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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
First Claim
Patent Images

1. A pharmaceutical composition, comprising a combination ofa) 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 groupsRd 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 whichR9 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 whichR13 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 whichR15 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 whichR16 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;

    whereinR20 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;

    whereinR22 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 whichR23 signifies hydrogen, carboxylic acid, alkoxycarbonyl or carboxamide which may be substituted, andR24 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.

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