Cross-linked glycopeptide-cephalosporin antibiotics
View Patent ↗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.
1. A compound of the formula:
or a salt thereof, wherein
X 1 and X 2 are independently selected from the group consisting of hydrogen and chloro;
R 1 is —Y a —(W) n —Y b —;
W is selected from the group consisting of —O—, —N(R d )—, —S—, —S(O)—, —S(O) 2 —, C 3-6 cycloalkylene, C 6-10 arylene and C 2-9 heteroarylene; wherein each arylene, cycloalkylene and heteroarylene group is optionally substituted with 1 to 3 substituents independently selected from R b ;
Y a and Y b are independently C 1-5 alkylene, or when W is cycloalkylene, arylene or heteroarylene, Y a and Y b are independently selected from the group consisting of a covalent bond and C 1-5 alkylene; wherein each alkylene group is optionally substituted with 1 to 3 substituents independently selected from —OR d , —NR d R e , —CO 2 R d , —C(O)NR d R e and —S(O) 2 NR d R e ;
R 2 is hydrogen or C 1-6 alkyl;
one of R 4 and R 5 is hydroxy and the other is hydrogen;
R 6 and R 7 are independently hydrogen or methyl;
R 8 is hydrogen or a group of formula (i):
each R a is independently selected from the group consisting of —OR d , halo, —SR d , —S(O)R d , —S(O) 2 R d , —S(O) 2 OR d , —S(O) 2 NR d R e , —NR d R e , —CO 2 R d , —OC(O)R d , —C(O)NR d R e , —NR d C(O)R e , —OC(O)NR d R e , —NR d C(O)OR e , —NR d C(O)NR d R e , —CF 3 and —OCF 3 ;
each R b is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and R a ;
each R c is independently selected from the group consisting of C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 3-6 heterocyclic; wherein each cycloalkyl, aryl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl and R f ;
each R d and R e is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl and C 3-6 heterocyclic; or R d and R e are joined, together with the atoms to which they are attached, to form a C 3-6 heterocyclic ring having 1 to 3 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein each alkyl, alkenyl and alkynyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of R e and R f ; and each aryl, cycloalkyl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of C 1-6 alkyl and R f ;
each R f is independently selected from the group consisting of —OH, —OC 1-6 alkyl, —SC 1-6 alkyl, —F, —Cl, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —OC(O)C 1-6 alkyl, —C(O)OC 1-6 alkyl, —NHC(O)C 1-6 alkyl, —C(O)OH, —C(O)NH 2 , —C(O)NHC 1-6 alkyl, —C(O)N(C 1-6 alkyl) 2 , —CF 3 and —OCF 3 ; and
n is 0 or 1.
2. The compound according to claim 1 , wherein n is 0 and Y a and Y b are independently C 1-5 alkylene groups wherein each alkylene group is optionally substituted with 1 to 3 substituents independently selected from —OR d , —NR d R e , —CO 2 R d , —C(O)NR d R e and —S(O) 2 NR d R e .
3. The compound according to claim 1 , wherein n is 0 and Y a and Y b are joined together to form a —(CH 2 ) 2-8 — group.
4. The compound according to claim 1 , wherein n is 0 and Y a and Y b are joined together to form a —CH 2 ) 2 —, —(CH 2 ) 3 —, —(CH 2 ) 4 —, —(CH 2 ) 5 — or —(CH 2 ) 6 — group.
5. The compound according to claim 1 , wherein n is 0 and Y a and Y b are joined together to form a —(CH 2 ) 3 — group.
6. The compound according to claim 1 , wherein n is 1 and Y a and Y b are the same or different and each is selected from the group consisting of a covalent bond and C 1-5 alkylene optionally substituted with 1 to 3 substituents selected from —OR d , —NR d R e , —CO 2 R d , —C(O)NR d R e and —S(O) 2 NR d R e .
7. The compound according to claim 6 , wherein W is C 6-10 arylene or —O—.
8. The compound according to claim 1 , wherein n is 1 and Y a and Y b are both —CH 2 — and W is C 6-10 arylene optionally substituted with 1 to 3 substituents independently selected from R b .
9. The compound according to claim 8 , wherein W is phenylene.
10. The compound according to claim 1 , wherein n is 1 and Y a and Y b are both —CH 2 CH 2 — and W is —O—.
11. The compound according to claim 1 , wherein R 2 is hydrogen.
12. The compound according to claim 1 , wherein R 4 is hydroxy; R 5 is hydrogen; R 6 is hydrogen; R 7 is methyl; R 8 is hydrogen; and X 1 and X 2 are both chloro.
13. The compound according to claim 12 , wherein R 1 is —Y a —(W) n —Y b —, where n is 0 and Y a and Y b are joined together to form a —(CH 2 ) 3 — group; and R 2 is hydrogen.