9-substituted minocycline compounds
View Patent ↗The present invention pertains, at least in part, to novel 9-substituted minocycline compounds. These minocycline compounds can be used to treat numerous tetracycline compound-responsive states, such as bacterial infections and neoplasms, as well as other known applications for minocycline and tetracycline compounds in general, such as blocking tetracycline efflux and modulation of gene expression.
1. A minocycline compound of formula I:
wherein:
X is CHC(R 13 Y′Y) or CR 6 R 6′ ;
R 2 , R 4′ and R 4″ are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, or heteroaromatic;
R 7′ and R 7″ are each independently alkyl;
R 4 is NR 4′ R 4″ , alkyl, alkenyl, alkynyl, aryl, hydroxyl, or halogen;
R 2′ , R 3 , R 10 , R 11 and R 12 are each hydrogen;
R 5 is hydroxyl, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, alkyl carbonyloxy, or aryl carbonyloxy;
R 6 and R 6′ are each independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl;
R 9 is an unsubstituted single-ring aromatic group having zero heteroatoms or a single-ring aromatic group having zero heteroatoms substituted with alkyl, alkenyl, alkynyl, aryl, halogen, hydroxyl, alkoxy, formyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylaminoacarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylarylamino, acylamino, alkylcarbonylamino, arylcarbonylamino, carbamoyl, ureido, amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, aryl or a heteroaryl;
R 8 is hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl; and
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or arylalkyl, or pharmaceutically acceptable salts or esters thereof.
2. The minocycline compound of claim 1 , wherein R 4 is NR 4′ R 4″ ; X is CR 6 R 6′ ; R 2 , R 5 , R 6 , R 6′ and R 8 , are each hydrogen; and R 4′ , R 4″ , R 7′ and R 7″ are each lower alkyl.
3. The minocycline compound of claim 2 , wherein R 4′ , R 4″ , R 7′ , and R 7″ are each methyl.
4. The minocycline compound of claim 1 , wherein R 9 is unsubstituted phenyl.
5. The minocycline compound of claim 1 , wherein R 9 is phenyl substituted with one or more substituents selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, halogen, hydroxyl, alkoxy, formyl, alkylcarbonyloxy, arylcarbonyloxy, carboxyl, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylaminocarbonyl, arylalkyl aminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, arylalkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonato, phosphinato, amino, acylamino, amido, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, aryl and a heteroaryl.
6. The minocycline compound of claim 5 , wherein said phenyl is substituted with one or more substituents selected from the group consisting of carboxylate, alkyl, alkenyl, alkynyl, aryl, heterocyclic, cyano, amino, halogen, alkoxy, alkoxycarbonyl, amido, alkylcarbonyl, and nitro.
7. A method for treating a bacterial infection in a subject, comprising administering to said subject aminocycline compound of claim 1 , such that said subject is treated, wherein said bacterial infection is caused by a gram-positive bacterium or a gram-negative bacterium and said gram-positive bacterium is selected from the group consisting of S. aureus, E. hirae and E. faecalis and said gram-negative bacterium is selected from the group consisting of E. coli, K. pneumoniae, Salmonella, A. baumanii, B. catarrhalis and P. aeruginosa.
8. The method of claim 7 , wherein said bacterial infection is caused by E. coli.
9. The method of claim 7 , wherein said bacterial infection is caused by S. aureus.
10. The method of claim 7 , wherein said bacterial infection is caused by E. faecalis.
11. The method of claim 7 , wherein said minocycline compound is administered with a pharmaceutically acceptable carrier.
12. The method of claim 7 , wherein said subject is a human.
13. A pharmaceutical composition comprising a therapeutically effective amount of aminocycline compound of claim 1 and a pharmaceutically acceptable carrier.
14. A minocycline compound of the formula
or a pharmaceutically acceptable salt thereof.
15. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
16. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
17. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
18. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
19. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
20. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
21. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
22. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
23. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
24. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
25. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
26. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
27. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
28. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
29. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
30. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
31. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
32. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
33. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
34. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
35. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
36. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
37. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
38. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
39. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
40. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
41. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.
42. The minocycline compound of claim 1 , wherein said compound is:
or a pharmaceutically acceptable salt thereof.