Depsipeptide and uses thereof
The present invention relates generally to novel depsipeptides, to methods for the preparation of these novel depsipeptides, to pharmaceutical compositions comprising the novel depsipeptides; and to methods of using the novel depsipeptides to treat or inhibit various disorders.
1. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (II):
or tautomer or pharmaceutically-acceptable salt thereof, thereby treating the bacterial infection in said subject.
2. The method of claim 1 , wherein the bacterial infection is caused by a Gram-positive bacterium.
3. The method of claim 2 , wherein the Gram-positive bacterium is selected from the group consisting of Streptococcus, Staphylococcus, Enterococcus, Corynebacteria, Listeria, Bacillus, Erysipelothrix, Mycobacterium, Clostridium, Propionibacterium , and Actinomycetales.
4. The method of claim 2 , wherein the Gram-positive bacterium is selected from the group consisting of methicillin-susceptible and methicillin-resistant staphylococci (including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus , and coagulase-negative staphylococci), glycopeptide intermediate-susceptible Staphylococcus aureus (GISA), penicillin-susceptible and penicillin-resistant streptococci (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sangius, Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus and Streptococci Group C, Streptococci Group G and Viridans streptococci), enterococci (including vancomycin-susceptible and vancomycin-resistant strains such as Enterococcus faecalis and Enterococcus faecium ), Clostridium difficile, Clostridium clostridiiforme, Clostridium innocuum, Clostridium perfringens, Clostridium tetani, Propionibacterium acnes, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansaii, Mycobacterium gordonae, Mycobacteria sporozoites, Listeria monocytogenes, Bacillus subtilis, Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Corynebacterium sporozoites, Erysipelothrix rhusiopathiae , and Actinomyces israelli.
5. The method of claim 2 , wherein the bacterial infection is caused by Bacillus anthracis.
6. The method of claim 1 , wherein the bacterial infection is caused by a Gram-negative bacterium.
7. The method of claim 6 , wherein the Gram-negative bacterium is selected from the group consisting of Haemophilus influenzae, Moraxella catarrhalis , and Escherichia coli.
8. The method of claim 1 , wherein said effective amount of the compound is 1 μg/kg-100 mg/kg.
9. The method of claim 1 , wherein said effective amount of the compound is 1 μg/kg-50 mg/kg.
10. The method of claim 1 , wherein said effective amount of the compound is 10 μg/kg-10 mg/kg.
11. The method of claim 1 , wherein said compound is administered via a route selected from the group consisting of oral, parenteral, transdermal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intraocular, intraaural, colorectal, rectal, intravaginal, and any combinations thereof.
12. The method of claim 1 , wherein said compound is administered daily, weekly, monthly or yearly.
13. The method of claim 1 , wherein said composition is administered daily for about a week, two weeks, three weeks, one month, three months, six months or a year.
14. The method of claim 1 , wherein said subject is a human.
15. A method of treating a bacterial infection in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula (III):
or a tautomer or pharmaceutically-acceptable salt thereof; wherein each R 1 -R 6 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, C(═O)R a and S(═O) 2 R b ; each R a is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl; and each R b is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, or aryl, thereby treating the bacterial infection in said subject.
16. The method of claim 15 , wherein the bacterial infection is caused by a Gram-positive bacterium.
17. The method of claim 16 , wherein the Gram-positive bacterium is selected from the group consisting of Streptococcus, Staphylococcus, Enterococcus, Corynebacteria, Listeria, Bacillus, Erysipelothrix, Mycobacterium, Clostridium, Propionibacterium , and Actinomycetales.
18. The method of claim 16 , wherein the Gram-positive bacterium is selected from the group consisting of methicillin-susceptible and methicillin-resistant staphylococci (including Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus hominis, Staphylococcus saprophyticus , and coagulase-negative staphylococci), glycopeptide intermediate-susceptible Staphylococcus aureus (GISA), penicillin-susceptible and penicillin-resistant streptococci (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus avium, Streptococcus bovis, Streptococcus lactis, Streptococcus sangius, Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus and Streptococci Group C, Streptococci Group G and Viridans streptococci), enterococci (including vancomycin-susceptible and vancomycin-resistant strains such as Enterococcus faecalis and Enterococcus faecium ), Clostridium difficile, Clostridium clostridiiforme, Clostridium innocuum, Clostridium perfringens, Clostridium tetani, Propionibacterium acnes, Mycobacterium tuberculosis, Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansaii, Mycobacterium gordonae, Mycobacteria sporozoites, Listeria monocytogenes, Bacillus subtilis, Bacillus anthracis, Corynebacterium diphtheriae, Corynebacterium jeikeium, Corynebacterium sporozoites, Erysipelothrix rhusiopathiae , and Actinomyces israelli.
19. The method of claim 16 , wherein the bacterial infection is caused by Bacillus anthracis.
20. The method of claim 15 , wherein the bacterial infection is caused by a Gram-negative bacterium.
21. The method of claim 20 , wherein the Gram-negative bacterium is selected from the group consisting of Haemophilus influenzae, Moraxella catarrhalis , and Escherichia coli.
22. The method of claim 15 , wherein said effective amount of the compound is 1 μg/kg-100 mg/kg.
23. The method of claim 15 , wherein said effective amount of the compound is 1 μg/kg-50 mg/kg.
24. The method of claim 15 , wherein said effective amount of the compound is 10 μg/kg-10 mg/kg.
25. The method of claim 15 , wherein said compound is administered via a route selected from the group consisting of oral, parenteral, transdermal, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, intraocular, intraaural, colorectal, rectal, intravaginal, and any combinations thereof.
26. The method of claim 15 , wherein said compound is administered daily, weekly, monthly or yearly.
27. The method of claim 15 , wherein said composition is administered daily for about a week, two weeks, three weeks, one month, three months, six months or a year.
28. The method of claim 15 , wherein said subject is a human.