Triterpenes having antibacterial activity

A therapeutic method of treating a mammal afflicted with a bacterial infection comprising administering to the mammal an effective anti-bacterial amount of a triterpene of formula (II):

• 50
• wherein
• one of R1 and R2 is —O—Y and the other is hydrogen or (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy, halo, halo(C1-C6)alkoxy or NRjRk wherein Rj and Rk are independently H, (C1-C6)alkyl or (C1-C6)alkonyl;
• or R1 and R2 together are oxo (═O);
• R3 is hydrogen, halo, carboxy, mercapto, (C1-C6)alkyl, (C3-C8)cycloalkyl, or —O—Y;
• R4 and R5 are each independently hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl;
• R6 is hydrogen or is absent when the adjacent --- is a bond;
• R7 is hydrogen or (C1-C6)alkyl;
• R8 is hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl and R11 is hydrogen, (C1-C6)alkyl, carboxy, or hydroxy(C1-C6)alkyl;
• or R8 and R11 together are —O—C(═X)—;
• R9 and R10 are each independently hydrogen or (C1-C6)alkyl;
• each of the bonds represented by --- is independently absent or is present;
• X is two hydrogens, oxo (═O) or thioxo (═S);
• each Y is independently H, aryl, P(O)(Cl)2, (C3-C8)cycloalkyl, adamantyl, —SO2Ra O═P(Rb)2, O═P(Rc)2OP(O)(Rd)—, Si(Re)3, tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and —N(Rf)—;
• wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (═O), hydroxy, carboxy, halo, mercapto, nitro, —N(Rg)(Rd), (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide;
• and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
• Ra is (C1-C6)alkyl or aryl;
• Rb, Rc, and Rd are each independently hydroxy, (C1-C6)alkoxy, hydroxy(C2-C6)alkoxy, adamantyloxy, adamantyl(C1-C6)alkoxy, norbomyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C1-C6)alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C3-C8)cycloalkyloxy, NRxRy, or aryloxy;
• Re is H, aryl or (C1-C6)alkyl;
• Rf is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl;
• Rg and Rh are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, adamantyl, adamantyl(C1-C6)alkyl, amino(C1-C6)alkyl, aminosulfonyl, (C1-C6)alkanoyl, aryl and benzyl;
• or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical;
• and
• Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, aryl or benzyl;
• wherein each aryl of Y, Ra-Rd, Rg-Rh, Rx and Ry may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NRiRj, (C1-C6)allcyl, (C1-C6)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, trifluoromethoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, or (C1-C6)alkanoyloxy;
• wherein R1 and Rj are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl, or benzyl;
• wherein any alkyl can optionally be substituted with one or more polyethyleneimine or poly(ethylene glycol);
• and wherein any alkyl can optionally be interrupted with one or more polyethyleneimine or poly(ethylene glycol);
• or a pharmaceutically acceptable salt thereof.

A method of inhibiting or killing a bacterium, comprising contacting the bacterium with an effective antibacterial amount of a triterpene of formula (I):

• 51
• wherein
• R1 is hydrogen or hydroxy;
• R2 is a direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C6-C10)aryl, or (C1-C6)alkyl;
• R3 is hydrogen, hydroxy, (C1-C6)alkyl, O═P(OH)2, O═P(OH)2OP(O)(OH)—, (C1-C5)alkanoyl, Si(R)3 wherein each R is H, phenyl or (C1-C6)alkyl, C(O)N(R)2, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C1-C4)alkoxy](C1-C4)alkyl, or a glycoside;
• R4 is hydrogen, hydroxy, (C1-C6)alkyl, O═P(OH)2, O═P(OH)2OP(O)(OH)—, (C1-C5)alkanoyl, Si(R)3 wherein each R is H, phenyl or (C1-C6)alkyl, C(O)N(R)2, benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C1-C4)alkoxy](C1-C4)alkyl, a glycoside, or amino;
• or R4 and R5 together are oxo or (═NOH);
• and
• R5 is direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C6-C10)aryl, or (C1-C6)alkyl;
• or R4 and R5 together are oxo or (═NOH);
• wherein any alkyl can optionally be substituted with one or more halo, hydroxy, (C6-C10)aryl, nitro, cyano, (C1-C6)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR7R8, wherein R7 and R8 are each independently hydrogen, (C1-C6)alkyl or polyethyleneimine;
• —OP(═O)(OH)2;
• or C(═O)OR9, wherein R9 is hydrogen, (C1-C6)alkyl, or polyethyleneimine;
• each of the bonds represented by --- is independently absent or is present;
• wherein any alkyl is optionally interrupted on carbon with one or more oxy, thio, sulfinyl, sulfonyl, polyethyleneimine, or poly(ethylene glycol);
• wherein any alkyl is optionally partially unsaturated;
• wherein any aryl can optionally be substituted with one or more halo, hydroxy, nitro, cyano, (C1-C6)alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR7R8, wherein R7 and R8 are each independently hydrogen, (C1-C6)alkyl or polyethyleneimine;
• or C(═O)OR9, wherein R9 is hydrogen, (C1-C6)alkyl, or polyethyleneimine;
• or a pharmaceutically acceptable salt thereof.

A method of inhibiting or killing a bacterium, comprising contacting the bacterium with an effective antibacterial amount of a triterpene of forimula (II):

• 52
• wherein
• one of R1 and R2 is —O—Y and the other is hydrogen or (C1-C6)alkyl optionally substituted by hydroxy, (C1-C6)alkoxy, halo, halo(C1-C6)alkoxy or NRjRk wherein Rj and Rk are independently H, (C1-C6)alkyl or (C1-C6)alkonyl;
• or R1 and R2 together are oxo (═O);
• R3 is hydrogen, halo, carboxy, mercapto, (C1-C6)alkyl, (C3-C8)cycloalkyl, or —O—Y;
• R4 and R, are each independently hydrogen, (C1-C6)alkyl, or hydroxy(C1-C6)alkyl;
• R6 is hydrogen or is absent when the adjacent --- is a bond;
• R7is hydrogen or (C1-C6)alkyl;
• R8 is hydrogen, (C1-C6)alkyl, or hydroxyl(C1-C6)alkyl and R11 is hydrogen, (C1-C6)alkyl, carboxy, or hydroxy(C1-C6)alkyl;
• or R8 and R11 together are —O—C(═X)—;
• R9 and R10, are each independently hydrogen or (C1-C6)alkyl;
• each of the bonds represented by --- is independently absent or is present;
• X is two hydrogens, oxo (═O) or thioxo (═S);
• each Y is independently H, aryl, P(O)(Cl)2, (C3-C8)cycloalkyl, adamantyl, —SO2Ra O═P(Rb)2, O═P(Rc)2OP(O)(Rd)—, Si(Re)3, tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and —N(Rf)—;
• wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (═O), hydroxy, carboxy, halo, mercapto, nitro, —N(Rg)(Rh), (C3-C8)cycloalkyl, (C3-C8)cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide;
• and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
• Ra is (C1-C6)alkyl or aryl;
• Rb, Rc, and Rd are each independently hydroxy, (C1-C6)alkoxy, hydroxy(C2-C6)alkoxy, adamantyloxy, adamantyl(C1-C6)alkoxy, norbomyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C1-C6)alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C3-C8)cycloalkyloxy, NRxRy, or aryloxy;
• Re is H, aryl or (C1-C6)alkyl;
• Rf is hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl or benzyl;
• Rg and Rh are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, adamantyl, adamantyl(C1-C6)alkyl, amino(C1-C6)alkyl, aminosulfonyl, (C1-C6)alkanoyl, aryl and benzyl;
• or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical;
• and
• Rx and Ry are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, aryl or benzyl;
• wherein each aryl of Y, Ra-Rd, Rg-Rh, Rx, and Ry may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NRiRj, (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C1-C6)alkyl, halo(C1-C6)alkyl, trifluoromethoxy, (C1-C6)alkanoyl, (C1-C6)alkoxycarbonyl, (C1-C6)alkylthio, or (C1-C6)alkanoyloxy;
• wherein Ri and Rj are each independently hydrogen, (C1-C6)alkyl, (C1-C6)alkanoyl, phenyl, or benzyl;
• wherein any alkyl can optionally be substituted with one or more polyethyleneimine or poly(ethylene glycol);
• and wherein any alkyl can optionally be interrupted with one or more polyethyleneimine or poly(ethylene glycol);
• or a pharmaceutically acceptable salt thereof.