AU2012233003B2

AU2012233003B2 - Useful combinations of monobactam antibiotics with beta-lactamase inhibitors

Info

Publication number: AU2012233003B2
Application number: AU2012233003A
Authority: AU
Inventors: Eric Desarbre; Berangere Gaucher; Malcolm G. P. Page; Patrick Roussel
Original assignee: Basilea Pharmaceutica AG
Current assignee: Basilea Pharmaceutica AG
Priority date: 2005-12-07
Filing date: 2012-09-28
Publication date: 2014-12-18
Anticipated expiration: 2026-12-07
Also published as: AU2012233003A1

Abstract

USEFUL COMBINATIONS OF MONOBACTAM ANTIBIOTICS WITH BETA-LACTAMASE INHIBITORS Abstract A pharmaceutical composition, comprising a combination of an antibiotically active 5 compound of the formula (1): with a -lactamase inhibitor of one of the formulae (II) to (XIII) are active against Gram-negative bacteria, in particular such bacteria which have become resistant against antibiotics such as aztreonam, carumonam and tigemonam. Optionally the compositions may comprise another p-lactamase inhibitor of one of the formulae (II) to (XIII), particularly of formula (V) or formula (VI). N'O ~ ~jR2 ,0 N O 'R1

Description

S&F Ref: 858706D2 AUSTRALIA PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address Basilea Pharmaceutica AG, of Grenzacherstrasse 487, of Applicant: CH-4005, Basel, Switzerland Actual Inventor(s): Berangere Gaucher Eric Desarbre Malcolm G. P. Page Patrick Roussel Address for Service: Spruson & Ferguson St Martins Tower Level 35 31 Market Street Sydney NSW 2000 (CCN 3710000177) Invention Title: Useful combinations of monobactam antibiotics with beta-lactamase inhibitors The following statement is a full description of this invention, including the best method of performing it known to me/us: 5845c(6743736_1) 1 Useful Combinations of Monobactam Antibiotics with beta-Lac tamase Inhibitors Field of the invention The present invention is concerned with pharmaceutical 5 compositions and methods for treating infections caused by pathogenic Gram-negative bacteria. Background of the invention 10 -Lactam antibiotics have been widely used for the treat ment of bacterial infections both in hospitals and in the gen eral public. There are several classes of P-lactam antibiotics that have found clinical application, these include the peni cillins, cephalosporins, cephamycins, carbacephems, oxace 15 phems, carbapenems and monobactams. The efficiency of all of these classes to cure bacterial infections has been impaired by the appearance of bacteria that are resistant towards the antibiotics. The prevalent 20 cause of this resistance in Gram-negative bacteria is the ex pression by the bacteria of enzymes known as B-lactamases that are able to hydrolyse the -lactam antibiotics rendering them inactive. Bacteria are able to produce a variety of $ lactamases, including penicillinases, cephalosporinases, 25 cephamycinases, carbapenemases, monobactamases, broad-spectrum P-lactamases and extended-spectrum P-lactamases. The possibility of rescuing individual D-lactam antibi otics by combination with a $-lactamase inhibitor that inac- -2 tivates the j-lactamase before it can hydrolyse the j-lactam antibiotic has been demonstrated with clinically useful combinations between penicillins such as amoxicillin, ampicillin and ticarcillin and p-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam. Further, potential combinations have been described involving 5 cephalosporins and newly developed p-lactamase inhibitors including bridged monobactams, penam sulfones, phosphonate esters, exomethylene penams and diazabicyclooctane derivatives. Monobactams have been regarded as stable towards many P-lactamases. However, 10 there are now many strains of Gram-negative bacteria that exhibit j-lactamase-mediated resistance towards the monobactam antibiotics (aztreonam, carumonan and tigemonam). The present invention aims to provide improved medicaments with novel monobactam antibiotics and combinations of monobactam antibiotics with j-lactamase 15 inhibitors that are active against aerobic Gram-negative bacteria that are resistant against treatments with monobactam antibiotics. Summary of the invention 20 Disclosed herein is a pharmaceutical composition, comprising a combination of a) an antibiotically active compound of the following formula I: 3 R4 N-O R6 H R5 R3 O J R2 0 -N, 0 Ri in which 5 Ri signifies SOH, OSO 3 H, CRaRa'COOH, OCRaRa'COOH, 5-tetra zolyl, SO 2 NHRb or CONHRc, wherein Ra and Ra' are independently selected from hydrogen; alkyl; allyl; benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, 10 alkylamino, dialkylamino and halogen; phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; alkylamino; dialkylamino; alkoxyalkyl and a 5-6 mem bered heteroaromatic ring which may be substituted with 1 to 15. 4 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; wherein Rb is hydrogen; alkyl; alkoxycarbonyl; alkylamino carbonyl; benzylaminocarbonyl in which the benzyl may be substituted with 1 to 5 substituents selected from alkyl, 20 hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; or phenylaminocarbonyl in which the phenyl may be sub stituted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino,dialkylamino and halogen; wherein Rc is hydrogen; alkyl; phenyl which may be substi 25 tuted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; A benzyl which may be substituted with 1 to 5 substituents se lected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; alkoxycarbonyl;

SO

2 phenyl;

SO

2 NHalkyl; or a 5-6 membered heteroaromatic ring which may 5 be substituted with 1 to 4 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; R2 and R3 independently signify hydrogen; alkyl; alkenyl; al kynyl; benzyl which may be substituted with 1 to 5 substitu 10 ents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; azido; halogen; dihalogenomethyl; trihalogenomethyl; alkoxycarbonyl; carboxyl; 15 sulfonyl or CH 2 X1, wherein X1 is azido; amino; halogen; hydroxyl; cyano; car boxyl; aminosulfonyl; alkoxycarbonyl; alkanoylamino; phenyl aminocarbonyl; alkylaminocarbonyl; aminocarbonyl; carbamoy loxy; alkylaminosulfonyl; phenylaminosulfonyl in which the 20 phenyl may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dial kylamino and halogen; phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; or benzyl which 25 may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; R4 signifies hydrogen; alkyl; C(Rx)(Ry)Z, wherein Rx and Ry are independently selected from hydrogen; 30 alkyl; allyl; (C 3

-C

6 )cycloalkyl; phenyl which may be substi tuted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halo- 5 gen; (C 2

-C

7 ) alkene and (C 2

-C

7 )alkyne; or Rx and Ry taken to gether may form an alkylene bridge -(CH 2 )n- with n being an integer number from 2 to 6; and Z is COOH; CH 2 N(OH)COR' wherein 5 R' is hydrogen, alkyl, alkylamino, alkoxy, benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen, phenyl ;hich may be substituted with 1 to 5 substituents selected from from alkyl, hydroxyl, alkoxy, 10 amino, alkylamino, dialkylamino and halogen, or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 4 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; or Z is one of the following six groups 15 0 O Re Re I I I N Rf N Rf Rd Rd ,N Ri NN Ri NO N \ N OH OH OH in which groups Rd, Re and Rf are independently selected from hydrogen; alkyl; amino'; monoalkylamino; carboxylaminoalkyl; alkoxy 20 carbonyl; benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; diphenyl methyl; trityl; and ORg wherein 6 Rg is hydrogen; alkyl; benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino and halogen; or phenyl which may be substituted with 1 to 5 substitu 5 ents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino and halogen; or, when Re and Rf are vicinal substituents, Re and Rf taken together may also be -O-CH=CH-CH 2 -, -O-CH 2

-CH

2 - -

CH

2

-CH

2

-CH

2 -, -CH 2

-CH

2

-CH

2

-CH

2 -, -CH=CH-CH=CH- or 10 CH=C(OH)-C(OH)=CH-; Ri is hydrogen; alkyl; alkyla-mino; alkoxy; benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; phenyl which may be substituted with 1 to 5 15 substituents selected from alkyl and hydroxyl; or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; R5 signifies hydrogen, alkyl, halogenomethyl, dihaloge 20 nomethyl, trihalogenomethyl, alkoxy, formylamino or alkylcar bonylamino; R6 signifies phenyl which may be substituted with 1 to 5 sub stituents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, dialkylamino and halogen; or a 5-6 membered het 25 eroaromatic ring which may be substituted with 1 to 4 sub stituents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, carbonylamino and halogen; or a pharmaceutically acceptable salt thereof; 30 and one or more P-lactamase inhibitors selected from the fol lowing groups b1) to bl1): 7 bl) a bridged monobactam derivative of the following formula II: R8'N H t .. 1H N. 0 R7 5 in which: R7 signifies SO3H, OSO 3 H or OCRjRj'COOH, wherein Rj and Rj I' are independently selected from hydro gen; alkyl; phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, 10 alkylamino, dialkylamino and halogen; benzyl which may. be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; alkylamino and alkoxyalkyl; R8 is alkoxycarbonylamino, the acyl residue of an a or -amino 15 acid, or a residue of the formula Q- (X)r-Y-, wherein Q is a 3-6 membered ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally fused to a phenyl ring or to a 5-6 membered heterocyclic ring and which is optionally substituted with 1 to 4 sub 20 stituents selected from alkyl, allyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, carboxamide which may be substituted, carboxylic acid, carbonylalkoxy, aminocar bonyl, alkylaminocarbonyl, halogen, halogenomethyl, diha logenomethyl, trihalogenomethyl, sulfamide, substituted 25 sulfamide with substituents selected from alkyl, allyl, 8 phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino and halogen and benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, 5 alkylamino, halogen and benzyl, urea which may be substi tuted with alkyl, aminoalkyl or alkoxy and carbamate which may be substituted with alkyl, aminoalkyl or alkoxy, X signifies a linear spacer of from 1 to 6 atoms length and containing carbon, nitrogen, oxygen and/or sulphur atoms, 10 of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulphur, r is an integer of from 0 to 1; and Y is selected from -CO-, -CS-, -NHCO-, -NHCONH- and -SO 2 -; or a pharmaceutically acceptable salt thereof, 15 or b2) a monobactam derivative of the general formula III: 20 R4 0, N R6- H N 0 I 0 S0 3 H in which R4' signifies hydrogen, alkyl or CH(Rx')Z', wherein Rx' is selected from hydrogen; (C2-C 6 )alkyl; allyl; phenyl and (C 3 -CG)cycloalkyl; and Z' signifies COOH or a group of 25 one of the following two formulae: 0 0 OH HO RI IRd Rd, Rd' 9 in which Rd' is hydrogen or hydroxy; and R6 is as defined for formula I; or a pharmaceutically accept able salt thereof, 5 or b3) a penam sulfone derivative of the general formulae IV or V: 10 R9 RIO C' S * Ru O O R10 R11 0 N_ 0 IV HO O V HO in which R9 signifies COOH or a 5-6 membered monocyclic or poly 15 cyclic heteroaromatic group; R10 signifies hydrogen or halogen; R11 signifies CH 2 R12; CH=CHR12 wherein R12 is hydrogen, halogen, cyano, carboxylic acid, acyl such as acetyl, car boxamide which may be substituted, alkoxycarbonyl or a 5-6 -20 membered heteroaromatic ring which is optionally substi tuted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; or which is optionally fused with a 5-6 membered het eroaromatic ring; CH=NR12' wherein R12' is amino, al 25 kylamino, dialkylamino, aminocarbonyl, acylamino such as acetylamino, hydroxy, alkoxy, or a pharmaceutically acceptable salt thereof; or 10 b4) an oxapenam derivative of the general formula VI: 0 R13 HO 0 VI 5 in which R13 signifies OR14; S(O),R14 or a 5-6 membered heteroaro matic ring which may be substituted with 1 to 5 substitu 10 ents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, dialkylamino and halogen; whereby n = 0, 1 or 2, and R14 is hydrogen, alkyl, (C 2

-C

7 )alkene, (C 2

-C

7 )alkyne or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, 15 alkoxy, amino, alkylamino, dialkylamino and halogen, or a pharmaceutically acceptable salt thereof; or 20 b5) a penem derivative of the general formula VII: R15 K s 0 HO HO O in which 25 R15 signifies a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from al kyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and 11 halogen; or which is optionally fused with a 5-6 membered heteroaromatic ring and/or which is optionally bound to the exo-methylene group over a -CH=CH- spacer being preferably in the (E)-configuration, 5 or a pharmaceutically acceptable salt thereof; or b6) a cephem sulfone derivative of the general formula VIII: R16

.

9 N / OCOCH 3 HO 0 Vill 10 in which R16 signifies COOR17, whereby R17 signifies hydrogen or al kyl; or a 5-6 membered heteroaromatic ring which is op 15 tionally fused with a 5-6 membered heteroaromatic ring be ing optionally substituted with 1 to 5 substituents se lected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, halogen; and/or being optionally bound to the exo-methylene group over a -CH=CH- spacer being preferably 20 in the (E)-configuration, or a pharmaceutically acceptable salt thereof; or 25 b7) a carbapenem derivative of the general formula IX: 12 '1HH N R18 0 HO 5 in which R18 signifies -S-alkyl, -S-(CH 2

)

2 -NH-CH=NH or a group of the following two formulae 0 NRkRI NRkRI NH NH -S _-s wherein Rk and RI are individually selected from hydrogen, al kyl, 2-, 3-, 4-carboxyphenyl and sulfamoyl, or a pharmaceu 10 tically acceptable salt thereof; or b8) a boronate derivative of the general formula X: OH IH R19 HO' B N /R X 15 wherein R19 signifies a 5-6 membered heteroaromatic ring which may be substituted with amino, alkylamino, dialkylamino or al kylsulfoxide, or a pharmaceutically acceptable salt thereof; 13 or b9) a boronate derivative of the general formula XI: H ... 'N '*rR21

R

2 ~R~ HO -BsOH 5 wherein R20 and 21 are independently selected from a 5-6 membered heteroaromatic ring or phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, 10 amino, alkylamino, dialkylamino and halogen and benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dial kylamino and halogen, or a pharmaceutically acceptable salt thereof; 15 or blO) a phosphonate derivative of the general formula XII: 0 0 N P O P / N R22 H /H 0 O OH 1 20 wherein R22 is selected from a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected 25 from alkyl, hydroxyl, alkoxy, amino, alkylamino, dial kylamino and halogen and which is optionally fused with a 14 5-6 membered heteroaromatic ring; phenyl which may be sub stituted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; and benzyl which may be substituted with 1 to 5 sub 5 stituents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, dialkylamino and halogen, or a pharmaceutically acceptable salt thereof; or 10 bl1) a diazabicyclooctane derivative of the general formula XIII: N R23 R24'N 15 in which R23 signifies hydrogen, carboxylic acid, alkoxycarbonyl or carboxamide which may be substituted, and 20 R24 signifies SO 3 H, OSO 3 H or OCRjRj'COOH, wherein Rj and Rj' are as defined for formula II, or a pharmaceutically acceptable salt thereof. As a preferred embodiment of the invention, the pharma 25 ceutical compositions may comprise two or more compounds se lected from one of the formulae II to XIII of bl) to bll), these two or more compounds being different from each other.

- 15 The object set is also solved by the novel monobactam antibiotics of formula Ia as described hereinafter, which may be used in the same combinations as outlined above. Specifically, a first aspect of the present invention provides a compound of the 5 following formula Ib: R4 HNN R HN R2 &<N 0 R1 wherein R1 is SO 3 H; R2 is H; 10 R3 is methyl; R4 is C (Rx) (Ry) Z; whereby Rx = Ry = H, and Z is a group of one of the formulae 0 0 Re R N Rf N Rf Rd Rd wherein Rd, Re and Rf are individually selected from hydrogen and hydroxy, with 15 the proviso that at least two of Rd, Re and Rf are hydroxy; and R5 signifies hydrogen; or a pharmaceutically acceptable salt thereof. Further objects of the invention are visible from the description hereinafter and 20 from the appended claims. Detailed description of the invention It has surprisingly been found that the efficacy of monobactam antibiotics of the 25 formula I against aerobic Gram-negative bacteria can be potentiated by co-using a lactamase inhibitor according to any one of the formulae II to XIII.

- 15a In formula I, when the oxoazetidine ring is lying in the plane of the paper, preferably R3 points downwards from the plane, and R2 points upwards from the plane. For the purposes of the present invention, the compounds of the above formula III 5 are not considered as "antibiotically active" compounds in the sense of claim 1. The compounds in formula I have the oximino group predominantly the "syn" configuration shown in formula I, whereas the compounds III have the oximino group specifically in the "anti" configuration shown in formula III. 10 The term "alkyl", as used in the present application, preferably means straight-chain or branched (Ci-C 7 )alkyl such as in particular methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, tert-butyl or neopentyl.

16 The term "alkoxy", as used in the present application, preferably means straight-chain or branched (C 1 -C,)alkoxy, such as in particular methoxy, ethoxy, propoxy, 1- or 2-butoxy, 1-, 2-, or 3-pentyloxy, 1-, 2- or 3-hexyloxy, 1-, 2-, 3-, or 4 5 heptyloxy or tert-butoxy. The term "alkylhydroxyl" as also used, shall be considered synonymous to "alkoxy"; in particu lar for the alkyl in "alkylhydroxyl" the same definition shall apply as given above for "alkyl". 10 The term "carboxamide which may be substituted" pref erably has the meaning that the carboxamide has 0 to 2 hydro gen atoms attached to the amino moiety, with the remainder of the substituents on the amino moiety being alkyl or phenyl which may be substituted. 15 The term "imine which may be substituted" preferably means that the imine bears at the imine nitrogen hydrogen, al kyl, phenyl which may be substituted or benzyl which may be substituted. 20 The terms "optionally substituted phenyl" and 'option ally substituted benzyl", if given without specifically indi cated substituents, shall preferably mean that the phenyl or benzyl is optionally substituted with 1 to 5 substituents se 25 lected from alkyl, alkoxy, dialkylamino and halogen, wherein the "alkyl" itself and the alkyl in dialkylamino and alkoxy has the meaning as defined above. The term "linear spacer", as used in the present ap 30 plication, preferably means a linear divalent group selected from -0-, -S-, -NH-, -NH-NH -, -CH 2 -, -CO-, -CH 2 0-, -CH 2

CH

2 -, CH=CH-, -CH 2 NH-, -S-CH 2 -, -SO 2 -, -CH 2 -, -0-CH 2 -, -S-CH 2

CH

2 -, - 17

CH

2

CH

2 -NH-, -CH 2

-NH-CO-CH

2

CH

2 -, -CH 2 -NH-CO-0-CH2CH2,

-CH

2

-NH-CO

NH-CH

2

CH

2 , -CH 2 -0-CO-NH-CH 2 CH2-, -CH(OH)-, -CH(COOH)-, CH(OSO 3 H)-, -CH(OCONH 2 )- and -CH[CH(CH 3 )21- 5 Some compounds of formula I may, when they contain an acidic group (such as when RI is SO 3 H, OSO 3 H, CRaRa'COOH, OCRaRa'COOH or SO 2 NHRb) be present as a salt with a pharma ceutically acceptable inorganic base (e.g. NaOH, KOH, 13,

K

2 C0 3 , Na 2

CO

3 , Na 2

HPO

4 or K 2 HP0 4 ) or organic base (e.g. NEt 3 , 10 HNiPr 2 , triethanolamine, TRIS or basic amino acids such as ar ginine and lysine) . The use of such salts of compounds of for mula I is encompassed by the invention. Also, some of the com pounds of formula I, when they contain both an acidic group (such as when R1 is SO 3 H, OSO 3 H, CRaRa'COOH, OCRaRa'COOH or 15 SO 2 NHRb) and a basic group (such as when R6 is 2-amino-1, 3 thiazol-4-yl, 5-amino-1, 2, 4-thiadiazol- 3 -yl, . 5-amino-1, 2

,

4 oxadiazol-3-yl, 3-aminoisoxazol-5-yl, 5-amino-1-methylpyrazol 3-yl, 5-aminopyrazol-3-yl, 6-amino-2-pyridyl, 4 aminopyrimidin-2-yl, 2-carbonylamino-1,3-thiazol-4-yl or 2 20 amino-5-chloro-1, 3-thiazol- 4 -yl) may form an inner, zwitteri onic salt; such inner salts are also intended to be encom passed by the claims. When R4 contains a 4-pyridone moiety, wherein Rd is se 25 lected from hydrogen and hydroxy, there is the possibility of tautomerism: 0 OH OH OH N N , H 18 The invention intends to encompass the use of any such tautomers. A first group of preferred examples of compounds of the 5 formula I for the combinations of the invention are aztreonam, carumonam, tigemonam, and compounds according to the following table 1 (R,5 is in these compounds always H) table 1 10 _____ Compound RI R2 R3 R4 R6 number 1 SO 3 H H CH 3 0 H2N N I IS N OH 2 SO 3 H H CH 3 O H 2 N N OH I S-N N CI OH 5_ SO3H H CH3 O OH H2N N N OH 6 SO 3 H H CH 3 0 H2N N OH NS N OH 4 S 3 RH C0 NR HNN 5S0 3 H HCH 3 OH HN S

N

19 7 SO 3 H H CH 3 0 H 2 N N OH 8 SO 3 H H CH 3 0 H2N HO S 9 O H O H N OH 9 SO 3 1Hi H H 0 OH CO H N OH

H

2

N

I I S N OH 10 S N 3 H H CH 3

CH

2

CH

2 N(OH)COCH3 H2N SO2 3 H H CH 3 OOH H 2 NS

NH

2

SO

3 H H CH 3 0 HN N OHNH2 N OH N 13 N H CH 3 0HN. 1 N OH N-N O H N OH 14 SO 2

NH

2 H CH 3 0 H 2 N ~N OH N 15S0 3 H H CH 3 0 H OH N-N II H N

OH

20 16 SO 3 H H CH 3 0 OH H2N 0-N N OH 17 SO 3 H H CH 3 0 OH H2 N N-O OH 18 S0 3 H H C3 O H 2 N OH| N-N I H 3 C O H N-N OH 19 SO 3 H H CH 3 0 H2N , OH NN O H NH-N OH OCH2COH H CH 3 O O H2N N OH 21 SO 3 H H CH 3 O H 2 N N OH I I N OH 22 S03CH H CH 3 0 HH 2 N YN N OH 23 OCH(C2COOH H CH 3 0 O H N N I I S N OH 24 OSO 3 CH OH HF CH 0 OHH N,N II S l N

OH

21 25 OSO 3 H CH 2 0CONTH H O OH HNN OH 2\ N OH 26 OSO 3 H OH 3

CH

3 0 H2NN N OH 27 S0 3 H H H 3 N H 2 N

S-

OH 28

SO

3 H H

CH

3 0 OH H2N OHH N S OH 29 OSO 3 H H

CH

3 0 H2N OS 3 H H H OH H2 C N OH 30 OSO3H H3 CH3 O0 O H2N - N, S-N N OH 31 OSO 3 H CH 3

CH

3 0 OH H2NN N OH 32 OS0 3 H CH 3

OH

3 H2_jN OH _ I I S-N N OH 33OCH 2 COOH OH 3

CH

3 0 OH s N OH _______ 22 34 OCH 2 COOH CH 3

CH

3 0 OH H 2 N .- IeN 1 I Sr Cl N OH 35 OCH 2 COOH CH 3

CH

3 0 OH 2 OH S-N N OH 37 ocH- 2 COl- c30OH H2 S-N N OH 38 OHCH CH CR 3 0 H~ OH 2 I IS N 38 S0 3 H CH 3

CH

3 0 OHHN N I SK N OH 30 S0 3 H CR 3

CR

3 0 HN-. N OH 2\ rN OH 40. S03CH CH3OCONH 2 H 0 2 OH I IN N OH 42 OCH 2 COOH CH 2

OCONH

2 H 0 OHH 2 N-,N N

OH______

23 43 OCH 2 COOH CH 2 0CONH 2 H 0 OH H2NN S-N N I OH 44 OCH 2 COOH CH 2 F H 0 OH H2NN I S _ N OH 45 OCH 2 COOH CH 2 F ' H O H 2 N-_ OH/ Sr CI N OH 46 OCH 2 COOH CH 2 F H 0 O H2N N S-N N OH 47 OSO 3 H CH 2

OCONH

2 H 0O H2NN OH 2 S r/ C1 N OH 48 OSO 3 H CH 2

OCONH

2 H 0 H 2 N N OH S-N N OH The numbering of the compounds as given in above table 1 is used in the following for the sake of conciseness. 5 The compounds of the above table 1 are, when their com pound numbers are underscored and bold, part of the present invention. 10 Among the compounds of formula I which are more preferred in the combinations of the invention and which are novel per se are those of the following formula Ia: 24 R4

N'

0 R6 R 5 R3 R6 NAd R2 0 ON -O-Rz 5 la wherein Rz is SO 3 H or CRaRa'COOH, wherein Ra and Ra' are as defined for formula I; 10 R2, R3, R5 and R6 are as defined for formula I; R4 is CH 2 Z; whereby Z is a group of one of the formulae 0 0 Re Re I I I N IRf N IRf Rd Rd wherein Rd, Re and Rf are as defined for the compounds of for mula I; and the pharmaceutically acceptable salts or inner 15 salts thereof. This first group of compounds forms part of the invention. when Rz is SO 3 H, then preferably both R2 and R3 are methyl. When Rz is CRaRa'COOH, then R2 is preferably selected from hydrogen, methyl, fluoromethyl and carbamoyloxymethyl; and R3 is preferably selected from or hydrogen and methyl; and 20 more preferably here, the absolute configuration at the carbon atom bearing R2 and R3 is (S) . Preferably, Ra and Ra' are each hydrogen. Preferably for all compounds of formula Ia, the Rd, Re and Rf are individually selected from hydrogen and hydroxy, with the proviso that at least two of Rd, Re and Rf are hy 25 droxy (most preferably Rd and Re are hydroxy and Rf is hydro- 25 gen). R5 is prefably hydrogen. R6 is preferably an optionally amino-substituted and optionally chloro-substituted 5-6 membered heteroaromatic ring, this ring being more preferably selected from 2-amino-1,3-thiazol-4-yl, 5-amino-1,2, 4 5 thiadiazol-3-yl, 5-amino-1,2,4-oxadiazol- 3 -yl, 3-ami noisoxazol-5-yl, 5-amino-l-methylpyrazol-3-yl, 5-aminopyrazol 3-yl, 6-amino-2-pyridyl, 4-aminopyrimidin- 2 -yl, 2-carbon ylamino-1,3-thiazol-4-yl, 2-amino-5-chloro-1,3-thiazol- 4 -yl and 2-thienyl. 10 More preferred examples of the compound of formula Ia are the compounds (12), (22), (23) , (24) , (25), (26), (29), (30), (31) , (32), (33) , (34), (35) , (36), (37), (41), (42) , (43), (44), (45), (46), (47) and (48) of above table 1. The most preferred compounds of formula Ia are compounds (22) , (23), 15 (26) and (31) The compounds of formula la, if Rz is SO 3 H, can be made by a methodology as outlined in scheme 4 below, until the R2,R3-disubstituted 3-amino-2-oxoazetidine hydroxysulfonate, 20 and reacting this further in a manner known per se to connect the 3-amino substituents. The compounds of formula Ia, if Rz is CRaRa'COOH, can be prepared following the synthesis scheme of compounds II to X as described in US-A-4,939,253 (column 15, line 26--to column 17, line 25), and reacting the obtained 25 oxoazetidine X further according to scheme 1 described here inafter. A second group of compounds of formula I which is pre ferred in the combinations of the invention and is novel are those of the following formula Ib: 30 26 R4 H2N N R2 NN 0 R1 5 Ib and the pharmaceutically acceptable salts thereof, wherein the residues R1, R2, R3, R4 and R5 are as defined for formula I. This second group of compounds also forms part of the in 10 vention. Preferably, in these compounds R1 is SO 3 H, R2 is H, R3 is methyl and R4 is C(Rx) (Ry)Z; whereby Rx = Ry = H, and Z is a group of one of the formulae 0 0 Re Re N IRf XN RfM Rd Rd wherein Rd, Re and Rf are individually selected from hydrogen 15 and hydroxy, with the proviso that at least two of Rd, Re and Rf are hydroxy (most preferably Rd and Re are hydroxy and Rf is hydrogen). The antibiotically active monobactams of formula I may firstly be combined with 20 bl) P-lactamase inhibitors of the above general formula II. In formula II, R8 is preferably of the formula Q-(X)r CO-. The following subgroups are more preferable within this 25 formula: 27 a) With x = -CH 2 - and r = 1; wherein Q is a pyridinium group which may be substituted with one to three substituents, preferably one to two substituents, selected from alkyl; per fluoroalkyl, in particular trifluoromethyl; phenyl; benzyl; 5 RuRvN-, wherein R, and R, are independently selected from hy drogen, alkyl, cycloalkyl, pyrrolidinyl, carbamoyl and N (carbamoylalkyl)carbamoyl, or wherein Ru and R, taken together form an alkvlene bridge -(CH 2 ) ,, ith w being an iteger num ber of 3 to 6; alkylcarbonyl; RuRvNCO-, wherein Ru and R, are 10 as defined before; (alkoxycarbonyl)alkyl; thiocarbamoyl and alkoxycarbonyl; or wherein Q is a pyridinium group which is fused with a 5-6 membered carbocycle; and thioamide. Examples within this subgroup are pyridinium, 2-, 3- or 4 aminopyridinium, 3-N-methylaminopyridinium, 3-N,N-di 15 methylaminopyridinium, 4-(N-methylamino)pyridinium, 4-(N,N dimethylamino)pyridinium, 3-carbamoylpyridinium, 3-(N-methyl carbamoyl)pyridinium, 3-(N,N-dimethylcarbamoyl)pyridinium, 4 carbamoylpyridinium, 4-(N-methylcarbamoyl)pyridinium, 4-(N,N dimethylcarbamoyl)pyridinium, 3-(N-cyclopropylcar 20 bamoyl)pyridinium, 4-(N-cylopropylcarbamoyl)pyridinium, 4-(N methylcarbamoyl)pyridinium, 3-(methoxycarbonyl)pyridinium, 3 (ethoxycarbonyl)pyridinium, 4-(methoxycarbonyl)pyridinium, 4 (ethoxycarbonyl)pyridinium, 3-thiocarbamoylpyridinium, 3-(N methylthiocarbamoyl)pyridinium, 3-(N,N-dimethylthiocar 25 bamoyl)pyridinium, 4-thiocarbamoylpyridinium, 4-(N-methyl thiocarbamoyl)pyridinium, 4-(N,N-dimethylthiocar bamoyl)pyridinium, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-, 3,6 dimethylpyridinium, 3- or 4-isopropylpyridinium, 3- or 4 (trifloromethyl)pyridinium, 3- or 4-phenylpyridinium, 3- or 4 30 benzylpyridinium, quinolinium, isoquinolinium, 5,6,7,8-tet rahydroquinolinium and 5,6,7,8-tetrahydroisoquinolinium. In this subgroup, R7 is preferably -SO 3 or -OS0 3 , to form a 28 pharmaceutically acceptable inner salt. The compounds II of this subgroup a) themselves are per se also part of the inven tion, but compound 102 of table 2 below is known from J. Med. Chem. 1998, 41(21), 3961, and does per se not form part of the 5 invention. b) With X = -SCH 2 - and r = 1; wherein Q is 1,2,3,4 etrazol-5-yl, which may be substituted at its 1-posit2fion with a substituent selected from alkyl, aminoalkyl or alkoxyalkyl. 10 Examples for this substituent are methyl, ethyl, propyl, bu tyl, 2-aminoethyl, 2-(N-methylamino)ethyl, 2-(N,N dimethylamino)ethyl, 3-aminopropyl, 3-(N-methylamino)propyl, 3-(N,N-dimethylamino)propyl, 2-(N-ethylamino)ethyl, 2-(N,N diethylamino) ethyl, 3- (N-ethylamino)propyl and 3- (N,N-di 15 ethylamino)propyl. In these compounds, R7 is preferably -SO 3 H or OSO 3 H, whereby the possibility of formation of an inner, acid addition salt may be allowed, to form a pharmaceutically acceptable inner salt. c) With X = -CH 2

NH

2 -- and r = 1; wherein Q is phenyl 20 which may be-substituted with one to two substituents selected from hydroxy and alkoxy, or a 5-6-membered heterocycle which preferably is selected from oxazol-2-yl, -3-yl or -4-yl, fu ran-2-yl or 3-yl, thiophen-2-yl or -3-yl, 1,3-thiazol-2-yl, 3-yl, -4-yl or -5-yl and which optionally may be substituted 25 with one to two substituents selected from alkyl and alkoxy. d) With X = -NH2- and r = 1, wherein Q is phenyl which may be substituted with one to two substituents selected from hydroxy; alkoxy and a substitued urea of the formula

H

2

N[(CH

2 )mOJn(CH 2 )oHNCONH- or a substituted carbamate of the 30 formula H 2

N[(CH

2 )mO)(CH 2 )oHNCOO-, wherein m and o are inde pendently integer numbers from 2 to 3 and n is an integer num ber from 0 to 1. Examples for Q here are phenyl, 2-, 3- and 4- 29 hydroxyphenyl, 2,3-, 2,4-, 2,6-, 3,4-, 3,5- and 3,6-di hydroxyphenyl, 2-, 3- and 4-methoxyphenyl, 3-[N'-(2-(2-amino ethoxy)et-hyl}carbamoylamino]phenyl, 3-[N'-(2-(3-aminopro poxy) et-hyl}carbamoylamino]phenyl, 3- [N'-(3- (2-aminoeth 5 oxy)propyl}carbamoylamino]phenyl, 3- [N '-(3- (3-aminopro poxy)propyl)carbamoylaminolphenyl, 4- [N' -{2- (2-aminoeth oxy) ethyl) carbamoylamino]phenyl, 4- [N' -{2 -(3-aminopro poxy)ethyl)carbanoylamino]phenyl, 4 -k (3 (2 aioeth oxy)propyl) carbamoylamino] phenyl, 4- [N' -(3- (3 -aminopro 10 poxy) propyl) carbamoylamino ] phenyl, 3- [N'-{2- (2-aminoethoxy)et hyl)carbamoyloxy]phenyl, 3-[N'-(2-(3-aminopropoxy)et hyl}carbamoyloxy]phenyl, 3- [N' -(3 -(2-aminoeth oxy)propyl)carbamoyloxylphenyl, 3- [N' -(3- (3-aminopro poxy)propyl)carbamoyloxy~phenyl, 4-[N'-{2-(2-aminoeth 15 oxy)ethyl)carbamoyloxy]phenyl, 4-[N'-{2- (3-aminopro poxy)ethyl}carbamoyloxy]phenyl, 4-[N'-(3-(2-aminoeth oxy)propyl)carbamoyloxy]phenyl and 4-[N'-(3-(3-aminopro poxy) propyl}carbamoyloxy]phenyl. 20 Particularly preferred examples of the compounds of for mula II are according to. the following table 2 table 2 Compound R7 R8 number 101 So 3 - 0 H N -" N 0 30 102 S0 3 ~ 0

H

2 N N 0 103 S0 3 ~ NH 2 N O 0 105 S0 3 -HN0 N O 105SO H 2 N O N O 0 1 0 7 S 0 3 -H N N O 0 31 108 SO3- 0 HN 0

NH

2 0 109 SO3 0 HN N 0 11 0 S0 3 ~ 0 NH 2

H

2 N N 0 So 3

-

0

H

2 N N 0 112 S0-N 0 113 S0 3 N 0 32 114 SO 3 ~ 0 0 115 SO 3 0 0 116 SO3 0 117 SO3- 0 N 0 118 S0 3 ~ H 2 N S N 0 119 S0 3 0 J N 0 33 120 S03- F F N O 0

SO

3 0 122 s0 3 N .NO H N1 N 123 so 3 N 0 124 so; C N 0 125 S0 3 H N 0 34 126 SO3- 0 NH 2

H

2 N 0 127 S03 0

H

2 N 0 128 SO 3 - H N

NH

2 0 N 0 129 SO3- 0 NH,

H

2 N 7 N2 N 0 201 SO 3 Na s o N-N 202 SO 3 Na N' 0 203

SO

3 H 0 S N N4 -N O 35 204 SO3 0 S HN NO 0 205 SO 3 H N-N 206 SO3Na ! . N, N-N 207 SO 3 H 0 HN 0 208 SO 3 H 0 HN - S N 0 209 S0 3 H 0 0

NH

2 210 S03H 0 N S NH0

NH

2 36 211 SO 3 H 0 HN NH 212 SO 3 H 0 NS 213 'SO3H H2N -. S 0 HN NH2 215 SO 3 H 0 HN 0 NH 301 S03Na H N 302 SO3Na HN 0 0 303 SO 3 Na OH HO~ 304 SO 3 Na H O N 0 0a 37 305 SO 3 Na 0 H

H

2 N N 306 SO 3 Na H HO N HO 307 SO 3 Na H H N N 0 0 308 SO 3 Na 0 0 H

H

2 N s N 309 SO 3 Na H SN 0 N 310 SO 3 Na 0 N 311

SO

3 Na H H20 312

SO

3 Na 0 H H2N N HN O 313 SO 3 Na N- 0 H O 1 / N< 314

SO

3 Na H N

O

38 315 SO 3 Na H H 2N N N 316 SO 3 Na H 3 -17

SO

3 NaH 00 318 S03H H N H 320 SO 3 Na H HO N 318 SO--H N 321 SO3Na H HO N 0 322 SO 3 H H N 323

SO

3 H NH2 H N N 0 H H 324 SO03H N H N N 'jNa H H 39 325 SO 3 H H HN N H (N 326 SO 3 H N N N~N~ 0 HN H 327 SO 3 Na H Ny

H

2 N 328 SO 3 Na H 2 N 0 H NY 0 329 SO3Na N NH ON H 330 SO 3 H 0 N N N H H 331

SO

3 H O HN N N Oi- H NON HN N 0 40 332 SO3H

NH

2 H N HN -. 0 333 SO 3 Na H 334 S0 3 H H 0N 335 SO3H H 33

SO

3 H H N 00 336

SO

3 H 0 HN N ONo 0 337 SO 3 H H N H H 338 S0 3 H H 339 S0 3 HHH _ _ _ _ _ _ _H H 340 S0 3 H H N Nl 41 341 SO 3 H O H 00 342 S0 3 H- H N 343 SO 3 H H N N 344 SO 3 H H N~ 0 N 401 SO3HN H2N4O 402 SO 3 H O N NH 2 403

SO

3 H H2N HO OH 404 SO 3 Na HO -N 0 42 405 SO 3 Na F HN 0N H O 406 S03H

H

2 N \ O 00

NH

2 407 S03 N \ 0 408 SO 3 Na H H H N N-..

H

2 N y . 0 The numbering of the preferred compounds of formula II as given in above table 2 is used in the following for the sake of conciseness. 5 The compounds of the above table 2 are, when their com pound numbers are underscored and bold, part of the present invention. Otherwise they are disclosed in EP-A-0-508 234, US B-6,566,355 and J. Med. Chem. 1998, 3961. These publications are hereby incorporated by reference. 10 The compounds of formula I may also be combined with other -lactamase inhibitors. These further inhibitors are: b2) monobactam derivatives of the above general formula III: 15 Examples of these compounds are disclosed in WO-A 99/10324 and WO-A--98/47895, incorporated herein by reference.

43 A preferred example of these compounds is 3-((2E)-3-[(1,5 dihydroxy-4-oxo (2-hydropyridyl) )methoxy) -2- (2-thienyl) -3 azaprop-2-enoylamino} (3S,4S)-4-methyl-2-oxoazetidinesulfonic acid disclosed in WO-A-98/47895. 5 b3) penam sulfone derivatives of the above general formulae IV and V: Here, preferred examples of the 5-6 membered heteroaro 10 matic ring as R12 are 1,3-thiazol-2-yl, 1,2,4-oxadiazol-3-yl and 1,2,3-triazol-1-yl. Particularly preferred examples of the compounds of for mula V are sulbactam, tazobactam and the compounds of the fol 15 lowing table (in parentheses the source): R10 R11 Compound number hydrogen (1Z)-2-cyanovinyl 501 EP-A-0 640 607 hydrogen (1E)-3-oxo-but-1- 502 en-1-yl EP-A-0 640 607 hydrogen (lZ)-2-(1,3- 503 thiazol-2-yl)vinyl EP-A-0 640 607 hydrogen (1E)-2-(1,2,4- 504 oxadiazol-3- EP-A-0 640 607 yl)vinyl carboxymethylene

CH

3 (Bioorg. Med. Chem. Lett. 1995, 1513) hydrogen (1E) -2-methoxy-2- US-A-5, 686,441 azavinyl hydrogen (1E)-2,3-diaza-4- US-A-5,686,441 oxo-pent-1-en-1-yl 44 The numbers used in the rightmost column of this table are also used in the tests for biological activity (see be low) 5 b4) oxapenam derivatives of the above general formula VI: A preerred compound. of formula VT is clauilanic acid or a 10 customary pharmaceutically acceptable salt thereof (i.e. a clavulanate). b5) penem derivatives of the above general formula VII: 15 Here, preferred examples of the 5-6 membered heteroaro matic ring which may be bound over a -CH=CH- spacer as R15 are 1, 2, 3-triazol-4-yl, 2H, 3H-imidazo [2, 1-b]1, 3-thiazolidin-6-yl and 2'-[l-methyl-1,2,3-triazolin-4-ylvinylidene. 20 Preferred examples for inhibitors of formula VII are e.g. 6-[(1-methyl(1,2,3-triazol-4-yl))methylene]-5-oxo-6aH azetidino[2,1-b]1,3-thiazoline-3-carboxylic acid and 6-(2H,3H imidazo [2, 1-b] 1, 3-thiazolidin-6-ylmethylene) -5-oxo-6aH azetidino[2,1-b]1,3-thiazoline-3-carboxylic acid (as described 25 in Antimicrob. Agents Chemother. 1989, 1580 and Antimicrob. Agents Chemother. 1991, 1748), and 6-[(2E)-3-(1-methyl(1,2,3 triazolin-4-yl) )prop-2-enylidene)-5-oxo-6aH-azetidinO[ 2 ,1 b]1,3-thiazoline-3-carboxylic acid (as described in J. Antibi otic 1997, 50, 350). 30 b6) cephem sulfone derivatives of the above general formula

VIII:

45 Here, a preferred example of the 5-6 membered heteroaro matic ring as R16 is 2-thienyl. Preferred examples are here 3-(acetyloxymethyl)-1,1,6 5 trioxo-7-(2-pyridylmethylene)-2H,7aH-azetidino[2,1-b)1,3 thiazine-4-carboxylic acid (Biorg. Med. Chem. Lett. 2000, 853 and Biorg. Med. Chem. Lett. 2000, 847) and 3 (acetyloxynethyl)-7-{[(tert-butyl)oxycarbonylimethyiele 1,1,6-trioxo-2H,7aH-azetidino[2,1-bl1,3-thiazine-4-carboxylic 10 acid (J. Med. Chem. 1995, 38, 1022). b7) carbapenem derivatives of the above general formula IX: Here, preferred combinations for Rk and Rl are: Rk = hy 15 drogen and RI = sulfamoyl or 3-carboxyphenyl (or vice versa); and Rk = Rl = methyl. Preferred examples these compounds are imipenem, mero penem, ertapenem and doripenem. 20 b8) boronate derivatives of the above general formula X. b9) boronate derivatives of the above general formula XI: 25 Examples of these compounds are 3-[(4-phenylsulfonyl-2 thienylsulfonyl)aminolphenyl]boronic.acid (Chem. Biol. 2001, 8, 593) and [3-[[4-[(4 carboxyphenylsul fonyl)amino]phenylsulfonyl)amino]phenyl)boronic acid (Chem. 30 Biol. 2001, 8, 594). blO) phosphonate derivatives of the above general formula XII 46 Preferred examples of these are ([(4 nitrophenoxy) (hydroxyphosphoryl) ]methyl} [benzylsulfonyll amine, [ [(4 nitro 5 phenoxy) (hydroxyphosphoryl) ]methyl (phenylsulfonyl) amineand { [(4-nitrophenoxy) (hydroxyphosphoryl) ]methyl) (2 thienylsulfonyl)amine, (benzo[b) thiophen-2-ylsulfonyl) { [(4 nitrophenoxy) (hydroxyphosphoryl) Jmethyi)arine and 2- [(4 nitrophenoxy) (hydroxyphosphoryl) )-1- (phenylsulfonyl)hydrazine 10 (all described in US-A-2004/082546 and US-A-2004/0 2 9 8 3 6 ); and b1l) diazabicyclooctane derivatives of the above general for mula XIII: 15 A preferred example of these is (1R, 2S, 5R) 2 (aminocarbonyl) -7-oxo-1, 6-diazabicyclo [3 .2. 1] octane-6-sulfonic acid (as described in WO-A-2002/01219, WO-A-2002/0101 7 2 , FR-A 2835186 and FR-A-2848210) 20 The pharmaceutical compositions of the present invention may comprise, besides the compound of formula I, two or more compounds selected from the above formulae II to XIII, being different from each other. Pharmaceutical compositions com prising triple combinations of a compound of formula I and two 25 different compounds selected from the groups bl) to b1l) are a preferred embodiment of the invention. Preferred combinations for the pharmaceutical composi tions of the invention are compounds of formula I, where 30 Rl is SO 3 H, OSO 3 H or OCRaRa'COOH, wherein Ra and Ra' are as de fined for formula I; R2, R3 and R5 are as defined for formula I; 47 R4 is C (Rx) (Ry) Z, with either: - Rx = Ry = H and Z is a group of one of the formulae 0O Re Re ZN Rf N R Rd Rd wherein Rd, Re and Rf are as diefiried for formula I; or 5 - Rx = Ry = methyl and Z = COOH; or R4 is 4-hydroxypyridino[3,2-b]pyridin-3-yl)methoxy; and R6 is 2-amino-1,3-thiazol-4-yl, 2-amino-5-chloro-1,3-thiazol 4-yl, 5-amino-1,2,4-thiadiazol-3-yl, 5-aminopyrazol-3-yl or 4 aminopyrimidin-2-yl; ; 10 with either one of (lS, 5R) -2- [2- (3-carbamoylpyridyl) acetyl] -7-oxo-2, 6-di azabicyclo[3.2.Olheptane-6-sulfonic acid, (1S,5R)-2-[2-(4 aminopyridyl)acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 sulfonic acid, (1S,5R)-2-[2-(3-carbamoyl-6 15 methylpyridyl)acetyl]-7-oxo-2,6-diazabicyclo[ 3 .2.0]heptane-6 sulfonic acid, (1S,5R)-2-[2-(5-methyl(1,3,4-thiadiazol-2-yl thio))acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid, sodium salt, (1S,5R)-2-[2-(1-methyl(1,2,3,4-tetraazol-5 ylthio))acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sul 20 fonic acid, sodium salt, (lS,5R)-2-(N-[4-(([2-(2-aminoeth oxy) ethyl] amino) carbonylamino) phenyl] carbamoyl } -7-oxo-2 , 6-di azabicyclo[3.2.0]heptane-6-sulfonic acid, (1S,5R)-2-[N-(4 {[(2-aminoethyl)amino]carbonylaminophenyl)carbamoyl]-7-oxo 2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid or (2S,3S,5R) 25 3-((1Z)-2-cyanovinyl)-3-methyl-4,4,7-trioxo-4-thia-1-azabicy clo[3.2.0]heptane-2-carboxylic acid.

48 More preferred are composition wherein the above double combinations are further combined with one of sulbactam, cla vulanic acid or a customary pharmaceutically acceptable salt thereof, i.e. a clavulanate. These compositions thus comprise 5 triple combinations. Particularly preferred are compositions with the fol lowing double and triple combinations (che numbers are as in the foregoing tables la, 1b, 2a and 2b): 10 Aztreonam Compound 102 Sulbactam Aztreonam Compound 102 Clavulanate Compound 1 Compound 501 Compound 1 Compound 102 Sulbactam Compound 1 Compound 102 Clavulanate Compound 1 Compound 103 Clavulanate Compound 1 Compound 111 Clavulanate Compound 1 Compound 202 Clavulanate Compound 1 Compound 206 Clavulanate Compound 1 Compound 323 Sulbactam Compound 1 Compound 323 Clavulanate Compound 1 Compound 324 Clavulanate Compound 12 Compound 102 Sulbactam Compound 12 Compound 102 Clavulanate Compound 12 Compound 103 Sulbactam Compound 12 Compound 323 Sulbactam Compound 12 Compound 324 Sulbactam Compound 21 Compound 102 Sulbactam Compound 21 Compound 102 Clavulanate Compound 21 Compound 323 Sulbactam Compound 21 Compound 323 Clavulanate Compound 21 Compound 324 Sulbactam Compound 22 Compound 102 Clavulanate Compound 22 Compound 324 Clavulanate Compound 22 Compound 324 Sulbactam Compound 26 Compound 102 Clavulanate Compound 26 Compound 102 Sulbactam Compound 26 Compound 324 Clavulanate Compound 26 Compound 324 Sulbactam Compound 29 Compound 102 Sulbactam Compound 29 Compound 102 Clavulanate 49 Compound 29 Compound 323 Sulbactam Compound 29 Compound 324 Sulbactam Pharmaceutical compositions with triple combinations of compound no. 1 according to formula I with any one of the com pounds of formula II and with clavulanate form a particularly 5 preferred embodiment of the invention, such as do kits-of parts (articles) with this combination. The compounds of formula I are compounds known from the above cited literature references, or can be made in an analo 10 gous manner, or can be made as described in the following. If in the following schemes a number is assigned to an intermedi ate then this intermediate is per se presumed novel and may form part of the invention. The compounds of formula I can generally be prepared by 15 reacting aryl or heteroaryl carboxylic acids of general formu la A with 3-amino-azetidin-2-one compounds of general formula B (scheme 1) . In this scheme, R4 may also have the meaning of a protecting group, which may then be removed, in order to subsequently connect the actually desired R4. 20 Scheme 1

.

H R R 3 2

N-

0 R OH + H2NR 2- R NR3 R2 o 0 R 0 o 'R A B The coupling reaction of compounds of general formula A with 25 compounds of general formula B can be performed with the cor responding acyl chlorides of the aryl or heteroaryl carboxylic acids of general formula A or with the carboxylic acids A themselves and DCC (Chem. Pharm. Bull 1983, 2200) or with an 50 activated ester of the aryl or heteroaryl carboxylic acids of general formula A, such as the N-hydroxysuccinimidyl ester (see Org. Process Res.& Dev. 2002, 863) or the benzothiazolyl thioester (see J. Antibiotics 2000, 1071) . Alternatively, com 5 pounds of formula I can also be prepared as outlined in scheme 2 (with R1 = SO3H see also J. Antibiotics 1985, 346; J. Org. Chem. 1981, 1557). Scheme 2 10 RR R Rs OH + 2 R R6 N-0 R2 R R R 0-k HH + R6_ - ''0 N_ A 0 H 0 R A) Preparation of compounds B 15 The preparation of compounds of general formula B can be carried out in different ways according to the substituents present in 1, 3 and 4-positions (Scheme 3, 4, 5). (J. Org. Chem. 1980, 410; J. Org. Chem. 1985, 3462; ; J. Antibiotics 20 1985, 346; J. Antibiotics 1985, 813; J. Antibiotics 1986, 76; Tetrahedron Lett. 1986, 2789, J. Med. Chem. 1985, 1447; Chem. Pharm. Bull. 1984, 2646, J. Am. Chem. Soc. 1990, 760). Scheme 3 25 51 . 0 OH -O OH reaction or 30 OH 3 HN):JR 3 Pyr. S0 3 HN R R2 2 Pd 0R3 H~ R 3 2

R

2 --------- _ HN OH 0 OH 0 0 0 0rN 3 1000 I -0 TOC~ DMF.S0 3 HN R 2 IFA H2N P O H 0 SO 3 ,H 0 SO 3 H Scheme 4 O 3 O R 0 0 0N R jfHN R R 0 R O R 0 O H B r. .0 R 2 0F Ra - COOEI TFA S3

H

2 N R. 2

H

2 N R 2 O 0 0 R OR HN Ra S0 3 H 5 COOEt Scheme 5 52 O H2N O Mitsunobu 0 HN R HNO Ra N N HN O conditions HN R 2

H

2 /Pd H2N R R2 'N R2 O o OH 0 N or Pyr.SO 3 0 N'..N 1000 N'N'N N N 1001 NH2 R3 OEt O Mitsunobu 0 O H2 R2

NH

2 OEt -0reaction ~ 2 ~~ R. OH HN /Pd O\ R2 conditions R 2 0Ra

HR

2 N a/r 0 N or Pyr.S0 3 0 Ra O OEt Ra' OEt Ra Ra 1002 RaR 0 A-1) In the above schemes 3 and 5, generally an enantiomeri cally pure N-protected $-hydroxy amino acid 1000 is required 5 as the starting material. This precursor 1000 can be prepared in different ways, as outlined in the following sections A-1 I) to A-1-IV): A-1-I) Where R 2 = R 3 = R and preferably is alkyl, alkenyl, al 10 kynyl, optionally substituted benzyl or optionally substituted phenyl, a synthesis according to the following scheme A-1-I or scheme A-1-Ta may be used: 53 Scheme A.1-1

H

3 C OH 3 1) 4 eq RMgX

H

3 C CH 3 1) H 2 0 / H+ (aceto 2) 2 eq Ac 2 O nide removal) OHC OAc R R 2) NalO 4 / H 2 0' R R R R MeOHpH-7 EtOOC COOEtR AcO OAc 1004 1003 RqN H 2 (R, = benzyl or allyl) R 1)HCN/ OHC,. N Rq Jacobsen's Schiff OAc base catalyst OH 2) Ac 2 O / formic acid NC RR recrystallize R R 1005

NH

2 N-protection with 1) 65% H2SO4 OH BOC-Cl or t-butyl 2) HCI conc. HOOC chloroformate 3) hydrogenolysis R R 1000 (2S)-1006 In the above scheme A-1-I, the configuration of the a-carbon atoms in the .starting diethyl tartrate needs not be defined. The indicated chiral Jacobsen' s catalyst for the asymmetric 5 Strecker synthesis of the amino acid (2S)-1006 has been known from Angew. Chem. Int. Ed. 2000 1279. As the catalyst is available in both enantiomers, the corresponding S-hydroxy amino acid with the D-configuration at the a carbon atom ((2R)-1006) may also be produced. The latter is suited for 10 producing N-protected P hydroxy amino acids 1000a where the hydrogen atom at the a carbon atom is replaced by R5 (see sec tion A-1-IV below).

54 Scheme A-1-Ia Rg TEMPO HN 0 RMgX HN 0 oxydation 1000 H OH HO OH 1007 R R 1010 APTS, DMP HC, THF 00 O0N - R M g X

H

3 COOC -HO 009 R R In the above scheme A-i-Ia, the preparation of the $,#i dialkylsubstituted #-hydroxy a-amino acid 1000 starts from the 5 commercially available enantiomerically pure N-BOC serine methyl ester 1007 (J. Org. Chem. 2003, 177, Tetrahedron, 1996, 11673). The synthesis follows the chemistry based on Rapoport's methodology, which is known to keep the conforma tional integrity of the starting amino acid (J. Org. Chem. 10 1989, 1866, J. Org. Chem. 1990, 3511) A-1-II) Similary, where R 2 and R 3 are different from each other and are preferably independently selected from alkyl, alkenyl, alkynyl, optionally substituted benzyl and optionally substi 15 tuted phenyl, the following scheme A-1--II, modified from scheme A-1-I, may be used to produce 1000: 55 Scheme A-1-Il C OH H3C CH H3 C CH3

H

3 C \

CH

3 1) 2 eq.

R

2 L1, 2 eq. TMSCI 0 O 1) 2eq. R 3 MgX O o 0 0 32 2) aq. workup 2) 2eq AC2O R R 3 EtOOC COOEt R 2

R

2 AcO OAc 1011 1012 1) H 2 0 / H* (aceto- NH, nide removal) OHCG OAc NH 3 / KCN OH 2) NalO 4 I H 2 0, 3X 2 HOOC MeOH pH -7 R R R R 1013 (2S)-1014/ N-protection with (2R)-1014 diastereomer NH 2 BOC-Cl or t-butyl separation OH chloroformate _ HOOC .- 1000 R3 2 (2S)-1014 In this scheme R 2 is particularly preferably methyl. The in troduction of the second residue R 3 into 1011 by Grignard re action gives, according to Cram, predominantly the shown di 5 astereomer of 1012, due to the chelating effect of the oxygen atom of the a-acetonide substituent. In the Strecker synthesis step without chiral auxiliary, both diastereomeric amino acids (2S)-1014 and (2R)-1014 may form as a mixture due to the newly formed chiral a-carbon atoms. The diastereomers of the so pro 10 duced P-hydroxy amino acids 1014 may be separated using ion exchange chromatography with aqueous buffers as the mobile phase, as is customary in the art. The correct diastereomer (2S)-1014 may be identified as the one that produces faster a dipeptide, when each of the diastereomers (2S)-1014 and (2R) 15 1014 is reacted under otherwise identical conditions with N benzoyl L-alanine methyl ester and carboxypeptidase Y as the 56 dipeptide-forming enzyme (for an appropiate experimental pro cedure see example 1 of EP-A-0 017 485). The other, undesired diasteromer (2R)-1014 may be used for the production of N protected P-hydroxy amino acids 1000a where the hydrogen atom 5 at the at carbon atom is replaced by R 5 other than hydrogen (see section A-1-IV below). Scheme A-1-ila o -DIBAH >/ 0 2 R2MqX OH APTS, DMP OtN N 3 Swern oxidation

H

3 COOC O R2 0

H

3 COOC 1007 1008 1015 R3MgX or R3Li 0O Jones oxidation O NH APTS, MeOH O N 1000 OH OH 1017 3OH 116 Scheme A-1-IIa outlines an alternative procedure starting from 10 protected serine 1007 and leading to disubstituted hydroxyl derivatives 1016 by controlling the stereochemistry of the ad dition of the second substituent; either with R3Li, giving the. Felkin adduct as major product, or with R3MgX, to obtain the anti-Felkin adduct as major product (Tetrahedron 1995, 8121). 15 A-1-III) where R 2 is preferably alkyl, alkenyl, alkynyl, op tionally substituted benzyl or optionally substituted phenyl, and R3 is H, or R2 is H and R3 is preferably alkyl, alkenyl, 57 alkynyl, optionally substituted benzyl or optionally substi tuted phenyl, a synthesis according to following scheme A-1 III) may be adopted to form 1000: Scheme A-1-ll racemate re solution with o (S)-mandelic 0 0 0 pivaloyl acid aldehyde Me, a Me-.'N BzC 'N, NHN N /-NL

NH

2 H 1020 Ht-Bu Nz 1018 t-Bu t-Bu 1021 1019 1) LDA, -70* 1) LDA, -70' 2) R2CHO, -100" 2) R3CHO, -100* 3) H 2 0/H*, RT 0 3) H 2 O/H, RT R Me''N R 1022 O R N H MeN OBz t-Bu H 1023 N H t-Bu

H

2 0H+. 1000

H

2 0/OH OH HOOC R 3 (2S,3R)-1026 0 R

NH

2 \ OH N-protection with BOC-Ci or 1024 N H t-butyl chloroformate t-Bu IPh 3 P / D EAD 1000 AcO N-protection with BOC-Cl or t-butyl chloroformate 1025 0 OH (25,351-020262 HOOC R2 S,3S)-1026 Me N OAc R 2N H

H

2 0/H* 100* B H 5 2t-Bu This methodology was developed by Seebach (Helv. Chim. Acta 1987. 237) . In scheme A-1-III, the conversions on the left pathway yield the N-protected P-hydroxy amino acid 1000 where 10 R 2 = hydrogen, in defined configuration. The conversions on 58 the right pathway yield the N-protected -hydroxy amino acid 1000 where R 3 = hydrogen, also in defined configuration. A-1-IV) When the azetidinone B contains R5 other than hydro gen, then an N-protected 0X-R5-substituted P-hydroxy amino acid 5 1000a is required, analogous to a corresponding above amino acid 1000, except for the additional R5 substituent. This amino acid 1000a may be used in above schemes 3 and 5 instead of 1000. 10 A-1-IVa) When R5 is preferably alkyl, and one of R2 and R3 is preferably hydrogen, and the other one preferably is alkyl, alkenyl, alkynyl, optionally substituted phenyl or option6.lly substituted benzyl (or both of R2 and R3 are preferably inde pendently selected from alkyl, alkenyl, alkynyl, optionally 15 substituted phenyl and optionally substituted benzyl) the technology described in part A-l-III (Helv. Chim. Acta 1987. 237) can be employed, but using 2-tert-butyl-A-benzoyl-1,3 oxazolidinone as chiral inductor (scheme A-1-Iva below) . The introduction of the electrophile R5-X leads to the compound 20 1029. A condensation with aldehyde R2CHO as second electro phile gives the R2,R5-disubstituted oxazolidinone 1030 with control of the stereochemistry. If desired, the configuration at the newly formed secondary alcohol in 1030 may be inverted, such as under Mitsunobu conditions, to form the epimeric 25 R2,R5-disubstituted oxazolidinone 1031. If onto 1029 a conden sation with ketone R2C(O)R3 as the second electrophile is car ried out, then R2,R3,R5-trisubstituted oxazolidinones 1032 may be produced. If necessary the formed epimers of 1032 may be separated, such as by chromatography. All three compounds 30 1030, 1031 and 1032 may subsequently be converted by hydroly sis of the benzoyl group and the oxazolidinone ring and re protection of the amino group desired compounds 1000a.

59 Scheme A-1-IVa 0 1)LDA,-70* O O 2) R5X, -100* (X = leaving group) Y BzCI 3) H 2 O/H+, RT y .. R5 HNBz NBz 12 t-Bu t-Bu t-Bu Y = N-Me, 0 1) LDA, -70* 2) R2CHO, -100* 1) LDA, -70* 2) R2C(O)R3, -100* O R2 f!2R2R Mitsunobu 0 R2 R3 OH .'"'OH OH R-5 1030 R51R5 1032 NBz NBz NBz t-Bu 1) H20H+ t-Bu 1) H20/H+ t-Bu 1) optional epimer 1)PO/~1 H 2 O resolution 2) amino group 2). amino group 2) H 2 0/H+ re-protection re-protection 3) amino group re-protection 1000a 1000a 1000a A-1-IVb) When the azetidinone B contains alkoxy as R5 and one of R3 or R2 preferably as hydrogen, and the other one pref era 5 bly as alkyl, alkenyl, alkynyl, optionally substituted phenyl or optionally substituted benzyl, then another example of preparation of amino acids 1000a is outlined in following scheme A-1-IVb (in'the scheme R3 is assumed as hydrogen). It is based on the chemical description written on Biochemistry 10 2004, 3385 and Fortschr. Chem. Org. Naturst., 1979, 327. The approach relies on i the established oxidation of an N-acyl a0 amino ester to a highly reactive intermediate N-acyl cc-imino ester, which then adds R5-containing nucleophiles (alcohols R'''OH wherein R'' 'O = RS). The various protecting groups R' 60 and R'' would be removed subsequently (not shown in the scheme). A-1-IVc) Similarly, for the case where azetidinone B contains 5 alkoxy as R5 and both R3 and R2 are preferably independently selected from alkyl, alkenyl, alkynyl, optionally substituted phenyl and optionally substituted benzyl, an approach acccord ing to following scheme A-1-IVc may be used. By this scheme iL is possible to prepare -disubstituted N-protected amino acids 10 1000a following the synthetic pathway described in scheme A-1 Ia and scheme A-1-IIa. Scheme A-1-IVb t-BuOCI removal of hydroxyl and R. NaOR" R 0 0 protecting carboxyl protec- O O (OR"' = R5) O R O groups R', R" 1000 tnR R2 O.R : 1000a NHBoc g (ex (2R)-1006 1033 1034 or (2R)-i 014; R3 =H) Scheme A-1-IVc hydroxyl and Synthesis accor carboxyl.protec- R'. ding to scheme R' tion (R', R") O O A-1-la or A-1-Ila 0 R2 R3 1000 .. R " , OH 1000a O NH~oc NHBc (ex (2R)-1 006 R NHBRc" or (2R)-1014 R2 = R3 = H) 1035 1036 In above scheme A-1-IVc, the conversions 1000 to 1035 are 15 analogous to the conversions of 1000 to 1034 in above scheme A-1-IVb.

61 A-2) A range of compounds B, where R2 = CH 2 X1 and R3 = H, can be directly made in analogy to the procedure described in J. Antibiotics, 1983 1201 followed by standard functional group 5 conversions (scheme A-2): 62 Scheme A-2 OTs tX H K+ X1- / 18-crown-6 CbzN C CH 3 CN /reflux CbzN : CAN 1038 NAr (X1 = F, CI, Br, NH N , azido, cyano) NAr 0 OH 0 (X1 =1) 1037 Ph 3 p 1) Zn" (X1 = 1) (X1 = azido) 2) RxOCOCI OH O NPPh CbzN z COOR 3CbzN CbzN O PzjNH 1039 NH

RYNH

2 NAr O (RY = alkyl, 0

CISO

2 NCO phenyl)OHI pheHl /COOH 1) RCOCI ~ H OCONH 2 CONHRH (R = H, alkyl) CbzN z CbzN H CbzN

H

2 0 2) H 2 0 1040 1041 NH NArNAr 0 OHO CAN NAN H NH 2 H NHCOR CONHR COOH CbzN CbzN -CbzN CO bN U Cz NH NH NH 0 0 O 1042 1043 1044 1045 This scheme shows how to form compounds B where x1 is prefera bly selected from halogen, azido, amino, hydroxyl, cyano, car boxyl, alkoxycarbonyl, alkanoylamino, phenylaminocarbonyl, al kylaminocarbonyl, aminocarbonyl, carbamoyloxy, alkylaminosul 5 fonyl and optionally substituted phenylaminosulfonyl. The com mon starting material shown in the upper left of scheme A-2 is known from J. Org. Chem. 1982. 2765. In this scheme, in all 63 the obtained compounds B the final removal of the Cbz protect ing group by hydrogenolysis is not shown. B) Preparation of compounds A 5 The preparation of compounds of general formula A required in schemes 1 and 2 can be carried out in a customary way by re acLing an appropriately R--substituted keto acid A3 with an appropriately R4-etherified hydroxylamine (schemes 6 and 7 be 10 low) Scheme 6 O'R 0 0 R6 ,-OR [0] OR NaOH / H 2 0 IOH NH 2 NO 0i --- R Rfl~r

R

6 QOH 0 A1 A2 A3 A ROH (R = Me, Et) R6 i, OH 0 AO 15 Scheme 7 O-R4 4 0 0 0 o NH 2 N' R )O" Rr- S R"Y R", OH ----- wR 61 OH A4 A5 0 A6 0 A3 0 A 0 The R6-substituted keto acid A3 required in both schemes 6 and 20 7 can be prepared via 2 different synthetic pathways, as de scribed in the following.

64 A3 may firstly be obtained by oxidation of an ester Al leading to the glyoxalate derivative A2, followed by hydrolysis of the ester group (scheme 6). The oxidising agent used in the con version from Al to A2 is not critical. Examples of suited oxi 5 dising agents are SeO 2 (J. Antibiotics 1983, p. 1020ff.), DMSO,

X

2 (Bull. Chem. Soc. Jpn. 1994, 1701), X 2 and pyridine-N-oxide (Bioorg. Med. Chem. 2003, 591) where X 2 is a halogen; with SeO 2 being preferred. 10 The R6-substituted keto acid A3 can also be prepared via the condensation of methyl methylthiomethyl sulfoxide according to above scheme 7 (J. Antibiotics, 1984, 546, J. Antibiotics, 1984, 557) in a 4 step synthesis from the esters A4 R6COCCH 3 or R6COOEt. The methyl methylthiomethylsulfoxide is first con 15 densed with A4 derivatives to give the methyl thioglyoxylate compound A6 after acidic treatment. Examples of preparation of intermediates AO, Al or A4 (scheme 6 and 7) are as outlined in the following subsections B--i-Ia) 20 to B-2-Id). Some of these intermediates are also commercially available. B-1-I) R6 can be a 5 membered heteroaromatic ring containing 1 to 4 heteroatoms such as N, 0, S and which may be substituted 25 with 1 to 4 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, carbonylamino and halogen such as F, Cl, Br or I, preferably Cl. B-1-Ia) Thiadiazole derivatives 30 The preparation of derivatives AO, Al or A4, where R6 is a thiadiazole, especially 1,2,4-thiadiazole, may be performed as described in Biorg. Med. Chem. 2006, 1644, included herein by 65 reference. Examples of compounds Al, may be prepared starting from 3-amino-5-methoxyisoxazole or methyl amidine in presence of thioesters, potassium thiocyanate or isothiocyanate as out lined in scheme B-1-Ia (Bull Chem Soc Jpn. 1994, 1701, J. An 5 tibiotics 1983, 1020). In this scheme, R is preferably se lected from hydrogen, alkyl, alkoxy, amino, alkylamino and carbonylamino. Scheme B-1-a R \ 1046 MeO N s RA OEt O NHCOOEt

NH

2 EtO NCS N N MeO N MeO o o a) protection of amino group b) base / CO 2 c) esterification

H

2 N CH 3 Br., KSCN N NH 2 -base NH N~ 10 B-1-Ib) Scheme B-1-Ib outlines examples of starting materials AO, Al and A4 (Helv. Chim. Acta 1982, 2606; Russ. J. Org. Chem. 2003; 1133, Tetrahedron Let. 1979, 2827) obtained from substituted thiohydrazines. Using BrCN and these as starting material, 1049 may by prepared and then can lead to 2-amino 15 (1,3,4-thiadiazol-5-yl) acetic acid 1050. In scheme B-1-Ib, R is preferably selected from hydrogen, alkyl, alkoxy, amino, alkylamino and carbonylamino.

66 Scheme B-1-lb 0 NH oR 1047 N-N S R NH 2 CICOCOOEt R O 1048 N-N BrCN a) amino silyl (R = CH 3 protection (R \ =b) base / CO 2 HO S' c) amino

H

2 N CH 3 deprotection S NH 2 N-N N-N 1049 1050 In the above schemes B-1-Ia and B-1-Ib, the reaction with base / CO 2 , optionally by silyl protection of the amino group, may 5 be carried out according to J. Antibiotics, 1984, 532 already cited above. B-l-Ic) 1,2,4-oxadiazole derivatives As outlined in the upper part of scheme B-1-Ic indicated be 10 low, amide oxime derivatives 1051, wherein R is preferably se lected from hydrogen, alkyl and alkoxy may be reacted with compounds such as carboxylic acid, acyl chloride or cyano de rivatives to form 1,2,4-oxadiazole rings 1052,which are new examples of heterocycles derivatives Al. The lower part of 15 scheme B-1-Ic, wherein R' is preferably selected from hydro gen, alkyl, alkoxy, carbonylamino and halogen (in particular Cl), shows the synthesis of carboxylates 1054, 1056 of type Al which are isomeric to 1052 (Tetrahedron Lett. 1998, 3931, J. Org. Chem 1995, 3112, J. Med. Chem. 1990, 1128, J. Pep. Re- 67 search 2003, 233, Z. Chem. 1975, 57, ). For instance, compound 1056 may be obtained from the condensation of 1055 with BrCN. Scheme B-1-1c EtOOCCH 2 COOEt or

H

2 N-OH N-OH EtOOCCH 2 COCI N- 0 o R-CN - R_-<' _ _ R'

NH

2 N OEt 1051 1052

H

2 N-OH EtO N-OH R'OCI EtO EtOOCCH 2 CN N R'

NH

2 N R 1053 1054 0 O HO N-OH BrCN HO N-O

'NH

2 NN 1055 1056 NH 2 5 B-1-Id) Triazole derivatives Other examples of acids AO outlined in scheme B-1-Id shown be low are triazolyl acetic acid derivatives, such as 1,2,4 triazolyl acetic acids 1057, which may optionally be substitu 10 ted by one substituent R preferably selected from amino, al kyl, alkoxy and carbonylamino. The exemplary synthesis of 2 (5-amino-1, 2, 4-triazol-3 -yl) acetic acid (R = NH 2 ) by this scheme is known from Russ. J. Org. Chem. 1995, 240. Scheme B-1-Id R NH HCO 3 + HO OH N 0 ) N 5__ OH H 1057 15 68 B-1-Ie) Thiazole and oxazole derivatives A versatile way for forming intermediates AO, Al or A4, whe 5 rein the residue R6 is an optionally substituted 1,3-thiazol 4-yl or 1,3-oxazol-4-yl, is according to the known reactions of a thioamide or amide with an c-haloketone derivatives, as outlined in scheme B-1-Ie): Scheme B-1-le R' O _ R X/ R' 1058 COOEt N X =CI, Br,I 1060 COOEt Y R

NH

2 Y 0 or S N 0 0 x COOEt 010591 X = C1, Br, I 0

H

2 N 0 ', + O Br H2N

H

2 N NH 2 COOEt COOEt 1062 In this scheme, R may preferably be selected from hydrogen, alkyl, alkoxy, amino, and alkylamino; and R' is preferably se lected from hydrogen and alkyl. From substituted thioamides, 15 and substituted ethyl halogeno pyruvate 1058 or compounds 1059 substituted 1,3-thiazol-4-yls 1060, 1061 may be obtained ac cording to examples described in the literature such as Tetra- 69 hedron Lett. 2005, 66; J. Chem. Soc. 1966, 1357; J. Chem. Soc. 1960, 925; J. Med. Chem. 1971, 1075; J. Het. Chem. 1980, 1255; J. Med. Pharm. Chem. 1959, 577. 5 From similar keto ester derivatives 1059 in the presences of amide or thioamide derivatives, substituted 1,3-oxazol-4-yl acetic acid esters may be prepared as reported for instance in Bioorg. Med. Chem, 2003, 4325; Heterocycles, 2001, 689; Chem. Pharm. Bull. 1986, 2840; Tetrahedron Lett. 1992, 1937. The 10 preparation of compounds 1062 from urea with ethyl bromo pyru vate is an example of preparation of 1,3-oxazole derivatives. If R' is hydrogen and X is sulphur, then the thiazole moiety in 1060 .or 1061 may subsequently be chlorinated using the pro cedure as described in "Preparation 1" of EP-A-0 055 465.

15 B-1-If) Pyrazole derivatives. Another example of heterocyclic intermediates AO, Al or A4 may be synthesised from substituted ethyl pyruvates in presence of hydrazine or substituted hydrazines according to the scheme B 20 1-If (J. Chem. Soc. 1945, 114; Helv. Chim. Acta 1955, 670, J. Am. Chem. Soc. 1959, 2456). In this scheme, R is preferably selected from hydrogen, alkyl and carbonylamino, and R' is preferably selected from hydrogen, alkyl, alkoxy, carbonyl amino, hydroxyl, amino, alkylamino and halogen (in particular 25 Cl).

70 Scheme B-1-if O R R R \N 0 H 1063 R N"NH, R R-NsNH

H

2 N N R' COOEt N 1064 COOEt The reaction shown in the lower part of the scheme is analo gous to a synthesis described in J. Org. Chem. 2004, 5168. 5 B-1-Ig) Isoxazole derivatives Many isoxazoles with a carboxyl substituent in the 3-position and with one or two substituents selected from amino, alkyl 10 (in particular methyl and ethyl) and hydroxyl are commer cially available. Similar commercially available isoxazoles with a methyl substituent in the 3-position and optionally one or two substituents R' and R'' preferably independently se lected from alkyl, alkoxy and halogen, may again be converted 15 to corresponding carboxylate-containing isoxazoles by convert ing that 3-methyl substituent to carboxylate using base and carbon dioxide (scheme B-1-Ig). For example, in US-A-4,394,50 4 3-amino-5-isoxazolyl-2-acetic acid 1065 was prepared from 3 amino-5-methylisoxazole in this way. 20 21 Scheme B-1-Ig R" OOH base IC0 2 1065 B-2) R6 can also be a phenyl ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, carbonylamino and halogen or a 6 5 membered heteroaromatic ring containing 1 to 5 heteroatoms such as N and which may be substituted with 1 to 5 substitu ents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, carbonylamino and halogen (such as F, Cl, Br, I, preferably Cl). 10 B-2-Ia) A very general way of obtaining keto acids A3 for above schemes 6 and 7 is by direct Friedel-Crafts acylation of an appropiately substituted corresponding phenyl or heterocy cle R6-H, using excess oxalyl chloride. This way is feasible 15 for all keto acids A3 where R6 is phenyl or a heterocycle which may be substituted by one to five substituents selected from alkyl, alkoxy, dialkylamino and halogen (in particular chloro), with the proviso that the phenyl or heterocycle has at least one unsubstituted carbon atom (the carbon atom that 20 will carry the gyloxaloyl substituent). The appropiately sub stituted corresponding phenyl or heterocycle R6-H (where H is bonded to the said unsubstituted carbon atom) is reacted with excess oxalyl chloride under Friedel-Crafts conditions, fol lowed by removal of excess oxalyl chloride and hydrolysis of 72 the remaining free acyl chloride group of the introduced gly oxaloyl moiety. Friedel-Crafts acylation is also feasible for such phenyls or heterocycles where some of the one to five substituents are hydroxyl, amino, alkylamino. These substitu 5 ents, however, are preferably protected as the before the acy lation step and the subsequently deprotected. B-2-Ib) E:ampies of intermediates A4 are commercially avai lable pyridinecarboxylic acids, such as picoline (2 10 pyridinecarboxylic acids), nicotinic acid (3 pyridinecarboxylic acids) or isonicotinic acid (3 pyridinecarboxylic acids), which may optionally be substituted at the pyridyl by a substituent selected from alkoxy, halogen (in particular chloro) and amino. 15 B-2-Ic) Further examples of acids AO are 2-pyridyl acetic acids, such as 2-(pyridyl-2) acetic acids 2-(pyridyl-3) acetic acids or 2-(pyridyl-4) acetic acids which may optionally be substituted at the pyridyl by a substi.tuent selected from al 20 koxy, halogen (in particular chloro) and amino. These can be obtained by deprotonating an appropriately sub stituted methylpyridine with a strong base such as N-BuLi or LDA and reacting the anion with carbon dioxide. In this reac tion, the methyl substituent of the methyl pyridine is at the 25 position where the acetic acid will be. The optional amino substituent at the pyridine may have been appropriately pro tected beforehand, such as with TMS-Cl. An exemplary reaction of this type can be found in DE-OS-284891 2 and J. Antibiotics 1984, 532. 30 B-2-Id) R6 can also be a pyrimidine derivative.

73 Scheme B-2-Id (below) shows that amidine derivatives (J. Org. Chem. 1962, 3608) can lead to either 2-substituted pyrimidine Al or A4 (DE-OS-2848912, J. Antibiotics 1984, 546) . Compounds 1068 (R = Cl) can easily be obtained by reaction with phospho 5 ryl chloride from 1067. The chlorine can then easily be sub stituted by nucleophiles such as ammonia, alkylamines or alco hols and lead to compounds 1068 with R = amino, alkylamino or alkoxy (J. Antibiotics 1984, 546) Scheme B-2-Id EtO

NNH

2 n=0 CK CN 1066 OEt NH O _NH 2 OH R n=1 NOEt N N W N NH 2 OHO

H

2 N OR

-

t- H 0 OEt 0 OEt 1067 1068 10 Another group of commercially available or synthetically ac cessible esters A4 are pyrimidyl-4 (ethyl 5,6 .diaminopyrimidine-4-carboxylate, ethyl 2-amino-5-chloro 15 pyrimidine-4-carboxylate), pyrimidyl-5 (ethyl 2,4 diaminopyrimidine-5-carboxylate, ethyl 2-chloro-4-amino-5 carboxylate, ethyl 2, 4-dichloropyrimidine-5-carboxylate) or py rimidyl-6 (ethyl 2-chloro-4-amino-pyrimidine-6-carboxylate, ethyl 4,5-diaminopyrimidine 6-carboxylate) which are also con 20 sidered as examples of 6-membered heterocyclic rings as R6 (Tetrahedron Lett. 1967, 1099; Chem Pharm. Bull. 1970, 1003. Justus Liebig Ann. Chem. 1954, 45).

74 B-3) The hydroxylamines required in both above schemes 6 and 7, can be prepared in several methods, as outlined in scheme 8 below. 5 These hydroxylamines may be prepared firstly according to J. Antibiotics, 2000, 1072 with N-hydroxyphthalimide via Mitsuno bu reaction conditions in presence of the alcohols R4-OH or by alkylation of N-hydroxyphthalimide in presence of activated 10 compounds R4-X (X can be halogens like Cl, Br, I, or activated sulfonate esters like mesylate, tosylate, triflate, etc.). When R4 has the structure C (Rx) (Ry) Z, with both Rx and Ry dif ferent from hydrogen, or is a tertiary alkyl, then N hydroxyphthalimide may simply be treated with a stoichiometric 15 amount of BF 3 .Et 2 O with the corresponding alcohol R4-OH (Tetra hedron Lett., 2005, 6667) . Formation of the final hydroxylami nes may be performed in presence of either hydrazine or methyl hydrazine. The oxaziridine technology developed by Ellman can also been employed to give directly deprotected O-substituted 20 hydroxylamines (J. Org. Chem. 1999, 6528). (scheme 8). Scheme B OHO R 4R H N PPh 3 /DEAD 0 N NH 2

NH

2 R Or x-R Base

NH

2 0, HN N--OH\H

BF

3 .Et 2 O 0 0

-R

4 base

H

75 Alcohols R4-OH or compounds R4-X are either commercially avai lable or may be prepared as described in following sections B 3-Ia) to B-3-Ie) 5 B-3-Ia) A first method, where R4 is C(Rx) (Ry)Z, with Z

CH

2 N(OH)COR', is outlined, as example, in the. following scheme B-3-Ia, using a-halogenoalcohols 1069 or 1071 and N-Boc-O-(P methoxybenzyl)hydroxylamine. The a-halogenoalcohols 1071 can 10 be prepared from derivatized epoxides 1070 which can. be opened in acidic conditions (Eur. J. Org. Chem. 2004, 2557). The LX halogenoalcohols 1069 can be obtained by chiral reduction of corresponding a-halogenoketones (Tetrahedron:Asymmetry 2005, 3955). 15 Scheme B-3-la epoxide o opening HO X Rx"- r Rx"_ Ry Ry (R)-1070, (R)-1071, (S)-1070, (S)-1071, 0 OtBu rac-1070 rac-1071 or or OMe N'OCH2CrH 0Me meso-1070 meso-1071 HO 2 H e (Rx=Ry(R xRx = Ry) BOCNHO 1072 base 1) alcohol protection 2) hydrolysis of BOC group chiral 3) RCOCI, base O X reduction HO X HOX 4) alcohol deprotection R R'" or H"". 5) hydroxylamine forma H R tion with oxaziridine (R = Rx or Ry, X = Cl, Br) (S)-1069 (R)-1 069 o R RxRY O 'CH2C6 HOMe

NH

2 1073 76 In the above scheme B-3-Ia, the epoxides meso-1070 may be made from a ketone with two identical residues Rx = Ry = R with trimethylsulfonium iodide and base. For the epoxides (R)-10 7 0 and (S)-1070 the synthesis may start from a ketone with two 5 different residues Rx # Ry, using an asymmetric epoxide for ming reaction such as the catalytic epoxidation developed by Aggarwal (Accounts of Chemical Research, 2004, 37, pp. 611ff.). The conversion of 1069 and 1071 to 1072 is analogous to the procedure of Bioorganic & Medicinal Chemistry Letters 10 1996, 6(17), 2077ff.. In the conversion of 1072 to 1073, again the oxaziridine technology developed by Ellman can be employed to give the hydroxylamine (J. Org. Chem. 1999, 6528). B-3-Ib) A second method, particular suited for hydroxylamines 15 where R4 is C(Rx) (Ry)COOH, is outlined in the following scheme B-3-Ib. These hydroxylamines may be obtained from the cor responding alcohols R4-OH via Mitsunobu reaction conditions in presence of N-hydroxyphthalimide. The starting material R4-OH in turn may be obtained, as shown in the upper parts of scheme 20 B-3-Ib, from an appropiately Rx,Ry-substituted ketone. To this ketone is added trimethylsilyl cyanide, either with or without a chiral catalyst, to obtain a silyl protected cyanohydrin 1074. The chiral thiourea catalyst indicated in scheme B-3-Ib, if used, and its conditions for use have been described in J. 25 Am. Chem. Soc. 2005, 8964. The protected cyanohydrin is then reduced with LiAlH 4 to the corresponding aldehyde 1075 and then esterified to 1076. As an alternative to the Mitsunobu reaction using R4-OH, the hydroxyl group of N hydroxyphthalimide can also be alkylated in presence of acti 30 vated compounds R4-X (X can be halogens like Cl, Br, I, or ac tivated sulfonate esters like mesylate, tosylate, triflate, etc; these are easily obtainable from the corresponding R4- 7 7 OH). Formation of the desired hydroxylamine may be performed in presence of either hydrazine or methyl hydrazine, as shown in the lower part of scheme B-3-Ib, following the procedure described in J. Antibiotics, 2000, 1071. 5 Scheme B-3-lb 0 Me 3 SiCN MeiO C N) 1) LAIHH 4 R' 'R 3. M i 2) -2 2 0/H' HO CHO 1075 Rx Ry Rx Ry 1074 o Me 3 SiCN chiral thiourea catalyst HO COOEt O'R Rx Ry

CF

3

CH

2 OH -78* Rx Ry H 1076 (R 4 = C(Rx)Ry)COOEt) B-3-Ic) A further variant for the preparation of hydroxylami nes where. R4 is C(Rx) (Ry)COOH, may start with the epoxides 10 1070 shown in above scheme B-3-Ia. These epoxides may be ope ned, as is customary, with aqueous base to form a vicinal di ol; in which the primary hydroxy group is then converted to the aldehyde and then to the ester as outlined in the above scheme B-3-Ib in the conversion of 1075 to 1076. 15 B-3-Id) For hydroxylamines where in R4 Z is 0 Re I i + N Rd wherein Re and Rd are ORg (Rg being preferably selected from hydrogen, alkyl or optionally substituted benzyl for each Re 78 and Rd), Rd is preferably hydrogen, alkyl, amino, monoalkyla mino, optionally substituted benzyl, alkoxycarbonyl or ORg (wherein Rg is as for Re and Rd); and wherein Rx = Ry = H; the following synthetic scheme B-3-Id may be adop 5 ted: Scheme B-3-id 0 0 0 HO TMSCI base

H

2 N-Rd TMSO ~ TMSO OH OH 0 OH N Rd N-hydroxy- 0 1) deprotection O 1077 phthalimide, with fluoride 0 PPh,, DEAD TMSO 2) Rg-X / base RgO hydrazine N ~Rgo 0

ONH

2 Rd O 0 N N Rd N Rd 1078 / \ 1079 N \ 1080 0 This scheme adheres to the synthetic procedure described in EP-A-0 251 299. The kojic acid used as the starting material 10 is commercially available. In the conversion from the silyl protected kojic acid to 1077 the reactands

H

2 N-Rd are amines, when Rd is hydrogen, alkyl or optionally substituted benzyl, they are hydrazines, when Rd is amino or monoalkylamino; they are carbamates, when Rd is alkoxycarbonyl; and when Rd is ORg, 15 these reactands are hydroxylamines. In the conversion of 1078 to 1079, the reactands Rg-X are hydrogen halides, alkyl hali des or benzyl halides, wherein X is preferably Br or I. These reactands Rg-X are known or easily made from the corresponding alcohols Rg-OH. In the above scheme, instead of trimethylsilyl 79 other protecting groups could also be used, such as benzyl, diphenyl or trityl as reported in J. Antibiotics 1990, 1450. B-3-Ie) For hydroxylamines where in R4 Z is 0 Re N Rf Rd 5 wherein Re and Rd are ORg (Rg being preferably selected from hydrogen, alkyl or optionally substituted benzyl for each Re and Rd) , Rf is preferably alkoxycarbonyl or alkylaminocarbo nyl; and wherein Rx = Ry = H; the following synthetic scheme B-3-Ie may be adopted: 10 Scheme B-3-le 0 0 O HO H 2 CO/ HO HO benzyl NaOH bromide I 0 I I 0 OBn OH OBn OH Diphenyi diazomethane o 0 DiphO MnO 2 DiphO III I 0 0 OH OBn OH OBn R'OH or RNH 2 (R' = alkyl) Amino acid coupling conditions. (DCCI, DMAP or HBTU) o 1 - Selective deprotection 2 - H 2 N-Rd DiphO DiphO 3 - N-hydroxyphthalimide, PPh 3 4 - Hydrazine O R X = OBn R 1082N2 R' X =0, NH 1081 18 80 The synthesis starts from kojic acid and is based on the known chemistry described in Biorg Med Chem Lett 2004, 3257; J. Med Chem 2002, 633; Bioorg Med. Chem. 2001 563 and J. Antibiotics 1990 1454. In the above scheme, the diphenylmethane protecting 5 group in 1082 may subsequently be removed and, if desired, the free hydroxy group be reacted with an appropiate halide R-X, wherein R is alkyl or optionally substituted benzyl. These last steos are not shown in the above scheme. 10 B-3-If) For hydroxylamines where in R4 Z is 0 Re N Rf Rd wherein Re and Rd are ORg (Rg being preferably selected from hydrogen, alkyl or optionally substituted benzyl for each Re and Rd), Rf is preferably alkyl; and wherein Rx = Ry = H; a 15 gain starting from from kojic acid and with adapted protecting group strategy, further examples of pyridone derivatives which can be prepared are according to following scheme B-3-If: 81 Scheme B-3-If DiphO Swern Oxydation DiphO 00 OH O O Wittig reaction R'P'PhCt (R' = alkyl) 0 0 DiphO DiphO C iphO Oa C R' NH OH R' 1085 1084 1083 O 0 0 HO

R'CH=CR'-CH

2 Br 0 180*C HO OH R OH R" O OH 0 R' R 1086 1087 HIPdC O 0 DiphO DiphO OH R R" O R" Rd O R' 109 NH, 1088 The upper part of scheme B-3-If is based on the possibility to run a Wittig reaction (J. Med. Chem 2004, 6349) on the aldehy 5 de obtained after Swern oxidation. The resulting product 1083 may be subjected to hydrogenolysis in presence of Pd/C simi larly to the preparation of compound 10' j in J. Med. Chem 2004, 6349. The resulting compound 1084 may then be treated as already outlined in above scheme 8 to obtain desired hydroxy 10 lamines 1085. The lower part of scheme B-3-Tf shows the prepa ration of hydroxylamines with linear or branched alkyl as Rf. In this part of scheme, R' and R' are preferably selected from alkyl (in particular methyl and ethyl) and hydrogen; more 82 preferably one of R and R' ' is hydrogen, or both R' and R' are hydrogen. A thermal rearrangement of products 1086, obtai nable by alkylation of the 4-hydroxyl group of kojic acid with appropiately R' ,R' -substituted allyl bromides (J. Am. Chem. 5 Soc. 1956, 2816) leads to 6-substituted pyridones 1087. These may again be converted in the usual way to hydroxylamines 1089. In the above formed hydroxylamines 1085 and 1089 the diphenylmethane group may subsequently be removed and, if de sired, the free hydroxy group be reacted with an appropiate 10 halide R-X, wherein R is alkyl or optionally substituted ben zyl. These last steps are not shown in the above scheme. B-3-Ig) For hydroxylamines where in R4 Z is 0 Re * N

CH

3 Rd 15 wherein Re is ORg (Rg being preferably selected from hydrogen, alkyl or optionally substituted benzyl) , and Rd is preferably selected from hydrogen, alkyl, amino, monoalkylamino, optio nally substituted benzyl or alkoxycarbonyl; and wherein Rx = 20 Ry = H; a synthesis analogous to the scheme B-3-Ig shown below may be used. Details of the syntheses in the upper part of this scheme can be found in J Med. Chem. 2004, 6349.

83 Scheme B-3-Ig 0 00 2 O HOO 0 CH0 CH 3 OH A OH C1 Diphenyldiazomethane 0 1 - H 2 N-Rd 2 - N-hydroxyphthalimide, PPh 3 DiphO DiphO 3 - hydrazine N N O CH3 N CH 3 OH I OH O Rd

H

2 N 1090 In the hydroxylamines 1090 obtained in above scheme B-3-Ig the diphenylmethane group may subsequently be removed and, if de 5 sired, the free hydroxy group be reacted with an appropiate halide R-X, wherein R is alkyl or optionally substituted ben zyl. These last steps are not shown in the above scheme. B-3-II) For hydroxylanines where Z is 10 N -* N OH the following scheme B-3-II may be used. In this scheme, the 15 naphthyridine hydroxylamine may be obtained from commercially available 4-hydroxy-1, 5-naphthyridine-3-carboxylic ethyl ester after diphenyl protection of the hydroxyl group and reduction of ester group. Mitsunobu reaction in presence of N- 84 hydroxyphthalimide and deprotection with hydrazine leads to the desired compound 1093. Scheme B-3-11 NaH,N NN Diphenyl NaBH 4

H,

bromide o _______M N N N 00 OH

H

2

N

0 0 1091 1092 1093 B-3-III) Further suited hydroxylamines are those where Z is selected from: H N , Ri O Ri Is\ RiN NN /N * * OH OH 10 wherein Ri is as defined in claim 1. Those substituted 5 membered rings are known as bioisosteres (Curr. Med. Chem. 2004, 11, 945) of the carboxylic acid group. One particularly preferred hydroxylamine of this type, tetrazole methyl hydro 15 xylamine 1094, may be obtained from commercially chloro methyl tetrazole with N-hydroxyphtalimide according to the method described in J. Antibiotics 2000, 1071 (scheme B-3-IIIa be low).

85 Scheme B-3-illa H N N O N.N. N ~ NH 2

-NH

2 N2 CI 011 H 2 N 09 1094 Isoxazole analogs (J. Heterocyclic Chem. 1997, 345, J. Med. Chem. 1996, 183) or isothiazoles (J. Med. Chem. 1998, 930) are 5 also known as bioisosteres of the carboxylic acid group and may be done in similar way as outlined in the scheme B-3-IIIb below based on the following literature (J. Chem. Soc., Perkin 1 1993, 2153; Synthesis 1996, 1177, Acta Chem. Scand. 1990, 96. 10 0OH Scheme-B-3-IIlb N MeOH/KOH O O HBr O OH OH 0 N N Y=OorS O 0 Br

NH

2

NH

2 1 N 0 ,0 - -H 2 N' 0 ,0 1095 N 0 86 In this scheme, the removal of the benzyl protecting group in the resulting hydroxylamine-containing isoxazoles and isothia zoles 1095 is not shown. 5 After formation of the ketoacid derivative A3, the condensati on with O-substituted hydroxylamine (prepared or commercially available like 0-methyl hydroxylamine) may be performed to lead to compounds of general formula A. The condensatiOn of the hydroxylamines R4-ONH 2 with the keto acid derivatives A3 10 to form the compounds A may then follow the procedure descri bed in J. Antibiotics 2000, 1071 and WO-A-02/2261 3 . B-4) As an alternative of preparing compounds A, the esters Al may firstly be oxidised to form compounds A2 as shown in sche 15 me 6, then reacted with hydroxylamine, followed by 0 protection and ester hydrolysis, to lead to the intermediate C, which can be coupled to the azetidinone B. Substituents R4, can be introduced by alkylation. This alternate route is shown in the following scheme 9: 20 Scheme 9

K

2 CO3 N' P-X N'O

N'

0 R 6R O - R - e OH C o R RR H2NgR 2 0 R R 4 B , 5OHH O H

RR

5 RN 2 XR H TFA R2 0 RN. O R'N 0 R 00 R 0 R 87 The compounds of formula II are compounds known from the above cited literature references (EP-A-0 508 284 and US-B 6,566,355) or can be made in an analogous manner or can be made as described in the following scheme 10. 5 The intermediate compound D (J. Med. Chem. 1998, 3961 and EP A-0 508 234) gives access to compounds of formula IIA, IIB or to IIC using different synthetic routes outlined in scheme 10. 10 Scheme 10 0 0N CC H "N.H 0 H

R

8 R 7 D 0 0 NR OH 9R N kO.N RO H o R N N R ' H R 'H H N, HH HO N, O SH H 0 SO 3 H 0 SO 3 H 0 S0 3 H IIA IIB 1c For the preparation of pyridinium carboxymethyl derivatives of 15 formula IIA, two synthetic routes are possible (scheme 11): - First pathway: Compound F, prepared from compound D in presence of bromo acetyl. bromide according to the proce dures described in J. Med. Chem. 1998, 3961 and EP-A--O 20 508 234, may be sulfonated (J. Org. Chem. 1982, 5160).

88 Pyridine derivatives, condensed at room temperature in dimethylformamide, are either commercially available or synthesized according to known literature procedures. - Second pathway: Compound D may be first hydrogenated in 5 presence of BOC 2 0 to afford the intermediate G (Tetrahe dron Lett. 1988, 2983). Then sulfonation of compound G followed by removal of the BOC protecting group generates compound H (J. med. Cheat. 1993, 3961 and J. Org. Chem. 1982, 5160). 10 At that stage the pyridinium carboxymethyl derivatives (prepared by analogy according to the procedures de scribed in Synthesis 2000, 1733 or J. Chem. Soc, Perkin Trans. I 1977, 1692) may be introduced to generate com pounds IIA. 15 Scheme 11 89

H

2 . Pd/C MSTFA, Py /, N MeOH HNCH2CI2 B SH H H H H O 0 D E F

H

2 , Pd/C DMF.SO,

BOC

2 O DMF MeOH O &H HBr N'H O 0 SOH G Py.S03, Py DMF

R

7 FCH 2 C1 2 H< _H j O N HN e ' N3H H' HOBt, DCC, DIPEA N, S 'SOH 0 SO 3 H DMSO O SO 3 H H llA The compounds of formula IIB may be obtained from com pound H and succinimidyl derivatives according to the follow 5 ing scheme 12: Scheme 12 10 90 Compound H may be prepared as previously described in scheme 11. Then the succinimidyl derivatives may be synthesized and introduced according to the procedures described in J. Med. Chem. 1998, 3961. 5 Compounds of formula IIC may be obtained either from compound E or compound H according to the following scheme 13: Scheme 1-3 10 1 0 HOH S N DMR S03 __ _ __ _ __ _ ___H__Rio,__ R 0H NH 0 0 So 3 H E 11C o 50 3 0 H The compounds IIC may be synthesized via two different routes: - either from compound E by first coupling with the thic acetic acid derivatives, followed by a sulfonation step 15 (J. Med. Chem. 1998, 3961), - or directly from compound H (see scheme 11) and thioace tic acid derivatives. The preparation of sodium salt of compound of formula I 20 and II can be performed either with the procedures described in WO-A-02/22613, US-B-6,566,355, J. Med. Chem. 1998, 3961 or in J. Antibiotics, 1985, 346.

91 In the above descriptions, the reactants are reacted to gether with a suitable solvent at elevated or low temperatures for sufficient time to allow the reaction to proceed to com pletion. The reaction conditions will depend upon the nature 5 and reactivity of the reactants. Wherever a base is used in a reaction, they are selected from e.g. triethylamine, tribu tylamine, trioctylamine, pyridine, 4-dimethylaminopyridine, diisopropylamine, 1,5-diazabicyclo[4,3,0]non-5-ene, 1,8 diazabicyclo [5, 4, O]undec-7-ene, sodium carbonate, sodium di 10 carbonate, potassium carbonate, potassium bicarbonate or ce sium carbonate. The deprotection of functional groups may be carried out either by hydrogenation or hydrolysis with appropriate acids 15 such as hydrochloric acid, formic acid, trifluoroacetic acid, acetic acid or p-toluenesulfonic acid; in solvents such as methanol, ethanol, propanol, ethyl acetate, acetonitrile, me thylene chloride or ethylene chloride. The hydrogenation is usually carried out in the presence of a metal catalyst, such 20 as Pd, Pt or Rh under normal to high pressure. The solvents of choice for the reaction are selected based upon the reactants used and from solvents such as ben zene, toluene, acetonitrile, tetrahydrofurane, ethanol, metha 25 nol, chloroform, ethyl acetate, methylene chloride, dimethyl formamide, dimethyl sulfoxide, hexa-methyl phosphoric triamide or the like. Solvents mixtures may also be used. Reaction temperatures would generally range from between 30 -70 0 C to 150 0 C. The preferred molar ratio of the reactants is 1:1 to 1:5. The reaction time range from 0.5 to 72 hours, de pending on the reactants.

92 The compounds of formula I, Ia and Ib and their pharma ceutically compatible salts can be used in accordance with the invention in the control or prevention of illness in mammals, 5 human and non-human, especially in combination with @ lactamase inhibitors. Thereby, the compound of formula I or pharmaceuticaIly compatible salts thereof with bases can be administered be 10 fore, simultaneously with or after the administration or in take of one or more @-lactamase inhibitors of formula II-XIII. The products in accordance with the invention can be adminis tered in the form of pharmaceutical compositions containing the combination of a compound of formula I or a phar 15 maceutically compatible salt thereof with a base, and one or more P-lactamase inhibitors of formula II-XIII; alternatively, they may also be administered separately from the P-lactamase inhibitors, simultaneously or sequentially, in whi-ch case the combination according to the invention may be present as a 20 kit-of-parts. Articles with such pharmaceutical combinations are also an object of the present invention. The compounds of formula I are active against a variety of bacterial organisms. They are active against aerobic Gram 25 negative bacteria that do not produce P-lactamases, including Enterobacteriaceae, for example Escherichia coli, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Kleb siella pneumoniae, Klebsiella oxytoca, Proteus vulgaris, P-rovidencia rettgeri; Pseudononas for example P. aeruginosa; 30 Acinetobacter for example A. baumannii; Burkholderia, for ex ample B. cepacea; Stenotrophomonas for example S. maltophilia. Combinations of compounds of formula I and formula II are ac- 93 tive against strains of the above organisms that do produce lactamases and this activitiy can be increased by additionally combining compounds of formula III-XIII with the combination comprising compounds of formulae I and II. 5 FORMULATIONS The pharmaceutical compositions and articles (kits-of parts) according to the present invention are administered by any route, preferably in the form of a pharmaceutical compo sition, or kit-of-parts of individual compositions, adapted to 10 such a route. Dosage and route of administration should be de termined by susceptibility of the causative organisms, se verity and site of infection, and the condition of the pa tient. The preferred types of pharmaceutical compositions are, for example, administered intravenously or by intramuscular 15 injection. Formulations for parenteral administration can be in the form of aqueous isotonic sterile injection solutions or sus pensions. These solutions or suspensions can be prepared from sterile powders, granules or lyophilizates. The compounds can 20 be dissolved in sterile water or in various sterile buffers that may contain sodium chloride, polyethylene glycol, propyl ene glycol, ethanol, sucrose, glucose, arginine, lysine, or lactic acid. The dry compositions can contain from 0.1% to 99% by weight, preferably 10% - 60% by weight, of each of active 25 ingredients. If the compositions contain dosage units, each unit preferably contains from 50mg to 4g of each active sub stance. The ratio of P-lactam antibiotic (compounds of formula I or pharmaceutically compatible salts thereof with a base) and 94 P-lactamase inhibitors (compounds of formula II and formula III-XIII, or pharmaceutically compatible salts thereof with a base) can also vary within wide limits and will be fitted to the individual requirements in each particular case. In gen 5 eral, a ratio of between 1 part of-antibiotic of general for mula I to 5 parts of any one P-lactamase inhibitor of general formula IT or III-XITI and 20 parts of antibiotic of general formula I to 1 part of any one -lactamase inhibitor of gen eral formula II or III-XIII should be appropriate. 10 . The dosage of the compound of formula I and of the phar maceutically compatible salts thereof with bases can vary within wide limits and will be fitted in each particular case to the individual requirements and to the p-lactamase produc ing pathogen to be controlled. In general, a dosage of about 15 0.1 to about 2 g of antibiotic administered one to four times over a 24 hours period should be appropriate. The present invention is further illustrated by the fol lowing non-limiting examples. 20 Example 1 (3S,4S)-3-((2Z)-2-(2-amino(1,3-thiazol-4-yl))-3-[(5 hydroxy-1-methyl-4-oxo (2 -hydropyridyl) ) methoxy -3 -azaprop-.2 enoylamino}-4-methyl-2-oxoazetidinesulfonic acid (6) 25 Preparation of 5-(diphenylmethoxy)-2-(hydroxymethyl)-1 methylhydropyridin-4-one 5- (Diphenylmethoxy) -2- (hydroxymethyl)pyran-4-one (J. An 30 tibiotics 1990, 189) (5.0 g, 16.22 mmol) and methyl amine (80,6 g, 1.04 mol) were stirred at room temperature overnight 95 in presence of methanol (1 mL). The precipitate observed was filtered off and the mother liquor was extracted 3 times with ethyl acetate. The organic phases were dried and the solvent evaporated. The total amount of collected product was 2.19. 5 1H-NMR (DMSO-d6) d: 3.49 (s, 3H), 4.29 (s, 2H), 6.22 (s, 1H), 6.74 (s, 1H) , 7.20 - 7.60 (m, 11H). Preparation of 2-( [5-(diphenylmethoxy)-1-methyl- 4 -oxo- 2 10 hydropyridyl] methoxy)benzofc] azoline-1,3-dione In THF (10.0 mL), containing triphenylphosphine (0.470 g, 1.79 mmol) and N-hydroxyphthalimide (0.293 g, 1.79 mmol) was added 5-(diphenylmethoxy)-2-(hydroxymethyl)-l-methylhydro 15 pyridin-4-one (0.240 g, 0.75 mmol). After cooling the solution at 0*C, diethyl-azodicarboxylate (0.312 g, 1.79 mmol) was added dropwise and stirred for 30 min at this temperature. The solution was then warmed up to room temperature and stirred overnight. A suspension was observed, filtered off and washed 20 to give 210 mg of the desired compound. 1H-NMR (DMSO-d6) d: 3.78 (s, 3H), 5.08 (s, 2H), 6.29 (s, 1H), 6.74 (s, 1H), 7.20 - 7.50 (m, 10H), 7.69 (s, 1H), 7.80 7.90 (m, 4H), 25 Preparation of 2-[(aminooxy)methyl]-5-(diphenylmethoxy) 1-methylhydro pyridin-4-one Hydrazine hydrate (0.023 mL, 0.47 mmol) was added to 30 ethanol (10 mL) already containing 2-([5-(diphenylmethoxy)-l methyl-4-oxo-2-hydropyridyl]methoxy}benzo[c] azoline-1,3-dione (0.200 g, 043 mmol). The resulting solution was refluxed for 2 96 hours. After cooling at room temperature the precipitate was collected and the ethanol was evaporated. The resulting resi due was triturated in ethyl acetate to give 130 mg of the ex pected compound. 5 1H-NMR (DMSO-d6) d: 3.51 (s, 3H), 4.43 (s, 2H), 6.21 (s, 1H), 6.29 ( br s, 2H), 6.74 (s, 1H), 7.20 - 7.50 (n, 10H), 7.56 (s, 1H). 10 Preparation of (2Z)-3-([5 (dipheflmethoxy)-1-methyl-4 oxo(2-hydropyridyl)) methoxy}-2-{ 2 -[(triphenyl methyl)amino] (1,3-thiazol-4-yl)}-3-azaprop-2-enoic acid In a mixture of ethanol (5 nL) / chloroform (3mL), 2 15 [(aminooxy)methyl]-5-(diphenylmethoxy)-l-methylhydropyridin- 4 one (0.076 g, 0.23 mmol) and 2-oxo-2-(2-[(triphenyl methyl)amino] (1,3-thiazol-4-yl)}acetic acid (0.085 g, 0.21 mmol) were stirred at room temperature for 12 hours. The sol vents were evaporated and ethyl acetate was added to the resi 20 due. The resulting suspension was filtered off to afford 77 mg of the desired compound. 1H-NMR (DMSO-d6) d: 3.49 (s, 3H), 5.00 (s, 2H), 6.24 (s, 1H), 6.72 (s, 2H), 6.83 (s, IH), 7.15 - 7.50 (m, 25H), 7.57 25 (s, 1H), 8.85 (s, 1H). Preparation of (3S,4S)-3-((2Z)-3-{[5-(diphenylmethoxy) 1-methyl-4-oxo (2-hydropyridyl) ]methoxy}- 2 -(2 [(triphenylmethyl)amino](1,3-thiazol-4-yl))-3-azaprop-2 30 enoylamino)-4-methyl-2-oxoazetidinesulfonic acid 97 (2Z) -3-{ [5- (diphenylmethoxy) -1-methyl-4-oxo (2-hydro pyridyl)]methoxy)-2-( 2 - [ (triphenyl methyl)amino] (1,3-thiazol 4-yl))-3-azaprop-2-enoic acid (0.380 g, 0.52 mmol), dicyclo hexylcarbodiimide (0.160 g, 0.78 mmol) and 1-hydroxy-7 5 azabenzotriazole (0.106 g, 0.78 mmol) were stirred at room temperature for 3 hours. Then (3S,4S)-3-amino-4-methyl- 2 oxoazetidinesulfonic acid (0.103 g, 1.04 mmol) and a catalytic amount of triethylamine were added to the previous solutiOn which was stirred for 16 hours at room temperature. The sol 10 vent was evaporated in vacuo and the residue was purified by column chromatography (silica gel, eluent; dichloromethane and methanol, 95/5, v/v). 100 mg of desired compound was obtained. 1H-NMR (DMSO-d6) d: 1.35 (d, 3H, J = 6.0 Hz), 3.55 15 3.60 (m, 1H) 3.83 (s, 3H), 4.34 (dd, 1H, J = 2.5, 7.7 Hz), 5.21. (s, 2H), 6.75 (m, 1H), 6.77 (s, 1H), 7.00 (s br, iH), 7.15 - 7.60 (m, 26H), 8.39 (s br, 1H) 8.83 (s, 1H), 9.33 (d, 1H, J = 7.7 Hz). 20 (3S,4S)-3-{(2Z)-2-(2-amino(1,3-thiazol-4-yl))-3-[(5 hydroxy-l-methyl-4-oxo(2-hydropyridyl) )methoxy]-3-azaprop- 2 enoylamino)-4-methyl-2-oxoazetidinesulfonic acid (6) (3S,45)-3-((2Z)-3-{[5-(diphenylmethoxy)-1-methyl-4 25 oxo(2-hydropyridyl)3methoxy)-2-(2-[(triphenyl methyl)amino] (1,3-thiazol-4-yl) -3-azaprop-2-enoylamino)-4 methyl-2-oxoazetidinesulfonic acid (0.076 g, 0.08 mmol) was dissolved in dichloromethane (3 mL). Triethylsilane (0.021 mL, 0.25 mmol) was added at -10 0 C and trifluoroacetic acid (0.327 30 mL, 4.25 mmol) was added dropwise and stirred for 1h at the same temperature. The solution reacted at room temperature for 2 hours. Then dichloromethane was evaporated in vacuo and the 98 residue was purified by preparative HPLC to give 35 mg of the desired compound. 5 Example 2 (3S,4S)-3-{ (2Z)-2-(2-armino(1,3-thia zol-4-y1) )-3- [(1,5 dihydroxy-4-oxo(2-hydropyridyl))methoxy]-3-azaprop- 2 enoylamino} -4 -methyl-2-oxoazetidiny1 hydroxYsulfofate (12) 10 The titled compound was prepared following scheme 1. (2Z)-3-{[1,5-bis(diphenylmethoxy)-4-oxo(2-hydro pyridyl)]methoxy}-2-( 2 -[(triphenylmethyl)amino) (1,3-thiazol- 4 yl)}-3-azaprop-2-enoic acid was prepared according to the pro 15 cedures described in J. Antibiotics, 1990, 1450 and WO-A 02/22613 and ( 3

S,

4 S)-3-amino-4-methyl-2-oxoazetidinyl hydrox ysulfonate was prepared according to the procedures described in J. Am. Chem. Soc, 1982, 6053 and J. Antibiotics, 1985, 1536. 20 Final assembly and deprotection steps were done simi larly according to the method described for the example 1. Example 3 25 (3S,4S)-3-{(2Z)-2-(4-aminopyrimi hydroxy-4-oxo (2-hydropyridyl) ) methoxy -3 -azaprop- 2 enoylaminol-4-methyl-2-oxoazetidinesulfonic acid (21) The titled compound was prepared following scheme 8. 30 (2z)-3-([1,5-bis(diphenylmethoxy)-4-oxo( 2 -hydro pyridyl)]methoxy)-2-{4-[(triphenylmfethyl)aminolpyrimidin- 2 yl)-3-azaprop-2-enoic acid was prepared according to the pro- 99 cedures described in J. Antibiotics, 1984, 546 and (3S,4S)-3 amino-4-methyl-2-oxoazetidinesulfonic acid was prepared ac cording to the procedures described in J. Org. Chem. 1980, 410. 5 Final assembly and deprotection steps were done simi larly according to the method described for the example 1. Example 4 10 2-((3S,4S)-3-{(2Z)-2-(2-amino(1,3-thiazol-4-yl))-3-[(1,5 dihydroxy-4-oxo (2-hydropyridyl) )methoxy] -3-azaprop- 2 enoylamino} -4-methyl-2-oxoazet idinyloxy) acetic acid (22) The title compound was prepared following scheme 1. 15 (2Z)-3-( [l,5-Bis(diphenylmethoxy)-4-oxo( 2 -hydro pyridyl) ]methoxy}-2-{2- E (triphenylmethyl)amino] (1,3-thiazol-4 yl)}-3-azaprop-2-enoic acid was prepared according to the pro cedures described in J. Antibiotics, 1990, 1450 and WO-A 02/22613 and 2-( (3S,4S)-3-amino-4-methyl-2-oxoazetidiny 20 loxy)acetic acid was prepared according to the procedure de scribed in J.. Med. Chem. 1985, 1447 and J. Antibiotics, 1985, 813. Final assembly and deprotection steps were done simi larly according to the method described for the example 1. 25 Example 5 (2)-2-((3S,4S)-3-((2Z)-2-(2-amino(1,3-thiazol-4-yl))-3 E(1,5-dihydroxy-4-oxo(2-hydropyridyl))methoxy]-3-azaprop- 2 enoylamino}-4-methyl-2-oxoazetidinyloxy)propanoic acid (23) 30 The titled compound was prepared following scheme 1. (2Z)-3-{[1,5-bis(diphenylmethoxy)-4-oxo(2-hydro- 100 pyridyl))methoxy}-2-{2-[(triphenylmethyl)aminO](1,3-thiazol- 4 yl)}-3-azaprop-2-enoic acid was prepared according to the pro cedures described in J. Antibiotics, 1990, 1450 and WO-A 02/22613 and (2S)-2-((3S,4S)-3-amino-4-methyl- 2 5 oxoazetidinyloxy)propanoic acid was prepared according to the procedure described in J. Med. Chem. 1985, 1447 and J. Antibi otics, 1985, 813. Final assembly and deprotection steps were done simi larly according to the method described for the example 1. 10 Example 6 (3S)-3-((2Z)-2-(2-amino(1,3-thiazol-4-yl))-3-[(1,5-di hydroxy-4-oxo(2-hydropyridyl))methoxyl-3-azaprop- 2 enoylamino}-4,4-dimethyl-2-oxoazetidinyl hydroxysulfonate (26) 15 The title compound was prepared following scheme 1. (2Z)-3-{[1,5-bis(diphenylmethoxy)-4-oxo( 2 -hydro pyridyl)]methoxy}-2-(2-[(triphenylmethyl)amino](1,3-thiazol-4 yl)}-3-azaprop-2-enoic acid was prepared according to the pro 20 cedures described in J. Antibiotics, 1990, 43, 1450 and WO-A 02/22613 and (3S)-3-amino-4,4-dimethyl-.2-oxoazetidinyl hydrox ysulfonate was prepared according to the procedure described in J. Org. Chem. 2003, 177 and Tetrahedron Lett., 1986, 2789. Final assembly and deprotection steps were done simi 25 larly according to the method described for the example 1. Example 7 (3S,4S)-3-{(2Z)-2-(2-amino-5-chloro(1,3-thiazol-4-yl))-3 [(1, 5-dihydroxy-4-oxo(2-hydropyridyl) )methoxy]--3-azaprop-2 30 enoylaminol -4-ethyl-2-oxoazetidiny. hydroxysulfofate (29) 101 The titled compound was prepared following scheme 1. (2Z)-3-{(1,5-bis(diphenylmethoxy)-4-oxo( 2 -hydro pyridyl) ]methoxy}-2-(5-chloro- 2 - [(triphenylmethyl)amino] (1,3 thiazol-4-yl)}-3-azaprop-2-enoic acid was prepared according 5 to the procedures described in J. Antibiotics, 1990, 1450 and WO-A-02/22613 and ( 3 S,4S)-3-amino-4-methyl-2-oxoazetidinyl hy droxysulfonate was prepared according to the procedure de scribed in J. Am. Chem. Soc, 1982, 6053 and J. Antibiotics, 1985, 1536. 10 Final assembly and deprotection steps were done simi larly according to the method described for the example 1. Example 8 (3S, 4S) -3-{2- (2-amino (1, 3-thiazol-4-yl) ) -3- [(5-hydroxy-l 15 methoxy-4-oxo (2-hydropyridyl) ) methoxyl -3-azaprop- 2 enoylamino)-4-methyl-2-oxoazetidinesulfonic acid (5) The title compound was prepared following scheme 1. The alcohol derivative 5-(diphenylmethoxy)-2-(hy 20 droxymethyl)-1-methoxyhydropyridin- 4 -one was obtained ac cording to the following procedure; 5- (diphenylmethoxy) -2- hydroxymethyll) -1-methoxyhydro pyridin-4-one 25 To a solution of DMF (20 mL) containing 5-(diphenyl methoxy)-1-hydroxy-2-(hydroxymethyl)hydropyridin-4-one (J. An tibiotics 1990, 1450) (2.0 g, 6.19 mmol) at 0 0 C was first added potassium tert-butoxyde (0.971 g, 8.66 mmol) and then iodo methane (4.23 g, 8.66 mol). The resulting mixture was 30 stirred for 30 min at OOC and then 2 h at room temperature. Then ethyl acetate (20 mL) and water (50 mL) was added. The observed precipitate was filtered off and the washed with ad- 102 ditional ethyl acetate. The total of amount of collected prod uct was 1.4 g. 1H-NMR (DMSO-d6) d: 3.87 (s, 3H), 4.38 (d, 2H, J 5 5.8Hz), 5.55 (t, 1H, J = 5.8Hz) 6.13 (s, 1H), 6.69 (s, IH), 7.20 - 7.50 (m, 10H), 7.88 (s, 1H). The compound of formula A (2Z) -3- (diphenylmethoxy) 1-methoxy-4-oxo (2-hydropyridyl) ]methoxy} - 2

-{

2 10 [ (triphenylmethyl ) amino] (1, 3 -thiazol-4-yl) } -3-azaprop-2-enoic acid was prepared according to the procedures described in ex ample 1 and. ( 3

S,

4 S)-3 -amino-4-methyl-2-oxoazetidinesulfonic acid was prepared according to the procedures described in J. Org. Chem. 1980, 410. 15 Final assembly and deprotection steps were done simi larly according to the method described for the example 1. Example 9 (3S, 4S) -3-{( (2Z) -2- (2 -amino (1, 3 -thiazol-4 -y1)) _-3- [ (1 20 hydroxy-5-methoxy-4-oxo (2 -hydropyridyl))methoxy]-3-azaprop- 2 enoylaminol-4-methyl-2-oxoazetidinesulfonic acid (7) The titled compound was prepared following scheme 1. 2-(hydroxymethyl)-5-methoxypyran-4-one was prepared from 25 kojic acid according to the procedure described in J.Org. Chem. 1950, 221 Then the preparation of the compound of formula A (2Z) 3-{ [l- (diphenylmethoxy) -5-methoxy-4-oxo (2-hydro pyridyl) ]methoxy}-2-{2- [ (triphenylmethyl) amino] (1, 3-thiazol- 4 30 yl)}-3-azaprop-2-enoic acid was prepared according to the pro cedures described in example 1 and (3S,4S)-3-amino-4-methyl-2- 103 oxoazetidinesulfonic acid was prepared according to the proce dures described in J. Org. Chem. 1980, 410. Final assembly and deprotection steps were done simi larly according to the method described for the example 1. 5 Example 10 (3S,4S)-3-((2Z)-2-(2-amino(1,3-thiazol-4-yl))- 3

-[

2 (hydroxyacetylamino) ethoxy]-3-azaprop-2-enoylamino}-4-methyl 2-oxoazetidinesulfonic acid (10) 10 The titled compound was prepared following scheme 1. The preparation of the compound of formula A (2Z)-3-(2 (N- [(4-methoxyphenyl)methoxyl acetylamino)ethoxy) -2-(2 (triphenylmethyl) amino] (1, 3-thiazol-4-yl) }-3-azaprop-2-enoic 15 acid was prepared according to the procedures described in Bioorg. Med. Chem. Lett. 1996, 2077 and (3S,4S)-3-amino- 4 methyl-2-oxoazetidinesulfonic acid was prepared according to the procedures described in J. Org. Chem. 1980, 410. Final assembly and deprotection steps were done simi 20 larly according to the method described for the example 1. Example 11 (3S, 4S)-3--{2- (2-amino (1, 3-thiazol-4 -yl) )-3-[ (1-amino-5 hydroxy-4-oxo (2-hydropyridyl) )methoxy] -3 -azaprop-2 25 enoylamino}-4-methyl-2oxoazetidinesulfonic acid (11) The titled compound was prepared following scheme 1. 1- [ (lE) -2- (4-nitrophenyl) -1-azavinyl] -5- (diphenyl methoxy)-2-(hydroxymethyl) hydropyridin-4-one was prepared 30 from kojic acid according to the procedure described in Helv. Chim. Acta 1960, 461 104 Compound of formula A 3-((1--[ (1E)-2-(4-nitrophenyl)-1 azavinyl) -5- (diphenylmethoxy) -4-oxo (2-hydro pyridyl))methoxy) (2Z)-2-{2- [(triphenylmethyl)amino ](1,3 thiazol-4-yl)}-3-azaprop-2-enoic acid was prepared according 5 to the procedures described in example 1 and (3S,45)-3-amino 4-methyl-2-oxoazetidinesulfonic acid was prepared according to the procedures described in J. Org. Chem. 1980, 410. Final assembly and deprotection steps were done simi larly according to the method described for the example 1. 10 Example 12 2- ((3S, 4S) -3-{ (2Z) -2- (2-amino-5-chloro (1, 3-thiazol-4 yl)) -3- [(1, 5-dihydroxy-4-oxo(2-hydropyridyl) )methoxy] -3 azaprop-2-enoylamino } -4- [ (aminocarbonyloxy) methyl] -2 15 oxoazetidinyloxy)acetic acid (42) The titled compound was prepared following scheme 1. The preparation of the compound of formula A (2Z)-3 [1, 5-bis (diphenylmethoxy) -4-oxo (2-hydropyridyl) )methoxy}- 2 20 (5-chloro-2- [(triphenylmethyl) amino) (1,3-thiazol-4-yl)}-3 azaprop-2-enoic acid was achieved according to the procedures described in J. Antibiotics, 1990, 1450 and WO-A-02/2 2 6 13 using 2 -{5--Chloro-2- [ (triphenylmethyl) amino] (1, 3 -thiazol- 4 yl)}-2-oxoacetic acid (obtained from 2-oxo-2-{2 25 I (triphenylmethyl)amino 3(1, 3-thiazol-4-yl) )acetic acid (DE2710902A1) and chlorination step achieved according to the procedures described in EP-A-0 055 465) and 2 [(aminooxy)methyl) -5- (diphenylmethoxy) -1-methylhydroxyridine 4-one (described in example 1). 30 The preparation of the compound of formula B 2 (trirnethylsilyl) -ethyl ((3S,4S) -3-amino- 4

-

105 [(aminocarbonyloxy)methyl]-2~oxoazetidinyloxy)acetate was pre pared as followed: Preparation of 2-[(tert-butoxy)carbonylamino]-3,4 dihydroxy-N-(phenylmethoxy) butanamide. 5 To solution of tetrahydrofuran (THF, 6L) and phosphoric acid buffer (0.025 M, KH 2

PO

4 /Na 2

HPO

4 ; ratio 1/1, 2L) containing ethyl 3-[(tert-butoxy)carbonylamino)-2-hydroxy-3-[N (phenylmethoxy) carbamoylpropanioate (compound prepared from diethyl tartrate according to the procedures described in Org. 10 Synth., Coll. Vol. 1998, 220, J. Org. Chem. 1983, 3556 and US A-4,794,108) (120 g, 31.38 mmol), sodium borohydride (59.35 g, 156.9 mmol) was added portion wise at 0 0 C over lh. The result ing mixture was stirred at 0 0 C for an additional 1h and at room temperature for 2h. The micxture was cooled at 0 0 C before 15 addition of 1M aqueous solution containing H 3 PO4 until the pH reach 8. NaCl (100g) was added to the mixture and the organic layer was separated. Extraction with ethyl acetate (3 x 1.5 L) was performed and the combined organic phases were washed with brine (1 L), dried over MgSO4 and evaporated under vacuo. The 20 residue as purified by column chromatography using hex ane/acetone as eluent to get 50g of white solid. -ESI-MS spectrum: m/z: 339 [M-1] '. 25 Preparation of 2-[(tert-butoxy)carbonylamino]-3-hydroxy N-(phenylmethoxy)-4-(1,1,2,2-tetramethyl-l silapropoxy)butanamide. [(Tert-butoxy)carbonylamino]-3,4-dihydroxy-N 30 (phenylmethoxy) butanamide (47 g, 138 mmol), imidazole (37.5 g, 552 mmol) and tert-butyldimethylsilyl chloride (57.7 g, 386.4 mmol) were stirred at 0 0 C for 1h and the room tempera- 106 ture for an additional 1 h in a mixture of dichloromethane (1.7 L) and dimethylformamide (17 mL). Water (250 mL) was added and after decantation, water (2 X 250 mL) and brine (250 mL) was used for washing the organic phases, which was dried 5 over Na2SO4. After evaporation of the solvent, the residue was purified by column chromatography using a mixture of ethyl acetate/ hexane (1/4) as eluent to get 28g of the desired product. 10 1H-NMR (CDCl 3 ) 5: 0.06 (s, 6H), 0.88 (s, 9H), 1.42 (s, 9H), 3.65 - 3.70 (m, 1l), 3.75 - 3.85 (m, 2H), 4.05 - 4.15 (m, 1H), 4.90 (s, 2H), 5.65 - 5.75 (m, 1H), 7.30 - 7.50 (m, 5H). Preparation of N-(( 3 5,4S)-2-oxo-1-(phenylmethoxy)- 4 15 [(1,1,2,2-tetramethyl-1-silapropoxy yl) (tert-butoxy)carboxamide. A solution of THF (1.5L) containing 2-E(tert butoxy)carbonylamino-3-hydroxy-N-(phenylmethoxy)-4-(1,1,2,2 20 tetramethyl-1-silapropoxy)butanamide (9.8 g, 21.56 mmol), triphenylphosphine (17.5 g, 66.8 mmol) and diethyl azodicar boxylate (11.26g, 64.7 mmol) was stirred at room temperature for 2h. The solvent was evaporated in vacuo and the residue was purified under column chromatography using a mixture of 25 ethyl acetate and hexane (1/4) as eluent to obtained 7.25g of the desired product. 1H-NMR (CDCl 3 ) 6: 0.09 (s, 6H), 0.89 (s, 9H), 1.40 (s, 9H), 3.40 - 3.45 (m, 1H), 3.62 (d, 1H, J = 7.2 Hz), 3.88 (d, 30 1H, J = 7.2 Hz), 4.83 (m, 1H), 4.94 (s, 2H), 5.51 (d, 1H, J = 6.5 Hz), 7.35 - 7.45 (m, 5H).

107 Preparation of N-[C(3S,4S)-4-(hydroxymethyl)-2-oxo-l (phenylmethoxy)azetidin-3-yl](tert-butoxy)carboxamide. 5 N-{(3S,43)-2-oxo-1-(phenylmethoxy)-4-[(1,1,2,2 tetramethyl-1-silapropoxy)methyllazetidin-3-yl}(tert butoxy)carboxamide (2.80 g, 6.41 mmol) was dissolved in THF (50 mL) and pyridine (5 mL). Pyridine-hydroluoride con plex(4.0 mL, 2.6 eq of pyridine, 24 eq of HF) was added at 10 20 0 C. After 10 min, the mixture was warmed up at room tempera ture and stirred for 3.5 h. Phosphoric acid buffer (0.025 M,

KH

2 PO4/Na 2 HPO4; ratio 1/1, 400 mL) was added and the resulting solution was extracted with ethyl acetate (3 X 100 mL). The organic phase was dried over Na 2

SO

4 and the solvent was evapo 15 rated in vacuo. 2.04 g of the desired product was obtained and used for the next step. 1H-NMR (DMSO-d6) 6: 1.38 (s, 9H), 3.50 - 3.60 (m, 2H), 3.95 - 4.05 (m, 1H), 4.70 - 4.80 (m, 1H), 4.94 (s, 2H), 5.00 20 5.10 (m, 1H), 7.20 - 7.30 (m, 1H), 7.35 - 7.50 (m, 5H). Preparation of {(2S,3S)-3-[(tert-butoxy)carbonylamino] 4-oxo-l-(phenylmethoxy)azetidin-2-yl}methyl aminooate (reac tion done according to procedures described in Chem., Eur. J. 25 2005, 1949) In anhydrous dichloromethane (100 mL), N-[(3S,4S)- 4 (hydroxymethyl)-2-oxo-l-(phenylmethoxy)azetidin-3-yll(tert butoxy)carboxamide (1.0 g, 3.1 mmol) and trichloroacetyl chlo 30 ride (1.11 mL, 9.3 mmol) were stirred at 5 0 C for 30 min. Then aluminium oxide (9.6g) was added and the solvent was remove in 108 vacuo. After 2h at room temperature, the residue was taking up with ethyl acetate (40 mL) and stirred for 30 min. The eluent was concentrated and the residue was purified by column chro matography using ethyl acetate/hexane (1/2) 'as eluent to af 5 ford 0.895 g of the desired compound. 1H-NMR (DMSO-d6) 5: 1.39 (s, 9H), 3.90 - 4.20 (m, 3H), 4.80 - 4.90 (m, 1H), 4.91 (s, 2H), 6.50 - 6.80 (broad band for

NH

2 , 2H), 7.30 - 7.50 (m, 5H), 7.55 - 7.60 (m, 1H). 10 Preparation of { (2S,3 S) -3- [ (tert-butoxy) carbonylaminol] 1-hydroxy-4-oxoazetidin-2-ylimethyl amir-ooate. { (2S, 3S) -3- E (tert-butoxy) carbonylamino] -4-oxo-l 15 (phenylmethoxy)azetidin- 2 -yl} methyl aminooate (0.086 g, 0.24 mmol) was dissolved in a mixture of ethyl acetate (4 mL) and methanol (4 mL) under hydrogen atmosphere at room temperature in presence of Pd/C (10 %, 25 mg) . The reaction was stirred for 2 h and the mixture was filtrated over celite bed. The 20 filtrate was evaporated in vacuo to give 0.055g of the desired compound. 1H-NMR (DMSO-d6) 8: 1.39 (s, 9H), 3.95 - 4.10 (m, 3H), 4.75 - 4.80 (m, 1H), 6.45 - 6.70 (broad band for NH 2 , 2H), 25 7.57 (d, 1H, J = 6.0 Hz). Preparation of (trimethylsilyl) -ethyl 2-{ (3S,4S)-3 amino-4- [ (aminocarbonyloxy) methyl] -2 oxoaZetidinyloxy} acetate. 30 The titled compound was prepared from ((2S,3S)-3-[(tert butoxy) carbonylamino] -l-hydroxy-4-oxoazetidin- 2 -yl)methyl ami- 109 nooate according to the procedures described in J. Med. Chem. 1985, 1447 and J. Antibiotics, 1985, 813. 1H-NMR (CDCl 3 ) 8: 0.02 (s, 9H), 0.99 (t, 2H, J= 8.6 Hz), 5 1.37 (s, 9H), 3.90 - 4.30 (m, 5H), 4.53 (dd, 2H, J = 16.4, 21.6 Hz), 4.84 (dd, 1H, J=5.4, 9.4 Hz), 6.70 - 6.40 (broad band for NH 2 , 2H), 7.48 (d, 1H, J = 9.6 Hz,) Final assembly and deprotection steps were done similar 10 ly according to the method described for the example I and J. Med. Chem. 1985, 1447. Example 13 ((2S,3S)-3-{ (2Z)-2-(5-amiLno(1,2,4-thiadiLazol-3-yl))-3 15 [(1,5-dihydroxy-4-oxo(2-hydropyridyl))methoxy]-3-azaprop- 2 enoylamino}-1-(hydroxysulfonyloxy)-4-oxoazetidin- 2 -yl)methyl aminooate (48) The titled compound was prepared following scheme 1. 20 The preparation of the compound of formula A (2Z)-3 {[1,5-bis(diphenylmethoxy)-4-oxo(2-hydropyridyl)]methoxy}-2 {5-[(triphenylmethyl)amino] (1,2,4-thiadiazol- 3 -yl))-3 azaprop-2-enoic acid was achieved according to the procedures described in example 1 from 2-oxo-2-{5 25 {(triphenylmethyl)amino](1,2,4-thiadiazol-3-yl)}acetic acid (EP-A-0 333 154 and GB-A-2102423) . The preparation of the compound of formula B ((2S,3S)-3 amino-1-(hydroxysulfonyloxy)-4-oxoazetidin-2-yl]methyl ami nooate was achieved according to the procedures described in 30 J. Antibiotics 1985, 1536 from {(2S,3S)-3-[(tert- 110 butoxy)carbonylamino]-l-hydroxy-4-oxoazetidin-2-yllmethyl ami nooate (example 12). Final assembly and deprotection steps were done similar 5 ly according to the method described for the example 1 and J. Med. Chem. 1985, 1447. Compound 8 was prepared in analogy to the procedures described 10 in WO-A-02/22613. The corresponding hydroxylamine derivative

(NH

2 -0-R4) was prepared in analogy to the procedure described in J. Med. Chem. 2004, 6349. Compound 9 was prepared in analogy to the procedures described 15 in WO-A-02/22613. The corresponding azetidinone ring of for mula B was prepared in analogy to the procedures described in J. Am. Chem. Soc. 1980, 7076 and J. Org. Chem. 1982, 5160. Compound 13 was prepared in analogy to the procedures de 20 scribed in WO-A-02/22613. The corresponding azetidinone ring or formula B was prepared in analogy to the procedures de scribed in J. Antibiotics 1986, 76. Compound 14 was prepared in analogy to the procedures de 25 scribed in WO-A-02/22613. The corresponding azetidinone of formula B was prepared in analogy to the procedures described in DE-A-3229439. Compound 15 was prepared in analogy to the procedures de 30 scribed in WO-A-02/22613. The corresponding heterocycle of the carboxylic acid derivative of formula A was prepared in anal- 111 ogy to the procedures described in Russ. J. Org. Chem. 1995, 240 and J. Antibiotics 1983 1020. Compound 16 was prepared in analogy to the procedures de 5 scribed in WO-A-02/22613. The corresponding heterocycle of the carboxylic acid derivative of formula A was prepared in anal ogy to the procedures described in Z. Chem 1975, 233 and J. AntibioLics 1903, 1020. 10 Compound 17 was prepared in analogy to the procedures de scribed in WO-A-02/22613. The corresponding heterocycle of the carboxylic acid derivative of formula A was prepared in anal ogy to the procedures described in US-A-4,394,504 and J. Anti biotics 1983, 1020. 15 Compounds 18 and 19 were prepared in analogy to the procedures described in WO-A-02/22613. The corresponding heterocycles of the carboxylic acid derivatives of formula A was prepared in analogy to the procedures described in J. Am. Chem. Soc. 1959, 20 2452, WO-A-95/33724 and J. Antibiotics 1983, 1020 using re spectively the methyl hydrazine and hydrazine as starting ma terial. Compound 20 was prepared in analogy to the procedures de 25 scribed in WO-A-02/22613. The corresponding heterocycle of the carboxylic acid derivative of formula A was prepared in anal ogy to the procedures described in US-A-4,394,504 but using 2 amino-6-picoline as starting material. 30 Compound 24 was prepared in analogy to the procedures de scribed in WO-A-02/22613. The corresponding azetidinone ring 112 of formula B was prepared in analogy to the procedures de scribed in example 13 and J. Antibiotics 1983, 1201. Compound 25 was prepared in analogy to the procedures de 5 scribed in WO-A-02/22613. The corresponding azetidinone ring of formula B was prepared in analogy to the procedures de scribed in example 13. Compound 27 was prepared in analogy to the procedures de 10 scribed in WO-A-02/22613. The corresponding hydroxylamine de rivative (NH 2 -O-R4) was prepared according to the synthetic scheme B-3-II. Compound 30 was prepared in analogy to the procedures de 15 scribed in example 7 using the same compound of formula B and the compound of formula A described in example 13. Compound 31 was prepared in analogy to the procedures de scribed in example 6 using the same compound of formula B and 20 the compound of formula A described in example 12. Compound 32 was prepared in analogy to the procedures de scribed in example 6 using the same compound of formula B and the compound of formula A described in example 13. 25 Compound 35 was prepared in analogy to the procedures de scribed in examples 4 and 6 for preparing the compound of for mula B and of example 13 for preparing compound of formula A. 30 Compound 36 was prepared in analogy to the procedures de scribed in example 4 using the same compound of formula B and the compound of formula A described in example 12.

113 compound 37 was prepared in analogy to the procedures de scribed in example 4 using the same compound of formula B and the compound of formula A described in example 13. 5 Compound 38 was prepared in analogy to the procedures de scribed in example 6 and after reduction of the N-hydroxy group o 1-i (J. Am. Chem. Soc. 1980, 7076) , the final sulfon ylation was performed in analogy to example 3 to obtain the 10 compound of formula B. Procedures of example 12 were used for preparing the compound of formula A. Compound 39 was prepared in analogy to the procedures de scribed in example 6 and after reduction of the N-hydroxy 15 group to NH (J. Am. Chem. Soc. 1980, 7076), the final sulfon ylation was performed in analogy to example 3 to obtain the compound of formula B. Compound 40 was prepared in analogy to the procedures de 20 scribed in example 6 and after reduction of the N-hydroxy group to NH (J. Am. Chem. Soc. 1980, 7076), the final sulfon ylation was performed in analogy to example 3 to obtain the compound of formula B. Procedures of example 13 were used for preparing the compound of formula A. 25 Compound 41 was prepared in analogy to the procedures de scribed in example 12 for preparing the compound of formula B. Compound 43 was prepared in analogy to the procedures de 30 scribed in example 12 for preparing the compound of formula B. Procedures of example 13 were used for preparing the compound of formula

A.

114 Compound 44 was prepared in analogy to the procedures de scribed in example 12 and J. Antibiotics 1983, 1201 for pre paring the compound of formula B. S Compound 45 was prepared in analogy to the procedures de scribed in example 12 and J. Antibiotics 1983, 1201 for pre paring thecompoud ofI formula a B. Procedures of example 12 were used for preparing the compound of formula A. 10 Compound 46 was prepared in analogy to the procedures de scribed in example 12 and J. Antibiotics 1983, 1201 for pre paring the compound of formula B. Procedures of example 13 were used for preparing the compound of formula A. 15 Compound 47 was prepared in analogy to the procedures de scribed in example 12 for preparing the compound of formula B. Procedures of example 12 were used for preparing the compound of formula A. 20 In the following table X the analytical data for all compounds of formula (I) made are presented: U); 00 U) co~U ~ ~ c o ~ ~ C-4 Lr in 00 00Cd N I r- 4I *r- 0 -0 Lf :iD In II 4a 00 C) to 44 m4 C4 C'1 to N I * C) Lfl L-4 to N NLr t I U) N * C) CY) CD * 4 to '0 N 0 in Hn ,C:N rcs - x) U)) to ' C ro . . c3 - .CI - *O' 44 r- M M m N . 0 o4 to H 0))C In ~ ~ -I -Z -4 LW co k44 -1- 0 H -- a) - N H H4 (D 0 - C inI Un N H 0- 0 CCO co N- N C . - C) COCN H kN -4H C)r -l c n 0 ) - N U) E m 00 co - m: N Nq .. i 10 .. CON3 oE ~-4 ~ - - (N - . I - ( N C - Cn N U) U) U) Nj O0 10 I H H H -4 - r4 -A - ~ ~ c cio- II-I: Hn L) 00 t- C))0 0 - 0 00 (Y) l E- Nr 0f) C-l - '. 1 - * - x O D U) 0n CD. 0 If)~~ - .0-- f C:) CC)0- N - ~ H ~ - ) . = *H, -. 1 ~ U r'1 (N cm (n r- 00 E2>. ~ - . z- i ko .. 02 Ff 3 Lf) a) '.0 it '.N ( H N N n Hv C '.0 - n , Li0 1 -- C > I-n m N .- 0' -ov 0)) - 0 ' .r0til U))N ~ ~ I 0 . CI C)ICIC . * 0-I + a)' 00 ro H - O) r- U N H 1 r- - -4 (Z) H H OH kfl tfl NN -l~ - Ni C -~~L '- HN -o * - -_) N N CN U C- H 4 4 N m 7NC4 co H CD R -H I U)~~~C 00( - N~d * rH -' . Cl C)H 4 - _ . 0 D U)) - U4 H N *N CNH 4C * cr~* m Cl In cD -n ICD 00 H~~- - - o oC fl co H o H t CN N =In U) H =.- H - ~ V r Lfl U)cq U I * -t N C) X Ln -H Hn co NN) r- co - *. In No Co NitC~ - N H n 0.) an an U) En --- t co( to N Y) U) t co -1 11. - 4 CN cN CZ-) U) C I* U) - C (N - IC In -En k.0N 'CC) -L ) Hn oDr-C lt ~ k, - co~~ L f H~U C-C- NN H U)i w1 r- C) U) co k ) _ -C1 in U) -. - - n c H C'n (N3 - t H H it I.. r- N t -17 00* - ; k H ~ ( VN- _N m m n ( In -H - (No - *5 in - In c C'- -%n oi C) I' ni (n If C-- (N - ( U)Lr '00 (LIN) , * N :11 El) N H -1>-3 C:) 00 00 - - I CN LO I c) V) Cl aDjl q rl - H4 cN ~ .~ C Cl C -in t- N -1 C)C) . C:) ~~~C m . - )- U H, Cl N C Q CH Cl - LfU) N. C)) En -nC)L) C D r M ml HQ '4 -1 C)- .. - C) C C:) _ E) -.- C - H CD C) rNN *r U)) () -q c U) c-- -. W. W. '1C) C) - H Example 14 (1S,5R)-2-[2-(3-carbamoyl-6-methypyridinium)acetyl]-7 oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt 5 (.111) The ied. compound was prepared folloiing scheme I.I. a) Preparation of 5-carbamoyl-1-carboxymethyl- 2 -methyl pyridinium bromide 10 A solution of 6-methyl nicotinamide (400 mg, 2.94 mmol., 1.0 eq) and bromoacetic acid (408 mg, 2.94 mmol, 1.0 eq) in DMF (10 mL) was stirred at room temperature for 6 days. The reaction mixture was monitored by LCMS. Solvent was then evaporated and the crude product was purified by preparative 15 HPLC to afford 136 mg of the expected compound. 1H-NMR (DMSO-d 6 ) 6 (ppm): 2.80 (s, 3H); 5.66 (s, 2H); 8.13 (s, 1H); 8.24 (d, J = 8.3, 1H); 8.53 (s, 1H); 8.92 (dd, J 1.8 and 8.3, 1H) ; 9.47 (s, 1H) 20 b) (13,5R)-2-[2-(3-carbamoyl-6-methylpyridin ium)acetyl--7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (111) 5-carbamoyl-1-carboxymethyl-2-methyl-pyridinium bromide 25 (91 mg, 0.47 mmol, 1.0 eg) was added at room temperature to a stirred solution of (1S,5R)-7-oxo-2,6-diazabicy clo[3.2.0]heptane-6-sulfonic acid (J. Med. Chem. 1998, 3961) (90 mg, 0.47 mmol, 1.0 eq) in.DMSO (4 mL), followed by 1-hy droxybenzotriazol (69 mg, 0.52 mmol, 1.1 eq), dicyclohexyl 30 carbodiimide (106 mg, 0.52 mmol, 1.1 eq) and diisopro pylethylamine (96 gL, 0.56 mmol, 1.2 eq). After stirring 123 overnight at room temperature, the reaction mixture was fil tered. The mother liquid was evaporated and the crude product was dissolved in CH 2 C1 2 (4 mL) and filtered. The resulting solid was purified by preparative HPLC to afford 46 mg of the 5 expected compound. 1H-NMR (DMSO-d 6 ) 5 (ppm): 1.82 (m, 1H); 2.42 (m, 1H); 2.73 (d, J= 5.3, 3H); 3.25 and 3.55 (2m, 1H)); 4.05 (m, 1H); 4.40 and 4.62 (2t, J 4.7, 1H); 5.19 and 5.31 (2d, J = 4.3, 10 1H); 5.55-6.05 (AB part of a ABX system, the X part being in the isN spectrum, 2H) ; 8.12 (d, J = 7.0, 1H); 8.22 (d, J = 8.3, 1H); 8.53 (d, J = 10.0, 1H); 8.89 (dd, J 1.8 and 8.3, 1H)); 9.36 (dd, J = 1.8 and 10.0, 1H). 15 Example 15 (1S, 5R) -2-{2- [3 - (N-methylcarbamoyl)pyridiniunlacetyl} 7 oxo-2,6-diazabicyclo [3 .2 .03heptane-6sulfonate, inner salt (101) The titled compound was prepared following scheme 11 and 20 in analogy to example 14 using (1S,5R)-7-oxo-2,6-diazabicy clo[3.2.0]heptane-6-sulfonic acid (compound H) and the com mercially available N-methyl nicotinamide as starting materi als. +ESI-MS spectrum: m/z: 289 [M+H-SO3). 25 Example 16 (1,SR)6-2-[2-(4-aminopyridinium)acetyl]-7-oxo-2,6-di azabicyclo[3.2.0]heptane-6-sulfonate, inner salt (103) 30 The titled compound was prepared following scheme 11 and in analogy to example 14 using ( 1 S,5R)-7-oxo-2,6-diazabicy- 124 clo[3.2.0]heptane-6-sulfonic acid (compound H) and the com mercially available 4-aminopyridine as starting materials. +ESI-MS spectrum: m/z: 326 [M]+. 5 Example 17 (1S,5R)-2-(2-(2-isoquinolinium)acetyl)-7-oxo-2,6-di azabicyclo[3.2.0]heptane-6-sulfonate, inner salt (104) The titled compound was prepared following scheme 11 and 10 in analogy to example 14 using (1S,5R)-7-oxo-2,6-diazabicy clo[3.2.0]heptane-6-sulfonic acid (compound H) and the com mercially available isoquinoline as starting materials. -ESI-MS spectrum: m/z: 360 (M-l]. 15 Example 18 (1S, 5R) -2- [2- (4-carbamoylpyridinium) acetyl -7-oxo-2, 6 diazabicyclo[3.2.03 heptane-6-sulfonate, inner salt (105) The titled compound was prepared following scheme 11 and 20 in analogy to example 14 using (1S,5R)-7-oxo-2,6-diazabicy clo[3.2.0)heptane-6-sulfonic acid (compound H) and the com mercially available isonicotinamide as.starting materials. 1H-NMR (DMSO-d 6 ): 1.78 (M, 1H); 2.40 (m, 1H); 3.20 and 25 3.50 (2m, 1H); 4.05 and 4.12 (2m, 1H); 4.43 and 4.60 (2t, J 4.7, 1H); 5.21 and 5.29 (2d, J = 4.3, 1H); 5.55-6.00 (AB part of a ABX system, the X part being in the ' 5 N spectrum, 2H); 8.27 (m, 1H); 8.46 (m, 2H); 8.65 (m, 1H); 9.12 (m, 2H). 30 Example 19 125 (1S, 5R) -7-oxo-2- (2 - (2 -5, 6 ,7, 8 -tetrahydroisoquinolin ium)acetyl)-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (106) 5 The titled compound was prepared following scheme 11 and in analogy to example 14 using (1S,5R)-7-oxo-2,6-diazabicy clo[3.2.0)heptane-6-sulfonic acid (compound H) and the com mercially available 5,6,7,8-tetrahydroisoquinoline as start ing materials. 10 +ESI-MS spectrum: m/z: 365 [M) Example 20 (1S, 5R) -2- [2- (3-aminopyridinium) acetyl] -7-oxo-2, 6-di 15 azabicycloE3.2.Oheptane-6-sulfonate, inner salt (107) The titled compound was prepared following scheme 11 and in analogy to example 14 using (1S,5R)-7-oxo-2,6-diazabicy clo[3.2.0)heptane-6-sulfonic acid (compound H) and the com 20 mercially available 3-aminopyridine as starting materials. +ESI-MS spectrum: m/z: 326 [M] *. Example 21 (1S,5R)-2-(2-{3- [N-(carbamoyl 25 methyl)carbamoylpyridiniumacetyl)-7-oxo- 2 ,6-diazabicy clo[3.2.03heptane-6-sulfonate, inner salt (108) The titled compound was prepared following scheme 11 and in analogy to example 14 using (lS,5R)-7-oxo-2,6-diazabicy 30 clo[3.2.0]heptane-6-sulfonic acid (compound H) and 3-[N-(car bamoylmethyl)carbamoylipyridine as starting materials. +ESI-MS spectrum: m/z: 411 [M] *.

126 3-[N-(carbamoylmethyl)carbamoyl]pyridine was prepared by reacting the commercially available nicotinyl chloride hydro chloride with glycinamide hydrochloride. 5 Example 22 (1S,5R)-2-{2-[3-(N-cyclopropylcar bamoyl)pyridiniumacetyl-7-oxo-2,6-diazabicy clo[3.2.O]heptane-6-sulfonate, inner salt (109)_ 10 The titled compound was prepared following scheme 11 and in analogy to example 14 using (lS, 5 R)-7-oxo-2,6-diazabicy clo[3.2.0]heptane-6-sulfonic acid (compound H) and the com mercially available nicotinoyl chloride hydrochloride and cyclopropylamine as starting materials. 15 1H-NMR (DMSO-d 6 ) : 0.60 (m, 2H) ; 0.78 (m, 2H) ; 1.77 (m, 1H); 2.40 (m, 1H); 2.92 (m, 1H); 3.23 and 3.50 (2m, 1H); 4.01 and 4.10 (2m, 1H); 4.41 and 4.61 (2t, J = 4.7, 1H); 5.20 and 5.29 (2d, J = 4.3, 1H); 5.58-6.05 (AB part of a ABX system, 20 the X part being in the 15N spectrum, 2H); 8.30 (m, 1H); 8.95 (m, 1H); 9.01-9.13 (m, 2H); 9.36 (m, 1H). Example 23 (13,5R)-2-{2-[4-(dimethylamino) p 25 2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (112) The titled compound was prepared following scheme 11 and in analogy to example 14 using (lS,5R)-7-oxo-2,6-diazabicy clo[3.2.0]heptane-6-sulfonic acid (compound H) and the com mercially available 4-(dimethylamino)pyridine as starting ma 30 terials. 1H-NMR (DMSO-d 6 ): 1.22 (s, 3H); 1.26 (s, 3H); 1.74 (m, 1H); 2.38 (m, 1H); 3.20-3.50 (m, 1H); 3.98 and 4.08 (2dd, J 127 8.6 and 11.2, 1H); 4.38 and 4.48 (2t, J = 4.7, 1H); 5.00-5.45 (m, 3H); 7.02 and 7.07 (2d, J = 7.9, 2H); 8.11 and 8.16 (2d, J = 7.9, 2H). 5 Example 24 2-(2-(3-[N-((3S)pyrrolidin-3 yl)carbamoyllpyridinium}acetyl) (1S,5R) -7-oxo2,6-diazabicy clo[3.2.Oheptane-6-sulfonate, inner salt (122) 10 Preparation of sodium (lS,5R)-2--(2bromacetyl)-7-oxo 2,6-diazabicyclo[3.2.0) heptane-6-sulfonate A solution of sulphur trioxide.DMF complex (4.92 g, 32.10 mmol, 1.5 eq) in DMF (10 mL) was added at 0 OC to a 15 stirred solution of (5S,IR)-4-(2-bromoacetyl)-4,7-diazabicy clo[3.2.0]heptan-6-one (compound F, 5.25 g, 21.40 mmol, 1.0 eq) in DMF (110 mL). After 5 hours stirring at 0 IC, the re action mixture was concentrated. The remaining oil was dis solved in a minimum amount of H20 and the pH was adjusted to 20 6 with saturated NaHCO 3 solution. The mixture was then con centrated under reduced pressure to afford 8.3 g of the ex pected sodium (lS,5R)-2-(2-bromoacetyl)-7-oxo- 2 ,6-diazabicy clo[3.2.0]heptane-6-sulfonate as a brown oil. 25 Preparation of ert-butyl (3S)-3-(3-pyridylcarbonyl amino)pyrrolidinecarboxylate Nicotinoyl chloride hydrochloride (286 mg, 1.61 mmol, 1.0 eq) was added at room temperature to a stirred solution 30 of (S)-3-amino-1-N-BOC-pyrrolidine (300 mg, 1.61 mmol, 1.0 eq) in CH 2 Cl 2 (9 mL), followed by triethylamine (337 tL, 2.42 mmol, 1.5 eq). After stirring overnight at room temperature, 128 the reaction mixture was extracted and the organic layer was dried over Na 2

SO

4 , filtered and evaporated to afford 457 mg of the expected compound. 5 Preparation of 2

-(

2 -[3-(N-{(3S)-l-[(tert-bu tyl)oxycarbonyllpyrrolidin-3 yl}carbamoyl)pyridinium)acetyl}(iS,5R)-7-oxo-2,6-diazabicy clo[3.2.0)heptane-6-sulfonate, inner salt 10 A solution of (1S,5R)-2-(2-bromoacetyl)-7-oxo-2,6-di azabicyclo(3.2.0]heptane-6-sulfonic acid (200 mg, 0.64 mmol, 1.0 eq) and tert-butyl ( 3 S)-3-(3-pyridylcarbonyl amino)pyrrolidinecarboxylate (149 mg, 0.51 mmol, 0.8 eq) in DMF (2 mL) was stirred at room temperature- for 3 days. The 15 reaction was monitored by LCMS. Then DMF was evaporated to afford 330 mg the expected crude product which was directly used in the next step. Preparation of 2-(2-(3-[N-((3S)pyrrolidin- 3 20 yl)carbamoyl]pyridinium} acetyl)- (1 5R)-7-oxo-2, 6-diazabicy clo[3.2.0]heptane-6-sulfonate, inner salt (122) A solution of 2-{2-[3-(N-{(3S)-1-[(tert-bu tyl) oxycarbonyl)pyrrolidin-3 25 yl)carbamoyl)pyridinium]acetyl}(iS,5R)-7-oxo-2,6-diazabicy clo[3.2.0)heptane-6-sulfonate, inner salt in DMF (4 mL) was cooled to 0 oC before the addition of trifluoroacetic acid (729 RL, 9.45 mmol, 15.0 eq) . After stirring overnight at room temperature, the reaction mixture was concentrated and 30 the crude was purified by preparative HPLC to afford 37 mg of the expected compound.

129 1H-NMR (DMSO-d 6 ): 1.80 (M, 1H) ; 2.05 (n, 1H) ; 2.23 (In, 1H); 2.40 (m, 1H); 3.33 (m, 5H); 4.01 and 4.10 (2m, 1H); 4.13 and 4.61 (2t, J = 4.7, IH); 4.56 (m, 1H); 5.18 and 5.30 (2d, J = 4.1, 1H); 5.60-6.05 (AB part of an ABX system, the X part 5 being in the 15 N spectrum, 2H); 8.35 (m, 1H); 9.07 (m, 3H); 9.38 (m, 111); 9.44 (s, 1I) Example 25 (IS, 5R) -2- [2- (3-carbamoylpyridinium) acetyl] -7-oxo-2, 6 10 diazabicyclo[3.2.0]heptane-6~-sulfonate, inner SaLt (102) The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)-4, 7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first 15 sulfonated (J. Org. Chem. 1982, 5160) and the commercially available nicotinamide as starting materials. 1H-NMR (DMSO-d 6 ): 1.78 (m, 1H); 2.40 (m, 1H); 3.23 and 3.50 (2m, 1H); 4.03 and 4.13 (2dd, J = 8.6 and 11.0, 1H); 20 4.42 and 4.63 (2t, J = 4.7, 1H); 5.20 and 5.32 (2d, J = 4.3, 1H); 5.55-6.05 (AB part of a ABX system, the X part being in the 15N spectrum, 2H); 8.18 (d, J = 3.7, 1H); 8.33 (q, J = 6.2 and 7.9, 1H); 8.57 and 8.62 (2s, 1H); 9.02-9.12 (m, 2H); 9.42 (d, J = 6.5, 1H) 25 Example 26 (1S,5R) -2- [2- (3,4-dicarbamoylpyridinia)acetyll -7-oxo 2,6-diazabicyclo[3 .2.0]heptane-6-sulfofate, inner salt (110) 30 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,lR)-4-(2-bromoacetyl)- 4

,

7

-

130 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 3,4-pyridine dicarboxamide as starting materials. 5 1H-NMR (DMSO-d 6 ): 1.74 (m, 1H) ; 2.40 (m, 1H) ; 3.25 and 3.49 (2m, IH); 4.03 and 4.11 (2m, 1H); 4.41 and 4.62 (2t, J 4.7, 1H); 5.22 and 5.29 (2d, J = 4.3, 1H); 5.55-6.00 (AB part of a ABX system, the X part being in the 1sN spectrum, 2H); 8.04 (m, 1H); 8.14 (d, J = 10.8, 1H); 8.24 (m, 2H); 8.45 (d, 10 J= 9.1, 1H); 9.10 (m, 1H); 9.24 (2s, 1H). Example 27 (1S, 5R) -2-{2- [4-- isopropyl1) pyridin diazabicyclo[3.2.0] heptane-6-sulfonate, inner salt (113) 15 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially 20 available 4-isopropyl pyridine as starting materials. 1H-NMR (DMSO-d 6 ) 1.28 and 1.30 (2d, J = 2.3, 6H); 1.77 (m, 1H); 2.42 (m, 1H); 3.10-3.55 (m, 2H); 4.00 and 4.10 (2m, 1H); 4.40 and 4.60 (2t, J = 4.7, 1H); 5.19 and 5.29 (2d, J = 25 4.2, 1H); 5.45-5.90 (AB part of a ABX system, the X part be ing in the 15N spectrum, 2H); 8.11 (m, 2H); 8.81 (d, J 6.7, 1H); 8.87 (d, J = 7.1, 1H). Example 28 30 (1S,5R)-2{2-([3-(methoxycarbonyl)-5-methylpyridin ium]acetyl}-7-oxo-2,6-diazabicyclo[3.

2 .Oheptaie-6-sulfonate, inner salt (114) 131 The titled compound was prepared following scheme 11 and in analogy to example 24 using (53,lR)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first 5 sulfonated (J. Org. Chem. 1982, 5160) and the commercially available methyl-5-methylnicotinate as starting materials. 1H-NMR (DMSO-d 6 ): 1.77 (m, 1H); 2.41 (m, 1H); 2.58 (d, J = 5.9, 3H); 3.24 and 3.49 (2m, 1H); 3.98 (d, J = 2.5, 3H); 10 4.02 and 4.12 (2m, 1H); 4.41 and 4.61 (2t, J = 4.7, 1H); 5.20 and 5.29 (2d, J= 4.3, 1H); 5.55-6.00 (AB part of a ABX sys tem, the X part being in the 1N spectrum, 2H); 8.95 (m, 1H); 9.06 and 9.15 (2s, 1H); 9.41 and 9.45 (2s, 1H). 15 Example 29 (IS, 5R) -2-{2- [3- (methoxycarbonyl) -2-methylpyridin ium]acetyl}-7-oxo-2,6-diazabicyclo[3.2.01heptane-6-sulfonatee inner salt (115) 20 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,lR)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 2-methyl nicotinic acid methyl ester as starting 25 materials. lH-NMR (DMSO-d 6 ): 1.82 (m, 1H); 2.40 (m, 1H) ; 2.81 (d, J = 2.8, 3H); 3.29 and 3.57 (2m, 1H); 3.96 (s, 3H); 4.06 (m, 1H); 4.40 and 4.62 (2t, J = 4.8, 1H); 5.20 and 5.34 (2d, J 30 4.3, 1H); 5.65-6.05 (AB part of a ABX system, the X part be ing in the 15N spectrum, 2H); 8.17 (m, 1H); 8.91 (m, 1H); 9.08 (m, 1H).

132 Example 30 (1S,5R)-2-{2- [3- (methoxycarbonyl)pyridiniumlacetyl}- 7 oxo-2,6-diazabicyclo(3.2.0]heptane-6-sulfonate, inner salt 5 (116) The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,lR)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first 10 sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 3-carboxypyridine methyl ester as starting materi als. 1H-NMR (DMSO-ds): 1.80 (m, 1H); 2.39 (m, 1H); 3.22 and 15 3.52 (2m, 1H); 3.98 (d, J = 2.3, 3H); 4.01 and 4.12 (2m, iH); 4.41 and 4.61 (2t, J= 4.7, 1H); 5.20 and 5.29 (2d, J= 4.2, 1H); 5.65-6.05 (AB part of a ABX system, the X part being in the 15N spectrum, 2H); 8.35 (m, 1H); 9.07 (m, 1H); 9.13 and 9.21 (2m, 1H); 9.57 and 9.62 (2s, 1H); 12.75 (br, 1H). 20 Example 31 (1S,5R)-7-oxo-2- [2-(4-propanoylpyridinium) acetyl3 -2,6 diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (117) 25 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,lR)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.Olheptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 4-propionyl pyridine as starting materials. 30 133 1H-NMR (DMSO-d 6 ) : 1.13 (dt, J 2.5 and 7.1, 3H); 1.80 (m, 1H); 2.41 (m, 1H); 3.15-3.55 (m, 3H); 4.02 and 4.11 (2dd, J = 8.8 and 11.1, 1H); 4.41 and 4.61 (2t, J = 4.7, 1H); 5.20 and 5.29 (2d, J = 4.3, 1H); 5.60-6.05 (AB part of a ABX sys 5 tem, the X part being in the 15N spectrum, 2H); 8.53 and 8.56 (2d, J = 7.1, 21); 9.11 and 9.18 (2d, J = 7.1, 2H). Example 32 (1S, 5R) -2-{2- [4- (aminothioxomethyl) pyridinium)acety1}-7 10 oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (118 ) The titled compound was prepared following scheme 11 and in analogy to example 24 using (SS,1R)-4-(2-bromoacetyl)- 4

,

7 15 diazabicyclo(3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 4-pyridine carbothioamide as starting materials. 1H-NMR (DMSO-d 6 ): 1.79 (m, 1H); 2.39 (m, 1H); 3.24 and 20 3.49 (2m, 1H); 4.00 and 4.10 (2m, 1H); 4.41 and 4.61 (2t, J 4.7, 1H); 5.21 and 5.28 (2d, J = 4.3, 1H); 5.55-5.95 (AB part of a ABX system, the X part being in the 1sN spectrum, 2H); 8.28 (dd, J = 6.8 and 10.8, 2H); 8.96 and 9.02 (2d, J = 6.8, 2H); 10.31 and 10.74 (2br, 2H); 12.7 (br, 1H). 25 Example 33 (1S,5R) -2-(2-(3- [ (ethoxycar bony1)methyl]PYridiniumlacetyl) -7-oxo-2, 6-diazabicy clo[3.2.01heptane-6-sulfonate, inner salt (119) 30 134 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-brombacetyl)- 4

,

7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially 5 available ethyl-3-pyridyl acetate as starting materials. 1H-NMR (DMSO-d 6 ): 1.22 (dt, J = 0.9 and 7.1, 3H); 1.75 (m, 1H); 2.41 (m, 1H); 3.22 and 3.49 (2m, 1H); 4.05 (m, 3H); 4.15 (dq, J = 0.9 and 7.1, 2H); 4.40 and 4.61 (2t, J = 4.6, 10 1H); 5.20 and 5.30 (2d, J = 4.3, 1H); 5.50-5.95 (AB part of a ABX system, the X part being in the 1 5 N spectrum, 2H) ; 8.19 (m, 1H); 8.61 (m, 1H); 8.87 and 8.92 (2m, 1H); 8.89 and 8.97 (2s, 1H). 15 Example 34 (1S,5R)-7-oxo-2-{2-[3-(trifluoro methyl)pyridinium)acetyl)-2,6-diazabicyclo[3.2.0]heptane-6 sulfonate, inner salt (120) 20 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 3-(trifluoromethyl)pyridine as starting materials. 25 1H-NMR (DMSO-d6) : 1.80 (m, 1H) ; 2.40 (m, 1H) ; 3.24 and 3.51 (2m, 1H); 4.04 and 4.12 (2m, 114); 4.42 and 4.62 (2t, J = 4.7, 1H); 5.21 and 5.29 (2d, J = 4.1, 1H); 5.65 - 6.05 (AB part of a ABX system, the X part being in the 15 N spectrum, 30 2H); 8.47 (m, 1H); 9.17 (n, 1H); 9.24 and 9.30 (2d, J = 6.2, 1H); 9.67 and 9.76 (2s, 1H); 12.7 (br, 1H).

135 Example 35 (1S,5R)-2-[2-(3,4-dimethylpyridinium)acety1]-7-oxo-2,6 diazabicycloC3.2.0] heptane-6-sulfonate, inner salt (121) 5 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 3,4-lutidine as starting materials. 10 1H-NMR (DMSO-d 6 ): 1.78 (m, 1H); 2.40 (d, J = 3.7, 3H); 2.47 (m, 1H); 2.55 (d, J = 3.6, 3H); 3.21 and 3.49 (2m, 1H); 4.06 (m, 1H); 4.40 and 4.60 (2t, J 4.7, 1H); 5.20 and 5.28 (2d, J = 4.3, 1H); 5.40-5.85 (AB part of a ABX system, the X 15 part being in the 15 N spectrum, 2H); 7.97 (m, 1H); 8.70 (m, 2H). Example 36 (1S, 5R) -7 -oxo-2- {2- [3-benzylpyridinium] acetyl} -2, 6-di 20 azabicyclo[3.2.0]heptane-6-sulfonate, inner salt (123) The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)- 4 ,7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first 25 sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 3-benzylpyridine as starting materials. 1H-NMR (DMSO-d 6 ): 1.78 (m, 1H); 2.40 (m, 1H); 3.21 and 3.41 (2m, 1H); 4.01 and 4.10 (2m, 1H); 4.21 (d, J = 7.3, 2H); 30 4.40 and 4.60 (2t, J = 4.7, 1H); 5.20 and 5.28 (2d, J= 4.2, 1H); 5.50-5.95 (AB part of a ABX system, the X part being in the 1 5 N spectrum, 2H); 7.31 (m, 5H); 8.12 (m, 1H); 8.55 (t, J 136 = 7.6, 1H); 8.80 and 8.85 (2d, J = 6.3, 1H); 8.90 and 9.00 (2s, IH) Example 37 5 (1S,5R)-7-oxo-2-[2-(3-phenylpyridinium)acetyl]-2,6-di azabicyclo[3.2.0]heptane-6-sulfonate, inner salt (124) The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)- 4

,

7 10 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 3-phenyl pyridine as starting materials. 1H-NMR (DMSO-d 6 ): 1.80 (m, 1H); 2.40 (m, 1H); 3.23 and 15 3.51 (2m, 1H); 4.10 (m, 1H); 4.42 and 4.62 (2t, J = 4.7, 1H); 5.21 and 5.33 (2d, J = 4.2, 1H); 5.60-6.00 (AB part of a ABX system, the X part being in the 1N spectrum, 2H); 7.62 (m, 313); 7.88 (m, 2H); 8.28 (m, 1H); 8.93 (2d, J = 6.3, 1H); 8.99 (m, 1H); 9.41 and 9.48 (2s, 1H). 20 Example 38 2-(2-(3- [W-((3R)pyrrolidin-3 yl)carbamoyllpyridinium}acetyl) (1S,5R)-7-oxo-2,6-diazabicy clo[3.2.0]heptane-6-sulfonate, inner salt (125) 25 The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,lR)-4-(2-bromoacetyl)-4,7 diazabicyclo[3.2.0)heptan-6-one (compound F) which was first sulfonated (J.. Org. Chem. 1982, 5160) and the commercially 30 available nicotinoyl chloride hydrochloride and (R)-3-amino 1-N-BOC-pyrrolidine as starting materials. 4ESI-MS spectrum: m/z: 423 [M]+.

137 Example 39 (19, 5R) -2- [2- (4-amino-3-carbamoylpyridinium)acetyl] -7 oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt 5 (126) The titled compound was prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)- 4

,

7 diazabicyclo[3.2.O]heptan-6-one (compound F) which was first 10 sulfonated (J. Org. Chem. 1982, 5160) and a the commercially available 4-amino-3-pyridinecarboxamide as starting materi als. 1H-NMR (DMSO-d 6 ): 1.75 (m, 1H); 2.40 (m, 1H); 3.22 and 15 3.45 (2m, IH) ; 4.01 and 4.10 (2dd, J = 8.6 and 11.3, 1H); 4.40 and 4.60 (2t, J = 4.8, 1H); 4.95-5.50 (m, 3H); 7.03 (dd, J = 7.4 and 9.4, 1H); 7.83 (br, 1H); 8.05 (m, 1H); 8.15 (br, 1H); 8.65 (m, 1H); 8.99 and 9.04 (2br, 2H). 20 Example 40 (IS, 5R) -2 - 2 - (3 -carbamoyl- 5 -methylpyridiLnium) acetyl1J -7 oxo-2,6-diazabicyclo[3.2.01 heptane-6-sulfonate, inner salt (127). 25 The titled compound has been prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoace tyl) -4, 7-diazabicyclo [ 3. 2. 0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the com mercially available 5-methyl nicotinamide as starting materi 30 als.

138 1H-NMR (DMSO-d 6 ): 1.78 (m, 1H); 2.39 (m, 1H); 2.54 (m, 3H); 3.23 and 3.49 (2m, 1E); 4.05 (m, 1H); 4.41 and 4.61 (2t, J = 4.7, 1H); 5.20 and 5.29 (2d, J = 4.3, 1H); 5.50-6.00 (AB part of a ABX system, the X part being in the 15N spectrum, 5 2H); 8.52 (d, J = 16.0, 1H); 8.89 (d, J = 7.2, 1H); 8.95 and 9.0 ( s, la), 9.24 (mP, 2!i):, 12.6C (br, 1HT). Example 41 (19,5R) -2-(2-[3-(aminocarbonylamino)pyridinium]acetyl) 10 7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (128). The titled compound has been prepared following scheme 11 and in analogy to example 24 using (5S,1R)-4-(2-bromoace tyl) -4,7 -diazabicyclo[C3.2.0]heptan-6-one (compound F) which 15 was first sulfonated (J. Org. Chem. 1982, 5160) and 3 pyridylcarbamide. 1H-NMR (DMSO-d 6 ): 1.78 (m, 1H); 2.40 (m, 1H); 3.23 and 3.49 (2m, 1H); 3.98 and 4.10 (2m, 1H); 4.40 and 4.59 (2t, J 20 4.7, 1H); 5.20 and 5.28 (2d, J = 4.2, 1H); 5.40-6.00 (AB part of a ABX system, the X part being in the 15 N spectrum, 2H); 6.51 (br, 2H); 8.00 (m, 1H); 8.28 (m, 1H); 8.49 (m, IH); 9..20 (m, iH); 9.67 (d, J = 12.2, 1H). 3-Pyridylcarbamide was prepared according to the proce 25 dure described in Heterocycles 1983, 1899. Example 42 (1S,5R)-2-[2-(5-amuino-3-carbamoylpyridinium)acetyll- 7 oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt 30 (129). The titled compound has been prepared following scheme 11 and in analogy to example 24 using (55,1R)-4-(2-bromoace- 139 tyl)-4,7-diazabicyclo[3.2.0)heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the com mercially available 5-amino-3-pyridinecarboxamide as starting materials. 5 l-IThIR (DMSO-d.;): 1.78 (m, IH)); 2.41 (m, 1H); 3.22 and 3.46 (2m, 1H); 3.98 and 4.09 (2m, IH); 4.40 and 4.59 (2t, J 4.6, IH); 5.20 and 5.26 (2d, J = 4.1, 1H); 5.40-5.85 (AB part of a ABX system, the X part being in the isN spectrum, 2H) ; 10 6.88 (d, J = 11.5, 2H); 7.95 (m, 1H); 8.07 (m, 2H); 8.41 (m, 2H). Example 43 (1S,5R)-2- E N-(4- ((2-amino 15 ethyl) amino] carbonylaminolphenyl) carbamoyl] -7-oxo-2,6-di azabicyclo[3.2.0]heptane-6-sulfonic acid (324) Preparation of (tert-butoxy)-N-{4-[(fluoren-9-ylmeth oxy) carbonylamino]phenyl} carboxamide 20 Triethylamine (7.36 mL, 52.82 mmol, 1.1 eq) was added at 0 0 C to a stirred solution of N-BOC-1,4-phenylene diamine (10.00 g, 48.02 mmol, 1.0 eq) in CH 3 CN (240 mL,), followed by 9-fluorenylmethyloxycarbonyl chloride (14.90 g, 57.62 mmol, 25 1.2 eq). The resulting mixture was allowed to come at room temperature. After 4 hours stirring at room temperature, the reaction mixture was filtered to afford 20.60 g of the crude expected product as a white powder which was used in the next step without any further purification. 30 140 IH-NMR (DMSO-d 6 ): 1.46 (s, 9H); 4.29 (t, J = 6.6, IH); 4.44 (d, J = 6.3, 2H); 7.30-7.45 (m, 8H) ; 7.75 (d, J = 7.4, 2H); 7.91 (d, J = 7.4, 2H); 9.22 (br, 1H); 9.59 (br, 1H). 5 Preparation of N-(4-aminophenyl) (fluoren-9-ylmeth oxy)carboxamide TFA (55.30 mL, 717.76 mmol, 15.0 eq) was added at 0 0 C to a stirred solution of (tert-butoxy)-N-(4-[(fluoren- 9 -yl 10 methoxy)carbonylamino]phenyl}carboxamide_(20.60 g, 47.85 mmol, 1.0 eq) in CH 2 Cl 2 (900 mL). The resulting solution was allowed to come at room temperature. After stirring overnight at room temperature, the reaction mixture was concentrated to dryness and the residue was triturated in water. Then the 15 mixture was filtered to afford 15.80 g of the expected crude product as a white powder. 1H-NMR (DMSO-d 6 ): 4.30 (t, J = 6.4, 1H); 4.49 (d, J 6.4, 2H); 7.06 (d, J = 7.7, 2H); 7.40 (m, 6H); 7.74 (d, J= 20 7.4, 2H); 7.91 (d, J 7.4, 2H); 8.95 (br, 2H); 9.73 (br, 1H). Preparation of N-{4-[(2,5-dioxoazolidiny loxy)carbonylamino]phenyll(fluoren-9-ylmethoxy)carboxamide 25 N,N'-Disuccinimidylcarbonate (16.20 g, 63.26 mmol, 1.1 eq) was added at room temperature to a stirred solution of N-(4 aminophenyl) (fluoren-9-ylmethoxy)carboxamide (20.00 g, 60.53 mmol, 1.0 eg) in CH 3 CN (1100 mL). After stirring overnight at room temperature, the reaction mixture was filtered to afford 30 28.50 g of the expected crude product as a white powder.

141 1H-NMR (DMSO-d 6 ): 2.83 (br, 4H); 4.31 (t, J 6.4, 1H); 4.48 (m, 2H); 7.20-7.50 (m, BH); 7.5 (d, J = 7.4, 2H); 7.91 (d, J = 7.4, 2H); 9.72 (br, 1H); 10.67 (br, 1H). 5 Preparation of N-{4-[({2-[(tert-bu toxy) carbonylaninol ethyl) amino) carbonylamino ]phenyl}(fluoren-9-ylmethoxy)carboxamide A solution of N-{4-[(2,5-dioxoazolidiny loxy)carbonylamino]phenyl)(fluoren-9-ylmethoxy)carboxamide 10 (16.10 g, 34.15 mmol, 1.0 eq) in H 2 0/CH 3 CN (1/1, v/v, 360 mL) was reacted at room temperature with NaHCO 3 (2.86 g, 34.15 mmol, 1.0 eq) and N-BOC-ethylene diamine (5.47 g, 34.15 mmol, 1.0 eq). After stirring overnight at room temperature, the reaction mixture was filtered to afford 16.36 g of the ex 15 pected crude product as a white solid. 1H-NMR (DMSO-d 6 ): 1.37 (s, 9H); 2.98 (m, 2H); 3.11 (m, 2H); 4.29 (t, J = 6.4, 1H); 4.44 (d, J = 6.4, 2H); 6.10 (m, 1H); 6.85 (m, 1H); 7.30-7.50 (m, 8H); 7.74 (d, J= 7.4, 2H); 7.90 (d, J = 7.4, 2H); 8.40 (s, 1H); 9.53 (br, 1H). 20 Preparation of N-(4-aminophenyl) ({2-[(tert-bu toxy)carbonylamino)ethyl}amino) carboxamide Piperidine (9.68 mL, 97.75 mmol, 5.0 eq) was added at room .temperature to a stirred solution of N-(4-((2-[(tert-bu 25 toxy)carbonylamino]ethyl)amino)carbonylamino]phenyl) (fluo ren-9-ylmethoxy)carboxamide (10.10 g, 19.55 mmol, 1.0 eq) in DMF (140 mL). After 2 hours stirring at room temperature, wa ter was added to the reaction mixture and precipitation oc cured. The resulting mixture was filtered, and the liquid 30 phase was concentrated to afford 6.75 g of the expected prod uct as an orange oil: 142 1H-NMR (DMSO-d6): 1.37 (s, 9H); 2.98 (m, 2H); 3.11 (m, 2H); 4.69 (s, 2H); 6.00 (t, J = 5.5, 1H); 6.44 (d, J = 8.6, 2H); 6.81 (t, J = 5.3, 1H); 6.97 (d, J = 8.6, 2H); 8.00 (s, 1H). 5 Preparation of ((2-[(tert-bu toxy) carbonylamino ] ethyl) amino) -N--{4- [ (2, 5-dioxoazolidiny loxy) carbonylamino] phenyl } carboxamide N,N'-Disuccinimidylcarbonate (5.49 g, 21.44 mmol, 1.1 eq) was 10 added at room temperature to a stirred solution of N-(4 aminophenyl) ({2-[ ( tert-bu toxy) carbonylamino ] ethyl) amino) carboxamide ( 6.75 g, 19.49 mmol, 1.0 eq) in CH 3 CN (350- mL). After stirring overnight at room temperature, the reaction mixture was filtered and to 15 afford 9.70 g of the expected crude product as a light brown solid. 1H-NMR (DMSO-d 6 ): 1.37 (s, 9H); 2.82 (br, 4H); 2.99 (m, 2H); 3.11 (m, 2H); 6.12 (t, J = 5.2, 1H); 6.85 (t, J = 5.5, 1H); 7.27 (d, J = 8.9, 2H); 7.36 (d, J = 8.9, 2H); 7.95 (s, 20 1H); 8.53 (s, 1H). Preparation of [(2-aminoethyl)amino]-N-{4-[(2,5-di oxoazolidinyloxy) carbonylaminojphenyl}carboxamide TFA (11.59 mL, 150.54 mmol, 5.0 eq) was added at room tem 25 perature to a stirred suspension of ({2-[(tert butoxy) carbonylamino] ethyl}amino) -N- (4- [(2 ,5 dioxoazolidinyloxy) carbonylamino]phenyl}carboxamide (13 .8 g, 30.11 mmol, 1.0 eq) in CH 2 Cl 2 (165 mL) . After stirring over night at room temperature, solvent was evaporated and the 30 crude product was triturated with Et20 to afford 14.2 g of the expected crude product as a beige solid and as the tri fucroacetic acid salt.

143 1H-NMR (DMSO-d 6 ): 2.82 (br, 4H); 2.88 (m, 2H) ; 3.30 (m, 2H); 6.51 (t, J = 5.6, 1H); 7.30 (d, J = 8.9, 2H); 7.40 (d, J = 8.9, 2H); 7.77 (br, 3H); 8.85 (s, 1H); 10.61 (s, 1H). 5 Preparation of (1S,5R)-2- [N-(4-{[ (2 aminoethyl) amino] carbonylamino)phenyl) carbamoyl3-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (324) (1S,5R)-7-oxo-2,6-diazabicyclo[3.2.0)heptane-6-sulfonic acid 10 (compound H-, 2.0 g, 10.41 mmol, 1.0 eq) was dissolved in H 2 0 (12.5 mL). Then CH 3 CN (100 mL) was added at room temperature to the solution, followed by NaHCO 3 (1.57 g, 18.73 mmol, 1.8 eq) and [(2-aminoethyl)amino]-N-(4-[(2,5 dioxoazolidinyloxy)carbonylamino]phenyl)carboxamide (6.89 g, 15 14.57 mmol, 1.4 eq). After stirring overnight at room tem perature, the reaction mixture was filtered to afford 3.27 g of the expected (IS,5R)-2-[N-(4-{[(2 aminoethyl) amino) carbonylamino}phenyl) carbamoyl) -7-oxo-2, 6 diazabicyclo[3.2.01 heptane-6-sulfonic acid as a white solid. 20 1H-NMR (DMSO-d 6 ): 1.65 (m, 1H); 2.30 (dd, J = 5.8 and 13.5, 1H); 2.90 (m, 2H); 3.18 (m, 1H); 3.30 (m, 2H); 3.98 (m, 1H); 4.41 (t, J = 4.7, 1H); 5.22 (d, J = 4.3, 1H); 6.23 (t, J = 5.7, 1H); 7.28 (d, J = 8.2, 2H); 7.33 (d, J = 8.2, 2H); 7.65 (br, 3H); 8.38 (s, 1H); 8.53 (s, 1H). 25 Example 44 Sodium (IS, 5R)-2- [N- (3,4-dihydroxyphenyl)carbamoyl l-7 oxo-2,6-diazabicyclo[3.2.o]heptane-6-sulfonate (306) 30 The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6- 144 diazabicyclo[3.2.0heptane-6-sulfonic acid (compound H) and the commercially available 4-amino-1,2-benzenediol as start ing materials. 5 1H-NMR (DMSO-d 6 ) 1.64 (m, IH); 2.29 (dd, J = 5.8 and 13.6, 1-!); 3.13 (m, 1H); 3.93 (dd, J = 8.3 and 11.0, 11-); 4.37 (t, J = 4.8, 1H); 5.20 (d, J = 4.3, 1H); 6.50-6.70 (m, 2H); 6.97 (m, 1H); 7.84 and 8.15 (2s, 1H); 8.35 and 8.43 (2s, 1H); 8.77 and 8.82 (2s, 1H). 10 Example 45 Sodium.(1S,5R)-2-(N-[3-(acetylmino)phenyllcarbooyll- 7 oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate (307) 15 The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and the commercially available 1-acetamido-3-aminobenzene as starting materials. 20 1H-NMR (DMSO-d 6 ): 1.66 (m, 1H); 2.02 (s, 3H); 2.31 (dd, J = 5.8 and 13.6, 1H); 3.17 (m, 1H); 3.98 (dd, J= 8.3 and 11.0, 1H); 4.40 (t, J = 4.8, 1H); 5.27 (d, J = 4.3, 1H); 7.05-7.25 (m, 3H); 7.64 (m, 1H); 8.54 (s, 1H); 9.86 (s, 1 ). 25 Example 46 Sodium (1S,5R)-7-oxo-2-[N-(3-sulfamoylphenyl)carbamoyl] 2,6-diazabicyclo[3.2.0]heptane-6-sulfonate (308) 30 The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and 145 the commercially available 3-aminobenzene sulfonamide as starting materials. 1H-NMR (DMSO-d 6 ) 1.68 (m, 1H) 2 .32 (dd, J = 5.8 and 5 13.5, lH); 3.21 (m, 1H); 4.02 (dd, J = 8.5 and 11.2, 1H); 4.43 (t, J = 4.7, 1H) ; 5.28 (0, J = 4.2, 1H) ; 7.31 (br, 2H) 7.38-7.46 (m, 2H); 7.72 and 7.74 (2t, J = 1.9, 1H); 8.05 (t, J = 1.7, 1H) ; 8.89 (br, 1H) 10 Example 47 Sodium (iS,5R)-2-{N-[4-(dimnethylamino)phenyl]carbamoyl) 7-oxo-2,6-diazabicyclo[3.2.O]heptane-6-sulfonate (309) The titled compound was prepared following scheme 12 and 15 in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 4-(dimethylamino)aniline as start ing materials. +ESI-MS spectrum: m/z: 354 [M + H)4 20 Example 48 Sodium (1S,5R)-2-[N-(4-{N-[2 (dimethylamino) ethyl ]carbanoyl)phenyl) carbamoyl] -7-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonate (310) 25 The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and the commercially available 4-aminobenzoic acid and 2 30 (dimethylamino)ethylamine as starting materials. +ESI-MS spectrum: m/z: 425 [M+HJ .

146 Example 49 Sodium (1g,5R)-2-(N-{4-[N (carbamoylmethyl)carbamoyllphenylcarbamoyl)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonate (312) 5 The titled compound was prenared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 4-aminobenzoic acid and glycina 10 mide hydrochloride as starting materials. 1H-NMR (DMSO-d 6 ): 1.68 (m, 1H); 2.32 (dd, J = 5.8 and 13.5, 1H); 3.21 (m, 1H); 3.78 (d, J = 5.7, 2H); 4.02 (dd, J 8.3 and 11.1, 1H); 4.42 (t, J = 4.7, 1H); 5.28 (d, J = 4.6, 15 1H); 7.02 (br, 1H); 7.23 (br, 1H); 7.58 (d, J = 9.1, 2H); 7.79 (d, J = 9.1, 2H); 8.50 (t, J = 5.8, 1H); 8.78 (s, 1H). Example 50 Sodium (1S,5R)-2-[N- (3-(1,3-oxazol-5 20 yl)phenyl)carbamoyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 sulfonate (318) The titled compound was prepared following scheme 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6 25 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 3-(1,3-oxazol-5-yl) aniline as starting materials. 1H-NMR (DMSO-d 6 ): 1.68 (m, 1H); 2.33 (dd, J = 5.8 and 30 13.7, 1H); 3.21 (m, 1H); 4.02 (dd, J = 8.1 and 11.0, 1H); 4.42 (t, J = 4.7, 1H); 5.27 (d, J = 4.3, 1H); 7.30-7.40 (m, 147 2H); 7.52 (m, 1H); 7.60 (s, 1H); 7.91 (s, 1H); 8.44 (s, 1H); 8.72 (br, 1H). Example 51 5 Sodium (1S,5R)-7-oxo-2- [N-(2-oxo(3-hydrobenzimidazol-5 yl))carbamoyl]-2,6-diaabicyclo[3.2.0]heptane-6-sulfonate (319) The titled compound was prepared following scheme 12 and 10 in analogy to example 43 using (lS,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 5 (6) -aminobenzoimidazolone as starting materials. 15 1H-NMR (DMSO-d 6 ): 1.65 (m, 1H); 2.30 (dd, J = 5.8 and 13.5, 1H); 3.17 (m, 1H); 3.96 (dd, J = 8.3 and 11.0, 1H); 4.39 (t, J = 4.7, 1H); 5.22 (d, J = 4.3, 1H); 6.78 (m, 1H); 6.95 (m, 1H); 7.22 (m, 1H); 8.07 and 8.37 (2s, 1H); 10.34 and 10.39 (2s, 1H); 10.46 and 10.50 (2s, 1H). 20 Example 52 Sodium (1S,5R)-2-(N-[3 (ethoxycarbonyl) phenyl] carbamoyl} -7-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonate (320) 25 The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S, 5R)-7-oxo-2,6 diazabicyclo[3.2.O]heptane-6-sulfonic acid (compound H) and the commercially available 3-aminobenzoic acid ethyl ester as 30 starting materials.

148 1H-NMR (DMSO-d 6 ): 1.32 (t, J = 7.1, 3H); 1.68 (m, 1H); 2.32 (dd, J = 5.8 and 13.5, 1H); 3.20 (m, 1H); 4.02 (dd,. J 8.3 and 11.0, 1H) ; 4.31 (q, J = 7.1, 2H) ; 4.42 (t, J = 4.7, 1H); 5.27 (d, J= 4.5, 1H); 7.39 (t, J = 8.0, 1H); 7.56 (2dd, 5 J = 1.2 and 1.6, 1H); 7.82 (m, 1H); 8.14(t, J = 1.9, 1H); 8.81 (br, 1H)W . Example 53 Sodium (1S,5R)-2-{N- [3- (hydroxymethyl)phenyl carbamoyl) 10 7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonate (321) The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and 15 the commercially available 3-(hydroxymethyl)aniline as start ing materials. 1H-NMR (DMSO-d) : 1.67 (m, 1H) ; 2.31 (dd, J = 5.8 and 13.5, 1H); 3.18 (m, 1H); 3.99 (dd, J = 8.3 and 11.4, 1H); 20 4.41 (t, J = 4.7, 1H); 4.45 (d, J = 5.8, 2H); 5.15 (t, J = 5.6, 1H); 5.27 (d, J = 4.3, 1H); 6.90 (m, 1H); 7.18 (t, J = 7.8, 1H); 7.39 (m, 1H); 7.45 (m, 1H); 8.52 (br, 1H). Example 54 25 (1S,5R)-2-{N-[4-({[2-(2 aminoetho~xy)ethyl]aminolcarbonylamino)phenyl] carbamoyl}-7 oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (323) The titled compound was prepared following scheme 12 and 30 in analogy to example 43 using (lS, 5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 1,4-benzene diamine and 2,2- 149 oxydiethylamine dihydrochloride (Eur. J. Org. Chem. 2002, 3004) as starting materials. 1H-NMR (DMSO-d 6 ): 1.65 (m, 1H); 2.30 (dd, J = 5.8 and 5 13.5, 1H); 2.99 (m, 2H); 3.16 (m, 1H); 3.29 (m, 2H); 3.49 (t, J = 5.7, 211); 3.60 (t, J 5.2, 2 ); 3.95 (mI, 1-); 4.39 (t, J = 4.7, 1H); 5.20 (d, J = 4.3, 1H); 6.13 (t, J = 5.7, 1H); 7.24 (d, J = 8.2, 2H); 7.31 (d, J = 8.2, 2H); 7.73 (br, 3H); 8.35 (s, 1H); 8.37 (s, 1H). 10 Example 55 (1S,5R)-7-oxo-2-(N-(4-[(4 piperidylamino)carbonylaminoJphenyl}carbamoyl)-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (325) 15 The titled compound was prepared following scheme 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 1,4-benzene diamine and 1-BOC-4 20 amino-piperidine hydrochloride as starting materials. 1H-NMR (DMSO-d 6 ): 1.52 (m, 2H); 1.68 (m, 1H); 1.98 (m, 2H); 2.31 (dd, J = 6.0 and 13.6, IH); 3.00 (m, 2H); 3.17 (m, 1H); 3.23 (m, 3H); 3.72 (m, 1H); 3.97 (dd, J= 8.3 and 11.0, 25 1H) ; 4.40 (t, J = 4.8, 1H) ; 5.21 (d, J = 4.2, 1H) ; 6.28 (d, J = 7.5, 1H); 7.23 (d, J = 9.2, 2H); 7.32 (d, J = 9.2, 2H); 8.12 (s, 1H); 8.28 (br, 1H); 8.38 (s, 1H). Example 56 30 (1S,5R)-7-oxo-2-{N-[4 (piperazinylcarbonylamino) phenyl) carbamoyl) -2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (326) 150 The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and the commercially available 1,4-benzene diamine and 1-BOC 5 piperazine as starting materials. 1H-NMR (DMSO-d 6 ): 1.65 (m, 1H); 2.32 (dd, J = 5.7 and 13.6, 1H); 3.13 (m, 4H); 3.19 (m, 1H); 3.62 (m, 4H); 3.92 (dd, J = 8.3 and 11.2, 1H); 4.40 (t, J = 4.7, IH); 5.31 (d, J 10 = 4.3, 1H); 7.28 (d, J = 9.2, 2H); 7.36 (d, J = 9.2, 2H); 8.42 (s, 1H); 8.58 (s, 1H); 8.63 (br, 1H). Example 57 Sodium (1S,5R)-2-[N-(4-aminophenyl)carbamoyl]-7-oxo-2,6 15 diazabicyclo[3.2.0] heptane-6-sulfonate (327) The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and 20 the commercially available N-BOC-1,4-phenylene diamine as starting materials. +ESI-MS spectrum: m/z: 326 [M + H] *. Example 58 25 Sodium (1S,5R)-2-[N-(2-carbamoylphenyl)carbamoyl]-7-oxo 2,6-diazabicyclo[3.2.01 heptane-6-sulfonate (328) The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 30 diazabicyclo(3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 2-aminobenzamide as starting mate rials.

151 1H-NMR (DMSO-d 6 ): 1.67 (m, IH); 2.36 (dd, J = 6.0 and 13.8, 1H) ; 3.23 (m, 1H); 3.97 (m, 1H); 4.42 (t, J 4.7, 1H); 5.24 (d, J = 4.2, 1H); 7.00 (m, 1H); 7.45 (m, 1H); 7.72 (br, 5 1H); 7.79 (dd, J = 1.2 and 7.9, IH); 7.91 (s, 1H); 8.28 (br, 1-2; 8.37 (dc, J = 1.2 and 9.4, 11). Example 59 Sodium (1S,5R)-7-oxo-2-[N-(4-(2 10 [(phenylmethoxy)carbonylanino]acetylaminoiphenyl)carbamoyl] 2,6-diazabicyclo[3.2.O]heptane-6-sulfonate (329) The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 15 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 1,4-benzene diamine and N carbobenzoxyglycine as starting materials. 1H-NMR (DMSO-d 6 ): 1.66 (m, 1H); 2.31 (m, 1H); 3.18 (m, 20 1H); 3.78 (d, J= 6.1, 2H); 3.98 (dd, J = 8.0 and 11.1, 1H); 4.40 (t, J = 4.8, 1H); 5.03 (s, 2H); 5.23 (d, J = 4.5, 1H); 7.22-7.58 (m, 10H); 8.49 (s, 1H); 9.83 (s, 1H). Example 60 25 (1S,5R)-2-[N-(4-{[(2-morpholin-4 ylethyl)amino carbonylamino}phenyl)carbamoyl -7-oxo-2, 6 diazabicyclo[3.2.0J heptane-6-sulfonic acid (330) The titled compound was prepared following scheme 12 and 30 in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and 152 the commercially available 1,4-benzene diamine and N-(2 aminoethyl)morpholine as starting materials. 1H-NMR (DMSO-d) : 1.67 (m, 1H) ; 2:31 (dd, J = 6.1 and 5 13.7, 1H); 3.00-3.25 (m, 5H); 3.40-3.75 (m, 6H); 3.97 (m, 3F); 4.41 (t, J = 4.'7, 1 ); 5.22 (d., JT 4.2, 1H); 6.28 (br, 1H); 7.28 (d, J = 9.2, 2H); 7.33 (d, J 9.2, 2H); 8.39 (s, 1H); 8.50 (s, 1H); 9.47 (br, 1H). 10 Example 61 (1S, 5R) -2- [N- (4-( [(2-{ [(2-morpholin-4 ylethyl) amino] carbonylamino} ethyl) amino] carbonylaminolphenyl) carbamoyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (331) 15 The titled compound was prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 1,4-benzene diamine, N-(2 20 aminoethyl)morpholine and ethylenediamine as startLing materi als. IH-NMR (DMSO-d 6 ): 1.66 (m, 1H); 2.31 (dd, J = 6.1 and 13.7, 1H); 3.00-3.22 (m, 11H); 3.49 (m, 2H); 3.61 (m, 2H); 25 3.96 (m, 3H); 4.39 (t, J = 4.7, 1H); 5.22 (d, J = 4.5, 1H); 6.11 (t, J = 5.8, 1H); 6.32 (m, 2H); 7.24 (d, J = 9.1, 2H); 7.33 (d, J = 9.1, 2H) ; 8.38 (d, J = 4.4, 1H) ; 9.53 (br, 1H) Example 62 30 (1S,5R)-2-(N-{4-[1-(2 aminoethyl) carbamoyl] phenyl}carbanoyl) -7-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (332) 153 The titled compound was prepared following scheme 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6 diazabicyclo[3.2.Olheptane-6-sulfonic acid (compound H) and 5 the commercially available 4-aminobenzamide and 2-bromo ethanamine as starting materials. 1H-NMR (DMSO-d6): 1.69 (m, 1H); 2.33 (dd, J= 5.8 and 13.7, 1H); 2.97 (m, 2H); 3.22 (m, 1H); 3.48 (m, 2H); 4.01 10 (dd, J = 8.2 and 11.0, 1H) ; 4.43 (t, J = 4.7, IH); 5.27 (d, J = 4.5, 1H); 7.61 (d, J = 9.1, 2H); 7.75 (m, 5H); 8.43 (m, 1H); 8.81 (s, 1H). Example 63 15 Sodium (1S,5R)-2-(t-{4-[(tert butoxy) carbonylamino] phenyl} carbamoyl) -7-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonate (333) The titled compound was prepared following scheme 12 and 20 in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and the commercially available N-BOC-1,4-benzene diamine as starting materials. 25 1H-NMR (DMSO-d 6 ): 1.46 (s, 9H); 1.64 (m, 1H); 2.30 (dd, J= 5.8 and 13.5, 1H); 3.16 (m, IH); 3.97 (dd, J= 8.5 and 11.3, 1H); 4.39 (t, J = 4.8, 1H); 5.22 (d, J = 4.3, 1H); 7.25-7.35 (m, 4H); 8.41 (s, 1H); 9.17 (s, 1H). 30 Example 64 154 Sodium (1S,5R)-2-{N-[(3,4 dihydroxyphenyl)methyl.)carbamoyl}-7-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonate (303) 5 The titled compound was prepared following scheme 12 and in aialogy to example 43 using ('S, 53-7-~-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and commercially available 3, 4-dihydroxybenzylamine. -ESI-MS spectrum: m/z: 356 [M - HI *. 10 Example 65 (1S,5R)-2-(N-[4--(morpholin-4-ylmethyl)phenyl carbamoyl) 7-oxo-2,6-diazabicyclo[3 .2 .0]heptane-6-sulfonic acid (334). The titled compound has been prepared following scheme 15 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and the commercially available 4- (morpholinomethyl) aniline as starting materials. 20 1H-NMR (DMSO-d 6 ): 1.67 (m, 1H); 2.30 (dd, J = 5.8 and 13.6, lH); 3.12 (m, 2H); 3.25 (m, 3H); 3.60 (t, J = 11.8, 2H); 3.97 (m, 3H); 4.26 (br, 2H); 4.42 (t, J= 4.7, 1H); 5.25 (d, J = 4.3, 1H); 7.36 (d, J = 8.2, 2H); 7.60 (d, J = 8.2, 2H); 8.74 (br, 1H); 9.61 (br, 1H). 25 Example 66 (IS, 5R) -2- [N- (4-morpholin-4 -ylphenyl) carbamoyl) -7 -oxo 2,6-diazabicyclo [3.2.0]heptane-6-sulfonic acid (335) The titled compound has been prepared following scheme 30 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and 155 the commercially available 4-morpholinoaniline as starting materials. 1H-NMR (DMSO-d 6 ): 1.67 (m, 1H); 2.32 (dd, J = 5.8 and 5 13.6, 1H); 3.19 (m, 1H); 3.32 (br, 4H); 3.85 (br, 4H); 3.98 (M, 1H) ; 4.42 (t, J 4.7, 11!); 5.25 (d, J = 4.3, 1H) ; 7.24 (br, 2H); 7.50 (d, J 8.6, 2H); 8.60 (br, 1H). Example 67 10 (1S, 5R) -2 - [N- (3 -morpholin-4 -ylphenyl) carbamoyl] -7-oxo 2,6-diazabicyclo[3.2.O]heptane-6-sulfonic acid (336). The titled compound has been prepared following scheme 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and 15 the commercially available 3-morpholino-4-ylaniline as start ing materials. 1H-NMR (DMSO-d 6 ): 1.67 (m, 1H); 2.32 (dd, J = 5.8 and 13.6, 1H); 3.19 (m, 1H); 3.26 (br, 4H); 3.82 (br, 4H); 3.99 20 (m, lH); 4.42 (t, J = 4.7, 1H); 5.25 (d, J = 4.3, 1H); 6.84 (d, J = 7.5, 1H1); 7.15 (d, J = 8.1, 1H); 7.23 (t, J 8.1, 1H); 7.48 (br, 1H); 8.60 (br, 1H). - -Example 68 25 (1S,5l3)-7-oxo-2-{N-[3 (piperazinylmethyl)phenyl] carbamoyl} -2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (337). The titled compound has been prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 30 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and the commercially available tert--butyl 4-(3 aminobenzyl) piperazine-1-carboxylate as starting materials.

156 The final deprotection step, using trifluoroacetic acid, has been performed in analogy to example 1. 1H-NMR (DMSO-d 6 ): 1.67 (m, 1H); 2.32 (dd, J = 5.8 and 5 13.6, 1H); 2.58 (br, 4H); 3.09 (br, 4H); 3.19 (m, 1H); 3.49 (br, 2H); 3.98 (n, 1); 4.41 (t, . = 4.7 , 1 ); 5.25 (d, J = 4.3, 1H); 6.89 (d, J = 7.5, 1H); 7.21 (t, J = 8.1, 1H); 7.37 (t, J = 8.1, IH); 7.52 (br, 1H); 8.44 (br, 2H); 8.55 (br, 1H). 10 Example 69 2-[N-((3S)pyrrolidin-3-yl)carbamoyl] (1S,5R)-7-oxo-2,G diazabicyclo [3.2.0]heptane-6-sulfonic acid (338). The titled compound has been prepared following scheme 15 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0heptane-6-sulfonic acid (compound H) and commercially available . (S)-3-amino-l-N-BOC-pyrrolidine as starting materials. The final deprotetion step, using trifluoroacetic acid, has been performed in analogy to exam 20 ple 1. +ESI-MS spectrum: m/z: 305 [M+H]+. Example 70 2- [1V-(4-( [ ((3S)pyrrolidin-3 25 yl)amino]carbonylamino)phenyl) carbamoyl](1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (339). The titled compound has been prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and 30 the commercially available 1,4-benzene diamine and also com mercially available (S)-3-aminc-1-N-BOC-pyrrolidine as start ing materials. The final deprotetion step, using 157 trifluoroacetic acid, has been performed in analogy to exam ple 1. 1H-NMR (DMSO-d 6 ): 1.65 (m, 1H); 1.82 (m, 1H); 2.17 (m, 1H); 2.31 (dd, J= 5.8 and 13.6, 1H); 3.06 (dd, J= 5.1 and 5 11.8, 1H); 3.19 (m, 2H); 3.29 (m, 2H); 3.96 (dd, J = 8.3 and 11., 1 )- . (mn, 1H); 4.40 (t, T = 4.7, 1H); 5.22 (d, J 4.3, 1H); 6.40 (d, J = 6.0, 1H) ; 7.26 (d, J 9.2, 2H); 7.33 (d, J = 9.2, 2H); 8.37 (s, 1H); 8.41 (s, 1H); 8.70 (br, 2H). 10 Example 71 (is, 5R) -2-{N- [4- (2-morpholin-4 ylethoxy)phenyl] carbamoyl} -7-oxo -2, 6 diazabicyclo[3.2.O]heptane-6-sulfonic acid (340). The titled compound has been prepared following scheme 15 12 and in analogy to example 43 using (l1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 4- (2-morpholin-4-ylethoxy) aniline as starting materials. 20 1H-NMR (DMSO-d 6 ): 1.66 (m, 1H); 2.31 (dd, J= 5.8 and 13.6, 1H); 3.18 (m, 3H); 3.54 (m, 4H); 3.70 (m, 2H); 3.96 (m, 3H); 4.29 (m, 2H); 4.41 (t, J = 4.7, 1H); 5.21 (d, J = 4.3, 1H); 6.93 (d, J = 9.0, 2H); 7.41 (d, J = 9.0, 2H); 8.44 (s, 1H); 9.81 (br, 1H). 25 Example 72 (IS,5R) -2-{N-[3-(2--morpholin-4 ylethoxy) phenyl] carbamoyl -7-oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (341). 30 The titled compound has been prepared following scheme 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6- 158 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 3- (2r-morpholin-4-ylethoxy) aniline as starting materials. 5 1H-NMR (DMSO-d 6 ): 1.66 (m, 1H); 2.31 (dd, J = 5.8 and 13.6, 1H); 3.18 (m, 3H); 3.54 (m, 4H); 3.70 (m, 2H); 3.98 (M, 3H); 4.29 (m, 2H); 4.41 (t, J = 4.7, lH); 5.23 (d, J = 4.3, 1H); 6.61 (dd, J 1.9 and 8.1, 1H); 7.04 (dd, J = 1.1 and 8.1, 1H); 7.19 (t, J = 8.1, 1H); 7.38 (s, 1H); 8.57 (s, 1H); 10 9.81 (br, 1H). Example 73 (1, 5R) -7 -oxo-2- [N- (4-piperidylphenyl) carbamoyll -2,6 diazabicyclo [3.2.0]heptane-6-sulfonic acid (342). 15 The titled compound has been prepared following scheme 12 and in analogy to example 43 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 4-(1-piperidino)aniline as start ing materials. 20 1H-NMR (DMSO-d 6 ): 1.40-2.00 (m, 7H); 2.30 (dd, J = 5.8 and 13.5, lH); 3.22 (m, lH); 3.45 (br, 4H); 3.98 (dd, J = 8.3 and 11.0, 1H); 4.42 (t, J = 4.7, 1H); 5.24 (d, J = 4.3, lH); 7.50-7.75 (m, 4H); 8.85 (br, 1H); 10.80 (s, 1H). 25 Example 74 (1S,5R)-2-EN-(6-morpholin-4-yl(3-pyridyl) )carbamoyl] -7 oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (343). The titled compound has been prepared following scheme 30 12 and in. analogy to example 43 using (1S, 5R) -7-oxo-2, 6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and 159 the commercially available 6-morpholinopyridine-3-amine as starting materials. 1H-NMR (DMSO-d 6 ): 1.70 (m, 1H); 2.34 (dd, J = 5.8 and 5 13.5, 1H); 3.22 (m, 1H); 3.54 (m, 4H); 3.76 (m, 4H); 3.98 (dd, J = 2.3 and 11.0, 1H); 4.42 (t, J= 4.7, 1H); 5.19 (d, J = 4.4, 1H) ; 7. 38 (d, J = 9.7, 1H) ; 8.06 (dd, J = 2.4 and 9.7, 1H); 8.29 (d, J= 2.4, 1H); 8.88 (br, 1H). 10 Example 75 (IS, 5R) -2 -{N- [ 4 - (4 -methylpiperazinyl ) phenyl ] carbamoyl} 7-oxo-2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (344). The titled compound has been prepared following scheme 12 and in analogy to example 43 using (lS,5R)-7-oxo-2,6 15 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and the commercially available 4-(4-methylpiperazino)aniline as starting materials. 1H-NMR (DMSO-d 6 ): 1.65 (m, 1H); 2.31 (dd, J = 5.8 and 20 13.6, 1H); 2.69 (m, 2H); 2.99 (m, 2H); 3.05-3.25 (m, 8H); 3.96 (dd, J = 8.3 and 11.0, 1H); 4.39 (t, J = 4.7, 1H); 5.31 (d, J = 4.3, iH); 6.91 (d, J = 9.0, 2H); 7.35 (d, J = 9.0, 2H); 8.36 (s, 1H). 25 Example 76 (1S, 5R)-2-{2- [1- (dimethylamino)-2-oxohydropyrimidin-4 ylthiolacetyl}-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 sulfonic acid (203) 30 The titled compound was prepared following scheme 12 in analogy to example 14 using (5S,lR)-4,7 diazabicyclo(3.2.0]heptan-6-one (compound E) and 2-[1- 160 (dimethylamino)-2-oxohydropyrimidin-4-ylthio]acetic acid. The resulting compound was then sulfonated according to the pro cedure described in J. Org. Chem. 1982, 5160. +ESI-MS spectrum: m/z: 404 [M+H] '. 5 2-[1-(dimethylamino)-2-oxohydropyrimidin-4-ylthiolacetic acid was prepared from the 3- (dimeThyamino) -6-sulfanyl-3 hydropyrimidin-2-one (US-A-4, 348, 518) and bromoacetic acid according to the procedures described in Russian J. Org. Chem. 2000, 761. 10 Example 77 (iS,5R)-7-oxo-2-{2-[4-(2 pyridiniumacetylamino)phenylthioJacetyl}-2,6 diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (204) 15 The titled compound was prepared following scheme 13 in analogy to example 14 using (5S,1R)-4,7 diazabicyclo[3.2.0]heptan-6-one (compound E) and the 2-[4-(2 pyridylacetylamino)phenylthio] acetic acid as starting materi 20 als. The resulting compound was then sulfonated according to the procedure described in J. Org. Chem. 1982, 5160. +ESI-MS spectrum: m/z: 397 [M+H-SO 3 ] *. Example 78 25 (1S,5R)-2-(2-(1-[2-(dimethylamino)ethyl3 (1,2,3,4 tetraazol-5-ylthio)}acetyl)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (205) The titled compound was prepared following scheme 13 in 30 analogy to example 14 using (5S,1R)-4,7 diazabicyclo[3.2.0]heptan-6-one (compound E) and 2-(1-[2 (dimethylamino)ethyl]-1,2,3,4-tetraazol-5-ylthio}acetic acid 161 as starting materials. The resulting compound was then sul fonated according to the procedure described in J. Org. Chem. 1982, 5160. 5 2-{l-[2-(dimethylamino)ethyl]-1,2,3,4-tetraazol-5 ylthio}acetic acid was prepared from commercially availablel (2-dimethylaminoethyl)-5-mercapto-1,2,3,4-tetrazole and bromo acetic acid according to the procedures described in Russian J. Org. Chem. 2000, 761 10 +ESI-MS spectrum: m/z: 406 [M+H] *. Example 79 Sodium (1S,5R)-2-[2-(1-methyl(1,3,4-thiadiazol- 2 ylthio))acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 15 sulfonate (202) The titled compound was prepared following scheme 13 in analogy to example 14 using (5S,1R)-4,7 diazabicyclo[3.2.0]heptan-6-one (compound E) and the commer 20 cially available 2-(5-methyl-1,3,4-thiadiazol-2-ylthio)acetic acid as starting materials. The resulting compound was then sulfonated according to the procedure described in J. Org. Chem. 1982, 5160. -ESI-MS spectrum: m/z: 363 [M - H] *. 25 Example 80 (lS,5R)-2-[2-(4-{N-[2 (dimethylamino) ethyl] carbamoyllphenylthio) acetyl] -7 -oxo-2, 6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (207). 30 [5-(2-Dimethylamino-ethylcarbamoyl)phenylthioacetic acid 162 To a suspension of commercially available 4-mercapto benzoic acid (1.54 g, 10 mmol) in water was added NaOH (0.88 g, 22 mmol) . The resulting solution was stirred at room tem perature for 30 min and then bromo acetic acid ethyl ester 5 (1.67 g, 10 mmol) was slowly added to the previous solution. After stirring at room temperature for 2 hours, an aqueous solution containing HC1 (lM) was added. The obtained precipi tate was filtrated, washed with water and dried to afford 1.5g of 4-ethoxycarbonylmethylthio benzoic acid. 10 -ESI-MS spectrum: m/z: 239 [M-H] '. Then the corresponding acid chloride of 4 ethoxycarbonylmethylthio benzoic acid was prepared in analogy to the procedure described in Synthesis, 1985, 517 and the condensation of the commercially available 2 15 dimethylaminoethyl amine and the hydrolysis of the ester group were performed in analogy to the procedure described in Bioorg. Med. Chem. Lett. 2003, 1517. +ESI-MS spectrum: m/z: 283 [M+H] +. 20 (lS,5R)-2-(2-(4-{N-(2 (dimethylamino)ethylJcarbamoyllphenylthio)acetyl)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (207). (5-(2-Dimethylamino-ethylcarbamoyl)phenylthio]acetic acid (144 mg, 0.49 mmcl, 1.0 eq) was added at room tempera 25 ture to a stirred solution of (1S,5R)-7-oxo-2,6 diazabicyclo(3.2.0]heptane-6-sulfonic acid (compound H, 100 mg, 0.49 mmol, 1.0 eq) in DMSO (4 mL), followed by 0 (benzotriazo-yl) -1,1, 3,3-tetramethyluronium hexafluorophos phate (HBTU) (225 mg, 0.59 mmol, 1.2 eq) and triethylamine 30 (83 pL, 0.59 mmol, 1.2 eg). After 4 hours stirring at room temperature, DMSO was evaporated, the crude was treated with acetonitrile. The resulting mixture was filtered to afford 163 the crude product as a yellow solid which was purified by preparative HPLC: 74 mg (30%). 1H-NMR (DMSO-d 6 ): 1.70 (m, 1H); 2.32 (m, 1H); 2.83 (s, 6H); 3.14 and 3.38 (2m, 1H); 3.26 (m, 2H); 3.57 (m, 2H); 5 3.96-4.23 (m, 3H); 4.34 and 4.51 (2t, J = 4.7, 1H); 5.16 and 5.31 (2d, J = 4.3, 1H); 7.43 (dd, J = 8.5 and 12.6, 2H) ; 7.78 (dd, J = 2.4 and 8.5, 2H); 8.62 (m, 1H); 9.18 (br, 1H) Example 81 10 (1S,5R)-2-[2-(5-{N-[2-(dimethylamino)ethy1]carbanoyl}(2 pyridylthio)) acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 sulfonic acid (208). The titled compound has been prepared following scheme 13 and in analogy to example 80 using (lS,5R)-7-oxo-2,6 15 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and [5-(2-dimethylaminoethylcarbamoyl)pyridin-2-ylthioJacetic acid as starting materials. 1H-NMR (DMSO-d 6 ): 1.66 (m, 111); 2.33 (m, 1H); 2.82 (s, 20 3H); 2.85 (s, 3H); 3.15 and 3.48 (2m, 1H); 3.26 (m, 2H); 3.61 (m, 2H); 3.98-4.~55 (m, 4H); 5.16 and 5.35 (2t, J = 4.3, IH); 7.48 (d, J = 8.4; 11H); 8.02 (m, 1H); 8.75 (m, 1H); 8.85 (dd, J = 1.8 and 7.5, 1H); 9.16 (br, 1H). [5-(2-Dimethylamino-ethylcarbamoyl)pyridin-2 25 ylthiolacetic acid was prepared in analogy to the procedure described in Bioorg. Med. Chem. Lett. 2003, 1517 using bromo acetic acid ethyl ester and commercially available 2 dimethylaminoethyl amine. 30 Example 82 164 (1S,5R) -2-(2-(4- [N- (2 aminoethyl)carbamoylphenylthio}acetyl) -7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (209). The titled compound has been prepared following scheme 5 13 and in analogy to example 80 using (1S,5R)-7-oxo- 2 ,6 diazabicyclo[3i..]etane-6--sulfonicacid (compound 1.) and (4- (2-tert butoxycarbonylaminoethylcarbamoyl) phenylthiol acetic acid as starting materials. The final deprotection step, using 10 trifluoroacetic acid, has been performed in analogy to exam ple 1. 1H-NYIR (DMSO-d 6 ): 1.72 (m, 1H); 2.33 (m, 1H); 2.97 (t, J = 6.0, 2H); 3.14 and 3.38 (2m, 1H); 3.48 (q, J = 6.0, 2H); 3.95-4.24 (m, 3H); 4.34 and 4.51 (2t, J = 4.8, 1H); 5.17 and 15 5.32 (2d, J = 4.3, 1H); 7.42 (dd, J = 8.5 and 13.l,.2H); 7.78 (dd, J = 2.5 and 8.5, 2H) ; 8.55 (m, 1H). [4-(2-Tert butoxycarbonylaminoethylcarbamoyl)phenylthiol acetic acid was prepared in analogy to the procedure described in example 80 20 using 4-ethoxycarbonylmethylthiobenzoic acid and commercially available (2-aminoethyl)carbamic acid tert-butyl ester. Example 83 (i5R)-2-(2-(4-[N- (2-aminoethyl)-N 25 methylcarbamoyljphenylthio}acetyl)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-su-lfonic acid (210). The titled compound has been prepared following scheme 13 and in analogy to example 80 using (1S,5R)-7-oxo-2, 6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and 30 (4-[(2- tert-butoxycarbonylaminoethyl)methyl carbamoyl]phenylthio)acetic acid as starting materials. The 165 final deprotection step, using trifluoroacetic acid, has been performed in analogy to example 1. -ESI-MS spectrum: m/z: 441 [M-H] (4- [ (2-Tert 5 butoxycarbonylaminoethyl)methylcarbamoylIphenylthio}acetic acid was preoare n analogy to the procedure described in example 80 using 4-ethoxycarbonylmethylsulfanylbenzoic acid and commercially available (2-methylamino-ethyl) carba-mic acid tert-butyl ester. 10 Exanple 84 (1S,5R)-2- [2-(4-(N-[2 (methylamino)ethylcarbamoyl}phenylthio)acetyl] -7-oxo-2, 6 diazabicyclo[3.2.Oheptane-6-sulfonic acid (211) 15 The titled compound has been prepared following scheme 13 and in analogy to example 80 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and {4- [2- ( tert-butoxycarbonylmethylamino) ethylcarbamoyl] phenyl thiolacetic acid as starting materials. The final deprotec 20 tion step, using trifluoroacetic acid, has been performed in analogy to example 1. -ESI-MS spectrum: m/z: 441 [M-H)l - (4-[2-(Tert butoxycarbonylmethylamino) ethylcarbamoyl ] phenylthio } acetic 25 acid was prepared in analogy to the procedure described in example 80 using 4-ethoxycarbonyl methylthiobenzoic acid and commercially available (2-aminoethyl)methylcarbamic acid tert-butyl ester. 30 Example 85 166 (lS,5R)-7-oxo-2-{2-[4 (piperazinylcarbonyl)phenylthio]acetyl}-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (212). The titled compound has been prepared following scheme 5 13 and in analogy to example 80 using (1S,5R)-7-oxo-2,6 diazabicyclo[3.2.03heptane-6-sulfonic acid (compound H) and 4-(4-carboxymethylthiobenzoyl)piperazine-l-carboxylic acid tert-butyl ester as starting materials. The final deprotec tion step, using trifluoroacetic acid, has been performed in 10 analogy to example 1. -ESI-MS spectrum: m/z: 453 [M-H]* 4-(4-Carboxymethylsulfanyl-benzoyl)piperazine-l carboxylic acid tert-butyl ester was prepared in analogy to the procedure described in example 80 using 4 15 ethoxycarbonylmethylthiobenzoic acid and commercially avail able piperazine-l-carboxylic acid tert-butyl ester. Example 86 (15, SR) -2-{2- [4- (2-aminoethoxy)phenylthio ]acetyl) -7-oxo 20 2,6-diazabicyclo [3.2.0]heptane-6-sulfonic acid (213). The titled compound has been prepared following scheme 13 and in analogy to example 80 using (lS,5R)-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and (4-(2-tert-butoxycarbonylaminoethoxy)phenylthio]acetic acid 25 as starting materials. The final deprotection step, using trifluoroacetic acid, has been performed in analogy to exam ple 1. -ESI-MS spectrum: m/z: 400 (M-H)* [4- (2-Tert-butoxycarbonylaminoethoxy)phenylthio acetic 30 acid was prepared in analogy to the procedure described in J. Med Chem.2000, 721 using first bromo acetic ethyl ester and 167 then the commercially available (2-bromoethyl)carbamic acid tert-butyl ester. Example 87 5 (1S,5R)-2-(2-(5-[N-(2-aminoethyl)carbamoyl] (2 pyridylthio)}acetyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 sulfonic acid (214). The titled compound has been prepared following scheme 13 and in analogy to example 80 using (1S,5R)-7-oxo-2,6 10 diazabicyclo[3.2.0]heptane-6-sulfonic acid (compound H) and [4-(2-tert butoxycarbonylaminoethylcarbamoyl)phenylthio]acetic acid as starting materials. The final deprotection step, using trifluoroacetic acid, has been performed in analogy to exam 15 ple 1. -ESI-MS spectrum: m/z: 428 [M-H]* [4-(2-Tert-butoxycarbonylamino-ethylcarbamoyl) phenylthio]acetic acid was prepared in analogy to the proce dure described in Bioorg. Med. Chem. Lett. 2003, 1517 using 20 bromo acetic acid ethyl ester and commercially available (2 aminoethyl)carbamic acid tert-butyl ester. Example 88 (1S,5R)-2-[2-(5-{N-[2-(methylamino)ethyl]carbamoyl)(2 25 pyridylthio))acetyl]-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 sulfonic acid (215). The titled compound has been prepared following scheme 13 and in analogy to example 80 using (lS,5R)-7-oxo- 2 ,6 diazabicyclo[3.2.0)heptane-6-sulfonic acid (compound H) and 30 (4-[2-(tert butoxycarbonylmethylamino)ethylcarbamoyllphenylthio} acetic acid as starting materials. The final deprotection step, us- 168 ing trifluoroacetic acid, has been performed in analogy to example 1. -ESI-MS spectrum: m/z: 442 [M-H]Y (4-[2-(Tert 5 butoxycarbonylmethylamino)ethylcarbamoyl]phenylthio}acetic acid was prepared in analogy to the procedure described in Bioorg. Med. Chem. Lett. 2003, 1517 using bromo acetic acid ethyl ester and commercially available (2-methylamino ethyl)carbamic acid tert-butyl ester. 10 Example 89 (1S,5R)-2-(2-[(3-carbamoylpyridyl 4)carbonylamino]acetyl}-7-oxo-2,6-diazabicyclo[3.2.0]heptane 6-sulfonic acid (402) 15 The titled compound was prepared following scheme 11 in analogy to example 24 using (5S,1R)-4-(2-bromoacetyl)-4,7 diazabicyclo[3.2.0]heptan-6-one (compound F) which was first sulfonated (J. Org. Chem. 1982, 5160) and the commercially available 3,4-pyridine dicarboxamide as starting materials. 20 +ESI-MS spectrum: m/z: 398 [M+H] *. Example 90 Sodium 2-(E(4s)-2-(2-hydroxyphenyl) (4,5-dihydro-1,3 thiazolin-4-yl)]carbonyl(iS,5R)-7-oxo-2,6 25 diazabicyclo[3.2.0]heptane-6-sulfonate (404) The titled compound was prepared following scheme 13 in analogy to example 14 using (5S,lR)-4,7 diazabicyclo[3.2.0]heptan-6-one (compound E) and the (4S) 30 4,5-dihydro-2-(2-hydroxyphenyl)-4-thiazolecarboxylic acid (JP59141554). The resulting compound was then sulfonated ac- 169 cording to the procedure described in J. Org. Chem. 1982, 5160. -ESI-MS spectrum: m/z: 397 [M+H) *. 5 Example 91 Sodium (1S,5R)-2-(2-[(5-fluoro-2-oxohydropyrimidin-4 yl)amino]acetyl)-7-oxo-2,6-diazabicyclo[3.2.0]heptane-6 sulfonate (405) 10 The titled compound was prepared following scheme 11 in analogy to example 22 using (5S,1R)-4-(2-bromoacetyl)-4,7 diazabicyclo[3.2.0]heptan-6-one (compound F) and the commer cially available 4--amino-5-fluoro pyridine-2-one. -ESI-MS spectrum: m/z: 361 [M+H] *. 15 Example 92 (lS,5R)-2-[2-amino-2-(4-carbamoylphenyl)acetyl]-7-oxo 2,6-diazabicyclo[3.2.0]heptane-6-sulfonic acid (406) 20 The titled compound was prepared following scheme 13 in analogy to example 14 using (5S,lR)-4,7 diazabicyclo[3.2.O]heptan-6-one (compound E) and 2-amino-2 (4carbamoylphenyl) acetic acid, obtained according to the procedure described in Eur. J. Med. Chem. 2003, 289 from 4 25 {[(tert-butoxy)carbonylamino](methoxycarbonyl) methyl}benzoic acid (WO-A-2000/076970). The resulting compound was then sul fonated according to the procedure described in J. Org. Chem. 1982, 5160. +ESI-MS spectrum: m/z: 368 [M+H] +. 30 Example 93 170 (iS,5R)-2-{2-[4-(imidazolylcarbonyl)-1 methylpiperazinium]acetyl}-7-oxo-2,6 diazabicyclo[3.2.0]heptane-6-sulfonate, inner salt (407) 5 The titled compound was prepared following scheme 13 in analogy to example 24 using (5S,lR) -4-(2-bromoacetyl)-4,7 diazabicyclo[3.2.0]heptan-6-one (compound F) and 1-(1H imidazol-1-ylcarbonyl)-4-methyl-piperazine (Ind. J. Chem., Section B, 1987, 748). 10 +ESI-MS spectrum: m/z: 426 [M] *. Example 94 Sodium (1.,5R)-2-([(4 carbamoylphenyl) amino] carbonylamino} -7 -oxo-2, 6 15 diazabicyclo[3..2.0]heptane-6-sulfonate (408) The titled compound was prepared following the procedure described for example 18 of US-B-6,566,355 using (5S,1R)-4,7 diazabicyclo[3.2.0)heptan-6-one (compound E) and 4-[(3 20 phenyl-1,2-oxaziridin-2-yl)carbonylamino]benzanide. The re sulting compound was then sulfonated according to the proce dure described in J. Org. Chem. 1982, 5160. -ESI-MS spectrum: m/z: 369 [M+H] *. 25 BIOLOGICAL EVALUATION 30 Antimicrobial activity of the compounds and of their combinations was determined against a selection of organisms according to the standard procedures described by the Na tional Committee for Clinical Laboratory Standards (National 171 Committee for Clinical Laboratory. Standards (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically-Fifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA, USA). 5 The compounds to be tested were dissolved in 100% DMSO or sterile broth according to their aqueous solubility and were diluted to the final reaction concentration (0.06 - 32 gg/mL) in microbial growth media (IsoSensiTest Broth + 16 10 pg/mL 2,2'-bipyridyl). In all cases the final concentration of DMSO incubated with the bacteria is less than or equal to 1%. For estimation of the minimal inhibitory concentrations (MIC) , 2-fold dilutions of compounds were added to wells of a microtitre plate containing 106 bacteria/mL. Plates were in 15 cubated overnight at an appropriate temperature (30 0 C or 37 0 C) and optical densities assessed by eye. The MIC value is defined as the lowest compound concentration completely in hibiting visible growth of the test organism. When combina tions between compounds of formula I with compounds of for 20 mula II and III-XIII are evaluated the compounds of formula I are tested in dilution series as described above while the compounds of formula II and III-XIII were present in all wells at a constant concentration of 4 pig/mL each. 25 The MIC values (in mg/L) of representative compounds and of representative combinations including these compounds are listed in tables 3, 4 and 5. Table 3 lists the MIC values obtained for two representative antibiotics of formula I when combined either with a compound of formula II or with a com 30 pound of formula III-XIII in comparison to the activity ob tained with a combination involving the antibiotic of formula I with a compound of formula II and a compound of formula 172 III-XIII together. Table 4 lists the activity of representa tive compounds of formula I alone or in combination with com pounds of formula II and formula III-XIII. Table 5 lists the MIC values obtained for representative compounds of formula 5 II with selected compounds of formula I and formula III-XIII. If in table 4 in the upper three rows a cell is left empty, then this means that in the combination of that column no compound of the category of that row was used. 10 Table 3: Activity of representative monobactam antibiotics alone and in representative combinations according to the in vention compound of for-1 Aztreonam mula I compound of for- 206 323 206 323 muta Il di E Supplemen-tary b- 501 S lactamase inhibitor . 501 n 501 Minimal Inhibitory Concentration (mg/L) of antibiotic at fixed Inhibitor concentration of 4 mg/L Strain B1102 >32 32 16 16 8 2 16 2 0.125 2 ATCC1 3047/ >32 >32 >32 >32 8 >32 >32 >32 8 8 Enterobac-ter cloacae M4018 32 >32 16 8 2 >32 >32 32 1 4 MRW >32 32 32 16 4 >32 32 32 1 2 173 Zayakosky >32 >32 >32 >32 16 >32 >32 532 16 8 Enterobac-ter aerogenes B1 32 >32 >32 16 4 16 >32 32 8 8 C) CD cn CD) I __________A A ~0 C a jeU~znAeO CN In C) Al Ln Cc N 0 e w eiNe A oo m C14 olul~ l CV) C D C4 u) Nl A AA ) N 6 6 o D cD C) CD N In v A A ____ 4 C 0 C' CV? C C14 CD C4A A A A CD eleuelnAepD 04CDC A - I' I- I D co I A C0 -A ~ -Aq jeUejnA~j3 00 CD CD CDC - C UN e CnDj CD4 N C) me~qn CD CD co t coCflE -I cDi N (o1o'2 l C C) C1D C CD 8H 8UejnAeO CD N4 o. N A o D) C C to alu4ne N N coa C) 0) ________A A CD A' A 0)0 00 04DCD C wuaz N Nl Nl Nl N l uilolw weoqls( C14 cD C __________ _________ A A A A A A ____ 0 .2 0 wuoojizxov N lu~~e 1 ol Cn m N lD (12 00 o 0uedoCarN CD C) D C CD CD CN __________ _____ A CD A A ' n E Au A C A n A NM N Eo ZH w.ed9e 0 Z: 0 '0 0 o C _______ E ______ N Nc E - 0 F r .0 2 0 0) ) gC 75 0) o 0 0 0 cn - a) fl.

5

U<

(N ~ ~ C 00 ____ N C D co CN C cN Wr co fl 0) 0N LOU CN _ _ _ N A 00 co N CD (N~~~jlA( (N CC) 0D V0 mi NN U (N A CC A A C m CN (N 0 __A CC co Ci) 0 CD cli Ni C3 Ci C 0 __A A co A A 0 mi weloqn m I Ci co -I 'r C -CIf) 04 weloqns (N CO 00iI ' cl N D C14 (N (Ni Cli Ci mi V) (N _____ A A CC A A cq (Ni V) C, C4 mi aleuelnAe]O C (N4 Ci co__ CIO CC C N N Cli weloeqn ((cN o l I CD (N eCuelAelO (N C A C', V c 6 It (DNC weo-n ***l** m r ~ - m cD 04 Ili 04 CN (NA A CD A A 00 C CD CI OlUeIlnAB2P -I Nto -CA Ci , A 0 ' ' E a3 r Cli cli Ci " 04 1N 0 A A A A A cD co (N aleueln~el BO(N ( _____ -A M' A (N, C: C1 Cil C4) " CIJ 04 CV - _ _ 5 A A A A A A A up eieuInAel.- D1 CD (N ~ i A A 0, VC - _ U aleu~ilnAE1 p 0 (Nl (i (N (D Ci) X A A A C> 6 IT .2 A A A co CDCI 0 ~ r CAflCl -DA A A A v r 6 0 CD Ci C, Ci C C E. A A 00 a) A C o N" m C') cl .)t A1i 100 A A CD CO 4J - E 0o (N (N (N ( o to~ A A 2i m CD -, 0 C 0 Cm Ca 'Z DC)( - < ICC.- 0 CA < ~ 0. m CLc -) cn

CD

n C) oi (N 04 C, C,-v C) (D 0P 0mC cDi olen el Cm) C) Cr) mN 0 to cv co0yjC CIS C) W (D C; N- C4CDc Ne0qn 0 10 CD 4 C pj v o' CC) -C. aleueIflAeI3 LO C Dt to () N N m _____ v CN (Ni 0 V CD ~ Lueloqln C (N 0 (N! Nl N N ci N S ____ V 'T (D ~ 6~UC)~lA2~CC. C) mD CD 0 E m ~ qn CV 04 (N 3 0 N (N r- c o coD oC ____4 CO c- 0 m mN f_ C.), Ccio (N CD -I N ID _ _ _ _ _ _ _ _ _ _ _ _ - _ _ =D C D A 0N N- N1 - (N4 (Y _ _ _ 0) C , N 0a ca. CD .N C: E '. Co co ~ N2 -- CD ow CD 0L 0 c E_

-

_ -C . 0 .S , I a) 7o C) (N (N 2 N N ' Z5_____ E CD :EAA 0 2~ ~ co2 2 5E 0C CC :aC uwC) CCCa E--4~~D I-C < (2m(rnC a Lm wu f ' A u _ _ _ co m _ ? CN PIDE Cl l DiUjlAepO (0 ( O 0 1 m0--I 10 10i IN IN ppe INC o I 1 10 m. CA - 0 ) ppe o0ueflnAejO NI 10 A 00 &L10 IN I P!p2 04 oiueflnAelo -I A -I co A A~ ci If) ~ oiueflnAelo ciN IN 1 A cD 1 D 0 0 ppe LO CD OiUInAepD -' 1 - E IN CV 10 10 CD 10 o A A A A -o IN m 10IDI 0) ) ININ4 A - CC)- A A CD ppe * a) C 0!D 0 10i 10 m C: IN ) IN Z5 m CD 0 10 W 0 Z5C Q) oo oI m LL S >2 A 0 o E Ea. oC 0 a *0 0~ .0D (D -W a, m <.fl~c o0___ ~JW)C C EL 2 0c 20 -178 Table 5: Activity of compounds of general formula II in rep resentative combinations MIC of antibiotic at fixed inhibitor concentration -_ (4 mg/L) f V. W . > M p 20 2 1n 0 1 32 Beipged 3o42- Supplementary Aztreona >32o >32 8U >3E3 3 3 b -I ~ W actam se in- Anti intic 0, 0 . 0r C, 10mu 1 clvlnt 1u >3 8O 4 2 2 0. 012 102~~~- clvlnt 1 4 4l 2 (D.2 .2 103l aunhibitor of of formula I U . . formulaVor 1 3 3 4 3 0 . Cn 5 2 2 0.125 C: a)) . E C 105c1Meropenem 2 2 1 0.125 <0.06 16 32 Cefeplme 32 32 4 2 4 0.125 4 SAztreonam >32 >32 8 >32 >32 32 >32 108 clavulanate 1 >32 >32 16 >32 >32 1 0.5 101 clavulanate 1 >32 8 4 32 2 0.5 0.125 102 clavulanate 1 4 4 2 4 12 0.25 0.125 103 clavulanate 1 8 8 4 32 0.5 0.25 0.125 104 clavulanate 1 >32 32 4 32 0.5 2 0.125 105 clavulanate 1 8 16 8 32 0.5 0.125 0.125 106 clavulanate 1 >32 32 4 -32 0.25 0.25 0.125 107 clavulanate 1 8 8 4 32 1 0.125 0.125 108 clavulanate 1 >32 >32 4 4 1 0.25 0.125 109 clavulanate 1 4 16 4 32 0.5 0.125 0.125 110 clavulanate 1 2 32 4 >32 0.125 0.25 0.125 119 davulanate 1 4 8 4 4 <0.06 0.25 0.125 112 clavulanate 1 16 >32 8 >32 <=0.06 0.5 0.125 113 clavulanate 1 >32 >32 4 32 0.125 0.25 0.25 114 clavulanate 1 >32 16 4 32 0.125 0.25 0.125 115 clavulanate 1 >32 16 4 32 0.125 0.25 0.125 116 clavulanate 1 16 8 16 32 0.5 0.25 0.125 117 clavulanate 1 >32 16 4 32 0.125 0.25 0.25 118 clavulanate 1 >32 132 4 132 0.125 0.25 0.125 119 clavulanate 1 >32 32 4 >32 0.125 0.25 0.125 120 clavulanate 1 32 16 8 32 0.25 0.25 0.125 121 clavulanate 1 >32 16 4 32 0.25 0.25 0.25 122 clavulanate 1 >32 16 4 16 0.125 0.25 0.125 123 clavulanate 1 >32 32 4 32 0.125 0.25 0.125 124 clavulanate 1 >32 32 8 32 0.125 0.25 0.125 125 clavulanate 11 4 16 8 32 <0.06 0.5 0.125 126 clavulanate 1 2 16 8 32 >32 0.125 0.125 201 clavulanate 1 4 32 8 32 >32 2 0.125 202 clavulanate 1 4 8 4 16 2 0.5 0.125 203 clavulanate 1 2 32 4 32 1 0.25 8 204 clavulanate 1 2 32 4 8 2 0.25 8 205 clavulanate 1 2 16 4 16 0.5 0.5 2 206 clavulanate 1 .4 >32 4 0 0.25 4 0.125 301 clavulanate 1 8 >32 4 16 1 0.25 0.125 302 clavulanate 1 >32 >32 4 32 2 0.25 0.125 303 clavulanate 1 >32 >32 4 32 2 0.5 0.125 304 clavulanate 1 >32 >32 4 32 1 0.25 0.125 305 clavulanate 1 >32 >32 4 4 4 0.25 0.25 306 clavulanate 1 >32 >32 4 32 2 0.5 0.25 307 clavulanate 1 >32 >32 8 32 2 0.25 0.125 308 clavulanate 1 >32 >32 4 16 0.5 0.5 0.125 309 clavulanate 1 >32 >32 4 32 2 0.5 0.125 310 clavulanate 1 >32 16 4 4 2 0.5 0.125 311 clavulanate 1 4 ->32 4 8 0.5 0.25 0.125 312 clavulanate 1 >32 >32 8 8 4 0.5 0.125 313 clavulanate 1 4 >32 4 16 0.5 0.25 0.125 314 clavulanate 1 4 >32 4 32 1 0.25 0.125 315 clavulanate 1 4 >32 4 8 1 0.25 0.125 316 clavulanate 1 16 32 4 8 0.5 0.25 0.125 317 clavulanate 1 16 >32 8 8 0.5 0.25 0.125 318 clavulanate 1 16 >32 4 >32 0.5 0.25 0.125 319 clavulanate 1 >32 >32 4 16 0.25 0.25 0.125 320 clavulanate 1 >32 >32 8 8 0.5 0.25 0.125 321 clavulanate 1 16 >32 4 >32 1 0.25 0.125 322 clavulanate 1 16 >32 8 >32 0.125 1 0.125 323 clavulanate 1 16 16 8 4 2 0.25 0.125 324 clavulanate 1 32 8 8 4 1 1 0.125 325 clavulanate 1 4 16 4 4 >32 0.25 0.125 326 clavulanate 1 4 32 4 8 >32 0.125 0.125 327 clavulanate 1 2. >32 2 32 2 0.25 0.125 328 clavulanate 1 8 32 4 4 1 1 0.125 331 clavulanate 1 >32 >32 4 4 0.5 2 0.125 332 clavulanate 1 >32 16 4 16 1 2 0.125 333 clavulanate 1 >32 32 4 32 1 0.25 0.125 401 clavulanate 1 4 >32 8 16 0.5 0.125 0.125 -180 402 clavulanate 1 8 32 4 32 <0.06 0.25 <0.06 403 clavulanate 1 8 >32 2 32 4 0.5 0.125 404 clavulanate 1 4 >32 4 16 0.5 0.25 0.25 406 clavulanate 1 >32 32 8 32 2 0.5 0.125 407 clavulanate 1 >32 >32 8 32 1 0.5 0.125 408 clavulanate 1 >32 >32 16 32 2 0.5 0.125 -181 Further objects of the invention according to the following paragraphs 1-2 are also disclosed herein: 1. A pharmaceutical composition, comprising a combination of 5 a) an antibiotically active compound of the following formula I: R4 N-O R6 _HR5 R3 R6 O N J R2 N I 0 RI in which 10 R1 signifies SO 3 H, OSO 3 H, CRaRa'COOH, OCRaRa'COOH, 5-tetra zolyl, SO 2 NHRb or CONHRc, wherein Ra and Ra' are independently selected from hydro gen; alkyl; allyl; benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, 15 amino, alkylamino, dialkylamino and halogen; phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; alkylamino; dialkylamino; alkoxyalkyl and a 5-6 membered heteroaromatic ring which may be substituted 20 with 1 to 4 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; wherein Rb is hydrogen; alkyl; alkoxycarbonyl; alkylamino carbonyl; benzylaminocarbonyl in which the benzyl may be substituted with 1 to 5 substituents selected from alkyl, 25 hydroxyl, alkoxy, amino, alkylamino, dialkylamino and -182 halogen; or phenylaminocarbonyl in which the phenyl may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino,dialkylamino and halo gen; 5 wherein Rc is hydrogen; alkyl; phenyl which may be substi tuted ith to 5 !ubsti tuen-ts selected from alkvl, hv droxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; benzyl which may be substituted with 1 to 5 substitu ents selected from alkyl, hydroxyl, alkoxy, amino, al 10 kylamino, dialkylamino and halogen; alkoxycarbonyl;

SO

2 phenyl; SO 2 NHalkyl; or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 4 substituents se lected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; 15 R2 and R3 independently signify hydrogen; alkyl; alkenyl; al kynyl; benzyl which may be substituted with 1 to 5 substitu ents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, dialkylamino and halogen; phenyl which may be sub stituted with 1 to 5 substituents selected from alkyl, hy 20 droxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; azido; halogen; dihalogenomethyl; trihalogenomethyl; alkoxy carbonyl; carboxyl; sulfonyl or CH 2 X1, wherein X1 is azido; amino; halogen; hydroxyl; cyano; car boxyl; aminosulfonyl; alkoxycarbonyl; alkanoylamino; 25 phenylaminocarbonyl; alkylaminocarbonyl; aminocarbonyl; carbamoyloxy; alkylaminosulfonyl; phenylaminosulfonyl in which the phenyl may be substituted with 1 to 5 substitu ents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, dialkylamino and halogen; phenyl which may be 30 substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamfino, dialkylamino and halogen; or which may be substituted with 1 to 5 substitu- PCT/CH2006/000685 -18 3 ents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, dialkylamino and halogen; R4 signifies hydrogen; alkyl; C(Rx) (Ry)Z, wherein Rx and Ry are independently selected from hydro 5 gen; alkyl; allyl; (C 3 -Cs)cycloalkyl; phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; (C 2 -C7) alkene and (C 2

-C

7 ) alkyne; or Rx and Ry taken together may form an alkylene bridge -(CH 2 )n- with n 10 being an integer number from 2 to 6; and Z is COOH; CH 2 N(CH)COR' wherein R' is hydrogen, alkyl, alkylamino, alkoxy, benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dial 15 kylamino and halogen, phenyl which may be substituted' with 1 to 5 substituents selected from from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halogen, or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 4 substituents selected from 20 alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; or Z is one of the following six groups 0 0 Re Re N Rf N Rf Rd Rd N N R i s N O H O HN N N OH OH

OH

-184 in which groups Rd, Re and Rf are independently selected from hydrogen; alkyl; amino; monoalkylamino; carboxylaminoalkyl; alkoxycarbonyl; benzyl which may be substituted with 1 5 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkvlamino and halogen; diphenyl methyl; trityl; and ORg wherein Rg is hydrogen; alkyl; benzyl which may be substi tuted with 1 to 5 substituents selected from alkyl, 10 hydroxyl, alkoxy, amino, alkylamino and halogen; or phenyl which may be substituted with 1 to 5 substitu ents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino and halogen; or, when Re and Rf 'are vicinal substituents, Re and Rf 15 taken together may also be -O-CH=CH-CH 2 -, -O-CH 2

-CH

2 -O-,

-CH

2

-CH

2

-CH

2 -, -CH 2

-CH

2

-CH

2

-CH

2 -, -CH=CH-CH=CH- or CH=C (OH) -C (OH) =CH-; Ri is hydrogen; alkyl; alkylamino; alkoxy; benzyl which may be substituted with 1 to 5 substituents selected 20 from alkyl, hydroxyl, alkoxy, amino, alkylamino, dial kylamino and halogen; phenyl which may be substituted with 1 to 5 substituents selected from alkyl andhy droxyl; or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from 25 alkyl, hydroxyl, alkoxyalkoxy, amino, alkylamino, dial kylamino and halogen; R5 signifies hydrogen, alkyl, halogenomethyl, dihaloge nomethyl, trihalogenomethyl, alkoxy, formylamino or alkylcar bonylamino; 30 R6 signifies phenyl which may be substituted with 1 to 5 sub stituents selected from alkyl, hydroxyl, alkoxyalkoxy, amino, alkylamino, dialkylamino and halogen; or a 5-6 membered het- -185 eroaromatic ring which may be substituted with 1 to 4 sub stituents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, carbonylamino and halogen; or a pharmaceutically acceptable salt thereof; 5 -with a P-lacarnase inhibibor of one of the following groups bl) to b1l) bl) a bridged monobactam derivative of the following formula 10 II: R8'N H'"- -'H JN. 0 R7 in which: R7 signifies SO 3 H, OSO 3 H or OCRjRj'COOH, wherein Rj and Rj' are independently selected from hydro gen; alkyl; phenyl which may be substituted with 1 to 5 15 substituents selected from alkyl, hydroxyl, alkoxyalkoxy, amino, alkylamino, dialkylamino and halogen; benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxyalkoxy, amino, alkylamino, dial kylamino and halogen; alkylamino and alkoxyalkyl; 20 R8 is alkoxycarbonylamino, the acyl residue of an oC or amino acid, or a residue of the formula Q-(X)r-Y-, wherein Q is a 3-6 membered ring which optionally contains nitrogen, sulphur and/or oxygen and which is optionally fused to a phenyl ring or to a 5-6 membered heterocyclic 25 ring and which is optionally substituted with 1 to 4 sub stituents selected from alkyl, allyl, hydroxyl, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxamide -186 which may be substituted, carboxylic acid, carbonylalkoxy, aminocarbonyl, alkylaminocarbonyl, halogen, haloge nomethyl, dihalogenomethyl, trihalogenomethyl, sulfamide, substituted sulfamide with substituents selected from al 5 kyl, allyl, phenyl which may be substituted with 1 to 5 u tituents selec ted from alkyl, hydroyl, al koyalkroxy, amino, alkylamino and halogen and benzyl which may be sub stituted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxyalkoxy, amino, alkylamino, halogen and ben 10 zyl, urea which may be substituted with alkyl, aminoalkyl, alkoxyalkyl or aminoalkoxyalkyl, and carbamate which may be substituted with alkyl, aminoalkyl,alkoxyalkyl or ami noalkoxyalkyl, X signifies a linear spacer of from 1 to 6 atoms length 15 and containing carbon, nitrogen, oxygen and/or sulphur at oms, of which up to 2 atoms can be nitrogen atoms and 1 atom can be oxygen or sulphur, r is an integer of from 0 to 1; and Y is selected from -CO-, -CS-, -NHCO-, -NHCONH- and -SO 2 -; 20 or a pharmaceutically acceptable salt thereof, or b2) a monobactam derivative of the general formula III: 25 /R4' 0 N R6 0 N O so 3H -187 in which R4' signifies hydrogen, alkyl or CH(Rx')Z', wherein Rx' is selected from hydrogen; (C 1 -Cs)alkyl; allyl; phenyl 5 and (C 3

-C

6 )cycloalkyl; and Z' signifies COCH or a group of one of the following two formulae: 0 0 OH HO N:'N Rd' Rd in which Rd' is hydrogen or hydroxy; and R6 is as defined for formula I; or a pharmaceutically ac 10 ceptable salt thereof; or b3) a penam sulfone derivative of the general formulae IV or 15 V: R9 0 0.* RIO s. O O R101 0 00 IV HO O V HO in which 20 R9 signifies COOH or a 5-6 membered monocyclic or poly cyclic heteroaromatic group; R10 signifies hydrogen or halogen; Rll signifies CH 2 R12; CH=CHR12 wherein R12 is hydrogen, halogen, cyano, carboxylic acid, acyl such as acetyl, car 25 boxamide which may be substituted, alkoxycarbonyl or a 5-6 membered heteroaromatic ring which is optionally substituted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; or which is optionally fused with a 5-6 membered het eroaromatic ring; CH=NR12' wherein R12' is amino, al 5 kylamino, dialkylamino, aminocarbonyl, acylamino such as acecyiainiro, hydroxy, ailkoxy, or a pharmaceutically acceptable salt thereof; or 10 b4) an oxapenam derivative of the general formula VI: 0 R13 HO O VI 15 in which R13 signifies OR14; S(O)nR14 or a 5-6 membered heteroaro matic ring which may be substituted with 1 to 5 substitu ents selected from alkyl, hydroxyl, alkoxy, amino, al kylamino, dialkylamino and halogen; whereby n = 0, 1 or 2, 20 and R14 is hydrogen, alkyl, (C 2

-C

7 )alkene, (C 2

-C

7 )alkyne or a 5-6 membered heteroaromatic ring which may be substi tuted with 1 to 5 substituents selected from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen, 25 or a pharmaceutically acceptable salt thereof; or b5) a penem derivative of the general formula VII: 30 -189 R15 S N / VII 0 HO O in which R15 signifies a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from -al 5 kyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen; or which is optionally fused with a 5-6 membered heteroaromatic ring and/or which is optionally bound to the exo-methylene group over a -CH=CH- spacer being pref erably in the (E)-configuration, 10 or a pharmaceutically acceptable salt thereof; or b6) a cephem sulfone derivative of the general formula VIII: 15 R16 '~S N / OCOCH 3 HO 0 VIII in which R16 signifies COOR17, whereby R17 signifies hydrogen or 20 alkyl; or a 5-6 membered heteroaromatic ring which is op tionally fused with a 5-6 membered heteroaromatic ring be ing optionally substituted with 1 to 5 substituents se lected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, halogen; and/or being optionally bound to -190 the exo-methylene group over a -CH=CH- spacer being pref erably in the (E)-configuration, or a pharmaceutically acceptable salt thereof; 5 or b7) a carbapenem derivative of the general formula IX: ' H N / R18 0 HO O 10 in which R18 signifies -S-alkyl, -S-(CH 2 )2-NH-CH=NH or a group of the following two formulae O NRkRI NRkRI NH NH -S wherein Rk and Rl are individually selected from hydrogen, 15 alkyl, 2-, 3-, 4-carboxyphenyl and sulfamoyl, or a pharma ceutically acceptable salt thereof; or 20 b8) a boronate derivative of the general formula X: OH I H R1 HOH HO'b N S 0 -191 wherein R19 signifies a 5-6 membered heteroaromatic ring which may be substituted with amino, alkylamino, dialkylamino or alkylsulfoxide, or a pharmaceutically acceptable salt thereof; 5 or b9) a boronate derivative of the general formula XI: H RN R21 HO B OH 10 wherein R20 and 21 are independently selected from a 5-6 membered heteroaromatic ring; phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, 15 amino, alkylamino, dialkylamino and halogen and benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dial kylamino and halogen, or a pharmaceutically acceptable salt thereof; 20 or blO) a phosphonate derivative of the general formula XII: 0 0 N P O0 R22 H //OH 0 1 25 wherein -192 R22 is selected from a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dial kylamino and halogen and which is optionally fused with a 5 5-6 membered heteroaromatic ring; phenyl which may be sub stituted with 1 to 5 substituenLs selected from alkyl, hy droxyl, alkoxy, amino, alkylamino, dialkylamino and halo gen; and benzyl which may be substituted with 1 to 5 sub stituents selected from alkyl, hydroxyl, alkoxy, amino, 10 alkylamino, dialkylamino and halogen, or a pharmaceutically acceptable salt thereof; or 15 b1l) a diazabicyclooctane derivative of the general formula XIII: N R23 R2 4 .N 20 in which R23 signifies hydrogen, carboxylic acid, alkoxycarbonyl or carboxamide which may be substituted, and R24 signifies S03H, OSO 3 H or OCRjRj'COOH, wherein Rj and 25 Rj' are as defined for formula II, or a pharmaceutically acceptable salt thereof. 2. Any embodiment as disclosed in the following claims 2 to 45, with their dependency or reference to claim 1 being re 30 placed by a reference to preceding paragraph 1.

Claims

1. A compound of the following formula Ib: R4 8

2 N N-0 LR N o RI wherein 5 R1 is SO3; R2 is H; R3 is methyl; R4 is C (Rx) (Ry) Z; whereby Rx = Ry = H, and Z is a group of one of the formulae 0 0 Re. Re Rf N Rf 10 Rd wherein Rd, Re and Rf are individually selected from hydrogen and hydroxy, with the proviso that at least two of Rd, Re and Rf are hydroxy; and R5 signifies hydrogen; or a pharmaceutically acceptable salt thereof. 15 2. The compound of claim 1, wherein Rd and Re are hydroxy and Rf is hydrogen.

3. The compound of claim 1, which is a compound (21) wherein: R4 is 0 OH I I N OH and R5 is hydrogen. 20 Basilea Pharmaceutica AG Patent Attorneys for the Applicant/Nominated Person SPRUSON & FERGUSON