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US 7,067,482 B2Granted
Cross-linked glycopeptide-cephalosporin antibiotics
AssigneeTheravance, Inc.
InventorsPaul R. Fatheree, Martin S. Linsell, Daniel Marquess, Sean G. Trapp, Edmund J. Moran, James B. Aggen
Life of this patent
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Abstract
This invention provides cross-linked glycopeptide—cephalosporin compounds and pharmaceutically acceptable salts thereof which are useful as antibiotics. This invention also provides pharmaceutical compositions containing such compounds; methods for treating bacterial infections in a mammal using such compounds; and processes and intermediates useful for preparing such compounds.
Claims28
A compound of formula I:
- or a pharmaceutically-acceptable salt thereof;
- wherein
- each of X1 and X2 is independently hydrogen or chloro;
- W is N or CCl;
- R1 and R2 are independently selected from hydrogen and C1-6 alkyl;
- 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 optionally substituted with COOH or 1 to 3 fluoro substituents;
- one of R4 and R5 is hydroxy and the other is hydrogen;
- R6 and R7 are 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 are optionally substituted with —COOH or 1 to 3 fluoro substituents;
- 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 each Z is independently selected from the group consisting of —OR′, —SR′, —F, —Cl, —N(R′)2, —OC(O)R′, —C(O)OR′, —NHC(O)R′, —C(O)N(R′)2, —CF3, —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;
- and 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′C(O), and C(O)NR′, precluding direct bonds between heteroatoms in Y and R″;
- each Rb and Rd is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
- each Rc is independently a direct bond or —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″;
- each Re is independently selected from the group defined by R″;
- n is an integer from 0 to 3;
- x is an integer from 0 to 2;
- and
- y is an integer from 0 to 2.
17 more elements
A compound of formula II:
- or a pharmaceutically acceptable salt thereof;
- wherein
- W is N or CCl;
- R9 is selected from the group consisting of hydrogen, C1-6 alkyl and C3-6 cycloalkyl, where alkyl and cycloalkyl are optionally substituted with —COOH or 1 to 3 fluoro substituents;
- the pyridinium ring has meta or para substitution;
- R10 is hydrogen, C1-4 alkyl or C2-4 alkenyl;
- R11 is C1-12 alkylene or C2-12 alkenylene;
- and
- R12 is hydrogen, C1-4 alkyl or C2-4 alkenyl.
6 more elements
A process for preparing compound of formula I:
- or a salt or protected derivative thereof;
- wherein
- each of X1 and X2 is independently hydrogen or chloro;
- W is N or CCl;
- R1 and R2 are independently selected from hydrogen and C1-6 alkyl;
- 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 optionally substituted with COOH or 1 to 3 fluoro substituents;
- one of R4 and R5 is hydroxy and the other is hydrogen;
- R6 and R7 are 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 are optionally substituted with —COOH or 1 to 3 fluoro substituents;
- 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 each Z is independently selected from the group consisting of —OR′, —SR′, —F, —Cl, —N(R′)2, —OC(O)R′, —C(O)OR′, —NHC(O)R′, —C(O)N(R′)2, —CF3, —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;
- and 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′C(O), and C(O)NR′, precluding direct bonds between heteroatoms in Y and R″;
- each Rb and Rd is independently selected from hydrogen, C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl;
- each Rc is independently a direct bond or —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″;
- each Re is independently selected from the group defined by R″;
- n is an integer from 0 to 3;
- x is an integer from 0 to 2;
- and
- y is an integer from 0 to 2:
- or a salt thereof, the process comprising comprising reacting a compound of formula 1:
- or a salt, or an activated and/or protected derivative thereof, with a compound of formula 2:
- or a salt or carboxy-protected derivative thereof;
- in the presence of a compound of formula 3:
- HOOC—Rc—COOH 3
- or a salt, activated derivative, or protected derivative thereof;
- to form the compound of formula I, or a salt or protected derivative thereof.
24 more elements
Dependencies are inferred from the claim text.