Lipo-glycopeptide cleavable derivatives and uses thereof
The present invention provides certain lipo-glycopeptide cleavable derivatives and methods for using the same for the treatment of bacterial infections, for example, pulmonary bacterial infections. The LGPC derivatives include a cleavable moiety that in certain embodiments, is designed to allow for cellular uptake and/or a more rapid clearance of the glycopeptide metabolite (i.e., the cleaved glycopeptide) from the site of administration (e.g., the lung) as compared to the uncleaved LGPC.
1. A method for treating a Gram positive pulmonary bacterial infection in a patient in need thereof, the method comprising:
administering to the lungs of the patient via a nebulizer, dry powder inhaler (DPI) or metered dose inhaler (MDI), a composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof:
wherein,
R 1 is —(CH 2 ) n1 —C(O)—NH—(CH 2 ) n2 —CH 3 ; —(CH 2 ) n1 —NH—C(O)—(CH 2 ) n2 —CH 3 ; or —(CH 2 ) n1 —O—C(O)—(CH 2 ) n2 —CH 3 ;
n1 is 1, 2, 3, 4 or 5;
n2 is 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;
R 2 is OH or NH—(CH 2 ) q —R 5 ;
q is 1, 2, 3, 4, or 5;
R 3 is H or
R 4 is H or CH 2 —NH—CH 2 —PO 3 H 2 ; and
R 5 is —N(CH 3 ) 2 , —N + (CH 3 ) 3 , —N + (CH 3 ) 2 (n-C 14 H 29 ), or
2. The method of claim 1 , wherein R 1 is —(CH 2 ) n1 —NH—C(O)—(CH 2 ) n2 —CH 3 or —(CH 2 ) n1 —O—C(O)—(CH 2 ) n2 —CH 3 .
3. The method of claim 1 , wherein R 1 is —(CH 2 ) n1 —O—C(O)—(CH 2 ) n2 —CH 3 .
4. The method of claim 1 , wherein R 1 is —(CH 2 ) n1 —NH—C(O)—(CH 2 ) n2 —CH 3 .
5. The method of claim 1 , wherein R 1 is —(CH 2 ) n1 —C(O)—NH—(CH 2 ) n2 —CH 3 .
6. The method of claim 5 , wherein n1 is 1.
7. The method of claim 5 , wherein n2 is 9, 10, 11, 12, 13, 14.
8. The method of claim 6 , wherein n2 is 9, 10, 11, 12 or 13.
9. The method of claim 1 , wherein R 1 is —(CH 2 ) n1 —C(O)—NH—(CH 2 ) n2 —CH 3 , R 2 is OH, R 3 is H, R 4 is H, n1 is 1 and n2 is 9.
10. The method of claim 1 , wherein the administering is carried out via a dry powder inhaler.
11. The method of claim 1 , wherein the Gram-positive pulmonary bacterial infection is a Gram-positive pulmonary cocci infection.
12. The method of claim 11 , wherein the Gram-positive pulmonary cocci infection is a Staphylococcus pulmonary infection.
13. The method of claim 11 , wherein the Gram-positive pulmonary cocci infection is an Enterococcus pulmonary infection.
14. The method of claim 11 , wherein the Gram-positive pulmonary cocci infection is a Streptococcus pulmonary infection.
15. The method of claim 12 , wherein the Staphylococcus pulmonary infection is a Staphylococcus aureus ( S. aureus ) pulmonary infection.
16. The method of claim 15 , wherein the S. aureus pulmonary infection is a methicillin-resistant S. aureus (MRSA) pulmonary infection.
17. The method of claim 1 , wherein the patient is a cystic fibrosis patient.
18. The method of claim 4 , wherein n1 is 2.
19. The method of claim 18 , wherein n2 is 10.
20. The method of claim 1 , wherein R 1 is —(CH 2 ) n1 —NH—C(O)—(CH 2 ) n2 —CH 3 , R 2 is OH, R 3 is H, R 4 is H, n1 is 2 and n2 is 10.