Useful Combinations of Monobactam Antibiotics With Beta-Lactamase Inhibitors

• US 20100056478A1
• Filed: 12/07/2006
• Published: 03/04/2010
• Est. Priority Date: 12/07/2005
• Status: Active Grant

• Current Assignee: Basilea Pharmaceutica Ag
• Original Assignee: Basilea Pharmaceutica Ag
• Inventors: Gaucher, Bérangère, Roussel, Patrick, Page, Malcolm G.P., Desarbre, Eric
• Granted Patent: US 8,901,293 B2
• Time in Patent Office: Days
• US Class Current: 514/64
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/43 Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula , e.g. penicillins, penems
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/4375 the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
• CPC Class Codes: A61K 31/4436 containing a heterocyclic ring having sulfur as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/4725 containing further heterocyclic rings
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/545 Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula: , e.g. cephalosporins, cefaclor, or cephalexine
• CPC Class Codes: A61K 31/662 Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A pharmaceutically composition, comprising a combination of an antibiotically active compound of the formula (I): with a β-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 β-lactamase inhibitor of one of the formulae (II) to (XIII), particularly of formula (V) or formula (VI).

Claims

1. A pharmaceutical composition, comprising a combination of

a) an antibiotically active compound of the following formula I:

in which

R1 signifies SO₃H, OSO₃H, CRaRa′

COOH, OCRaRa′

COOH, tetrazol-5-yl, SO₂NHRb 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, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

alkylamino;

diallylamino;

alkoxyalkyl and a 5-6 membered heteroaromatic ring which may be substituted with 1 to 4 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

wherein Rb is hydrogen;

alkoxycarbonyl;

alkylaminocarbonyl;

benzylaminocarbonyl in which the benzyl may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

or phenylaminocarbonyl in which the phenyl may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

wherein Rc is hydrogen;

alkyl;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

alkoxycarbonyl;

SO₂phenyl;

SO₂NHalkyl;

or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 4 substituents selected from alkyl, hydroxyl, alkylhydroxylamino, alkylamino, dialkylamino and halogen;

R2 and R3 independently signify hydrogen;

alkyl;

alkenyl;

alkynyl;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

azido;

halogen;

dihalogenomethyl;

trihalogenomethyl;

alkoxycarbonyl;

carboxyl;

sulfonyl or CH₂X1,

wherein X1 is azido;

amino;

hydroxyl;

cyano;

carboxyl;

aminosulfonyl;

alkoxycarbonyl;

alkanoylamino;

phenylaminocarbonyl;

alkylaminocarbonyl;

alkylaminosulfonyl;

phenylaminosulfoxy in which the phenyl may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

or phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

R4 signifies hydrogen;

alkyl;

C(Rx)(Ry)Z,

wherein Rx and Ry are independently selected from hydrogen;

alkyl;

allyl;

(C₃-C₆)cycloalkyl;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

(C₂-C₇) alkene and (C₂-C₇)alkyne;

or Rx and Ry taken together may form an alkylene bridge —

(CH₂)_n—

with n being an integer number from 2 to 6; and

Z is COOH;

CH₂N(OH)COR′

wherein R is hydrogen, alkyl, alkylamino, alkylhydroxy, benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen, phenyl which may be substituted with 1 to 5 substituents selected from from alkyl, hydroxyl, alkylhydroxyl, 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, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

or Z is one of the following six groups

in which groups

Rd is hydrogen;

amino;

monoalkylamino;

carboxylamino alkyl;

alkoxycarbonyl;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

diphenylmethyl;

trityl;

or ORg whereby Rg is hydrogen, alkyl, benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

Re and Rf are independently selected from hydrogen;

alkyl;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

ORg whereby Rg is hydrogen, alkyl, benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

diphenylmethyl;

trityl or alkoxycarbonyl;

or, when Re and Rf are vicinal substituents, Re and Rf taken together may also be —

O—

CH═

CH—

CH₂—

, —

O—

CH₂—

CH₂—

O—

, —

CH₂—

CH₂—

CH₂—

, —

CH₂—

CH₂—

CH₂—

CH₂—

, —

CH═

CH—

CH═

CH—

or —

CH═

C(OH)—

C(OH)═

CH—

;

Ri is hydrogen;

alkyl;

alkylamino;

alkylhydroxy;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, diallylamino and halogen;

R5 signifies hydrogen, alkyl, halogenomethyl, dihalogenomethyl, trihalogenomethyl, alkoxy, formylamino or alkylcarbonylamino;

R6 signifies phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, 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, alkylhydroxy, amino, alkylamino, carbonylamino and halogen;

or a pharmaceutically acceptable salt thereof;

with a β

-lactamase inhibitor of one of the following groups b1) to b11);

b1) a bridged monobactam derivative of the following formula II;

in which;

R7 signifies SO₃H, OSO₃H or OCRjRj′

COOH,

wherein Rj and Rj′

are independently selected from hydrogen;

alkyl;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

alkylamino and alkoxyalkyl;

R8 is alkoxycarbonylamino, the acyl residue of an α

or β

-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 ring and which is optionally substituted with 1 to 4 substituents selected from alkyl, allyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino, carboxamide which may be substituted, carboxylic acid, carbonylalkoxy, aminocarbonyl, alkylaminocarbonyl, halogen, halogenomethyl, dihalogenomethyl, trihalogenomethyl, sulfamide, substituted sulfamide with substituents selected from alkyl, allyl, phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen and benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, halogen and benzyl, urea which may be substituted with alkyl, aminoalkyl or alkylhydroxyl and carbamate which may be substituted with alkyl, aminoalkyl or alkylhydroxyl,

X signifies a linear spacer of from 1 to 6 atoms length and containing carbon, nitrogen, oxygen and/or sulphur atoms, 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— and

—

SO₂—

;

or a pharmaceutically acceptable salt thereof,

or

b2) a monobactam derivative of the general formula III;

in which

R4′

signifies hydrogen, alkyl, C(Rx′

)(Ry′

)Z′

,

wherein Rx′ and

Ry′

are independently selected from hydrogen, alkyl and (C₃-C₆)cycloalkyl; and

Z′

signifies COOH or a group of one of the following two formulae

in which

Rd is hydrogen;

amino;

monoalkylamino;

alkyl;

alkoxycarbony;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

diphenylmethyl;

trityl;

or ORg whereby Rg is hydrogen, alkyl, benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

Re and Rf are independently selected from hydrogen;

alkyl;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

ORg whereby Rg is hydrogen, alkyl, benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino and halogen;

diphenylmethyl;

trityl or alkoxycarbonyl;

or, when Re and Rf are vicinal substituents, Re and Rf taken together may also be

—

O—

CH═

CH—

CH₂—

, —

O—

CH₂—

CH₂—

O—

, —

CH₂—

CH₂—

CH₂—

, —

CH₂—

CH₂—

CH₂—

CH₂—

, —

CH═

CH—

CH═

CH—

or —

CH═

C(OH)—

C(OH)═

CH—

;

R6′

signifies phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

or a 5-6 membered heteroaromatic ring which may be substituted with amino, alkyl amino, carbonylamino or halogen;

or

b3) a penam sulfone derivative of the general formulae IV or V;

in which

R9 signifies COOH or a 5-6 membered monocyclic or polycyclic heteroaromatic group;

R10 signifies hydrogen or halogen;

R11 signifies CH₂R12;

CH═

CHR12 wherein R12 is hydrogen, halogen, cyano, carboxylic acid, carboxamide which may be substituted, alkoxycarbonyl or a 5-6 membered heteroaromatic ring which is optionally substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

or which is optionally fused with a 5-6 membered heteroaromatic ring;

CH═

NR12′

wherein R12′

is amino, alkylamino, dialkylamino, aminocarbonyl, hydroxy, alkylhydroxy,

or a pharmaceutically acceptable salt thereof;

or

b4) an oxapenam derivative of the general formula VI;

in which

R13 signifies OR14;

S(O)_nR14 or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

whereby n=0, 1 or 2, and R14 is hydrogen, alkyl, (C₂-C₇)alkene, (C₂-C₇)alkyne or a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen,

or a pharmaceutically acceptable salt thereof;

or

b5) a penem derivative of the general formula VII;

in which

R15 signifies a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, 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 preferably in the (E)configuration,

or a pharmaceutically acceptable salt thereof;

or

b6) a cephem sulfone derivative of the general formula VIII;

in which

R16 signifies COOR17, whereby R17 signifies hydrogen or alkyl;

or a 5-6 membered heteroaromatic ring which is optionally fused with a 5-6 membered heteroaromatic ring being optionally substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino, halogen;

and/or being optionally bound to the exo-methylene group over a —

CH═

CHspacer being preferably in the (E)-configuration,

or a pharmaceutically acceptable salt thereof;

or

b7) a carbapenem derivative of the general formula IX;

in which R18 signifies —

S-alkyl, —

S—

(CH₂)₂—

NH—

CH═

NH or a group of one of the following two formulae

wherein Rk and Rl are individually selected from hydrogen, alkyl, 2-, 3-, 4-carboxyphenyl and sulfamoyl, or a pharmaceutically acceptable salt thereof;

or

b8) a boronate derivative of the general formula X;

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;

or

b9) a boronate derivative of the general formula XI;

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, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen and benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen,

or a pharmaceutically acceptable salt thereof;

or

b10) a phosphonate derivative of the general formula XII;

wherein

R22 is selected from a 5-6 membered heteroaromatic ring which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen and which is optionally fused with a 5-6 membered heteroaromatic ring;

phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen; and

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkylhydroxyl, amino, alkylamino, dialkylamino and halogen;

or

b11) a diazabicyclooctane derivative of the general formula XIII;

in which

R23 signifies hydrogen, carboxylic acid, alkoxycarbonyl or carboxamide which may be substituted, and

R24 signifies SO₃H, OSO₃H or OCRjRj′

COOH, wherein Rj and Rj′

are independently selected from hydrogen, alkyl, phenyl which may be substituted, benzyl which may be substituted, aminoalkyl and alkoxy.

2. The composition of claim 1, furthermore comprising a compound of one of the formulae II to XIII as defined in claim 1, but different from the compound of b1) to b11) of claim 1.

3. The composition of claim 1, wherein in formula I:

R1 is SO₃H, OSO₃H or CRaRa′

COOH;

R4 is C(Rx)(Ry)Z, with either;

Rx=Ry=H and Z a group of one of the formulae

wherein Rd, Re and Rf are as defined for formula I;

or

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-amino-1H-1,2,4-triazol-3-yl, 5-aminopyrazol-3-yl or 4-aminopyrimidin-2-yl;

and wherein the compound of the one of the formulae II to XIII is a compound of formula II having R7 and R8 according to one of the rows of the following table;

Compound Number R7 R8 102 SO₃—

103 SO₃—

111 SO₃—

202 SO₃Na 206 SO₃Na 323 SO₃H 324 SO₃H

or a compound of formula V (501) wherein R10 is hydrogen and R11 is (1Z)-2-cyanovinyl.

4. The composition of claim 1, wherein in formula I:

R1 is SO₃H or OSO₃H;

R2 and R5 are hydrogen;

R3 is methyl;

R4 is C(Rx)(Ry)Z, with either;

Rx=Ry=H and Z a group of one of the formulae

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, preferably that Rd and Re are hydroxy and Rf is hydrogen;

or

Rx=Ry=methyl and Z=COOH; and

R6 is 2-amino-1,3-thiazol-4-yl, 5-aminopyrazol-3-yl or 4-aminopyrimidin-2-yl;

and wherein the compound of the one of the formulae II to XIII is a compound of formula II having R7 and R8 according to one of the rows of the following table;

Compound number R7 R8 102 SO₃—

103 SO₃—

111 SO₃—

202 SO₃Na 206 SO₃Na 323 SO₃H 324 SO₃H

5. The composition of claim 1, furthermore comprising sulbactam or clavulanic acid.

6. The composition of claim 1, comprising one of the following combinations A) to W):

A) as the compound of formula I, aztreonam

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

either a compound of formula V, which is sulbactam;

or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof,

or

B) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

either a compound of formula V, which is sulbactam;

or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof,

or

C) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is

hydrogen and R6 is 2-amino-1,3-thiazol-4-yl,

and

a compound of formula V (501) wherein R10 is hydrogen and R11 is (1Z)-2-cyanovinyl,

or

D) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl,

and

a compound of formula II (103), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

E) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl,

and

a compound of formula II (111), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

F) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl,

and

a compound of formula II (202), wherein R7 is SO₃Na and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

G) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl,

and

a compound of formula II (206), wherein R7 is SO₃Na and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

H) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl,

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

I) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl, and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

J) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

K) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (103), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam

or

L) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is

hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

M) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

N) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

O) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

P) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

Q) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl,

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof,

or

R) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl,

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

S) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl,

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

T) as the compound of formula I, the compound (22) wherein R1 is OCH₂COOH, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

U) as the compound of formula I, the compound (22) wherein R1 is OCH₂COOH, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

V) as the compound of formula I, the compound (26) wherein R1 is OSO₃H, R2 is CH₃, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is

clavulanic acid or a pharmaceutically acceptable salt thereof

or

W) as the compound of formula I, the compound (26) wherein R1 is OSO₃H, R2 is CH₃, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof.

7. Articles containing a compound of formula I as defined in claim 1, as an agent for treating infections caused by pathogenic Gram-negative bacteria, and a compound of one of the formulae II to XIII as defined in claim 1, as a combination for the simultaneous, separate or successive administration in the treatment of infections caused by pathogenic Gram-negative bacteria.

8. The articles of claim 7, furthermore containing another compound of one of the formulae II to XIII as defined in claim 1.

9. The articles of claim 7, wherein for the compound of formula I:

R1 is SO₃H or OSO₃H;

R2 and R5 are hydrogen;

R3 is methyl;

R4 is C(Rx)(Ry)Z, with either;

Rx=Ry=H and Z a group of one of the formulae

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, preferably that Rd and Re are hydroxy and Rf is hydrogen;

or

Rx=Ry=methyl and Z=COOH; and

R6 is 2-amino-1,3-thiazol-4-yl, 5-aminopyrazol-3-yl or 4-aminopyrimidin-2-yl;

and wherein the compound of the one of the formulae II to XIII is selected from the compounds of formula II wherein R7 and R8 are according to one of the rows of the following table;

Compound Number R7 R8 102 SO₃—

103 SO₃—

111 SO₃—

202 SO₃Na 206 SO₃Na 323 SO₃H 324 SO₃H

10. The articles of claim 7, wherein for the compound of formula I:

R1 is SO₃H, OSO₃H or OCHRaRa′

COOH;

R2 is hydrogen or methyl;

R3 is methyl;

R4 is C(Rx)(Ry)Z, with either;

Rx=Ry=H and Z a group of one of the formulae

wherein Rd, Re and Rf are as defined for formula I;

or

Rx=Ry=methyl and Z=COOH;

or R4 is 4-hydroxypyridino[3,2-b]pyridin-3-yl)methoxy;

R5 is hydrogen; 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-amino-1H-1,2,4-triazol-3-yl, 5-aminopyrazol-3-yl or 4-aminopyrimidin-2-yl;

and wherein the compound of the one of the formulae II to XIII is selected from the compounds of formula II wherein R7 and R8 are according to one of the rows of the following table;

Compound Number R7 R8 102 SO₃—

103 SO₃—

111 SO₃—

202 SO₃Na 206 SO₃Na 323 SO₃H 324 SO₃H

and a compound of formula V (501) wherein R10 is hydrogen and R11 is (1Z)-2-cyanovinyl.

11. The articles of claim 7, furthermore comprising sulbactam or clavulanic acid.

12. The articles of claim 7, comprising as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl, and a compound of formula V (501) wherein R10 is hydrogen and R11 is (1Z)-2-cyanovinyl.

13. The articles of one of claim 7, furthermore containing another compound of one of the formulae II to XIII as defined in claim 1.

14. The articles of claim 13, wherein the further compound is a compound of the formula V or a compound of the formula VI.

15. The articles of claim 14, comprising one of the following combinations A) to V):

A) as the compound of formula I, aztreonam

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

either a compound of formula V, which is sulbactam;

or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof,

or

B) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

either a compound of formula V, which is sulbactam;

or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof,

or

C) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (103), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

D) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (111), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

E) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (202), wherein R7 is SO₃Na and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

F) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is

hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (206), wherein R7 is SO₃Na and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

G) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

H) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

I) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

J) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (103), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam

or

K) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R2 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

L) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

M) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

N) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is

clavulanic acid or a pharmaceutically acceptable salt thereof

or

O) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

P) as the compound of formula I, the compound (22) wherein R1 is OCH₂COOH, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

Q) as the compound of formula I, the compound (22) wherein R1 is OCH₂COOH, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

R) as the compound of formula I, the compound (26) wherein R1 is OSO₃H, R2 is CH₃, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

S) as the compound of formula I, the compound (26) wherein R1 is OSO₃H, R2 is CH₃, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

T) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

U) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

V) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam.

16. Compounds of formula I as defined in claim 1, wherein R6 is 4-aminopyrimidin-2-yl, or a pharmaceutically acceptable salt thereof.

17. Compounds of the formula I as defined in claim 1, wherein R5 is hydrogen, R2 points upward from the plane of the azetidinone ring and R3 points below the plane of the azetidinone ring, and R1, R2, R3, R4 and R6 are according to one of the rows of the following table:

Compound number R1 R2 R3 R4 R6 5 SO₃H H CH₃ 6 SO₃H H CH₃ 7 SO₃H H CH₃ 8 SO₃H H CH₃ 9 SO₃H H H 10 SO₃H H CH₃ CH₂CH₂N(OH)COCH₃ 11 SO₃H H CH₃ 13 H CH₃ 14 SO₂NH₂ H CH₃ 15 SO₃H H CH₃ 16 SO₃H H CH₃ 17 SO₃H H CH₃ 18 SO₃H H CH₃ 19 SO₃H H CH₃ 20 SO₃H H CH₃ 21 SO₃H H CH₃ 27 SO₃H H CH₃ 28 SO₃H H CH₃ 38 SO₃H CH₃ CH₃ 39 SO₃H CH₃ CH₃ 40 SO₃H CH₃ CH₃

or a pharmaceutically acceptable salt thereof;

and compounds of the following formula Ia;

in which

Rz is SO₃H or CRaRa′

COOH, 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, 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 with 1 to 4 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen;

R2 and R3 independently signify hydrogen;

alkyl;

alkenyl;

alkynyl;

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 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen;

azido;

halogen;

dihalogenomethyl;

trihalogenomethyl;

alkoxycarbonyl;

carboxyl;

sulfonyl or CH₂X1,

wherein X1 is azido;

amino;

halogen;

hydroxyl;

cyano;

carboxyl;

aminosulfonyl;

alkoxycarbonyl;

alkanoylamino;

phenylaminocarbonyl;

alkylaminocarbonyl;

aminocarbonyl;

carbamoyloxy;

alkylaminosulfonyl;

phenylaminosulfonyl in which the phenyl 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 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen;

or benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen;

R4 is CH₂Z, with Z a group of one of the formulae

wherein Rd, Re and Rf are independently selected from hydrogen;

alkyl;

amino;

monoalkylamino;

carboxylaminoalkyl;

alkoxycarbonyl;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino and halogen;

diphenylmethyl;

trityl; and

ORg wherein

Rg is hydrogen;

alkyl;

benzyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino and halogen;

or phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, amino, alkylamino and halogen;

or, when Re and Rf are vicinal substituents, Re and Rf taken together may also

be —

O—

CH═

CH—

CH₂—

, —

O—

CH₂—

CH₂—

O—

, —

CH₂—

CH₂—

CH₂—

, —

CH₂—

CH₂—

CH₂—

CH₂—

, —

CH═

CH—

CH═

CH—

or —

CH═

C(OH)—

C(OH)═

CH—

;

R5 signifies hydrogen, alkyl, halogenomethyl, dihalogenomethyl, trihalogenomethyl, alkoxy, formylamino or alkylcarbonylamino;

R6 signifies phenyl which may be substituted with 1 to 5 substituents selected from alkyl, hydroxyl, alkoxy, 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, carbonylamino and halogen;

or a pharmaceutically acceptable salt or inner salt thereof.

18. The compounds of claim 17, which are a compound of formula Ia as defined in claim 17, and wherein R6 is an optionally amino-substituted and optionally chloro-substituted 5-6-membered heteroaromatic ring, being preferably selected from 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, 2-amino-5-chloro-1,3-thiazol-4-yl and 2-thienyl.

19. The compounds of claim 17, wherein R5 is hydrogen.

20. The compounds of one of claim 17, wherein Rz is SO₃H.

21. The compounds of claim 20, wherein R2 and R3 are methyl.

22. The compounds of claim 20, wherein R5 is hydrogen, and R2, R3, R4 and R6 are according to one of the rows of the following table:

Compound number R2 R3 R4 R6 12 H CH₃ 24 CH₂F H 25 CH₂OCONH₂ H 26 CH₃ CH₃ 29 H CH₃ 30 H CH₃ 31 CH₃ CH₃ 32 CH₃ CH₃ 47 CH₂OCONH₂ H 48 CH₂OCONH₂ H

or a pharmaceutically acceptable salt or inner salt thereof.

23. The compounds of claim 21, wherein R5 is hydrogen, and R4 and R6 are according to the following table:

Compound number R4 R6 26

24. The compounds of claim 21, wherein R5 is hydrogen, and R4 and R6 are according to the following table:

Compound number R4 R6 31

25. The compounds of claim 17, wherein Rz is CRaRa′

COOH.

26. The compounds of claim 25, wherein Ra and Ra′

are selected from hydrogen and methyl.

27. The compounds of claim 26, wherein Rz is

28. The compounds of claim 21, wherein R2 is selected from hydrogen, methyl, fluoromethyl and carbamoyloxymethyl;

and R3 is selected from hydrogen and methyl.

29. The compounds of claim 28, wherein the configuration at the carbon atom to which R2 and R3 are connected is (S).

30. The compounds of claim 25, wherein R5 is hydrogen, and Rz, R2, R3, R4 and R6 are according to one of the rows of the following table:

Compound number Rz R2 R3 R4 R6 22 CH₂COOH H CH₃ 23 CH(CH₃)COOH H CH₃ 33 CH₂COOH CH₃ CH₃ 34 CH₂COOH CH₃ CH₃ 35 CH₂COOH CH₃ CH₃ 36 CH₂COOH H CH₃ 37 CH₂COOH H CH₃ 41 CH₂COOH CH₂OCONH₂ H 42 CH₂COOH CH₂OCONH₂ H 43 CH₂COOH CH₂OCONH₂ H 44 CH₂COOH CH₂F H 45 CH₂COOH CH₂F H 46 CH₂COOH CH₂F H

31. A pharmaceutical composition comprising a compound of one of claim 17.

32. The composition of claim 1, wherein the compound of formula I is a compound of formula Ia as defined in claim 17.

33. The composition of claim 32, comprising two or more compounds different from each other and being selected from the formulae II to XIII as defined in claim 1.

34. The composition of claim 33, wherein one of the two or more compounds selected from the formulae II to XIII is a compound of formula V or a compound of formula VI.

35. The compositions of claim 6, wherein the combination is one of I), J), K), L), P), Q), R), S), T), U) or T).

36. Compounds of the formula II as defined in claim 1, wherein R7 and R8 are according to one of the rows of the following table:

Com- pound number R7 R8 101 SO₃—

103 SO₃—

104 SO₃—

105 SO₃—

106 SO₃—

107 SO₃—

108 SO₃—

109 SO₃—

110 SO₃—

111 SO₃—

112 SO₃—

113 SO₃—

114 SO₃—

115 SO₃—

116 SO₃—

117 SO₃—

118 SO₃—

119 SO₃—

120 SO₃—

121 SO₃—

122 SO₃—

123 SO₃—

124 SO₃—

125 SO₃—

126 SO₃—

127 SO₃—

128 SO₃—

129 SO₃—

207 SO₃H 208 SO₃H 209 SO₃H 210 SO₃H 211 SO₃H 212 SO₃H 213 SO₃H 214 SO₃H 215 SO₃H 325 SO₃H 326 SO₃H 334 SO₃H 335 SO₃H 336 SO₃H 337 SO₃H 338 SO₃H 339 SO₃H 340 SO₃H 341 SO₃H 342 SO₃H 343 SO₃H 344 SO₃H

37. A method of treating infections caused by Gram-negative bacteria comprising administering to a patient in need of such treatment a combination of an antibiotically active compound of the formula I and a β

-lactamase inhibitor according to one of the formulae II to XIII, both as defined in claim 1.

38. A method in accordance with claim 37, wherein said combination includes an additional compound selected from the formulae II to XIII as defined in claim 1.

39. A method in accordance with claim 37, wherein in formula I:

R1 is SO₃H or OSO₃H;

R2 and R5 are hydrogen;

R3 is methyl;

R4 is C(Rx)(Ry)Z, with either;

Rx=Ry=H and Z is selected from the formulae

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;

or

Rx=Ry=methyl and Z=COOH; and

R6 is 2-amino-1,3-thiazol-4-yl, 5-aminopyrazol-3-yl or 4-aminopyrimidin-2-yl;

and wherein the compound of the one of the formulae II to XIII is selected from the compounds of formula II wherein R7 and R8 are according to one of the rows of the following table;

compound number R7 R8 102 SO₃—

103 SO₃—

111 SO₃—

202 SO₃Na 206 SO₃Na 323 SO₃H 324 SO₃H

and a compound of formula V (501) wherein R10 is hydrogen and R11 is (1Z)-2-cyanovinyl.

40. A method in accordance with claim 37, wherein said combination contains sulbactam or clavulanic acid.

41. A method in accordance with claim 37, wherein said combination comprises, as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl, and

a compound of formula V (501) wherein R10 is hydrogen and R11 is (1Z)-2-cyanovinyl.

42. A method in accordance with claim 38, wherein said additional compound is a compound of formula V or a compound of formula VI.

43. A method in accordance with claim 38, wherein said combination is a member selected from the group consisting of combinations A) to V):

A) as the compound of formula I, aztreonam

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

either a compound of formula V, which is sulbactam;

or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof,

or

B) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

either a compound of formula V, which is sulbactam;

or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof,

or

C) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (103), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

D) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (111), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

E) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (202), wherein R7 is SO₃Na and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

F) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (206), wherein R7 is SO₃Na and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

G) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

H) as the compound of formula I, the compound (1) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

I) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

J) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (103), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam

or

K) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

L) as the compound of formula I, the compound (12) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

M) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

N) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl

and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

O) as the compound of formula I, the compound (21) wherein R1 is SO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 4-amino-pyrimidin-2-yl and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

P) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl,

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

Q) as the compound of formula I, the compound (22) wherein R1 is OCH₂COOH, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

R) as the compound of formula I, the compound (22) wherein R1 is OCH₂COOH, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

S) as the compound of formula I, the compound (26) wherein R1 is OSO₃H, R2 is CH₃, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (102), wherein R7 is SO₃— and

R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

T) as the compound of formula I, the compound (26) wherein R1 is OSO₃H, R2 is CH₃, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam, or a compound of formula VI, which is clavulanic acid or a pharmaceutically acceptable salt thereof

or

U) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl and

a compound of formula II (323), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam

or

V) as the compound of formula I, the compound (29) wherein R1 is OSO₃H, R2 is hydrogen, R3 is CH₃, R4 is (1,5-dihydroxy-4-oxo-1H-pyridin-2-yl)methylene, R5 is hydrogen and R6 is 2-amino-5-chloro-1,3-thiazol-4-yl

and

a compound of formula II (324), wherein R7 is SO₃H and R8 is

and

a compound of formula V, which is sulbactam.

44. A method in accordance with claim 37, wherein the Gram-negative bacteria are resistant against monobactam antibiotics available for clinical use, including aztreonam, carumonam and tigemonam.

45. A method in accordance with claim 37, wherein the Gram-negative bacteria are selected from:

Achromobacter species (including A. xylosooxidans);

Acinetobacter species (including A. baumannii, A. junii, A. lwoffi);

Burkholderia species (including B. cepacia);

Enterobacteriaceae including but not exclusively Enterobacter species (as including E. aerogenes, E. cloacae), Escherichia species (including E. coli), Klebsiella species (including K. oxytoca, K. pneumoniae), Proteus species (including P. mirabilis, P. penneri, P. vulgaris), Serratia species (including S. marcescens);

Pseudomonas species (including P. aeruginosa and P. putida); and

Stenotrophomonas maltophilia.