Antibacterial compounds, methods of making them, and uses thereof
View Patent ↗The present invention relates to novel therapeutics with antibacterial activity, processes for their preparation, and pharmaceutical, veterinary and nutritional compositions containing them as active ingredients. The present invention also relates to uses of the novel therapeutics, for example, as medicants or food additives in the treatment of bacterial infections or to aid body mass gain in a subject.
1. An isolated therapeutic having a structure of formula I as follows:
wherein:
the carbohydrate anomeric carbon designated * is in the R or S configuration;
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , arylalkyl, and heteroarylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —NO 2 , —OR 12 , or —NR 12 R 13 ;
R 2 is selected from the group consisting of H, —OR 12 , —NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 3 is selected from the group consisting of H, halogen, —OR 12 , —NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) q R 12 , —CN, —NO 2 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;
R 4 is selected from the group consisting of H, halogen, —OR 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , phenyl, benzyl, ═NOR 14 , ═NR 14 , a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 6 is optionally present and, if present, is selected from the group consisting of H, —OR 12 , NR 12 R 13 , —(CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
or R 5 and R 6 can combine to form a heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and optionally substituted 1 to 3 times with halogen, oxo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 7 is selected from the group consisting of H, halogen, —OR 12 , —NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) q R 12 , —CN, —NO 2 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;
R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n C(O)NR 12 R 13 , —OR 12 , phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, and benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and an amino acid group;
or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;
R 10 is optionally present and, if present, is selected from the group consisting of H, —OR 12 , (CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, benzyl, a carbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , phenyl, or benzyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 12 and R 13 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n NR 16 R 17 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 16 R 17 , (CH 2 ) n OC(O)NR 16 R 17 , —(CH 2 ) n NR 16 C(O)OR 17 , —(CH 2 ) n NC(O)NR 16 R 17 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n NR 16 R 17 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 16 R 17 , —(CH 2 ) n OC(O)NR 16 R 17 , —(CH 2 ) n NR 16 C(O)OR 17 , —(CH 2 ) n NC(O)NR 16 R 17 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, C 1 -C 4 alkoxy, an amino acid group, or [NR 11 C(O)(CH 2 ) n ] m NR 16 R 17 , which is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy, aryl alkyl, wherein the C 1 -C 4 alkyl and the aryl alkyl substituents are optionally substituted 1 to 3 times with halogen, alkyl, OH, NH 2 , —CO 2 H, —C(O)NH 2 , —NHC(O)NH 2 , —NHC(NH)NH 2 , imidazole, pyrrolidine, SMe, SH, or SeH;
or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 14 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —S(O) q R 12 , —(CH 2 ) n NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , (CH 2 ) n NR 11 C(O)OR 12 , —(CH 2 ) n NC(O)NR 12 R 13 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , —(CH 2 ) n NR 11 C(O)OR 12 , —(CH 2 ) n NC(O)NR 12 R 13 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —NO 2 , OR 12 , —NR 12 R 13 , or an amino acid group;
R 15 is H, C 1 -C 4 alkyl, arylalkyl, heteroarylalkyl C 1 -C 4 haloalkyl, or phenyl, wherein each of C 1 -C 4 alkyl, arylalkyl, heteroarylalkyl C 1 -C 4 haloalkyl, and phenyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 16 and R 17 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , —C(O)OR 15 , phenyl, or benzyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and an amino acid group;
or R 16 and R 17 are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
X is O or N;
Y is O or N;
m is 0, 1, 2, or 3;
n is 0 to 5;
q is 0, 1, or 2; and
represents an optional double bond;
with the provisos: (1) if R 1 is H, R 2 is OCH 3 , R 3 is H, R 4 is OH or H, R 5 is H, R 7 is H, R 8 and R 9 are combined to form an oxo, R 10 is H, and X and Y are O, then at least one of R 1 to R 10 is a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, or a carbonate moiety; and (2) that X, R 6 , R 8 , and R 9 can form a dihydroquinone ring;
or a pharmaceutically acceptable salt thereof.
2. The therapeutic according to claim 1 , wherein R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , arylalkyl, and heteroarylalkyl, wherein n is 1.
3. The therapeutic according to claim 1 , wherein R 2 is —OR 14 or —NR 12 R 13 .
4. The therapeutic according to claim 1 , wherein R 3 is selected from the group consisting of H, halogen, —NR 12 R 13 , and —NO 2 .
5. The therapeutic according to claim 1 , wherein R 4 is OH.
6. The therapeutic according to claim 1 , wherein R 4 is ═NOH.
7. The therapeutic according to claim 1 , wherein R 5 is H or C 1 -C 6 alkyl.
8. The therapeutic according to claim 1 , wherein R 6 is selected from the group consisting of H, —OR 14 , and —(CH 2 ) n (O)R 11 .
9. The therapeutic according to claim 1 , wherein R 7 is H or halogen.
10. The therapeutic according to claim 1 , wherein R 8 is C 1 -C 6 alkyl or phenyl, wherein phenyl is optionally substituted from 1 to 3 times with halogen.
11. The therapeutic according to claim 1 , wherein R 9 is OH.
12. The therapeutic according to claim 1 , wherein R 8 and R 9 are combined to form an oxo group.
13. The therapeutic according to claim 1 , wherein R 10 is H or —OR 14 .
14. The therapeutic according to claim 1 , wherein X is O.
15. The therapeutic according to claim 1 , wherein X is N.
16. The therapeutic according to claim 1 , wherein Y is O.
17. The therapeutic according to claim 1 , wherein Y is N.
18. The therapeutic according to claim 1 , wherein X is N, R 6 is —NR 12 R 13 , and R 12 is H.
19. The therapeutic according to claim 1 , wherein X, R 6 , R 8 and R 9 form a dihydroquinone ring having the formula:
20. The therapeutic according to claim 1 , wherein at least one of R 1 to R 10 is a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, or a carbonate moiety.
21. The therapeutic according to claim 1 , wherein the structure is selected from the group consisting of:
22. The therapeutic according to claim 1 , wherein the structure is selected from the group consisting of:
23. The therapeutic according to claim 1 , wherein the structure is selected from the group consisting of:
24. The therapeutic according to claim 1 , wherein the structure is selected from the group consisting of:
25. The therapeutic according to claim 1 , wherein the structure is selected from the group consisting of:
26. The therapeutic according to claim 1 having the formula:
27. The therapeutic according to claim 1 , wherein the structure is selected from the group consisting of:
28. The therapeutic according to claim 1 having the formula:
29. A pharmaceutical composition comprising a therapeutically effective amount of the therapeutic according to claim 1 and a pharmaceutically acceptable carrier.
30. A method of treating a bacterial infection comprising:
selecting a subject with a bacterial infection; and
administering to the subject a therapeutically effective amount of a therapeutic according to claim 1 .
31. The method according to claim 30 , wherein the subject is a human and the bacterial infection is a multi-drug resistant bacterial infection.
32. The method according to claim 31 , wherein the multi-drug resistant bacterial infection is a multi-drug resistant strain of Staphylococcus aureus, Streptococcus pneumoniae , or Enterococci.
33. The method according to claim 30 , wherein the bacterial infection is selected from the group consisting of epidermal infection, acne, complicated skin and soft tissue bacterial infection, and bacterial pneumonia.
34. An isolated therapeutic having a structure of formula I as follows:
wherein:
the carbohydrate anomeric carbon designated * is in the R or S configuration;
R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , arylalkyl, heteroarylalkyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , arylalkyl, and heteroarylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —NO 2 , —OR 12 , or —NR 12 R 13 ;
R 2 is selected from the group consisting of H, —OR 12 , —NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 3 is selected from the group consisting of H, halogen, —OR 12 , —NR 12 R 13 , —NR 12 C(O)R 13 , NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) q R 12 , —CN, —NO 2 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;
R 4 is selected from the group consisting of H, halogen, —OR 12 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , phenyl, benzyl, ═NOR 14 , ═NR 14 , a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;
R 5 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 6 is optionally present and, if present, is selected from the group consisting of H, —OR 12 , —NR 12 R 13 , —(CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n (O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
or R 5 and R 6 can combine to form a heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and optionally substituted 1 to 3 times with halogen, oxo, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 7 is selected from the group consisting of H, halogen, —OR 12 , —NR 12 R 13 , —NR 12 C(O)R 13 , —NR 12 C(O) 2 R 13 , —NR 12 C(O)NR 12 R 13 , —S(O) q R 12 , —CN, —NO 2 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, heteroaryl, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , an amino acid group, and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 12 , or —NR 12 R 13 ;
R 8 and R 9 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , —OR 12 , phenyl, benzyl, a benzyl ether moiety, a carbamate moiety, and a carbonate moiety, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , phenyl, and benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and an amino acid group;
or R 8 and R 9 can combine to form an oxo, thio, imine, or an ═NR 14 moiety;
R 10 is optionally present and, if present, is selected from the group consisting of H, —OR 12 , (CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, benzyl, a carbohydrate, a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, and a carbonate moiety, wherein each of —(CH 2 ) n C(O)R 11 , —(CH 2 ) n C(O)NR 12 R 13 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, —NO 2 , —NR 12 R 13 , —OR 12 , C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
or R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each, independently, an O-glycosidic bond, an N-glycosidic bond, a C-glycosidic bond, or a peptide bond;
R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , phenyl, or benzyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 12 and R 13 are each independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n NR 16 R 17 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 16 R 17 , (CH 2 ) n OC(O)NR 16 R 17 , —(CH 2 ) n NR 16 C(O)OR 17 , —(CH 2 ) n NC(O)NR 16 R 17 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n NR 16 R 17 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 16 R 17 , —(CH 2 ) n OC(O)NR 16 R 17 , —(CH 2 ) n NR 16 C(O)OR 17 , —(CH 2 ) n NC(O)NR 16 R 17 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, OH, C 1 -C 4 alkoxy, an amino acid group, or [NR 11 C(O)(CH 2 ) n ] m NR 16 R 17 , which is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy, aryl alkyl, wherein the C 1 -C 4 alkyl and the aryl alkyl substituents are optionally substituted 1 to 3 times with halogen, alkyl, OH, NH 2 , —CO 2 H, —C(O)NH 2 , —NHC(O)NH 2 , —NHC(NH)NH 2 , imidazole, pyrrolidine, SMe, SH, or SeH;
or R 12 and R 13 are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 14 is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —S(O) q R 12 , —(CH 2 ) n NR 12 R 13 , —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , (CH 2 ) n NR 11 C(O)OR 12 , —(CH 2 ) n NC(O)NR 12 R 13 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —(CH 2 ) n C(O)R 11 , —(CH 2 ) n OC(O)R 11 , —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n NC(O)NR 12 R 13 , —(CH 2 ) n OC(O)NR 12 R 13 , —(CH 2 ) n NR 11 C(O)OR 2 , —(CH 2 ) n NC(O)NR 12 R 13 , aryl, heteroaryl, arylalkyl, and heteroarylalkyl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 12 , —NR 12 R 13 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —NO 2 , —OR 12 , —NR 12 R 13 , or an amino acid group;
R 15 is H, C 1 -C 4 alkyl, arylalkyl, heteroarylalkyl C 1 -C 4 haloalkyl, or phenyl, wherein each of C 1 -C 4 alkyl, arylalkyl, heteroarylalkyl C 1 -C 4 haloalkyl, and phenyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, or an amino acid group;
R 16 and R 17 are each independently H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , —C(O)OR 15 , phenyl, or benzyl, wherein each of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, and benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, and an amino acid group;
or R 16 and R 17 are taken together with the nitrogen to which they are attached to form a five- to seven-membered heterocyclic ring, which may be saturated or unsaturated and comprises from 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and is optionally substituted from 1 to 4 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, oxo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
X is O or N;
Y is O or N;
m is 0, 1, 2, or 3;
n is 0 to 5;
q is 0, 1, or 2; and
represents an optional double bond;
with the provisos: (1) if R 1 is H, R 2 is OCH 3 , R 3 is H, R 4 is OH or H, R 5 is H, R 7 is H, R 8 and R 9 are combined to form an oxo, R 10 is H, and X and Y are O, then at least one of R 1 to R 10 is an O-glycosidic bond, an N-glycosidic bond, a C-glycosidic bond, or a peptide bond; and (2) that X, R 6 , R 8 , and R 9 can form a dihydroquinone ring;
or a pharmaceutically acceptable salt thereof.
35. The therapeutic according to claim 34 , wherein R 1 is selected from the group consisting of H, C 1 -C 6 alkyl, —(CH 2 ) n C(O) 2 R 11 , —(CH 2 ) n C(O)NR 12 R 13 , arylalkyl, and heteroarylalkyl, wherein n is 1.
36. The therapeutic according to claim 34 , wherein R 2 is —OR 14 or —NR 12 R 13 .
37. The therapeutic according to claim 34 , wherein R 3 is selected from the group consisting of H, halogen, —NR 12 R 13 , and —NO 2 .
38. The therapeutic according to claim 34 , wherein R 4 is OH.
39. The therapeutic according to claim 34 , wherein R 4 is ═NOH.
40. The therapeutic according to claim 34 , wherein R 5 is H or C 1 -C 6 alkyl.
41. The therapeutic according to claim 34 , wherein R 6 is selected from the group consisting of H, —OR 14 , and —(CH 2 ) n (O)R 11 .
42. The therapeutic according to claim 34 , wherein R 7 is H or halogen.
43. The therapeutic according to claim 34 , wherein R 8 is C 1 -C 6 alkyl or phenyl, wherein phenyl is optionally substituted from 1 to 3 times with halogen.
44. The therapeutic according to claim 34 , wherein R 9 is OH.
45. The therapeutic according to claim 34 , wherein R 8 and R 9 are combined to form an oxo group.
46. The therapeutic according to claim 34 , wherein R 10 is H or —OR 14 .
47. The therapeutic according to claim 34 , wherein X is O.
48. The therapeutic according to claim 34 , wherein X is N.
49. The therapeutic according to claim 34 , wherein Y is O.
50. The therapeutic according to claim 34 , wherein Y is N.
51. The therapeutic according to claim 34 , wherein X is N, R 6 is —NR 12 R 13 , and R 12 is H.
52. The therapeutic according to claim 34 , wherein X, R 6 , R 8 and R 9 form a dihydroquinone ring having the formula:
53. The therapeutic according to claim 34 , wherein at least one of R 1 to R 10 is a benzyl ether moiety, a carbamate moiety, an ═NR 14 moiety, or a carbonate moiety.
54. The therapeutic according to claim 1 , wherein the structure is selected from the group consisting of:
55. The therapeutic according to claim 34 , wherein the structure is selected from the group consisting of:
56. The therapeutic according to claim 34 , wherein the structure is selected from the group consisting of:
57. The therapeutic according to claim 34 , wherein the structure is selected from the group consisting of:
58. The therapeutic according to claim 34 , wherein the structure is selected from the group consisting of:
59. The therapeutic according to claim 34 having the formula:
60. The therapeutic according to claim 34 , wherein the structure is selected from the group consisting of:
61. The therapeutic according to claim 34 having the formula:
62. A pharmaceutical composition comprising a therapeutically effective amount of the therapeutic according to claim 34 and a pharmaceutically acceptable carrier.
63. A method of treating a bacterial infection comprising:
selecting a subject with a bacterial infection; and
administering to the subject a therapeutically effective amount of a therapeutic according to claim 34 .
64. The method according to claim 63 , wherein the subject is a human and the bacterial infection is a multi-drug resistant bacterial infection.
65. The method according to claim 64 , wherein the multi-drug resistant bacterial infection is a multi-drug resistant strain of Staphylococcus aureus, Streptococcus pneumoniae , or Enterococci.
66. The method according to claim 63 , wherein the bacterial infection is selected from the group consisting of epidermal infection, acne, complicated skin and soft tissue bacterial infection, and bacterial pneumonia.
67. A method for making a product compound having the formula:
said method comprising:
culturing a culture medium comprising Streptomyces strain AMRI-45379 under conditions effective to produce a suspension comprising the product compound, and
isolating the product compound.