Cross-linked glycopeptide-cephalosporin antibiotics

A compound of formula II:

• or a pharmaceutically acceptable salt thereof;
• wherein
• W is selected from N and CCl;
• R9 is selected from hydrogen, C1-6 alkyl, and C3-6 cycloalkyl, where alkyl and cycloalkyl may be substituted with —COOH or 1 to 3 fluorine atoms;
• the pyridinium ring has meta or para substitution;
• R10 is hydrogen or C1-6 alkyl;
• and
• R11 is C1-12 alkylene.

A process for preparing a compound of formula I:

• or a salt thereof, wherein:
• each of X1 and X2 is independently hydrogen or chloro;
• W is selected from N and CCl;
• R2 is hydrogen or C1-6 alkyl;
• one of R4 and R5 is hydroxy and the other is hydrogen;
• each of R6 and R7 is independently hydrogen or methyl;
• R8 is hydrogen or a group of the formula:
• R9 is selected from hydrogen, C1-6 alkyl, and C3-6 cycloalkyl, where alkyl and cycloalkyl may be substituted with —COOH or 1 to 3 fluorine atoms;
• each R3 is independently selected from C1-6 alkyl, —OR, halo, —SR, —S(O)R, —S(O)2R, and —S(O)2OR, where each R is independently C1-6 alkyl, which may be substituted with COOH or 1 to 3 fluorine atoms;
• n is 0, 1, 2 or 3;
• x is 0, 1 or 2;
• y is 0, 1 or 2;
• Ra is —Y—R″—, where
• R″ is selected from C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C3-6 cycloalkylene, C6-10 arylene, C2-9 heteroarylene, C3-6 heterocycle, and combinations thereof, and is optionally substituted with 1 or 2 groups selected from Z, where Z consists of —OR′, —SR′, —F, —Cl, —N(R′)2, —OC(O)R′, —C(O)OR′, —NHC(O)R′, —C(O)N(R′)2, —CF3, and —OCF3, and side chains of naturally occurring amino acids, where each R′ is independently hydrogen or C1-4 alkyl;
• and R″ contains at most 20 non-hydrogen atoms;
• Y, which links R″ to the pyridinium ring at a meta or para position, is selected from a direct bond, NR′, O, S, C(O), NR′(CO), and (CO)NR′, precluding direct bonds between heteroatoms in Y and R″;
• each Rb and Rd is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rc is independently —Y′—R″—Y′—, where each Y′ is independently selected from a direct bond, O, and NR′, precluding direct bonds between heteroatoms in Y′ and R″;
• and
• each Re is independently selected from R″;
• wherein the process comprises reacting a compound of formula 1:
• or a salt or activated or protected derivative thereof, with a compound of formula 3 or 4:
• or a salt or activated or protected derivative thereof to provide a compound of formula I or a salt thereof.

A process for preparing a compound of formula I:

• or a salt thereof, wherein:
• each of X1 and X2 is independently hydrogen or chloro;
• W is selected from N and CCl;
• R2 is hydrogen or C1-6 alkyl;
• one of R4 and R5 is hydroxy and the other is hydrogen;
• each of R6 and R7 is independently hydrogen or methyl;
• R8 is hydrogen or a group of the formula:
• R9 is selected from hydrogen, C1-6 alkyl, and C3-6 cycloalkyl, where alkyl and cycloalkyl may be substituted with —COOH or 1 to 3 fluorine atoms;
• each R3 is independently selected from C1-6 alkyl, —OR, halo, —SR, —S(O)R, —S(O)2R, and —S(O)2OR, where each R is independently C1-6 alkyl, which may be substituted with COOH or 1 to 3 fluorine atoms;
• n is 0, 1, 2 or 3;
• x is 0, 1 or 2;
• y is 0, 1 or 2;
• Ra is —Y—R″—, where
• R″ is selected from C1-12 alkylene, C2-12 alkenylene, C2-12 alkynylene, C3-6 cycloalkylene, C6-10 arylene, C2-9 heteroarylene, C3-6 heterocycle, and combinations thereof, and is optionally substituted with 1 or 2 groups selected from Z, where Z consists of —OR′, —SR′, —F, —Cl, —N(R′)2, —OC(O)R′, —C(O)OR′, —NHC(O)R′, —C(O)N(R′)2, —CF3, and —OCF3, and side chains of naturally occurring amino acids, where each R′ is independently hydrogen or C1-4 alkyl;
• and R″ contains at most 20 non-hydrogen atoms;
• Y, which links R″ to the pyridinium ring at a meta or para position, is selected from a direct bond, NR′, O, S, C(O), NR′(CO), and (CO)NR′, precluding direct bonds between heteroatoms in Y and R″;
• each Rb and Rd is independently selected from the group consisting of hydrogen, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• each Rc is independently —Y′—R″—Y′—, where each Y′ is independently selected from a direct bond, O, and NR′, precluding direct bonds between heteroatoms in Y′ and R″;
• and
• each Re is independently selected from R″;
• wherein the process comprises reacting a compound of formula 5:
• or a salt or activated or protected derivative thereof;
• with a compound of formula 2:
• or a salt or activated or protected derivative thereof;
• to provide a compound of formula I or a salt thereof.