinyl)-7-oxo-2H-pyrido[l,2,3-de j-1,4-benzoxazine-6-yljcarbonyljthiojmethylj-8-oxo-5-thia-l-azabicyclo [4.2.0 joc-2-ene-2-carboxylic,

acid [6R-(6a,7[3) j-a-[[[2-carboxy-3-[[[[6,8-difluoro-l- (2-25 fluoroethyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-

quinolyljcarbonyljthio jmethylj-8-oxo-5-thia-l-azabicyclo[4.2.0 j oct-2-ene-7-yljaminojcarbonyljbenzene-acetic,

acid [6R- (6a,7(5) j—7-[[ (2-amino-4-thiazolyl) (methoxyimino) acetyljaminoj-3-[[[[6-fluoro-1-(4-fluorophenyl)-l,4-dihydro-7-30 (4-methyl-l-piperazinyl)-4-oxo-3-quinolyljcarbonyljthiojmethylj-8-

oxo-5-thia-l-azabicyclo[4.2.0joct-2-ene-2-carboxylic,

Example A

Production of dry ampoules for intramuscular administration.

35. A 1 g lyophilized powder of qk is prepared in the usual way.

35

The monosodium trihydrate salt of [6R-[6a,7(3(Z)]J-7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-3-[[[[6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-0x0-3-quinolyllcarbonyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is introduced into an ampoule. The sterile water ampoule contains 10% propylene glycol. Before administration, the lyophilized powder is treated with 2.5 mL of a 2% aqueous lidocaine hydrochloride solution.

10

15

20

25

36

Claims (20)

DEMANDS 1. Process for the preparation of acylated derivatives of formula Co], R2 H f m CH^SCO- —' COOH in which m is zero, 1 or 2, R is a hydrogen or an o acyl group; R is a hydrogen, a lower alkoxy, a 01 lower alkylthio or lower alkanylamino; R is hydrogen, lower alkyl, lower alkenyl, C3-C7 cycloalkyl, lower haloalkyl, phenyl or mono-, di- or tri-halophenyl; Z is R3®-C or nitrogen; ÎA O A 01 R is a hydrogen or a halogen, or R and R, taken together, represent an alkylene group at C3-C5, an alkylene monooxy group at C2-C4 or an alkylene dioxy group at ' R is a hydrogen, a halogen, a lower alkyl, or an optionally substituted 5- or 6-membered heterocycle containing one, two, or three oxygen, nitrogen, and/or sulfur atoms; and RJJ is a hydrogen or a halogen, or R and R, taken together, represent a C⁻¹-C⁻¹ alkylenedioxy group, and the readily hydrolyzable esters or salts of these compounds and the hydrates of the compounds of formula I or their esters or salts, which includes (a) for the preparation of a readily hydrolyzable ester of a carboxylic acid of formula I, the reaction of a compound of formula 30 35 37 II CH2 Hal 10 1? in which m, R and R are as above, Hal is a halogen and R' is the remainder of a readily hydrolyzable ester, with a salt of a carbothioic acid of formula 15 20 25 H SCO III 31 • 32 33 in which R, R and R are as above, Or (b) for the preparation of a carboxylic acid of formula I, the conversion of an ester of formula RXNH' [o] R2 H m 0^ COOR CH-.SCO- —, IV 30 1? 31 3? 33 in which m, R, R, R, R and R are as above and R is an ester protecting group, in the carboxylic acid of formula I, or (c) for the manufacture of a compound of formula I, in which m is zero, the reduction of a compound of formula 35 10 15 20 25 1 9 in which R , R are as above, Or (d) for the manufacture of a compound of formula I in which m is 1 or 2, or of an ester or salt thereof, the oxidation of a compound of formula •CH2 SCO- COOH VI 1 O 11 -iO ■J'5 in which R, R, R, R and R are as above and the dotted lines indicate the presence of a double bond A2 or A3, or of an ester or a salt thereof, or 1 (e) for the manufacture of a compound of formula I, wherein R contains an amino substituent, or an ester or salt thereof, the cleavage of the amino-protecting group of the substituent R1® of a compound of formula 30 35 Q 39 R10NH •CH23 CO- COOII VII 9 31 39 33 in which m, R, R, R and R are as cx- above and 10 R is an acyl group containing a protected amino group, or an ester or salt thereof, or (f) for the manufacture of a readily hydrolyzable ester of a compound of formula I, the corresponding esterification of a carboxylic acid of formula I, or (g) for the manufacture of salts or hydrates of a compound of formula I or hydrates of said salts, the conversion of a compound of formula I into a salt or hydrate or into a hydrate of said salt. 2. A process for manufacturing a compound according to claim 1 where m is zero and R is hydrogen, characterized in that correspondingly substituted starting materials are used. 3. A process for preparing a compound according to claim 1 or 2, where Z is R30-C, where R30 is hydrogen or a 31 halogen, RJi is a lower alkyl, an inferior haloalkyl 39 or a C3-C7 cycloalkyl, RJ is an alkyl xnférx_eur, a 33 piperazinyl or a lower alkylpiperazinyl and R is a hydrogen or a halogen, characterized in that correspondingly substituted starting materials are used. 4. Process for preparing a compound according to the 30 31 claim 3 where RJ" is a hydrogen or a fluorine, R is a 3 9 ethyl, a fluoroethyl or a cyclopropyl, R is a piperazinyl or a 4-methylpiperazinyl and R33 is a hydrogen or a fluorine, characterized in that correspondingly substituted starting materials are used. 10 40 5. Method for preparing a compound according to one of 1 any of claims 1 to 4 where R is an acyl group chosen from the group consisting of (a) an aliphatic group of formula r5-c0- in which R^ is chosen from the group consisting of a lower alkyl, a C3-C^ cycloalkyl, a lower alkoxy, a lower alkenyl, a C3-C7 cycloalkenyl or a cyclohexadienyl; or a lower alkyl or a lower alkenyl substituted by one or more halogen groups, cyano, nitro, amino, mercapto, lower alkylthio or cyanomethylthio; (b) a carbocyclic aromatic group selected from the group consisting of 15 20 25 * R 7 (cH2)n-c- N<0^.chJ- ' 30 .8 Y^(LCH,_0J_ R7 "8 35 q 15 r7 20 25 RVX^ch-p 6 L \=/ nh ^03" m + c 7 o where n is 0, 1, 2 or 3; R , R and R are each independently chosen from the group consisting of a hydrogen, a halogen, a hydroxy, a nitro, an amino, a cyano, a trifluoromethyl, an alkyl of 1 to 4 carbon atoms, an alkoxy of 1 to 4 atoms of 90 carbon or an aminomethyl; and R is chosen from the group consisting of an amino, a hydroxy, a carboxy salt, a protected carboxy, a formyloxy, or an azido; and M is a cation; (c) a heteroaromatic group chosen from the group consisting of 30 35 42 r101-(ch2)n-co- r101-ch-co- r 90 10 r101-o-ch2)-co- r101-s-ch2)-co- 15 20 r101-co-co- qa where n is 0, 1, 2 or 3; R is as defined above; and R101 is a 5, 6 or 7 substituted or unsubstituted heterocycle containing 1, 2, 3 or 4 nitrogen, oxygen and/or sulfur atoms. (d) a [[(4-substituted-2,3-dioxo-l-piperazinyl)carbonyl] aminojarylacetyl group corresponding to the formula 25 30 35 120 -CO—NH—CH—CO— A , in which R111 is a lower alkyl, a lower hydroxyalkyl, or an aromatic group of formula 10 15 20 25 30 43 r 7 o in which R, R' and R are as previously defined, or a 101,190 heteroaromatic ring as defined for R, and R is a lower alkyl or a substituted lower alkyl (the alkyl group being substituted by one or more halogeno, cyano, nitro, amino and/or mercapto groups); (e) a (substituted oxyimino)arylacetyl group corresponding to the formula 130 r -0-n=c-c0-i r101 1 al 1 30 in which R is as defined above and R is a hydrogen, a lower alkyl, a C3-C7 cycloalkyl/ C3-C7 carboxycycloalkyl or a substituted lower alkyl (whose alkyl group is substituted by one or more halogeno, cyano, nitro, amino, mercapto, alkylthio substituents) 111 lower, aromatic group (as defined for R), carboxy (including corresponding salts), lower alkanoylamino, lower alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl or di-(lower alkoxy)phosphinyl); (f) an (acylamino)arylacetyl group corresponding to the formula 140 r -co-nh-ch-co-i axl1 in which R111 is as defined above and R1^® is r7 r6 r8 35 £70 (in which R, R, R and n are as previously defined), a hydrogen, a lower alkyl, a substituted lower alkyl, an amino, an alkylamino, a (cyanoalkyl)amino or a q- 44 acylamino; and (g) a [[[3-substituted-2-oxo-l-imidazolidinyl]carbonyl] aminojarylacetyl group corresponding to the formula o 5 » i c C R —Vf* ^N—CO—NH—CH—CO— ! A CHj-GH2 r in which R111 is as defined above and R15 is a hydrogen, an alkylsulfonyl, -N=CHR111 (where R111 is as 10 1 fi 1 fi defined above), R CO- (where R is a hydrogen, an alkyl, or a halogen-substituted alkyl), an aromatic group (such as 111 defined for R above), a lower alkyl or a substituted lower alkyl (where the lower alkyl group is substituted by one or more halogeno, cyano, nitro, amino and/or mercapto groups), characterized in that starting materials are used and substituted in a corresponding manner. 6. A process for preparing a compound according to any one of claims 1 to 4, where R is an acyl group comprising a carbocyclic aromatic group of formula 15 20 30 R7 R6 25 \_/ UO 35 90 in which R is chosen from the group consisting of an amino, an acylamino, a hydroxy, a carboxyl salt, a fi 7 8 benzyloxycarbonyl, a formyloxy and an azido and R, R and R are chosen from the group consisting of a hydrogen, a halogen, a hydroxy, a nitro, an amino, a cyano, a trifluoromethyl, a C^-C4 alkyl, an alkoxy and an aminomethyl, characterized in that starting materials are used and substituted in a corresponding manner. 7. Process for preparing a compound according to the 10 45 6 7 8 90 claim 7 where R, R, R are hydrogen and R is hydrogen or hydroxy, characterized in that correspondingly substituted starting materials are used. 8. Method for preparing a compound according to one of 1 any of claims 1 to 4 where R is an acyl group comprising a group of formula r130-o-n=c-co- r101 101 in which R is a heterocycle with 5, 6 or 7 unsubstituted or substituted links containing 1, 2, 3 or 4 nitrogen atoms, of oxygen and/or sulfur, the heterocycle can be substituted by a halogen, a hydroxyl, a nitro, an amino, a cyano, a trifluoromethyl, a C-C alkyl or an alkoxy and 130 R is a hydrogen, a lower alkyl, a cycloalkyl in C3-C7, a C3-C7 carboxy-cycloalkyl or a substituted lower alkyl where the lower alkyl is substituted by one or more halogeno, cyano, nitro, amino, mercapto, alkylthio 111 inferior, aromatic group (as defined by R in claim 5), carboxy (including its salts), inferior alkanoylamino, inferior alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, inferior hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy(phenylmethoxy)phosphinyl or inferior di-alkoxy-phosphinyl, characterized in that starting materials are used and substituted in a corresponding manner. 9. Method for preparing a compound according to one 1 any of claims 1 to 4 where Rx is an acyl group of formula 30 21 NOR 15 20 25 .OR ^ 35 46 20 in which R is a hydrogenated or a group 91 amino-protectant, R is a hydrogen, a lower alkyl group, or a group of formula r22 5 I -c-cooh I r23 99 91 10 in which R and R are chosen from the group constituted by a hydrogen, a lower alkyl group, or, taken together with the carbon atom to which they are attached, form a carbocyclic ring with 3 to 7 links, characterized in that starting materials are used and substituted in a corresponding manner. 10. Process for preparing a compound according to the 90 91 claim 9 where R is a hydrogen, R is a methyl or E22 20' -c-cooh I r23 where R22 and R23 are chosen from the group consisting of a hydrogen and a methyl group, characterized in that starting materials are used and substituted in a corresponding manner. 11. A process for preparing a compound according to claim 1 of formula 30 35 47 , nor21 5 R20nh'/ 10 15 Ib 01 in which R has the meaning indicated in the 01 0 0 Claim 9 and Z, R, R and B have the meaning given in claim 1, characterized in that starting materials are used and substituted in a corresponding manner. 12. A process for preparing a compound according to claim 11 where R is a methyl group or a group of formula R22I -c-cooh I r23 20 in which R22 and R23 are a hydrogen or a methyl, Z is R3®-C where R3® is a hydrogen or a halogen, R31 is a lower alkyl, a lower haloalkyl, or a C3-Crj cycloalkyl, R32 is a lower alkyl, a piperazinyl, or a 0 0 lower alkylpiperazinyl and R is a hydrogen or a 2^ halogen, characterized in that starting materials are used and substituted in a corresponding manner. 13. A process for preparing a compound according to claim 12 where R30 is a hydrogen or a fluorine, R31 is a q o 30 ethyl, a fluoroethyl or a cyclopropyl, R is a methyl, an o o 4-Methylpiperazinyl or uft piperazinyl and R is a hydrogen or a fluorine, characterized in that correspondingly substituted starting materials are used. 14. Process for preparing a compound according to the 35 claim 1 which is an acid [6R-[6ot,7|3(Z) ]]-7-[[(2-amino-4- 48 thiazolyl)(R21-oxyimino)acetyl]amino]-3-[[[[6-R33,8-R30-l-(1-R31)-1,4-dihydro-7-(4-R3^-l-piperazinyl)-4-oxo-3-quinolyljcarbonyl] thiojmethylj-8-oxo-5-thia-l-azabicyclo[4.2.0joct-2-ene-2-carboxylic and its salts suitable for pharmaceutical use and the hydrates of these acids and salts where R and R are a hydrogen or a halogen, m R is a hydrogen, a lower alkyl, or a lower haloalkyl, R3^ is a hydrogen or a lower alkyl, and R21 is the r22 group. -c-cooh 22 23 where R and R are chosen from the group consisting of a hydrogen and a lower alkyl group, characterized by the use of correspondingly substituted starting materials. 15. A process for preparing a compound according to claim 14 where R and R are both a methyl, characterized in that correspondingly substituted starting materials are used. 16. Process for preparing a compound according to the 33 30 31 claim 15 where R and R are hydrogen or fluorine, R is an ethyl or 2-fluoroethyl group and R3^ is a methyl group, characterized in that starting materials are used and substituted in a corresponding manner. 17. A process for preparing a compound according to claim 15 wherein R33 and R30 are a fluorine and R31 is a 2-fluoroethyl, characterized in that correspondingly substituted starting materials are used. 18. Process for preparing a compound according to the 3 3 30 31 Claim 14 where R is a fluorine, R is a fluorine, R is a 2-fluoroethyl and R3^ is a methyl, characterized in that correspondingly substituted starting materials are used. 49 19. Process for preparing a compound according to the O O O A 11 claim 14 where R is a fluorine, R is a hydrogen, R is an ethyl and R3^ is a methyl, characterized in that correspondingly substituted starting materials are used. 20. A process for preparing a compound according to claim 14 where R is a fluorine, R is a 2-fluoroethyl, R3® is a hydrogen and R3^ is a methyl, characterized in that correspondingly substituted starting materials are used. 21. A process for preparing a compound according to any one of claims 8 to 20 wherein the groups N-O-R130 N-O-R21 -è- and -C- are in the syn form, that is, the Z form, or in the form of mixtures in which the syn form predominates, characterized in that correspondingly substituted starting materials are used 22. A process for preparing a compound according to claim 1, which is [6R-[6a,7(3(Z) ]]-7-[[2-amino-4-thiazolyl)(methoxyimino)-acetyl]amino]-3-[[[[6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-7-(4-methyl-l-piperazinyl)-4-oxo-3-quinolyl]-carbonyl]thio]methyl]-8-oxo-5-thia-l-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, as well as salts of this compound and hydrates of this compound and its salts, characterized in that correspondingly substituted starting materials are used. 23. A method according to any one of claims 1 to 22, characterized in that one of the possible operating modes (a), (b), (c) and (d) is carried out. 24. A process for manufacturing pharmaceutical preparations comprising mixing a compound of formula I, as defined in claim 1, or a readily hydrolyzable ester or salt of such a compound, or a hydrate of a compound of formula I or an ester or salt thereof, as an active ingredient, with non-toxic, inert, therapeutically compatible solid or liquid carriers and/or excipients commonly used in such preparations. $ SS? ", * & 50 C,- "4 to b & 25. Use of the final products defined in one^T v-" c comviîs^ v' any of claims 1 to 22 in the treatment or prophylaxis of diseases. 26. Use of the final products defined in any one of claims 1 to 22 in the treatment or prophylaxis of infectious diseases. 27. Use of the final products defined in any one of claims 1 to 22 for the manufacture of medicinal products for the treatment or prophylaxis of diseases 10 infectious. 28. New compounds, new compositions, new operating methods and new processes essentially as described here. ORIGINAL ef» pa§as 25 containing cross-references, openwork word .——.crossed-out word null Jose^ Council in Prq 26bl,I Boul. MOUNT! 20 By proxy'®}*} cîe^. / % ci(çj_ tuûuu (?c?c|v«. -g, r (Ut - SYl Q • 25 30 35