Methods of preparing substituted tetracyclines with transition metal-based chemistries
View Patent ↗The present invention relates to 9-substituted tetracycline derivatives as well as compositions and use thereof.
1. A 9-substituted tetracycline analog, wherein said substituent at the 9 position is connected with a —C—C— linkage, and wherein said substituent comprises an aromatic or heteroaromatic moiety.
2. A 9-substituted tetracycline analog, wherein said substituent at the 9 position is connected with a —C—C— linkage, and wherein said substituent comprises a —C═C— bond adjacent to said —C—C— linkage.
3. The 9-substituted tetracycline analog of claim 2 , wherein said substituent is of the formula
wherein R 2 and R 3 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aryloxycarbonyl, amino, hydroxy, cyano, alkoxy, aryloxy, carboxyl, alkoxycarbonyl, aryloxycarbonyl; or R 2 and R 3 , taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having 5 to 15 atoms in the ring.
4. The 9-substituted tetracycline analog of claim 3 , wherein R 2 is hydrogen, and R 3 is carboxyl, wherein said carboxyl is
and where R 4 is hydrogen, cyano, or a C 1 -C 5 alkoxy group.
5. The 9-substituted tetracycline analog of claim 3 , wherein R 2 and R 3 , taken together, form a substituted or unsubstituted carbocyclic or heterocyclic ring having 5 to 15 atoms in the ring.
6. The 9-substituted tetracycline analog of claim 5 , wherein said substituted or unsubstituted carbocyclic or heterocyclic ring is selected from the group consisting of conjugated and unconjugated aromatic ring systems.
7. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted oxytetracycline or demeclocycline.
8. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted doxycycline or tetracycline.
9. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted chelocardin, rolitetracycline, or lymecycline.
10. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted sancycline.
11. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted methacycline.
12. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted apicycline, guamecycline, or meglucycline.
13. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted penimepicycline, pipacycline, or penimocycline.
14. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said tetracycline analog is 9-substituted minocycline.
15. The 9-substituted tetracycline analog of claim 14 , wherein said tetracycline analog is 9-phenyl minocycline.
16. The 9-substituted tetracycline analog of claim 1 , wherein said substituent is
17. The 9-substituted tetracycline analog of claim 1 , wherein said substituent is
18. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said analog has an MIC value of 10 μg/mL or less against tetracycline-resistant strains of E. coli, S. aureus or E. faecalis.
19. The 9-substituted tetracycline analog of claim 18 , wherein said analog has an MIC value of 1 μg/mL or less against tetracycline-resistant strains of E. coli, S. aureus or E. faecalis.
20. The 9-substituted tetracycline analog of claim 1 or 2 , wherein said analog has an MIC value of 10 μg/mL or less against tetracycline sensitive strains of E. coli, S. aureus or E. faecalis.
21. The 9-substituted tetracycline analog of claim 20 , wherein said analog has an MIC value of 1 μg/mL or less against tetracycline sensitive strains of E. coli, S. aureus or E. faecalis.
22. A pharmaceutical composition, comprising a 9-substituted tetracycline analog of claim 1 or 2 and a pharmaceutically acceptable carrier.
23. A method of treating a subject, comprising administering an effective amount of a substituted tetracycline compound of claim 1 or 2 to a subject suffering from a microorganism infection caused by E. coli, S. aureus, S. warnerii, E. hirae or E. faecalis , such that said subject is treated.
24. The method of claim 23 , wherein said subject is a mammal.
25. The method of claim 24 , wherein said mammal is a human.