Lipo-glycopeptide cleavable derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-11071769-B2
Application number	US-201816615214-A
Country	US
Kind code	B2
Filing date	May 22, 2018
Priority date	May 22, 2017
Publication date	Jul 27, 2021
Grant date	Jul 27, 2021

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Insmed Inc

Inventors

• Heckler Ryan
• Konicek Donna
• Plaunt Adam
• Malinin Vladimir
• Perkins Walter

Classifications

• C07K9/008

  directly attached to a hetero atom of the saccharide radical, e.g. actaplanin, avoparcin, ristomycin, vancomycin · CPC title

• A61P31/04 Primary

  Antibacterial agents · CPC title

• A61K38/14 Primary

  Peptides containing saccharide radicals; Derivatives thereof {, e.g. bleomycin, phleomycin, muramylpeptides or vancomycin} · CPC title

• A61K9/19

  lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)} · CPC title

• A61K9/1617

  Organic compounds, e.g. phospholipids, fats · CPC title