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 formula II:
or a salt thereof; wherein
P 1 and P 2 are independently hydrogen or an amino-protecting group;
P 3 is hydrogen or a carboxy-protecting group; or P 3 is absent and —C(O)OP 3 forms a —C(O)O − group;
Q is a leaving group or a group of the formula:
wherein
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;
each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, C 2-9 heteroaryl, C 3-6 heterocyclic and R a ; or two adjacent R 3 groups are joined to form C 3-6 alkylene or —O—(C 1-6 alkylene)-O—; wherein each alkyl, alkylene, alkenyl and alkynyl group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of R a and R c ; and each aryl, cycloalkyl, heteroaryl and heterocyclic group is optionally substituted with 1 to 3 substituents independently selected from the group consisting of R b ;
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 c 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 ;
X − is an optionally present anion;
m is 0, 1, 2 or 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 3 , 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 4 , 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 Q is halo.
13. The compound according to claim 1 , wherein Q is a group of the formula:
14. The compound according to claim 13 , wherein m is 0.
15. The compound according to claim 13 , wherein m is 1 or 2 and each R 3 is independently selected from the group consisting of C 1-6 alkyl, C 3-6 cycloalkyl, —OR d , —SR d , —F or —Cl; or two adjacent R 3 groups are joined to form C 3-6 alkylene.
16. The compound according to claim 1 , wherein P 1 is hydrogen or tert-butoxycarbonyl.
17. The compound according to claim 1 , wherein P 2 is hydrogen or triphenylmethyl.
18. The compound according to claim 1 , wherein P 3 is hydrogen or p-methoxybenzyl.
19. A compound of formula II:
or a salt thereof; wherein
P 1 is hydrogen or tert-butoxycarbonyl;
P 2 is hydrogen or triphenylmethyl;
P 3 is hydrogen or p-methoxybenzyl; or P 3 is absent and —C(O)OP 3 forms a —C(O)O − group;
R 1 is —(CH 2 ) 3 —;
R 2 is hydrogen; and
Q is a group of the formula:
where X − is an optionally present anion.
20. The compound according to claim 19 , wherein P 1 is hydrogen.
21. The compound according to claim 19 , wherein P 1 is tert-butoxycarbonyl.
22. The compound according to claim 19 , wherein P 2 is hydrogen.
23. The compound according to claim 19 , wherein P 3 is hydrogen.
24. The compound according to claim 19 , wherein X − is chloro.