HRP970588A2 - Vinylpyrrolidinon cephalosporin derivatives - Google Patents

Description

The proposed invention relates to cephalosporin derivatives of the general formula I

[image]

where

R 1 represents hydrogen, lower alkyl, phenyl, benzyl, styryl, naphthyl or heterocyclyl; wherein lower alkyl, phenyl, benzyl, styryl, naphthyl or heterocyclyl can be optionally substituted with at least one halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted phenyl, amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkylcarboxy or lower alkylcarbamoyl;

R4, R5 independently represent hydrogen, lower alkyl or phenyl;

X is S, O, NH or CH 2 ;

n is 0, 1 or 2;

m is 0 or 1;

s is 0 or 1;

R2 represents hydrogen, hydroxy, -CH2-CONHR6, lower alkyl-Qr, cycloalkyl-Qr, lower alkoxy, lower alkenyl, cycloalkenyl-Qr, lower alkynyl, aralkyl-Qr, aryl-Qr, aryloxy, aralkyl, heterocyclic ring or heterocyclyl-Qr, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cyclo-alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkoxy and the heterocyclic ring may be substituted with at least one group selected from carboxy, amino, nitro, cyano, - SO2NHR6, optionally with fluorine substituted lower alkyl, lower alkoxy, hydroxy, halogen, -CONR6R7, -CH2CONR6R7, -N(R7)COOR8, -R7CO-, R7OCO-, R7COO-, -C(R7R9)CO2R8, -C( R7R9)CONR7R10, wherein

R 6 represents hydrogen, lower alkyl, cycloalkyl or aryl;

R7 and R9 independently represent hydrogen or lower alkyl;

R8 is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; and

R10 is hydrogen, ω-hydroxy-alkyl, phenyl, naphthyl or heterocyclyl, whereby phenyl, naphthyl or heterocyclyl is unsubstituted or substituted with at least one optionally protected hydroxy group, and halogen, with an arbitrarily substituted lower alkyl or ω-hydroxy- an alkyl group, optionally substituted with a lower alkoxy and/or cyano group; or the groups R7 and R10 together form a group of the formula

[image]

Q is -CHR-, CO or -SO2-;

r is 0 or 1;

R is hydrogen or lower alkyl; and

R 3 represents hydroxy, -O-, lower alkoxy, or -, where M represents an alkali metal;

as well as their esters which can immediately hydrolyze, pharmaceutically acceptable salts of said compounds and hydrates of compounds of formula I and their esters and salts.

The compounds of the proposed formula I can be used for the treatment of infectious diseases caused by gram-positive bacteria, especially infectious diseases caused by susceptible and resistant staphylococci, pneumococci, enterococci and the like.

In the above compounds of formula I, a substituent in position 3 may be present

[image]

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Compounds of formula I, i.e. those in which the substituent in the 3-position is in the E-form, are generally preferred.

In a special embodiment of compounds of formula I, n is 1.

As used herein, unless otherwise indicated, the term “halogen” or “halo” refers to all four forms, that is, chlorine or chloro; bromine or bromine; iodine or iodine; and fluorine or fluoro.

As used herein, the term "alkyl" or "lower alkyl" refers to both types of saturated hydrocarbon groups, i.e. straight and branched, having 1 to 8, preferably 1 to 4 carbon atoms, for example methyl, ethyl, n- propyl, isopropyl, tertiary butyl and the like.

By "optionally substituted lower alkyl" is meant a "lower alkyl" unit, as defined above", substituted with, for example, halogen, amino, hydroxy, cyano, carboxy, etc., such as carboxymethyl, 2-fluoroacetyl, trifluoromethyl , 2,2,2-trifluoroethyl, 2-chloroethyl, 2-hydroxy-ethyl and the like.

As used herein, the term "lower alkoxy" refers to a straight or branched chain hydrocarbonoxy group in which the "alkyl" portion is a lower alkyl group as defined above. Examples include methoxy, ethoxy, n-propoxy, and the like. The "alkyl" moiety may be substituted as defined above.

As used herein, the terms "alkenyl" and "lower alkenyl" refer to an unsubstituted or substituted hydrocarbon radical chain having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, and having at least one olefinic double bond, e.g. allyl, vinyl, etc.

As used herein, the term "lower alkynyl" refers to an unsubstituted or substituted hydrocarbon radical chain having from 2 to 8 carbon atoms, preferably from 2 to 4 carbon atoms, having at least one triple bond.

By "cycloalkyl" is meant a saturated carbocyclic unit having 3 to 7 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

As used herein, the term "cycloalkenyl" refers to a carbocyclic ring radical having at least one olefinic double bond.

The term "aryl" refers to a radical derived from an aromatic hydrocarbon by removing one hydrogen atom and which can be saturated or unsaturated. An aromatic hydrocarbon can be mononuclear or polynuclear. Examples of aryl of the mononuclear type include phenyl, tolyl, xylyl, mesityl, cumenyl, and the like. Examples of polynuclear type aryls include naphthyl, natryl, phenanthryl and the like. The aryl group may have at least one substituent selected from, for example, halogen, hydroxy, cyano, carboxy, nitro, amino, lower alkyl, lower alkoxy, carbamoyl, such as 2,4-difluorophenyl, 4-carboxyphenyl, 4-nitrophenyl, 4-aminophenyl, 4-methoxyphenyl.

The term "aralkyl" refers to an alkyl group containing an aryl group. It is a hydrocarbon group that has both aromatic and aliphatic structures, that is, a hydrocarbon group in which the hydrogen of the lower alkyl group is substituted with a monocyclic aryl group, eg phenyl, tolyl, etc.

As used herein, “aryloxy” is an oxygen radical having an aryl substituent (ie, -O-aryl).

As used herein, "aralkoxy" is an oxygen radical having an aralkyl substituent.

As used herein, the term "lower alkylamino and di-lower alkylamino" refers to mono- and dialkylamino moieties in which the alkyl group is as defined above, for example methylamino, 2-ethylamino, -CH2NHCH3, -CH2CH2NHCH3, -CH2CH2N(CH3 )2, N-methylamino, N-ethylamino, N,N-dimethylamino, N,N-diethylamino and the like.

As used herein, the term "heterocyclic ring" refers to an unsaturated or saturated, unsubstituted or substituted 4-, 5-, 6-, or seven-membered heterocyclic ring containing at least one heteroatom selected from the group consisting of oxygen, nitrogen, or sulfur. Examples of heterocyclic rings include, but are not limited to, for example, the following groups: azetidinyl, pyridyl, pyrazinyl, piperidyl, piperidino, N-oxido-pyridyl, pyrimidyl, piperazinyl, pyrrolidinyl, pyridazinyl, N-oxy-pyridazinyl, pyrazolyl, triazinyl , imidazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 -oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1H-tetrazolyl, 2H-tetrazolyl; furyl, 1H-azepinyl, thiophenyl, tetrahydrothiophenyl, isoxazolyl, isothiazolyl, oxazolidinyl, etc. Substituents for the heterocyclic ring include, for example, lower alkyls such as methyl, ethyl, propyl, etc., lower alkoxy groups such as methoxy, ethoxy, etc., halogens. such as fluorine, chlorine, bromine, etc., halogen-substituted alkyls such as trifluoromethyl, trichloroethyl, etc., amino, mercapto, hydroxyl, carbamoyl, or carboxy groups. A further substituent is oxo, such as 2-oxo-oxazolidin-3-yl, 1,1-dioxo-tetrahydrothiophen-3-yl. Further examples of substituted heterocycles are 6-methoxy-pyridin-3-yl, 5-methyl-isoxazol-3-yl, 1-methyl-pyridinium-2-yl, -3-yl, -4-yl, 1-carbamoylmethyl-pyridinium -2-yl, 1-carbamoylmethyl-pyridinyl-3-yl, 1-carbamoylmethyl-pyridinyl-2-yl, -3-yl, -4-yl, 1-[N-(3-fluoro-4-hydroxy)phenyl ]-carbamoylmethyl-pyridinium-2-yl.

The term "substituted phenyl" refers to phenyl mono- or disubstituted with halogen, optionally substituted lower alkyl, optionally protected with a hydroxy or amino group, nitro or trifluoromethyl.

The term "optionally protected hydroxy group" refers to a hydroxy group or to a hydroxy group protected by, for example, t-butyloxycarbonyl, trimethylsilyl, t-butyldimethylsilyl, tetrahydropyranyl, trifluoroacetyl, or refers to an ester group, for example phosphate, sulfate and similar to.

The term "optionally protected amino" refers to an amino or an amino group protected for example with BOC[t-butoxy-carbonyl; other names: (1,1-dimethylethoxy)-carbonyl], benzyloxycarbonyl and allyloxycarbonyl.

As used herein, "pharmaceutically acceptable salts" in the present invention include salts derived from metals, ammonium salts, quaternary ammonium salts derived from organic bases, and salts of amino acids. Examples of preferred metal salts are those derived from alkali metals, for example lithium (Li+), sodium (Na+) and potassium (K+). Examples of quaternary ammonium salts derived from organic bases include tetramethylammonium (N+(CH3)4), tetraethylammonium (N+(CH2CH3)4), benzyltrimethylammonium, (N+(C6H5CH2)(CH3)3), phenyltriethylammonium (N+(C6H5)(CH2CH3)3 ), and similar. These amine-derived salts include salts with N-ethylpiperidine, procaine, dibenzylamine, N,N'-dibenzylethylenediamine, alkylamines or dialkylamines, as well as salts with amino acids such as, for example, salts with arginine or lysine. Furthermore, particularly preferred salts are hydrochlorides, sulfates, phosphates, lactates, mesylates or internal salts.

The term "amino protecting group" refers to protecting groups that are commonly used to replace the acidic proton of an amino group. Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 7, John Wiley and Sons, Inc. (1981), p. 218-287, which is incorporated herein by reference. These examples include primarily carbamates, eg fluorenyl-methyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)-ethyl, t-butyl, allyl, benzyl. Further protecting groups are 3,5-dimethoxybenzyl, p-nitrobenzyl, diphenylmethyl, triphenylmethyl, benzyl, formyl, acetyl, trifluoroacetyl, chloroacetyl, cyclic imides N-phthaloyl, N-trimethylsilyl, N-benzenesulfonyl, N- toluenesulfonyl, N-p-methylbenzylsulfonyl. A preferred group is BOC[t-butoxycarbonyl, otherwise known as (1,1-dimethylethoxy)carbonyl], benzyloxycarbonyl and allyloxycarbonyl.

The term "carboxyl protecting group" refers to groups that are commonly used to replace the acidic proton of a carboxyl group. Examples of such groups are described in Green, T., Protective Groups in Organic Synthesis, Chapter 5, p. 152-192 (John Wiley and Sons, Inc. 1981), which is incorporated herein by reference. Preferred examples include especially methoxymethyl, methylthiomethyl, 2,2,2-trichloroethyl, 2-haloethyl, 2-(trimethylsilyl)ethyl, t-butyl, allyl, benzyl, triphenylmethyl (trityl), benzylhydryl, p-nitrobenzyl, p- methoxybenzyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, i-propyl-dimethylsilyl. Benzylhydryl, t-butyl, p-nitro-benzyl, p-methoxybenzyl and allyl are preferred.

The term "hydroxy protecting group" refers to protecting groups commonly used in the art, such as trimethylsilyl, t-butyldimethylsilyl, dimethylphenylsilyl, triphenylmethyl, lower alkanoyl, acetyl, tetrahydropyranyl, benzyl, p-bitrobenzyl or t-butyloxy- carbonyl.

As esters of compounds of formula I which can immediately hydrolyze, here are meant compounds of formula I whose carboxy group(s) (for example 2-carboxy group) is/are present in the form of an ester group which can immediately hydrolyze. Examples of such esters, which may be of the usual type, are lower alkanoyloxy-alkyl esters (e.g. acetoxymethyl, pivaloyloxymethyl, 1-acetoxyethyl and 1-pivaloyloxyethyl ester), lower alkoxycarbonyloxyalkyl esters (e.g. methoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl and 1- -isopropoxy-carbonyl-oxyethyl ester), lactonyl esters (e.g. phthalidyl and thiophthalidyl ester), lower alkoxymethyl esters (e.g. methoxy-methyl ester) and lower alkanoylaminomethyl esters (e.g. acetamidomethyl ester). Other esters (eg, benzyl and cyanomethyl esters) may also be used. Other examples of such esters are the following: (2,2-dimethyl-1-oxo-propoxy)methyl ester; 2-[(2-methylpropoxy)carbonyl]-2-pentenyl ester; 1-[[(1-methylethoxy)carbonyl]oxy]ethyl ester; 1-(acetyloxy)ethyl ester; (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester; 1-[[(cyclo hexyloxy ]carbonyl]oxy-ethyl ester; and 3,3-dimethyl-2-oxobutyl ester. One skilled in the art can see that the compounds of the proposed invention can form esters, which can immediately hydrolyze, on the free hydroxy group of the compound, on for example on the carboxy group in position 1 or any other carboxy group.

Examples of salts of compounds of formula I are defined above under "pharmaceutically acceptable salts".

A preferred embodiment of the invention consists of compounds of formula I in which

R1 is selected from the group consisting of phenyl, 2,4,5-trichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-trifluoromethylphenyl, 4-methoxyphenyl, 4-hydroxymethylphenyl, 3,4-dimethoxyphenyl , 4-methyl-1,2,4-triazol-5-yl, 1-methyl-tetrazol-5-yl, pyrimidin-2-yl, optionally substituted pyrimidin-1-yl, -2-yl, -3- yl or 4-yl, benzylimidazol-2-yl, 2-benzithiazolyl, 4-pyridinyl, (2-amino)-thiazol-4-yl, 2-naphthyl, benzyl and

R2 is methylcyclopropyl, 2-, 3- or 4-hydroxybenzyl, pyrrolidin-3-yl or a group of the formula

[image]

where

Q1 is -CH2-;

r is 0 or 1;

R11 is hydrogen, lower alkyl, ω-hydroxy alkyl, benzyl or alkylheterocyclyl, wherein benzyl or heterocyclyl is unsubstituted or substituted with at least one of the groups cyano, carboxy or hydroxy; or -CH 2 CONR 7 R 10 ; in which they are

R7 and R10 defined as above.

The compounds of formula I as well as their salts and esters which can immediately hydrolyze can be hydrated. Hydration can be carried out during the production process or it can be carried out gradually as a result of the hygroscopic properties of the initially anhydrous product.

Particularly preferred compounds of formula I are

(E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-[2-(2,4,5-trichlorophenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate,

[image]

(E)-(6R,7R)-3-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8 -oxo-7-[2-(1-benzothiazol-2-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate,

[image]

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(2,4,5-trichloro-phenylsulfanyl)-acetylamino ]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

[image]

(E)-(6R,7R)-7-[2-(benzothiazol-2-ylsulfanyl)-acetyl-amino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidene-methyl)-8- oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

[image]

(E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-[2-(pyridin-4-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate,

[image]

(E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo -pyrrolidin-3-ylidene-methyl]-8-oxo-7-(2,4,5-trichlorophenylsulfanyl)-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2 -carboxylate,

[image]

(E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-(2-phenylsulfanyl)-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate,

[image]

(E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo -pyrrolidin-3-ylidenemethyl]-7-[2-(naphthalen-2-yl-sulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene- 2-carboxylate,

[image]

(E)-(6R,7R)-7-[2-(3,4-dichloro-phenylsulfanyl)-acetyl-amino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl) -methyl]-pyridin-1-ij-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene- 2-carboxylate,

[image]

(E)-(6R,7R)-3-[1-(3-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(2,4,5-trichloro- phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

[image]

(E)-(6R,7R)-3-[1-(3-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-naphthalen-2-ylsulfanyl)-acetyl- amino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

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mixture of (E)-(6R,7R)-8-oxo-[(R)- and -[(S)-2-oxo-[1,3']bi-pyrrolidinyl-3-ylidenemethyl]-8-oxo- 7-[2-(2,4,5-trichloro-phenyl-sulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride,

[image]

(E)-(6R,7R)-8-oxo-3-[(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-(2-phenylsulfanyl-acetylamino)-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride (1:1),

[image]

(E)-(6R,7R)-3-[1-[1(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidene-methyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate,

[image]

(E)-(6R,7R)-7-[2-(2,5-dichloro-phenylsulfanyl)-acetyl-amino]-3-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl] -pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate ,

[image]

(E)-(6R,7R)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(naphthalen-1-ylsulfanyl)-acetylamino]-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1),

[image]

The compounds of the proposed invention can be used as antibiotics that have strong and broad antibacterial activity, especially against gram-positive organisms, eg methacillin-resistant staphylococci (MRSA).

The products according to the invention can be used as medicines, for example in the form of pharmaceutical preparations for parenteral administration and for this purpose they are preferably processed into preparations as lyophilisates or as dry powders for dilution with usual means such as water or isotonic saline.

Depending on the nature of the pharmacologically active compound, pharmaceutical preparations may contain a compound for the prevention and treatment of infectious diseases in mammals, humans and animals, with a daily dose of approx. 10 mg to approx. 4000 mg, especially approx. 50 mg to approx. 3000 mg, and usually with a dosage that is evaluated by an expert and that depends on the age, the condition of the mammal and the type of disease that is to be prevented or treated. The daily dose can be given in a single dose or it can be divided into several doses. An average single dose can be of approx. 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg and 2000 mg.

Featured compounds of the proposed invention (A to F, below) were tested. The activity in vitro was determined using the minimum concentration of inhibition of the microorganism spectrum by the agar dilution method in Mueller Hinton agar, inoculum = 104 CFU/spot.

A: (E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidenemethyl]-8-oxo-7-[2-(2,4,5-trichloro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2- carboxylate,

B: (E)-(6R,7R)-3-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl] -8-oxo-7-[2-(1-benzothiazol-2-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate,

C: (E)-(6R,7R)-7-[2-(benzothiazol-2-ylsulfanyl)-acetyl-amino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidene-methyl)- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

D: (E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidenemethyl]-8-oxo-7-[2-(pyridin-4-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate,

E: (E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2 -oxo-pyrrolidin-3-ylidenemethyl]-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene -2-carboxylate,

F: (E)-(6R,7R)-3-[1-(3-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(2,4,5- trichloro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

G: (E)-(6R,7R)-3-[1-(3-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-naphthalen-2-ylsulfanyl)- acetyl-amino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid,

H: mixture of (E)-(6R,7R)-8-oxo-3-[(R)- and -[(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-8- oxo-7-[2-(2,4,5-trichloro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride,

I: (E)-(6R,7R)-3-[1-[1(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo -pyrrolidin-3-ylidene-methyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate.

In vitro action against sensitive and resistant

S. aureus, MIC [µg/ml]

[image]

Dilution method on Mueller Hinton agar,

inoculum = 104 CFU/spot.

Compounds of the formula according to the invention, as well as their pharmaceutically acceptable salts, hydrates or esters which can immediately hydrolyze, can be produced according to the invention by

a) compound of formula II

[image]

where

R2 is defined as above,

Rf is hydrogen or trimethylsilyl; and

Rg is hydrogen, benzhydryl, p-methoxybenzyl, t-butyl, trimethylsilyl or allyl, or a salt thereof,

treated with a carboxylic acid of the general formula III

[image]

wherein R 1 , X s , R 4 , R 5 and m are as defined above and Y is -OH, or with a reactive functional derivative thereof wherein Y represents, for example halogen, such as chloride or bromide, or 1-imidazolyl, 2- mercaptobenzotriazolyl, 1-hydroxy-benzotriazolyl or pivaloyloxy, or with an activating agent such as HBTU (ortho-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium-hexafluorophosphate), DCC (N,N'- di-cyclohexyl-carbodiimide), CDI (1,1'-carbonyl-dimidazole), CDT (1,1'-carbonyl-1,2,4-ditriazole) or thionyl chloride and the like,

b) for compounds of formula I in which X is S, O or NH, by processing the compound of formula IV

[image]

wherein R4, R5, m, n, R2 and Rg are as defined above and Hal is halogen such as bromine or chlorine or iodine, preferably bromine,

with the corresponding thiol or thioalt or the corresponding alcohol or alcoholate or the corresponding amine in the presence of a base,

c) for the preparation of esters of compounds of formula I which can immediately hydrolyze, compounds of formula I are subjected to appropriate esterification, or

d) for the production of salts or hydrates of compounds of formula I or their hydrates or their salts, compounds of formula I are converted into salts or hydrates or into hydrates of said salts.

The reaction of the compound of formula II, prepared in accordance with embodiment (a), with the compound of formula III, or with its reactive derivative, can be carried out in a manner known per se. Carboxy groups in compounds of formula II (carboxy group in position 2 and/or carboxy groups optionally present in R2) in compounds of formula III (carboxy groups optionally present in R1) can be protected intermediately or in situ, for example by esterification, thus to give an ester which can be immediately cleaved off, such as a silyl ester (eg trimethylsilyl ester) or a p-methoxy-benzhydryl ester.

Furthermore, amino groups present in compounds of formula II (at position 7 and/or present in R2 if necessary) and/or present in R1 of compounds of formula III can be protected, for example, with protecting groups that can be cleaved by acid hydrolysis (e.g. tert .butoxycarbonyl or trityl groups) or by basic hydrolysis (e.g. trifluoroacetyl group), hydrazinolysis (e.g. phthalimido group) or catalytic cleavage in the presence of Pd (allyloxycarbonyl group). Preferred protecting groups are t-butyloxycarbonyl, allyloxycarbonyl, chloroacetyl, bromoacetyl and iodoacetyl groups, especially the chloroacetyl group. The last mentioned protecting groups can be cleaved by treatment with thiourea. Another preferred protecting group is phenylacetyl, which can be cleaved by treatment with PCl5 or enzymatically.

The 7-amino group in a compound of formula II can be protected in situ, for example, with a silyl protecting group, such as a trimethylsilyl group.

In the reaction of a 7-amino compound of formula II with a carboxylic acid of formula III, or with a reactive functional derivative thereof, for example, the free carboxylic acid can be reacted with the above-mentioned ester of a compound of formula II in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, in an inert solvent such as ethyl acetate, acetonitrile, dioxane, chloroform, methylene chloride, benzene or dimethylformamide, and then the ester group can be cleaved off.

Prepared according to another embodiment, an acid salt of formula II (e.g., a trialkylammonium salt, as a triethylammonium salt) is reacted with a reactive functional derivative of a carboxylic acid of formula III, as mentioned earlier, in an inert solvent (e.g., in dimethylformamide, dimethylacetamide , dimethylsulfoxide and the like).

The reaction of the 7-amino compound of formula II with the carboxylic acid of formula III, or with its reactive derivative is usually carried out at a temperature between approx. -40oC and +60oC, eg at room temperature.

Embodiment (b) of the process of the present invention involves treating a compound of formula IV with a suitable thiol or thiolate or with a suitable alcohol or alcoholate or with a suitable amine in the presence of a base, for example a trialkylamine, such as trimethylamine, triethylamine, sodium bicarbonate, DBU (1.8 -diazabicyclo[5,4,0]undec-7-ene(1,5-5) to give the corresponding thioether, ether or amine, if necessary the amino, hydroxy or carboxyl groups present can be intermediately protected with the groups described above.

Deprotection (removal of the protecting group) of the protected amino, hydroxy or carboxyl groups present in the compound of formula II, III or IV can be carried out as follows.

Removal of the amino protecting group

Possible amino-protecting groups are those used in peptide chemistry, such as the protecting groups mentioned above. These examples include primarily carbamates, ie fluorenylmethyl, 2,2,2-trichlorenyl, t-butyl, triphenylmethyl, allyl, benzyl. Further protecting groups are p-nitrobenzyl, diphenylmethyl, triphenylmethyl, benzyl, formyl, trifluoroacetyl, chloroacetyl, cyclic imides of N-phthaloyl, N-trimethylsilyl, N-benzenesulfonyl, N-toluenesulfonyl. A preferred group is BOC (t-butoxycarbonyl; otherwise known as (1,1-dimethylethyloxy)carbonyl), benzyloxycarbonyl, allyloxycarbonyl or trimethylsilyl.

Amino protecting groups can be cleaved by acid hydrolysis (eg t-butoxycarbonyl or triphenylmethyl group), eg with aqueous formic acid, with trifluoroacetic acid or basic hydrolysis (eg trifluoroacetyl group). Chloroacetyl, bromoacetyl and iodoacetyl groups are separated by treatment with thiourea. The trimethylsilyl group is cleaved by hydrolysis or alcoholysis.

Amino protecting groups, which can be cleaved off by acid hydrolysis, are preferably removed with the help of a lower alkanecarboxylic acid, which can be halogenated. In particular, formic acid or trifluoroacetic acid is used. The reaction is carried out in acid or in the presence of a co-solvent such as a halogenated lower alkane, eg methylene chloride. Acid hydrolysis is generally carried out at room temperature, although it can also be carried out at a slightly higher or slightly lower temperature (eg at a temperature ranging from approx. -30oC to +40oC). Protecting groups, which can be cleaved off under basic conditions, are generally hydrolyzed with dilute caustic alkali at 0oC to 30oC. Chloroacetyl, bromoacetyl and iodoacetyl protecting groups can be cleaved off using thiourea in an acidic, neutral or alkaline environment at approx. 0oC-30oC. The phthalimido group can be cleaved with hydrazine at -20oC to +50oC.

Removal of hydroxy protecting groups

Possible hydroxy protecting groups are those generally known in the art, such as trimethylsilyl, t-butyldimethylsilyl, dimethylphenylsilyl, triphenylmethyl, lower alkanoyl, acetyl, trifluoroacetyl, tetrahydropyranyl, benzyl, p-bitrobenzyl or t-butoxycarbonyl. These groups are removed in the presence of inorganic bases such as sodium bicarbonate.

Removal of protective groups on the carboxy functional

group

As carboxyl protecting groups, ester forms can be used which can easily be converted into free carboxyl groups under mild conditions, for example benzhydryl, t-butyl, p-nitrobenzyl, p-methoxybenzyl, allyl, etc.

These protecting groups can be removed as follows:

benzhydryl: trifluoroacetic acid with anisole, phenol, cresol or triethylsilane at approx. -40oC; hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran; BF3-etherate in acetic acid at approx. 0 to 50oC;

t-butyl: formic acid or trifluoroacetic acid with or without anisole, phenol, cresol or triethylsilane and a solvent such as dichloromethane at approx. -10oC to room temperature;

p-nitrobenzyl: sodium sulfide in acetone/water at approx. 0oC to room temperature; or hydrogen with Pd/C in an alcohol such as ethanol or in tetrahydrofuran;

p-Methoxybenzyl: formic acid at approx. 0oC to 50oC; or trifluoroacetic acid and anisole, phenol or triethylsilane at approx. -40oC to room temperature;

allylic: by a palladium(O)-catalyzed transalkylation reaction in the presence of the sodium or potassium salt of 2-ethyl-hexanoic acid, see for example J. Org. Chem. 1982, 47, 587.

trimethylsilyl: hydrolysis or alcoholysis at room temperature.

In order to produce esters of carboxylic acids of formula I which immediately hydrolyze in accordance with embodiment (c) of the process given by the proposed invention, the carboxylic acid of formula I is preferably reacted with a suitable halide, preferably an iodide containing the desired ester group. The reaction can be accelerated by a base such as an alkali metal hydroxide, an alkali metal carbonate, or an organic amine such as triethylamine. Esterification is preferably carried out in an inert organic solvent such as dimethylacetamide, hexamethylphosphoric acid triamide, dimethyl sulfoxide or, especially, in dimethylformamide. The reaction is preferably carried out at a temperature in the range of approx. 0-40oC.

The production of salts and hydrates of compounds of formula I, or hydrates of said salts in accordance with execution (D) of the procedure given by the proposed invention, can be carried out in a manner known per se; for example, by reacting a carboxylic acid of formula I or a salt thereof with an equivalent amount of the desired base, usually in a solvent such as water or in an organic solvent (eg ethanol, methanol, acetone and the like). In accordance with this, salt formation occurs with the addition of organic or inorganic salt. The temperature at which salt formation occurs is not critical. Salt formation generally takes place at room temperature, but it can also take place at a slightly higher or slightly lower temperature, for example in the range from 0oC to +50oC.

Hydrate production usually occurs spontaneously during the production process or as a result of the hygroscopic properties of the initial anhydrous product. For controlled hydrate production, the fully or partially anhydrous carboxylic acid of formula I, or a salt thereof, can be exposed to a humid atmosphere (eg at approx. +10oC to +40oC).

An example of a procedure for obtaining a product according to the invention are the following reaction schemes 1 and 2 below.

Scheme 1, execution (a)

[image]

where X represents -CH2-, O, NH, and the remaining symbols are as defined above.

Scheme 2, execution (b)

[image]

where X represents O, S, NH and X' corresponds to OH or O-, SH or S- or NH2, and the remaining symbols are as defined above.

Examples

Method A

Example A1

(E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-[2-(2,4,5-trichloro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[image]

40.9 mg (0.25 mmol) was added to a solution of 68.4 mg (0.25 mmol) of (2,4,5-trichloro-phenylsulfanyl)acetic acid in 3 ml of N,N-dimethylacetamide with stirring and in an argon atmosphere ) 1,1'-carbonyldiimidazole, After 30 minutes, 136.4 mg (0.21 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[( 4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[ 4.2.0]oct-2-ene-2-carboxylate trifluoroacetate. After 3 hours, the reaction mixture was poured into diethyl ether. The solid was collected by filtration and triturated with ethyl acetate.

Yield: 112.0 mg (67.5%) beige powder.

IR(KBr): 1770, 1678, 1642 cm-2,

MS(ISP): 790.2 (M+).

In accordance with the procedure from example A1, the following compounds were additionally prepared:

Example A2

(E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-[2-(1-benzothiazol-2-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[image]

With 70.0 mg (0.43 mmol) of 1,1'-carbonyldiimidazole, 96.0 mg (0.43 mmol) of (benzothiazol-2-ylsulfanyl)-acetic acid and 233.8 mg (0.36 mmol) ( E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin- 3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]-oct-2-ene-2-carboxylate trifluoroacetate in 4 ml of N,N-dimethyl acetamide.

Yield: 92.0 mg (34.4%) of yellow powder.

IR(KBr): 1769, 1679, 1643, 1625 cm-2,

MS(ISP): 743.3 (M+).

Example A3

(E)-(6R,7R)-3-[1-[1-[(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(2,4,5 -trichloro-phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 180.0 mg (1.11 mmol) of 1,1'-carbonyldiimidazole, 301.4 mg (11.1 mmol) of (2,4,5-trichloro-phenylsulfanyl)-acetic acid and 323.2 mg (0, 92 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2 .0]oct-2-ene-2-carboxylic acid in 8 ml of N,N-dimethylacetamide.

Yield: 337.0 mg (60.4%) brown powder.

IR(KBr): 1773, 1668, 1621 cm-2,

MS(ISP): 602.2 (M+).

Example A4

(E)-(6R,7R)-7-[2-(benzothiazol-2-ylsulfanyl)-acetylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidene-methyl)-8-oxo- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 220.0 mg (1.35 mmol) of 1,1'-carbonyldiimidazole, 304.1 mg (1.35 mmol) of (benzothiazol-2-ylsulfanyl)-acetic acid and 394.8 mg (1.13 mmol) ( E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct -2-ene-2-carboxylic acid in 7 ml of N,N-dimethylacetamide.

Yield: 173.0 mg (27.5%) of orange powder.

IR(KBr): 1772, 1665, 1623 cm-2,

MS(ISP): 557.1 (M+).

Example A5

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-(2-phenylsulfanyl)-acetylamino]-5-thia-1-aza -bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 167.0 mg (1.03 mmol) of 1,1'-carbonyldiimidazole, 173.0 mg (1.03 mmol) of 2-(phenylthio)-acetic acid and 300.0 mg (0.86 mmol) (E) -(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]-oct -2-ene-2-carboxylic acid in 6 ml of N,N-dimethyl-acetamide.

Yield: 271.5 mg (63.1%) brown powder.

IR(KBr): 1773, 1662, 1624 cm-2,

MS(ISP): 500.3 (M+).

Example A6

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-(2-pyridin-4-ylsulfanyl-acetylamino)-5-thia- 1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 111.0 mg (0.68 mmol) of 1,1'-carbonyldiimidazole, 116.0 mg (0.68 mmol) of (pyridin-4-ylsulfanyl)-acetic acid and 200.0 mg (0.57 mmol) ( E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]- of oct-2-ene-2-carboxylic acid in 4 ml of N,N-dimethylformamide.

Yield: 79.0 mg (27.5%) beige solid.

IR(KBr): 1769, 1667, 1624

MS(ISP): 501.1 (M+H+).

Example A7

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-naphthalen-2-ylsulfanyl)-acetyl-amino]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 167.0 mg (1.03 mmol) of 1,1'-carbonyldiimidazole, 225.0 mg (1.03 mmol) of (naphthalen-2-ylsulfanyl)-acetic acid and 300.0 mg (0.86 mmol) ( E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct -2-ene-2-carboxylic acid in 4 ml of N,N-dimethylformamide.

Yield: 320.0 mg (62%) brown powder.

IR(KBr): 1769, 1662, 1623 cm-2,

MS(ISP): 550.2 (M+).

Example A8

(E)-(6R,7R)-7-[2-(2-aminothiazol-4-yl)-acetylamino]-3-[1-[1-[(4-hydroxyphenylcarbamoyl)-methyl]-pyridin-1- ij-4-yl-methyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate

[image]

With 54.5 mg (0.34 mmol) of 1,1'-carbonyldiimidazole, 53.0 mg (0.34 mmol) of (2-aminothiazol-4-yl)-acetic acid and 182.0 mg (0.28 mmol ) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2- oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml of N,N-dimethylformamide. The obtained solid was purified by reverse phase chromatography (RP-18 LiCropPrep gel, water:acetonitrile = 9:1). The organic solvent was removed by evaporation on a rotary evaporator and the aqueous phase was freeze-dried.

Yield: 49.0 mg (24.7%) of beige lyophilizate.

IR(KBr): 1775, 1680, 1650 cm-1,

MS(ISP): 676.2 (M+).

Example A9

(E)-(6R,7R)-7-[2-(2-amino-thiazol-4-yl)-acetylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8- oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 167.0 mg (1.03 mmol) of 1,1'-carbonyldiimidazole, 163.0 mg (1.03 mmol) of (2-aminothiazol-4-yl)-acetic acid and 300.0 mg (0.86 mmol ) (E)-(6R,7R)-7-amino-3-(1-cyclo-propylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo-[ 4.2.0]oct-2-ene-2-carboxylic acid in 6 ml of N,N-dimethylformamide. The obtained solid was purified by reverse phase chromatography (RP-18 LiCropPrep gel, water:acetonitrile = 9:1). The organic solvent was removed by evaporation on a rotary evaporator and the aqueous phase was freeze-dried.

Yield: 120.0 mg (28.6%) of beige lyophilizate.

IR(KBr): 1769, 1664, 1620 cm-1,

MS(ISP): 490.2 (M+).

Example A10

(E)-(6R,7R)-3-[1-[1-[(4-hydroxyphenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-[2-(pyridin-4-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[image]

With 70.0 mg (0.43 mmol) of 1,1'-carbonyldiimidazole, 72.8 mg (0.43 mmol) of (pyridin-4-ylsulfanyl)-acetic acid and 232.8 mg (0.36 mmol) ( E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo- pyrrolidine-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml of N,N-dimethylacetamide. The obtained solid was purified by column chromatography on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 58.0 mg (30.0%) of beige lyophilizate.

IR(KBr): 1772, 1670, 1625 cm-1,

MS(ISP): 687.3 (M+H+).

Example A11

(E)-(6R,7R)-3-[1-[1-[(4-hydroxyphenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-(2-phenylsulfanyl)-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[image]

With 70.0 mg (0.43 mmol) of 1,1'-carbonyldiimidazole, 71.0 mg (0.43 mmol) of (phenylthio)-acetic acid and 188.4 mg (0.29 mmol) of (E)-( 6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo-pyrrolidine- 3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml of N,N-dimethylacetamide. The resulting solid is suspended in 6 ml of water:acetonitrile (1:1) and HCl is added until all the compound is dissolved. After column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1) the organic solvent was removed by rotary evaporation rinse and the aqueous phase is freeze-dried.

Yield: 105.6 mg (64.4%) of beige lyophilizate.

IR(KBr): 1770, 1680, 1643 cm-1,

MS(ISP): 686.3 (M+H+).

Example A12

(E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo -pyrrolidine-3

-ylidene-methyl]-7-[2-(naphthalen-2-yl-sulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2- carboxylate

[image]

With 58.3 mg (0.36 mmol) of 1,1'-carbonyldiimidazole, 78.5 mg (0.36 mmol) of (naphthalen-2-ylsulfanyl)-acetic acid and 200.0 mg (0.30 mmol) ( E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxyphenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2- oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml of N,N-dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 55.0 mg (24.0%) of beige lyophilizate.

IR(KBr): 1770, 1680, 1650, 1628 cm-1,

MS(ISP): 754.3 (M+H+).

Example A13

(E)-(6R,7R)-7-[2-(3,4-dichloro-phenyl-sulfanyl)-acetylamino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl) -methyl]-pyridin-1-ij-4-yl-methyl]-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylate

[image]

With 60.0 mg (0.36 mmol) of 1,1'-carbonyldiimidazole, 85.0 mg (0.36 mmol) of [(3,4-dichloro-phenyl-sulfanyl)thio]acetic acid and 200.0 mg ( 0.30 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl -4-yl-methyl]-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate trifluoro -acetate in 4 ml of N,N-dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 70.0 mg (30.2%) of beige lyophilizate.

IR(KBr): 1772, 1680, 1642, 1617 cm-1,

MS(ISP): 772.3 (M+H+).

Example A14

(E)-(6R,7R)-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-7-[2-(2,4, 5-trichloro-phenyl-sulfanyl)-acetyl-amino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 146.0 mg (0.90 mmol) of 1,1'-carbonyldiimidazole, 244.4 mg (0.90 mmol) of (2,4,5-trichloro-phenyl-sulfanyl)-acetic acid and 301.0 mg ( 0.73 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidene-methyl]-8 -oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate in 5 ml of N,N-dimethylacetamide.

Yield: 180.0 mg (37.7%) of beige lyophilizate.

IR(KBr): 1767, 1664, 1614 cm-1,

MS(ISP): 654.1 (M+H+).

Example A15

(E)-(6R,7R)-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-7-[2-naphthalen-2-yl -sulfanyl)-acetyl-amino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 146.0 mg (0.90 mmol) of 1,1'-carbonyldiimidazole, 196.5 mg (0.90 mmol) of (naphthalen-2-yl-sulfanyl)-acetic acid and 301.0 mg (0.73 mmol ) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5 -thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate in 5 ml of N,N-dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 65.0 mg (14.6%) of beige lyophilizate.

IR(KBr): 1771, 1663, 1589 cm-1,

MS(ISP): 602.2 (M+H+).

Example A16

(E)-(6R,7R)-8-oxo-3-[(R)- and [(S)-2-oxo-[1,3']bipyrrolidinyl-3-ylidene-methyl]-8-oxo- 7-[2-(2,4,5-trichloro-phenyl-sulfanyl)-acetyl-amino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride

[image]

Grade a:

A mixture of (E)-(6R,7R)-3-[(R)- and [(S)-1'-allyloxy-carbonyl-2-oxo-[1,3']bipyridinyl-3-ylidene-methyl]- 8-oxo-7-[2-(2,4,5-trichloro-phenyl-sulfanyl)-acetyl-amino]-5-thia-1-aza-bicyclo-[4.2.0]oct-2-en-2 -carboxylic acids

[image]

With 115.2 mg (0.71 mmol) of 1,1'-carbonyldiimidazole, 193.4 mg (0.71 mmol) of (2,4,5-trichlorophenyl-sulfanyl)-acetic acid and 329.1 mg (0, 59 mmol) mixture of (E)-(6R,7R)-3-[(R)- and [(S)-1'-allyloxycarbonyl-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7 -amino-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate in 6 ml of N,N-dimethylacetamide. Prepared analogously to example A1.

Yield: 220.0 mg (66.0%) beige powder.

IR(KBr): 1774, 1678, 1624 cm-1,

MS(ISP): 703.2 (M+H+).

Grade b:

A mixture of (E)-(6R,7R)-8-oxo-3-[(R)- and [(S)-2-oxo-[1,3']-bipyrrolidinyl-3-ylidene-methyl]-8- oxo-7-[2-(2,4,5-trichloro-phenyl-sulfanyl)-acetyl-amino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acids hydrochloride

The product prepared in step a (220.0 mg, 0.31 mmol) was suspended in 12 ml of dichloromethane and 124 µ (0.50 mmol) of N,O-bis-(trimethylsilyl)-acetamide was added. When a clear solution is formed, add 5.60 mg (8.56 µmol) of palladium-bis-(triphenylphosphine) dichloride, 0.36 ml (6.30 mmol) of acetic acid and 0.8 ml (3.0 mmol) of tributyl- tin hydride. After 45 minutes, 40 µl of water is added to the suspension and the reaction mixture is poured into 200 ml of diethyl ether, which contains 2 ml of a saturated solution of HCl in diethyl ether, while stirring. The solid is collected by filtration and triturated with 40 ml of ethyl acetate.

Yield: 180.0 mg (87.8%) beige powder.

IR(KBr): 1771, 1661, 1582 cm-1,

MS(ISP): 619.1 (M+H+).

Example A17

(E)-(6R,7R)-3-[1-[1-(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo- pyrrolidine-3-ylidene-methyl]-8-oxo-7-(2-phenyl-sulfanyl-acetyl-amino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

[image]

With 175.0 mg (1.08 mmol) of 1,1'-carbonyldiimidazole, 182.0 mg (1.08 mmol) of 2-(phenylthio)-acetic acid and 500.0 mg (0.75 mmol) (E) -(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]- 2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml of N,N-dimethylacetamide . The resulting solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 90.0 mg (20.6%) of beige lyophilizate.

IR(KBr): 1772, 1680, 1648 cm-1,

MS(ISP): 704.4 (M+H+).

Example A18

(E)-(6R,7R)-3-[1-[1-(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-yl-methyl]-2-oxo- pyrrolidine-3-ylidene-methyl]-8-oxo-7-[2-(4-trifluoro-methyl-phenyl-sulfanyl-acetyl-amino)-5-thia-1-aza-bicyclo[4.2.0]oct- 2-ene-2-carboxylate

[image]

With 66.8 mg (0.48 mmol) of 1,1'-carbonyldiimidazole, 97.3 mg (0.41 mmol) of [2-(4-trifluoromethyl)-phenylthio]-acetic acid and 250.0 mg ( 0.37 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl -4-yl-methyl]-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate trifluoro -acetate in 4 ml of N,N-dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 89.0 mg (30.8%) of slightly yellow lyophilisate.

IR(KBr): 1777, 1678, 1650 cm-1,

MS(ISP): 772.3 (M+H+).

Example A19

(E)-(6R,7R)-7-[2-(2,5-dichloro-phenyl-sulfanyl)-acetylamino]-3-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl] -pyridin-1-ij-4-yl-methyl]-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene -2-carboxylate

[image]

With 72.9 mg (0.45 mmol) of 1,1'-carbonyldiimidazole, 106.5 mg (0.45 mmol) of (2,5-dichloro-phenyl-sulfanyl)acetic acid and 250.0 mg (0.37 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4- yl-methyl]-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml of N,N-dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1, 2:1, 1:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 74.5 mg (21.3%) of beige lyophilizate.

IR(KBr): 1772, 1680, 1650 cm-1,

MS(ISP): 772.3 (M+H+).

Example A20

(E)-(6R,7R)-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-7-(2-phenyl-sulfanyl)- acetyl-amino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 121.0 mg (0.75 mmol) of 1,1'-carbonyldiimidazole, 125.6 mg (0.75 mmol) of (phenylthio)-acetic acid and 250.0 mg (0.62 mmol) of (E)-( 6R,7R)-7-amino-3-[1-[(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0 of ]oct-2-ene-2-carboxylic acid trifluoroacetate in 4 ml of N,N-dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 189.5 mg (55.2%) of yellow lyophilisate.

IR(KBr): 1764, 1664, 1612 cm-1,

MS(ISP): 552.2 (M+H) + .

Example A21

(E)-(6R,7R)-7-[2-(3,4-dimethoxy-phenylsulfanyl)acetylamino]-3-[1-[(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

With 121.1 mg (0.75 mmol) of 1,1'-carbonyldiimidazole, 170.6 mg (0.75 mmol) of 2-(3,4-dimethoxyphenylthio)-acetic acid and 250.0 mg (0.62 mmol ) (E)-(6R,7R)-7-amino-3-[1-[(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1- of aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate in 4 ml of N,N-dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (1:0, 4:1, 3:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 175.6 mg (46.1%) of pale yellow lyophilisate.

IR(KBr): 1766, 1664, 1588 cm-1,

MS(ISP): 612.2 (M+H) + .

Example A22

(E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidine -3-ylidene-methyl]-8-oxo-7-[2-(2,4,5-trichloro-phenylsulfanyl)-ylidenemethyl]-5-thia-1-aza-bicyclo[4.2.0]oct-2- ene-2-carboxylate

[image]

With 60.0 mg (0.36 mmol) of 1,1'-carbonyldiimidazole, 99.0 mg (0.36 mmol) of (2,4,5-trichloro-phenylsulfanyl)-acetic acid and 200.0 mg (0, 30 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)methyl]-pyridin-1-yl-4-ylmethyl] -2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid trifluoroacetate in 4 ml of N,N- dimethylacetamide. The obtained solid is purified by column chromatography on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (2:1, 1:1). The organic solvent is removed by evaporation on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 140.0 mg (57.8%) of beige lyophilizate.

IR(KBr): 1763, 1666, 1645 cm-1,

MS(ISP): 806.3; 808.3 (M+H)+.

The following compounds were produced analogously to example A1.

Example A23

(E)-(6R,7R)-7-[2-(benzothiazol-2-ylsulfanyl)acetylamino]-3-[1-[(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 66.0% beige solids.

IR(KBr): 1772, 1669, 1613 cm-1,

MS(ISP): 609.4 (M+H)+,

Example A24

(E)-(6R,7R)-3-[1-(1H-4-benzoimidazol-2-ylmethyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(phenylsulfanylcarbonyl-methyl-amino )-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 91.6% brown solid.

MS(ISP): 576.1 (M+H)+,

IR(KBr): 1770, 1673, 1625 cm-1.

Example A25

(E)-(6R,7R)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidene-methyl)-7-[2-(naphthalene-1-sulfanyl)-acetylamino]-8-oxo- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 41.6% beige solids.

MS(ISP): 536.3 (M+H)+,

IR(KBr): 1769, 1664, 1624 cm-1.

Example A26

(E)-(6R,7R)-3-[1-(4-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[2-(naphthalene-1-sulfanyl)-acetylamino]-8- oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 67.7% beige solid.

MS(ISP): 602.2 (M+H+,

IR(KBr): 1771, 1667, 1614 cm-1.

Example A27

(E)-(6R,7R)-7-[2-(benzothiazol-2-ylsulfanyl)-acetylamino]-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 78.5% of a slightly yellow solid.

MS(ISP): 543.2 (M+H)+,

IR(KBr): 1769, 1665, 1624 cm-1.

Example A28

(E)-(6R,7R)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidene-methyl)-7-[2-(3,5-dimethyl-phenyl-sulfanyl)-acetylamino]- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 67.0% beige solid.

MS(ISP): 514.3 (M+H)+,

IR(KBr): 1765, 1653, 1621 cm-1.

Example A29

(E)-(6R,7R)-7-[2-(4-bromo-phenylsulfanyl)-acetylamino]-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 75.5% light yellow solid.

MS(ISP): 566.1 (M+H)+,

IR(KBr): 1767, 1661, 1622 cm-1.

Example A30

(E)-(6R,7R)-7-[2-(benzooxazol-2-ylsulfanyl)-acetylamino]-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 67.2% beige solid.

MS(ISP): 527.1 (M+H)+,

IR(KBr): 1770, 1670, 1625 cm-1.

Example A31

(E)-(6R,7R)-7-[2-(4-bromo-phenylsulfanyl)-acetylamino]-8-oxo-3-[2-oxo-1-(2,2,2-trifluoro-ethyl) -pyrrolidin-3-ylidene-methyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 86.3% yellow powder.

MS(ISP): 608.3 (M+H)+,

IR(KBr): 1769, 1682, 1611 cm-1.

Example A32

(E)-(6R,7R)-8-oxo-3-[2-oxo-1-(2,2,2-trifluoroethyl)-pyrrolidin-3-ylidenemethyl]-7-(2-phenylsulfanyl-acetylamino )-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 78.6% yellow powder.

MS(ISP): 528.3 (M+H)+,

IR(KBr): 1771, 1681, 1612 cm-1.

Example A33

(E)-(6R,7R)-3-(1-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza -bicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 85.0% brown solid.

MS(ISP): 536.4 (M+H)+,

IR(KBr): 1767, 1667, 1622 cm-1.

Example A34

(E)-(6R,7R)-3-[1-(4-fluoro-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanylacetyl-methyl-amino)- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 91.0% beige solid.

MS(ISP): 554.5 (M+H)+,

IR(KBr): 1766, 1665, 1622 cm-1.

Example A35

(E)-(6R,7R)-3-[1-(4-methoxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 87.1% beige solid.

MS(ISP): 566.5 (M+H)+,

IR(KBr): 1773, 1672, 1611 cm-1.

Example A36a

(E)-(6R,7R)-3-[1-(4-allyloxy-carbonylamino-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanylacetyl-methyl-amino )-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1) RO-65-2011

Yield: 82.3% brown solid.

MS(ISP): 652.5 (M+H)+,

IR(KBr): 1770, 1726, 1667, 1613 cm-1.

Example A36b

(E)-(6R,7R)-3-[1-(4-amino-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanylacetyl-methyl-amino)- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

(E)-(6R,7R)-3-[1-(4-allyloxy-carbonylamino-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid-imidazole salts (1:1) (400.0 mg, 0.57 mmol) was suspended in 20 ml of dichloromethane and was mixed with N,O-bis(trimethylsilyl)-trifluoroacetamide (240.7 mL, 9.11 mmol). After 15 minutes, bis(triphenylphosphine)-palladium(II) chloride (10.0 mg, 0.014 mmol), acetic acid (0.65 ml, 11.4 mmol) and tributyltin hydride (1.53 ml, 5.70) were added. mmol). After 45 minutes, the suspension is poured with stirring into 250 ml of diethyl ether containing 3 ml of diethyl ether solution saturated with hydrochloric acid and stirred for 1 hour. The solid is collected by filtration, suspended in 4 ml water:acetonitrile (1:1) and adjusted to pH 2 with 1M hydrochloric acid. An equal amount of MCI 75-150 µ, Mitsubishi Kasei Corporation is added to the suspension), the organic solvent is evaporated and the residue is chromatographed on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (9:1, 4:1, 2:1, 1:1, 1:3). The organic solvent is evaporated and the aqueous phase is freeze-dried.

Yield: 18.0% beige solids.

MS(ISP): 551.5 (M+H)+,

IR(KBr): 1769, 1667, 1626 cm-1.

Example A37

(E)-(6R,7R)-3-[1-(1,1-dioxo-tetrahydro-thiophen-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2 -phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1) (1:1 mixture of epimers)

Yield: 56.1% beige solid.

MS(ISP): 581.4 (M+H)+,

IR(KBr): 1771, 1673, 1618 cm-1.

Example A38a

(E)-(6R,7R)-3-[1-(1-allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl-ylidenemethyl) )-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 74.5% of beige lyophilizate.

MS(ISP): 585.5 (M+H)+,

IR(KBr): 1775, 1678, 1626 cm-1.

Example A38b

(E)-(6R,7R)-3-(1-azetidin-1-yl-3-yl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-(2-phenylsulfanyl-acetylamino)- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

(E)-(6R,7R)-3-[1-(1-allyloxycarbonyl-azetidin-3-yl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl-acetyl amino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid-imidazole salt (1:1) (448.0 mg, 0.69 mmol) was dissolved in 20 ml of dichloromethane. Acetic acid (0.79 ml, 3.70 mmol), bis(triphenylphosphine)-palladium(II) chloride (11.9 mg, 0.017 mmol) and tributyltin hydride (1.86 ml, 6.90 mmol) were added successively. . After 45 minutes, the suspension is poured with stirring into 250 ml of diethyl ether containing 3 ml of diethyl ether solution saturated with hydrochloric acid and stirred for 1 hour. The solid is collected by filtration, suspended in water:acetonitrile (1:1) and adjusted to pH 2 with 1N hydrochloric acid. To the suspension is added an equal amount of MCI 75-150 µ, Mitsubishi Kasei Corporation), the organic solvent is evaporated and the residue chromatographed on MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (9:1, 4:1, 2:1, 1:1, 1:3). The organic solvent is evaporated and the aqueous phase is freeze-dried.

Yield: 23.2% of beige lyophilizate.

MS(ISP): 501.4 (M+H)+,

IR(KBr): 1766, 1673, 1620 cm-1.

Example A39

(E)-(6R,7R)-3-[1-(4-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia- 1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 68.0% yellow solid.

MS(ISP): 552.5 (M+H)+,

IR(KBr): 1773, 1667, 1614 cm-1.

Example A40

(E)-(6R,7R)-8-oxo-3-(2-oxo-phenylcarbamoylmethyl-pyrrolidin-3-ylidenemethyl)-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[ 4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 52.0% brown solid.

MS(ISP): 579.4 (M+H)+,

IR(KBr): 1770, 1665, 1599 cm-1.

Example A41a

(E)-(6R,7R)-3-[(R)-1'-allyloxycarbonyl-2-oxo-[1,3']-bi-pyrrolidinyl-3-ylidenemethyl]-8-oxo-7-(2 -phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 81.3% brown solid.

MS(ISP): 562.3 (M+H)+,

IR(KBr): 1776, 1670, 1631 cm-1.

Example A41b

(E)-(6R,7R)-8-oxo-3-[(R)-2-oxo-[1,3']-bipyrrolidinyl-3-ylidenemethyl]-7-(2-phenylsulfanyl-acetylamino)-5 -thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

(E)-(6R,7R)-3-[(R)-1'-allyloxycarbonyl-2-oxo-[1,3']-bipyrrolidinyl-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl -acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid-imidazole salt (1:1) (370.0 mg, 0.62 mmol) was dissolved in 20 ml of dichloromethane and mixed with bis(triphenylphosphine)palladium(II) chloride (10.9 mg, 0.015 mmol), acetic acid (0.71 ml, 12.4 mmol) and tributyltin hydride (1.67 ml, 6 , 20 mmol). After 40 minutes, the suspension is poured into 250 ml of diethyl ether containing 3 ml of diethyl ether solution saturated with hydrochloric acid and stirred for 1 hour. The suspension is filtered, the solid is triturated with ethyl acetate for 1 hour and dried under high vacuum.

Yield: 25.5% beige solids.

MS(ISP): 515.3 (M+H)+,

IR(KBr): 1776, 1666, 1632 cm-1.

Example A42

(E)-(6R,7R)-7-[2-(4-chloro-phenylsulfanyl)-acetylamino]-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 70.7% slightly yellow solid.

MS(ISP): 520.4 (M+H)+,

IR(KBr): 1775, 1667, 1625 cm-1.

The following compounds were prepared analogously to Example A10.

Example A43

(E)-(6R,7R)-8-oxo-3-[2-oxo-1-(2-oxo-oxazolin-3-yl)-pyrrolidin-3-ylidenemethyl)-7-(2-phenylsulfanyl)- acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 36.0% beige lyophilizate.

MS(ISP): 548.4 (M+H)+,

IR(KBr): 1770, 1689, 1612 cm-1.

Example A44

(E)-(6R,7R)-8-oxo-3-(2-oxo-1-pyridin-2-yl-pyrrolidin-3-ylidenemethyl)-7-(2-phenylsulfanyl)-acetylamino)-5-thia -1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 18.0% of brown lyophilizate.

MS(ISP): 523.5 (M+H)+,

IR(KBr): 1770, 1680, 1610 cm-1.

Example A45

(E)-(6R,7R)-3-[1-(6-Methoxy-pyridin-3-yl)-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl)-acetylamino)-5 -thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 12.0% beige lyophilizate.

MS(ISP): 553.5 (M+H)+,

IR(KBr): 1769, 1677, 1619 cm-1.

Example A46

(E)-(6R,7R)-7-[2-(1H-benzoimidazol-2-ylsulfanyl)-ylidene-methyl]-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidine-3 -ylidene-methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 11.2% of beige lyophilizate.

MS(ISP): 592.5 (M+H)+,

IR(KBr): 1769, 1664, 1614 cm-1.

Example A47

(E)-(6R,7R)-3-(1-isobutyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-(2-phenylsulfanyl)-ylidenemethyl)-5-thia-1-azabicyclo -[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 15.8% colorless lyophilisate.

MS(ISP): 502.4 (M+H)+,

IR(KBr): 1768, 1660, 1625 cm-1.

Example A48

(E)-(6R,7R)-3-(1-cyclohexylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-(2-phenylsulfanyl)-ylidenemethyl)-5-thia-1-aza -bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 10.0% colorless lyophilisate.

MS(ISP): 542.4 (M+H) + .

Example A49

(E)-(6R,7R)-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(3-phenyl-propionylamino)-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Yield: 17.0% beige lyophilisate.

MS(ISP): 534.4 (M+H)+,

IR(KBr): 1778, 1662, 1602 cm-1.

Example A50

(E)-(6R,7R)-3-[(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-[2-(4-hydroxymethyl-phenoxy)-acetylamino]-8-oxo- 5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 21.2% beige lyophilisate.

MS(ISP): 566.4 (M+H)+,

IR(KBr): 1773, 1665, 1566 cm-1.

Example A51

(E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidine -3-ylidene-methyl]-7-[2-(4-hydroxymethyl-phenoxy)acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

Yield: 14.1% beige lyophilisate.

MS(ISP): 718.3 (M+H)+,

IR(KBr): 1769, 1681, 1613 cm-1.

Example A52

(E)-(6R,7R)-7-(2-benzoylamino-acetylamino)-3-[1-[(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5 -thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate imidazole salt (1:1)

Yield: 32% beige lyophilisate.

MS(ISP): 562.0 (M+H)+,

IR(KBr): 1771, 1658, 1602 cm-1.

Example A53

(E)-(6R,7R)-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenylamino-acetylamino]-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 20.5% beige lyophilisate.

MS(ISP): 535.4 (M+H)+,

IR(KBr): 1780, 1670, 1608 cm-1.

Example A54

(E)-(6R,7R)-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-(2-phenoxy-acetylamino]-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:0.8)

Yield: 34.6% beige lyophilisate.

MS(ISP): 536.2 (M+H)+,

IR(KBr): 1776, 1673, 1600 cm-1.

Example A55

(6R,7R)-3-[(E)-1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[(Z)-2-styrylsulfanyl-acetylamino ]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

Yield: 31.6% beige lyophilisate.

MS(ISP): 578.4 (M+H)+,

IR(KBr): 1775, 1663, 1619 cm-1.

Example A56

(E)-(6R,7R)-3-[1-(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidene -methyl]-8-oxo-7-[(Z)-2-styrylsulfanyl-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

imidazole salt

Yield: 14.6% beige lyophilisate.

MS(ISP): 730.5 (M+H)+,

IR(KBr): 1769, 1677, 1642 cm-1.

Example A57

(E)-(6R,7R)-7-[2-(4-chlorophenylsulfanyl)-acetylamino]-3-[1-(3-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8- oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 29.0% light yellow lyophilizate.

MS(ISP): 586.3 (M+H)+,

IR(KBr): 1769, 1669, 1600 cm-1.

Example A58

(E)-(6R,7R)-7-[2-(4-bromo-phenylsulfanyl)-acetylamino]-3-[1-[1-[3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridine -1-ij-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

Yield: 13.3% of beige lyophilizate.

MS(ISP): 748.1 (M+H)+,

IR(KBr): 1769, 1676, 1642 cm-1.

Example A59

(E)-(6R,7R)-7-[2-(3,5-dimethyl-phenylsulfanyl)-acetylamino]-3-[1-[1-[3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl] -pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

Yield: 24.0% of light brown lyophilizate.

MS(ISP): 732.4 (M+H)+,

IR(KBr): 1766, 1667, 1644 cm-1.

Example A60

(E)-(6R,7R)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidene-methyl)-8-oxo-7-[2-(pyridin-4-yl-sulfanyl)-acetylamino ]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 46.0 mg of light yellow lyophilisate.

MS(ISP): 486.4 (M+H) + .

IR(KBr): 1769, 1664, 1619 cm-1.

Example A61

(E)-(6R,7R)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidene-methyl)-8-oxo-7-[2-(pyridin-4-yl-sulfanyl)-acetylamino ]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1)

Yield: 41.0 mg of light yellow lyophilisate.

MS(ISP): 487.2 (M+H) + .

IR(KBr): 1772, 1672, 1623 cm-1.

Example A62

(E)-(6R,7R)-7-[2-(4-fluoro-phenylsulfanyl)-acetylamino]-8-oxo-3-(2-oxo-1-phenylcarbamoyl-methyl-pyrrolidin-3-ylidene-methyl )-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

(4-Fluorophenylthio)acetic acid (102.7 mg, 0.55 mmol) was dissolved in N,N-dimethylacetylamide and 1,1'-carbonyldiimidazole (89.0 mg, 0.55 mmol) was added in one portion. The solution was stirred for 1 hour and then (E)-(6R,7R)-7-amino-8-oxo-3-(2-oxo-1-phenylcarbamoyl-methyl-pyrrolidin-3-ylidenemethyl)-5-thia was added -1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid. After 6 hours, the mixture is poured into 250 ml of diethyl ether and the solid is collected by filtration. The solid is converted into its sodium salt by suspending it in 6 ml of water, the pH is adjusted to 7 with 1M sodium hydroxide solution. The solution is chromatographed on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (10:1, 8:2, 7:3). The organic solvent is evaporated on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 75.2% of yellow lyophilizate.

MS(ISP): 597.2 (M+H) + .

IR(KBr): 1770, 1668, 1630 cm-1.

The following compounds were produced analogously to Example A62.

Example A63

(E)-(6R,7R)-8-oxo-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidene-methyl)-7-(2-phenylsulfanyl)-acetylamino)-5-thia-1 -aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 56.3% beige lyophilisate.

MS(ISP): 522.2 (M+H) + .

IR(KBr): 1765, 1682, 1622 cm-1.

Example A64

(E)-(6R,7R)-3-[1-(2-methyl-allyl)-2-oxo-pyrrolidin-3-ylidene-methyl]-8-oxo-7-(2-phenylsulfanyl)-acetylamino) -5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 40.8% beige lyophilisate.

MS(ISP): 500.2 (M+H) + .

IR(KBr): 1765, 1667, 1614 cm-1.

Example A65

(E)-(6R,7R)-7-[2-(benzooxazol-2-ylsulfanyl)-acetylamino]-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidene]- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 43.3% beige lyophilisate.

MS(ISP): 593.2 (M+H) + .

IR(KBr): 1770, 1670, 1615 cm-1.

Example A66

(E)-(6R,7R)-7-(2-benzylsulfanyl-acetylamino)-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 38.7% beige lyophilisate.

MS(ISP): 583.3 (M+H) + .

IR(KBr): 1764, 1664, 1614 cm-1.

Example A67

(E)-(6R,7R)-7-[2-(5-acetylamino[1,3,4]thiadiazol-2-yl-sulfanyl)-acetylamino]-3-[1-(4-hydroxy-benzyl) -2-oxo-pyrrolidine-3-ylidene]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 40.4% of yellow lyophilizate.

MS(ISP): 617.2 (M+H) + .

IR(KBr): 1766, 1657, 1614 cm-1.

Example A68

(E)-(6R,7R)-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidene]-7-(2-methylsulfanyl-acetylamino)-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 43.0% beige lyophilisate.

MS(ISP): 490.3 (M+H) + .

IR(KBr): 1764, 1664, 1614 cm-1.

Example A69

(E)-(6R,7R)-7-[2-(4-bromo-phenylsulfanyl)-acetylamino]-8-oxo-3-(2-oxo-1-phenyl-pyrrolidin-3-ylidenemethyl)-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt

Yield: 53.0% of yellow lyophilizate.

MS(ISP): 602.1 (M+H) + .

IR(KBr): 1764, 1673, 1618 cm-1.

Example A70

(E)-(6R,7R)-7-[2-(naphthalen-2-ylsulfanyl)-acetylamino]-8-oxo-3-[2-oxo-(2,2,2-trifluoro-ethyl)-pyrrolidine -3-ylidene-methyl)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1); compound with imidazole (1:0.5)

Yield: 28.3% of yellow lyophilisate.

MS(ISP): 578.1 (M+H) + .

IR(KBr): 1770, 1682, 1620 cm-1.

The following compounds were produced analogously to example A1.

Example A71

1:1 mixture of (E)-(6R,7R)-8-oxo-3-[2-oxo-1-[(R)- and [(S)-tetrahydro-furan-2-ylmethyl]-pyrrolidin-3 -ylidenemethyl]-7-(2-phenyl-sulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 88.0% of yellow lyophilizate.

MS(ISP): 530.2 (M+H) + .

IR(KBr): 1772, 1672, 1619 cm-1.

Method B

Example B1

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-(2-thiophen-2-yl-acetylamino)-5-thia- 1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

To a suspension of 300.0 mg (0.86 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidene-methyl)-8-oxo -5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid 80.0 mg (0.95 mmol) of sodium bicarbonate is added to 8 ml of N,N-dimethylformamide. When cooled to 0oC, 101.0 µl (0.95 mmol) of 2-thiophenacetyl chloride is added. After 1.5 hours, the solvent is removed on a rotary evaporator and the residue is poured into diethyl ether. The solid is collected by filtration and triturated for 1.5 hours with 25 ml of ethyl acetate and 15 ml of water.

Yield: 150.0 mg (36.9%) beige powder.

IR(KBr): 1779, 1669, 1626, 1540 cm-1.

MS(ISP): 472.2 (M+H+).

Example B2

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[(R)- and [(S)-2,3-diphenyl-propionylamino) ]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

From 100.0 mg (0.29 mmol) (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia -1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 26.4 mg (0.31 mmol) sodium bicarbonate and 77.0 mg (0.31 mmol) 2,3-diphenyl -propionyl chloride in 8 ml of N,N-dimethyl-formamide.

Yield: 82.0 mg (51.4%) yellow powder.

MS(ISP): 558.4 (M+H+).

IR(KBr): 1782, 1671 cm-1.

Example B3

(E)-(6R,7R)-7-[2-(4-chloro-phenylsulfanyl)-2-methyl-propionyl-amino)]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidene- methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1).

It is produced analogously to example B1.

The beige solid is suspended in water and the pH is adjusted to 7 with 1M sodium hydroxide solution. The resulting solution is chromatographed on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (9:1, 8:2, 2:7, 7:3). The organic solvent is removed on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 56.0 mg (51.4%) of beige lyophilisate.

IR(KBr): 1765, 1669, 1620 cm-1.

MS(ISP): 562.3 (M+H+).

Method C

Example C1a

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridine-1- ij-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate

[image]

To a suspension of 280.0 mg (0.42 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl] -pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate of trifluoroacetate in 4 ml of dichloromethane, 0.37 µl (1.40 mmol) of N,O-bis-(trimethylsilyl)-trifluoroacetamide is added. When a clear solution is formed, 36.8 µl (0.42 mmol) of bromoacetyl bromide is added and the reaction mixture is stirred for 3 hours. 25.6 µl (1.42 mmol) of water and 25 ml of diethyl ether are added to this solution. The precipitate is filtered off and washed with diethyl ether.

Yield: 210.0 mg (77.8%) beige powder.

IR(KBr): 1782, 1686, 1643 cm-1.

MS(ISP): 676.2 (M+H+).

Example C1b

(E)-(6R,7R)-3-(1-[1-[3-(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo -pyrrolidin-3-ylidene-methyl]-7-[2-(4-methyl-4H-[1,2,4]-triazol-3-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1- aza-bicyclo[4.2.0]-oct

-2-ene-2-carboxylate

[image]

K solution of 230.0 mg (0.34 mmol) (E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-[1-[(3-fluoro-4-hydroxy -phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]- 40.0 mg (0.37 mmol) of 4-methyl-4H-[1,2,4]-triazole-3-thiol is added to oct-2-ene-2-carboxylate in 5 ml of N,N-dimethylformamide. 47.0 µ (0.34 mmol) of triethylamine was added over 1 hour and stirring was continued for another 12 hours.The solution was poured into diethyl ether and the resulting solution was purified by MCI gel chromatography (75-150 µ, Mitsubishi Kasei Corporation) with a gradient water: acetonitrile (1:0, 4:1, 3:1, 2:1) The organic solvent was removed on a rotary evaporator and the aqueous phase was freeze-dried.

Yield: 48.4 mg (20.0%) of beige lyophilisate.

IR(KBr): 1780, 1660, 1647 cm-1.

MS(ISP): 709.3 (M+H+).

Example C2

(E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidine -3-ylidene-methyl]-7-[2-(4-hydroxy-phenylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-en-2

-carboxylate

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl- 4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]-oct-2-ene-2-carboxylate (see Example C1a) (300.0 mg, 0.45 mmol) was dissolved in 3 ml of N,N-dimethylformamide, then 4-mercaptophenol (58.0 mg, 0.45 mmol) was added, and then triethylamine (62.7 ml, 0 .45 mmol). After 22 hours, the reaction mixture is poured into diethyl ether and the solid is collected by filtration. The brown solid was suspended in water:acetonitrile (1:1) and chromatographed on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (9:1, 4:1, 3:1). The organic solvent is removed on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 14.0% beige solids.

IR(KBr): 1769, 1671, 1643 cm-1.

MS(ISP): 720.4 (M+H) + .

Example C3

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(thiophen-2-ylsulfanyl)-acetyl-amino]- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid

It is produced analogously to example C1.

Yield: 24.2% beige lyophilisate.

IR(KBr): 1781, 1719, 1667 cm-1.

MS(ISP): 506.2 (M+H) + .

Example C4a

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza- bicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

(E)-(6R,7R)-7-amino-3-[(1-cyclopropyl-2-oxo-3-pyrrolidinylidene)methyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2. 0]-oct-2-ene-2-carboxylic acid sodium trifluoroacetate (1:0.25) (8.0 g, 22.0 mmol) is suspended in 100 ml of dichloromethane and N-methyl-N- (trimethylsilyl)trifluoroacetamide (9.0 mL, 48.4 mmol). After 45 minutes, the resulting solution was cooled to 0°C and mixed with bromoacetyl bromide (2.10 ml, 24.2 mmol). After 30 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 2.5 hours. The volatiles are evaporated and the residue converted to its sodium salt by suspending in water and adjusting the pH to 6.5 with 1M sodium hydroxide solution. The solution is freeze-dried and the crude lyophilisate is purified by reverse-phase chromatography (RP-18 Li(ChroPrep gel) with a gradient of water:acetonitrile (10:9, 9:1). The organic solvent is evaporated and the aqueous phase is freeze-dried.

Yield: 60.0% of slightly yellow lyophilizate.

IR(KBr): 1766, 1672, 1620 cm-1.

MS(ISP): 465.2 (M+H) + .

Example C4b

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl]-7-[2-(1H-imidazol-2-ylsulfanyl)-acetylamino]-8-oxo- 5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza- bicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1) (200.0 mg, 0.42 mmol) was dissolved in 4 ml of N,N-dimethylformamide and added in one portion 2-mercaptoimiazole sodium salt (56.2 mg, 0.46 mmol) was added. After 15 h, the solvent was removed on a rotary evaporator. The residue was dissolved in water and purified by reverse phase chromatography (RP-18 Li(ChroPrep gel) with water gradient :acetonitrile (10:0, 9:1, 8:2) The organic solvent is evaporated and the aqueous phase is freeze-dried.

Yield: 82.2% of colorless lyophilizate.

IR(KBr): 1764, 1664, 1620 cm-1.

MS(ISP): 476.1 (M+H) + .

The following compounds were produced analogously to example C4.

Example C5

(E)-(6R,7R)-7-[2-(4-carboxy-phenylsulfanyl)-acetylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5- thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:2)

Yield: 57.6% of yellowish lyophilizate.

IR(KBr): 1755, 1658, 1589 cm-1.

MS(ISP): 530.2 (M+H) + .

Example C6

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(4-carboxy-phenylsulfanyl)-acetylamino]-8-oxo-5- thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 72.2% of yellow lyophilizate.

IR(KBr): 1764, 1661, 1620 cm-1.

MS(ISP): 502.0 (M+H) + .

Example C6

(E)-(6R,7R)-7-[2-(1-carboxymethyl-1H-tetrazol-5-yl-sulfanyl)-acetylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl )-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid disodium salt

Yield: 49.1% beige lyophilisate.

IR(KBr): 1764, 1622 cm-1.

MS(ISP): 558.2 (M+H) + .

Example C8

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(1-phenyl-1H-tetrazol-5-yl- sulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 81.8% of colorless lyophilizate.

IR(KBr): 1764, 1672, 1619 cm-1.

MS(ISP): 554.2 (M+H) + .

Example C9

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(2-oxo-3,7-dihydro-2H- Purin-6-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 40.6% lyophilisate of light beige color.

IR(KBr): 1762, 1625 cm-1.

MS(ISP): 554.4 (M+H) + .

Example C10

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(pyrimidin-2-ylsulfanyl)-acetyl-amino]- 5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 27.0% colorless lyophilizate.

IR(KBr): 1763, 1671, 1618 cm-1.

MS(ISP): 488.4 (M+H) + .

Example C11

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(1-methyl-1H-tetrazol-5-ylsulfanyl)-acetylamino]- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 38.1% colorless lyophilizate.

IR(KBr): 1764, 1678, 1618 cm-1.

MS(ISP): 492.4 (M+H) + .

Example C12

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(4-hydroxy-pyrimidin-2-ylsulfanyl)-acetylamino]-8- oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 47.3% lyophilizate of light beige color.

IR(KBr): 1762, 1670, 1616 cm-1.

MS(ISP): 504.4 (M+H) + .

Example C13

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-[2-(3,4-dihydroxy-phenyl)-5-methyl- [1,2,4]triazol[1,5-a]pyrimidin-7-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene- 2-carboxylic acid sodium salt (1:1)

Yield: 27.3% colorless lyophilizate.

IR(KBr): 1768, 1660, 1618 cm-1.

MS(ISP): 450.4 (M+H) + .

Example C14

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(4-methyl-5-trifluoromethyl-4H-[1,2,4 ]-triazol-3-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 48.6% of light yellow lyophilizate.

IR(KBr): 1763, 1672, 1618 cm-1.

MS(ISP): 559.4 (M+H) + .

Example C15a

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza

-bicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt

(E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0] -oct-2-ene-2-carboxylic acid (3.50 g, 10.0 mmol) was suspended in 50 ml of dichloromethane and N-methyl-N-trimethylsilyltrifluoroacetamide (4.62 ml, 25.0 mmol). After 1 hour, the resulting solution is cooled to 0oC. Bromoacetyl bromide (1.04 ml, 12.0 mmol) was added to this solution. After 30 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 4 hours. The volatiles are evaporated and the residue is suspended in water and adjusted to pH 6.8 with 1N sodium hydroxide solution. The solution is freeze-dried and the crude lyophilisate is purified by reverse-phase chromatography (RP-18 Li(ChroPrep gel) with a gradient of water:acetonitrile (9:1, 8:2, 7:3). The organic solvent is evaporated and the aqueous phase is freeze-dried .

Yield: 67.1% of yellow lyophilizate.

IR(KBr): 1766, 1665, 1622 cm-1.

MS(ISP): 470.0 (M+H) + .

The following compounds were produced analogously to example C4.

Example C15b

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(3H-[1,2,3]-triazol- 4-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 52.1% of yellowish lyophilizate.

IR(KBr): 1764, 1664, 1619 cm-1.

MS(ISP): 491.4 (M+H) + .

Example C16

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-[2-(3,4-dihydroxy-phenyl)-5-methyl- [1,2,4]-triazol[1,5-a]-pyrimidin-7-ylsulfanyl]-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2- ene-2-carboxylic acid sodium salt (1:1)

Yield: 38.8% colorless lyophilizate.

IR(KBr): 1766, 1665, 1593 cm-1.

MS(ISP): 664.1 (M+H) + .

Example C17

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(1H-[1,2,4]-triazol- 3-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 51.2% of yellowish lyophilisate.

IR(KBr): 1765, 1664, 1619 cm-1.

MS(ISP): 491.4 (M+H) + .

Example C18

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(1H-pyrazolo[3,4-d]pyrimidine- 4-yl-sulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 20.1% of yellowish lyophilisate.

IR(KBr): 1764, 1666, 1625 cm-1.

MS(ISP): 542.3 (M+H) + .

Example C19

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(4-methyl-5-trifluoromethyl-4H-[1,2,4 ]-triazol-3-ylsulfanyl)-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 52.2% of yellowish lyophilizate.

IR(KBr): 1763, 1665, 1612 cm-1.

MS(ISP): 573.3 (M+H) + .

Example C20

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(1-methyl-4H-tetrazol-5-ylsulfanyl)-acetylamino]- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 50.8% of yellowish lyophilisate.

IR(KBr): 1763, 1667, 1615 cm-1.

MS(ISP): 506.3 (M+H) + .

Example C21a

A mixture of (E)-(6R,7R)-7-[(R)- and -[(S)-2-bromo-propionylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1), see Example D1a.

Example C21b

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[(R)- and -[(S)-2-(4-methyl- 5-trifluoromethyl-4H-[1,2,4]triazol-3-ylsulfanyl)-propionyl-amino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2

-carboxylic acid sodium salt (1:1)

Produced analogously to example C4.

Yield: 55.8% colorless lyophilisate.

IR(KBr): 1765, 1670, 1618 cm-1.

MS(ISP): 587.3 (M+H) + .

Example C22

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[(R)- and -[(S)-2-( 3H-[1,2,4]triazol-3-ylsulfanyl)-propionyl-amino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1 :1)

Yield: 63.3% beige lyophilisate.

IR(KBr): 1764, 1657, 1621 cm-1.

MS(ISP): 505.2 (M+H) + .

Example C23

(E)-(6R,7R)-7-[2-(1H-benzoimidazol-2-ylsulfanyl)-acetyl-amino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidene-methyl)- 8-oxo-5-thia-1-aza-bicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-cyclopropyl-methyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1- aza-bicyclo [4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1) (see example C4a) (200 mg, 0.42 mmol) was dissolved in 4 ml of N,N-dimethylformamide and in 2-mercaptobenzimidazole sodium salt (79.2 mg, 0.46 mmol) is added to one portion. at the end of the reaction, the solvent is extracted on a rotary evaporator. The residue was dissolved in water and chromatographed on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (10:1, 9:1). The organic solvent is evaporated and the aqueous phase is freeze-dried.

Yield: 57.0% beige lyophilizate.

IR(KBr): 1763, 1668, 1617 cm-1,

MS(ISP): 526.0; (M+H)+.

The following compounds were produced analogously to example C23.

Example C24

Mixture (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(1H)-pyrazole[3,4-d] Pyrimidin-4-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo-[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 20.0% of slightly yellow lyophilisate.

IR(KBr): 1764, 1667, 1618 cm-1.

MS(ISP): 528.4 (M+H) + .

Example C25

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(2,6-dimethyl-5-oxo-2,5-dihydro- [1,2,4]-triazin-3-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1 :1)

Yield: 33.3% of beige lyophilisate.

IR(KBr): 1762, 1629, 1478 cm-1.

MS(ISP): 533.4 (M+H) + .

Example C26

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(2-dihydroxy-5-methyl[1,2,4]triazole[ 1,5-a]-pyrimidin-7-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1: 1)

Yield: 45.5% colorless lyophilizate.

IR(KBr): 1765, 1668, 1598 cm-1.

MS(ISP): 572.5 (M+H) + .

Example C27

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-[2-(4-hydroxy-phenyl)-5-methyl[1, 2,4]-triazol[1,5-a]pyrimidin-7-ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 22.5% colorless lyophilizate.

IR(KBr): 1765, 1666, 1613 cm-1.

MS(ISP): 634.4 (M+H) + .

Example C28

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(4-methyl-4H-[1,2,4]triazole-3 -ylsulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 53.5% beige lyophilisate.

IR(KBr): 1764, 1673, 1615 cm-1.

MS(ISP): 491.4 (M+H) + .

Example C29

(E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(pyrimidin-2-yl-sulfanyl)-acetyl-amino ]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 55.2% of yellowish lyophilizate.

IR(KBr): 1762, 1664, 1614 cm-1.

MS(ISP): 502.1 (M+H) + .

Example C30a

A mixture of (E)-(6R,7R)-7-[(R)- and -[(S)-2-bromo-propionylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt, see Example D1a.

The following compounds were produced analogously to example C4.

Example 30b

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[(R)- and -[(S)-2-( 1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)-propionylamino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid

sodium salt (1:1).

Yield: 56.2% of yellowish lyophilizate.

IR(KBr): 1764, 1666, 1621 cm-1.

MS(ISP): 556.2 (M+H) + .

Example 31

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[(R)- and -[(S)-2-(4-methyl- 4H-[1,2,4]-triazol-3-ylsulfanyl)-propionylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid

sodium salt (1:1)

Yield: 64.0% beige lyophilisate.

IR(KBr): 1764, 1667, 1619 cm-1.

MS(ISP): 519.2 (M+H) + .

Example 32

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[(R)- and -[(S)-2-( 2,4,5-trichloro-phenyl-sulfanyl)-propionylamino]-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt (1:1).

Yield: 60.2% colorless lyophilizate.

IR(KBr): 1760, 1670, 1618 cm-1.

MS(ISP): 617.0 (M+H) + .

Example 33

(E)-(6R,7R)-7-[2-[2-(3,4-dihydroxy-phenyl)-5-methyl-[1,2,4]-triazol[1,5-a]pyrimidine- 7-ylsulfanyl]-acetylamino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl- 4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate (see Example C1a) ( 337.0 mg, 0.50 mmol) was dissolved in 4 ml of N,N-dimethylformamide and 4-[7-mercapto-5-methyl-s-triazol[1,5-a]pyrimidin-2-yl- pyro-catechol sodium salt (162.4 mg, 0.55 mmol). After 6 hours, the reaction mixture is poured into diethyl ether and the solid material is filtered off. The brown powder was suspended in 8 ml of water:acetonitrile (3:1), the pH was adjusted to 3 with 1M hydrochloric acid and the suspension was chromatographed on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (4: 1, 3:1, 2:1, 1:1, 1:2, 1:3). The organic solvent is removed on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 12.0% of brown lyophilizate.

IR(KBr): 1774, 1680, 1664 cm-1.

MS(ISP): 868.4 (M+H) + .

Example 34a

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

(E)-(6R,7R)-7-amino-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza- bicyclo [4.2.0]-oct-2-ene-2-carboxylic acid (736.0 mg, 1.83 mmol) was suspended in 20 ml of dichloromethane and N,O-bis(tri-methylsilyl)-trifluoroacetamide (1 .94 ml, 7.32 mmol). After 45 minutes, bormoacetyl bromide (167 ml, 1.92 mmol) was added dropwise. After 1 hour, the reaction mixture is poured into 200 ml of diethyl ether containing 160 ml of water. After 15 minutes, the solid is collected by filtration, washed with diethyl ether and dried under high vacuum.

Yield: 84.1% yellowish solid.

IR(KBr): 1779, 1667, 1615 cm-1.

MS(ISP): 522.3 (M+H) + .

Example 34b

(E)-(6R,7R)-7-[2-(4-cabroxy-phenylsulfanyl]-acetylamino]-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:2)

The disodium salt of 4-mercaptobenzoic acid (83.0 mg, 0.42 mmol) was dissolved in 4 ml of N,N-dimethylformamide and (E)-(6R,7R)-7-(2-bromo) was added in one portion. -acetylamino)-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2- ene-2-carboxylic acid (200 mg, 0.40 mmol). After 2 hours, the reaction mixture was poured into diethyl ether and the solid material was collected by filtration. The beige solid was suspended in water and the pH was adjusted to 7 with 1M sodium hydroxide. The resulting solution is chromatographed on an MCI gel (75-150 µ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitrile (9:1, 8:2, 7:3). The organic solvent is removed on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 50.0% beige lyophilisate.

IR(Nujol): 1763, 1663, 1592 cm-1.

MS(ISP): 569.1 (M+H) + .

The following compounds were produced analogously to example C34.

Example 35

(E)-(6R,7R)-7-[2-[5-cabroxy-2-(3,4-dihydroxy-phenyl)-5-methyl[1,2,4]triazolo[15-a]pyrimidine- 7-ylsulfanyl]-acetyl-amino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidine -3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:2)

Yield: 20.0% beige lyophilisate.

IR(KBr): 1775, 1673, 1643 cm-1.

MS(ISN): 896.3 (M-H-).

Example 36

(E)-(6R,7R)-7-[2-(4-cabroxy-phenoxy)-acetylamino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]- Pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

sodium salt (1:2)

Yield: 20.0% of brown lyophilizate.

IR(KBr): 1766, 1668, 1643 cm-1.

MS(ISP): 748.4 (M+H) + .

Example 37

(E)-(6R,7R)-7-[2-[2-(3,4-dihydroxy-phenyl)-5-methyl-[1,2,4]-triazol[1,5-a]pyrimidine- 7-ylsulfanyl]-acetylamino]-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0] oct-2-ene-2-carboxylic acid

(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-[1-(4-hydroxy-benzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5- Thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid (see Example C34a) (200.0 mg, 0.38 mmol) was dissolved in 4 ml of N,N-dimethyl-formamide and 4-[7-mercapto-s-triazol[1,5-a]-pyrimidine-2-pyrocatechol sodium salt (124.0 mg, 0.42 mmol) was added. After 5 hours, the reaction mixture is poured into diethyl ether and the suspension is filtered. The solid is digested for 1 hour with 10 ml of ethyl acetate:water (1:1), filtered and dried under high vacuum.

Yield: 70.0% beige solid.

IR(KBr): 1774, 1670 1596 cm-1.

MS(ISP): 716.3 (M+H) + .

The following compound was produced analogously to example C23.

Example 38

(E)-(6R,7R)-7-[2-(4-amino-phenylsulfanyl)-acetylamino]-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5- thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1)

Yield: 37.0% beige lyophilisate.

IR(KBr): 1782, 1623 1599 cm-1.

MS(ISP): 501.2 (M+H) + .

The following compounds were produced analogously to example C33.

Example 39

(E)-(6R,7R)-7-[2-(2,6-dichloro-phenylsulfanyl]-acetylamino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl ]-pyridin-1-ij-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2- carboxylate

Yield: 19.0% beige lyophilisate.

IR(KBr): 1768, 1663, 1643 cm-1.

MS(ISP): 772.3 (M+H) + .

Example 40

(E)-(6R,7R)-7-[2-(3,5-dichloro-phenyl-sulfanyl]-acetylamino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl) -methyl]-pyridin-1-ij-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene- 2-carboxylate

Yield: 19.0% beige lyophilisate.

IR(KBr): 1769, 1677, 1643 cm-1.

MS(ISP): 772.3 (M+H) + .

Method D

Example D1a

A mixture of (E)-(6R,7R)-7-[(R)- and -[(S)-2-bromo-propionylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)- 8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt

[image]

The suspension (E)-(6R,7R)-7-amino-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo-[4.2. O]oct-2-ene-2-carboxylic acid (3.50 g, 10.0 mmol) in 50 ml of dichloromethane was mixed with N-methyl-N-trimethylsilyl-trifluoroacetamide (4.40 ml, 24.0 mmol). . After 1 hour, a yellow solution is formed, into which 2-bromo-propionyl bromide (1.30 ml, 12.0 mmol) is added drop by drop at 0°C. The reaction mixture was stirred for 30 minutes at 0°C and 3 hours at room temperature and then concentrated under vacuum. The oily residue was suspended in water and the pH was adjusted to 6.8 using 1N sodium hydroxide solution. The resulting solution was purified by reverse phase chromatography (RP-18 LiChroPrep gel, water:acetonitrile = 1:0, 4:1).

Yield: 2.80 g (55.0%).

IR(KBr): 1765, 1667 cm-1.

MS(ISP): 482.1 (M-Na) + .

Example D1b

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[(R)- and -[(S)-2-(2,5- dichloro-phenyl-sulfanyl)-propionylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid

[image]

0.05 N solution of the mixture (E)-(6R,7R)-7-[(R)- and -[(S)-2-bromo-propionylamino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidine- 3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid sodium salt in DMSO (500 µl) was mixed with a 0.05 N soln. of 2,5-dichlorobenzenethiol in DMSO (500 µl) for 24 hours at room temperature.

MS(ISP): 599.2 (M+NH4)+.

The following compounds were synthesized according to the procedure described above.

Example D2

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[(R)- and -[(S)- [2-(1-methyl -1H-tetrazol-5-ylsulfanyl)-propionylamino]-8-oxo-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylic acid

sodium salt

[image]

MS(ISP): 537.3 (M+NH4)+.

Example D3

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[(R)- and -[(S)-[2- (pyrimidin-2-yl-sulfanyl)-propionylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid

[image]

MS(ISP): 533.2 (M+NH4)+.

Example D4

A mixture of (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[(R)- and -[(S)-[2-(4-methoxy -phenyl-sulfanyl)-propionylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]-oct-2-ene-2-carboxylic acid

[image]

MS(ISP): 561.2 (M+NH4)+.

Method E

Example E1

(E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl )-8-oxo-7-[2-(pyridin-1-yl-1-yl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate bromide

[image]

To a suspension of 260.0 mg (0.40 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridine-1 -ij-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 212 µl (0.80 mmol) of N,O-bis(trimethylsilyl)-trifluoroacetamide was added to 3 ml of dichloromethane. When a clear solution is formed, 65 µl (0.80 mmol) of pyridine and 35 µl (0.40 mmol) of bromoacetyl bromide are added drop by drop and the reaction mixture is stirred for 6 hours. 3 ml of diethyl ether and 10 µl of water are added to this solution. The precipitate is filtered off, dissolved in 250 µl of water:acetonitrile (3:2) and purified by reverse phase chromatography (RP-18 LiChroPrep gel, water:acetonitrile = 9:1). The organic solvent is removed on a rotary evaporator and the aqueous phase is freeze-dried.

Yield: 110.0 mg (45.3%) of beige lyophilisate.

IR(KBr): 1768, 1682, 1574 cm-1.

MS(ISP): 655.4 (M+H) + .

Claims (12)

1. Cephalosporin derivatives of general formula I [image] indicated by that R 1 represents hydrogen, lower alkyl, phenyl, benzyl, styryl, naphthyl or heterocyclyl; wherein lower alkyl, phenyl, benzyl, styryl, naphthyl or heterocyclyl can be optionally substituted with at least one halogen, hydroxy, optionally substituted lower alkyl, optionally substituted alkoxy, optionally substituted phenyl, amino, lower alkylamino, di-lower alkylamino , carboxy, lower alkylcarboxy or lower alkylcarbamoyl; R4, R5 independently represent hydrogen, lower alkyl or phenyl; X is S, O, NH or CH 2 ; n is 0, 1 or 2; m is 0 or 1; s is 0 or 1; R2 represents hydrogen, hydroxy, -CH2-CONHR6, lower alkyl-Qr, cycloalkyl-Qr, lower alkoxy, lower alkenyl, cycloalkenyl-Qr, lower alkynyl, aralkyl-Qr, aryl-Qr, aryloxy, aralkyl, heterocyclic ring or heterocyclyl-Qr, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cyclo-alkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkoxy and the heterocyclic ring may be substituted with at least one substituent selected from the group consisting of carboxy, amino, nitro, cyano, -SO2NHR6, optionally substituted with fluorine lower alkyl, lower alkoxy, hydroxy, halogen, -CONR6R7, -CH2CONR6R7, -N(R7)COOR8, -R7CO-, R7OCO-, R7COO-, -C(R7R9)CO2R8, -C(R7R9)CONR7R10, wherein R6 represents hydrogen, lower alkyl, cycloalkyl or aryl; R7 and R9 independently represent hydrogen or lower alkyl; R8 is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; and R10 is hydrogen, ω-hydroxy-alkyl, phenyl, naphthyl or heterocyclyl, whereby phenyl, naphthyl or heterocyclyl is unsubstituted or substituted with at least one optionally protected hydroxy group, and halogen, with an arbitrarily substituted lower alkyl or ω-hydroxy- an alkyl group, optionally substituted with a lower alkoxy and/or cyano group; or the groups R7 and R10 together form a group of the formula [image] Q is -CHR-, CO or -SO2-; r is 0 or 1; R is hydrogen or lower alkyl; and R 3 represents hydroxy, -O-, lower alkoxy, or -OM, where M represents an alkali metal; as well as their esters which can immediately hydrolyze, pharmaceutically acceptable salts of said compounds and hydrates of compounds of formula I and their esters and salts. 2. Cephalosporin derivatives according to claim 1, characterized in that R1 represents halogen, phenyl, benzyl, naphthyl or heterocyclyl, wherein phenyl, benzyl, naphthyl or heterocyclyl can optionally be substituted with at least one halogen, hydroxy, optionally substituted lower alkyl or alkoxy, or amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkylcarboxy or lower alkylcarbamoyl; R4, R5 independently represent hydrogen, lower alkyl or phenyl; X is S, O, NH or CH 2 ; n is 0, 1 or 2; m is 0 or 1; s is 0 or 1; R 2 represents hydrogen, hydroxy, lower alkyl-Qr, cycloalkyl-Qr, lower alkoxy, lower alkenyl, cycloalkenyl-Qr, lower alkynyl, aralkyl-Qr, aryl-Qr, aryloxy, aralkyloxy, heterocyclic ring or heterocyclyl-Qr, lower alkyl, cycloalkyl, lower alkoxy, lower alkenyl, cycloalkenyl, lower alkynyl, aralkyl, aryl, aryloxy, aralkyl and hetero-cyclic ring can be substituted with at least one group selected from carboxy, amino, nitro, cyano, if necessary with fluorine substituted lower alkyl, lower alkoxy, hydroxy, halogen, -CONR6R7, -N(R7)COOR8, -R7CO-, R7OCO-, R7COO-, -C(R7R9)CO2R8, -C(R7R9)CONR7R10, where R 6 represents hydrogen, lower alkyl or cycloalkyl; R7 and R9 independently represent hydrogen or lower alkyl; R8 is hydrogen, lower alkyl, lower alkenyl or a carboxylic acid protecting group; and R10 is hydrogen, ω-hydroxy alkyl, phenyl, naphthyl or heterocyclyl, wherein phenyl, naphthyl or heterocyclyl is unsubstituted or substituted with at least one optionally protected hydroxy group, halogen, optionally substituted lower alkyl or ω-hydroxyalkyl group, by optionally substituted with a lower alkoxy and/or cyano group; or R7 and R10 together form a group of the formula [image] Q is -CHR-, CO or -SO2-; r is 0 or 1; R is hydrogen or lower alkyl; and R 3 represents hydroxy, -O-, lower alkoxy, or -OM, where M represents an alkali metal; as well as their esters which can immediately hydrolyze, pharmaceutically acceptable salts of said compounds and hydrates of compounds of formula I and their esters and salts. 3. Compounds according to claims 1 or 2, characterized in that n is 1. 4. Compounds according to claims 1, 2 or 3, characterized in that R1 is selected from the group consisting of phenyl, 2,4,5-trichlorophenyl, 3,4-dichlorophenyl, 2,5-dichlorophenyl, 4-trifluoro-methylphenyl, 4-methoxyphenyl, 4-hydroxymethylphenyl, 3,4-di-methoxyphenyl, 4-methyl-1,2,4-triazol-5-yl, 1-methyl-tetrazol-5-yl, pyrimidin-2-yl, as needed substituted pyrimidin-1-yl, -2-yl, -3-yl or 4-yl, benzylimidazol-2-yl, 2-benz-thiazolyl, 4-pyridinyl, (2-amino)-thiazol-4-yl, 2 -naphthyl, benzyl. 5. Compounds according to any of claims 1 to 4, characterized in that R2 is methylcyclopropyl, 2-, 3- or 4-hydroxybenzyl, pyrrolidin-3-yl or a group of the formula [image] where Q1 is -CH2-; r is 0 or 1; R11 is hydrogen, lower alkyl, ω-hydroxy alkyl, benzyl or alkylheterocyclyl, wherein the benzyl or heterocyclyl group is unsubstituted or substituted with at least one of the cyano, carboxy or hydroxy groups; or -CH2CONR7R10; in which they are R7 and R10 defined as in claim 1. 6. Compounds according to claim 1, indicated by the fact that they are from the group they form (E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl ]-8-oxo-7-[2-(2,4,5-trichlorophenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, (E)-(6R,7R)-3-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8 -oxo-7-[2-(1-benzothiazol-2-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, (E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidenemethyl]-8-oxo-7-[2-(pyridin-4-ylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2 -carboxylate, (E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo -pyrrolidine-3 -ylidene-methyl]-8-oxo-7-(2,4,5-trichlorophenylsulfanyl)-acetylamino)-5-thia-1-aza-bicyclo-[4.2.0]oct-2-en-2 -carboxylate, (E)-(6R,7R)-3-[1-[1-[(4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidenemethyl]-8-oxo-7-(2-phenylsulfanyl)-acetylamino)-5-thia-1-aza-bicyclo-[4.2.0]oct-2-ene-2-carboxylate, (E)-(6R,7R)-3-[1-[1-[(3-fluoro-4-hydroxy-phenyl-carbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo -pyrrolidine-3 -ylidenemethyl]-7-[2-(naphthalen-2-yl-sulfanyl)-acetylamino]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2 -carboxylate, (E)-(6R,7R)-7-[2-(3,4-dichloro-phenylsulfanyl)-acetyl-amino]-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl) -methyl]-pyridin-1-ij-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene- 2 -carboxylate, (E)-(6R,7R)-3-[1-[1(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3 -ylidene-methyl]-8-oxo-7-(2-phenylsulfanyl-acetylamino)-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate, (E)-(6R,7R)-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-7-[2-(2,4,5-trichloro-phenylsulfanyl) -acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (E)-(6R,7R)-7-[2-(benzothiazol-2-ylsulfanyl)-acetyl-amino]-3-(1-cyclopropylmethyl-2-oxo-pyrrolidin-3-ylidene) -methyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (E)-(6R,7R)-3-[1-(3-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-(2,4,5-trichloro -phenylsulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, (E)-(6R,7R)-3-[1-(3-hydroxybenzyl)-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-7-[2-naphthalen-2-ylsulfanyl) -acetyl-amino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid, mixture of (E)-(6R,7R)-8-oxo-8-[(R)- and -[(S)-2-oxo-[1,3']-bipyrrolidinyl-3-ylidenemethyl]-8-oxo -7-[2-(2,4,5 -trichloro-phenyl-sulfanyl)-acetylamino]-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride, (E)-(6R,7R)-8-oxo-3-[(R)-2-oxo-[1,3']bipyrrolidinyl-3-ylidenemethyl]-7-(2-phenylsulfanyl-acetylamino)-5- thia-1 -aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid hydrochloride (1:1), (E)-(6R,7R)-7-[2-(2,5-dichloro-phenylsulfanyl)-acetyl-amino]-3-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl] -pyridin-1-yl-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-en-2 -carboxylate, (E)-(6R,7R)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-7-[2-(naphthalen-1-ylsulfanyl)-acetylamino]-8 -oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid imidazole salt (1:1). 7. Compounds according to any of claims 1 to 5, characterized in that they are used as pharmaceutical active substances, especially for the treatment and prophylaxis of infectious diseases. 8. A process for the production of compounds prepared in accordance with any of claims 1 to 6, characterized in that it includes treatment of the compound of formula II [image] where R2 is defined as in claim 1, Rf is hydrogen or trimethylsilyl; and Rg is hydrogen, benzhydryl, p-methoxybenzyl, t-butyl, trimethylsilyl or allyl, or a salt thereof, with a carboxylic acid of general formula III [image] wherein R1, X, s, R4, R5 and m are as defined in claim 1 and Y is -OH, or a reactive functional derivative thereof, for compounds of formula I wherein X is S, O or NH, treatment of compounds of formula IV [image] wherein R4, R5, m, n, R2 and Rg are as defined above and Hal is halogen, with the corresponding thiol or thioalt or the corresponding alcohol or alcoholate or the corresponding amine in the presence of a base, for the preparation of esters of compounds of formula I which can immediately hydrolyze, compounds of formula I are subjected to appropriate esterification, or for the production of salts or hydrates of compounds of formula I or their hydrates or their salts, compounds of formula I are converted into salts or hydrates or into hydrates of said salts. 9. Pharmaceutical preparation, characterized in that it contains a compound prepared according to any of claims 1 to 6 and a therapeutically inert carrier, especially for the treatment and prophylaxis of infectious diseases. 10. Compounds prepared according to any of claims 1 to 6, characterized in that they are prepared in accordance with the process according to claim 8 or an apparently equivalent process. 11. The use of compounds prepared according to any of claims 1 to 6, characterized in that they are used for the treatment and prophylaxis of infectious diseases or for the production of drugs for the treatment and prophylaxis of infectious diseases. 12. New compounds, formulations, processes and methods, characterized in that they are actually in accordance with those described herein.