Lipo-glycopeptide cleavable derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-2022024980-A1
Application number	US-201917295360-A
Country	US
Kind code	A1
Filing date	Nov 20, 2019
Priority date	Nov 21, 2018
Publication date	Jan 27, 2022
Grant date	—

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. The bacterial infection can comprise intracellular bacteria, planktonic bacteria, bacteria present in a biofilm, or a combination thereof.

First claim

1 . (canceled)

2 . A compound of Formula (II), or a pharmaceutically acceptable salt thereof:

wherein,
R 1 is —(CH 2 ) n1 —C(O)—O—(CH 2 ) n2 —CH 3 ; —(CH 2 ) n1 —C(O)—NH—(CH 2 ) n2 —CH 3 ; —C(O—CH 2 ) n2 —CH 3 ;

 (CH 2 ) n1 —NH—C(O)—(CH 2 ) n2 —CH 3 ; —(CH 2 ) n1 —O—C(O)—(CH 2 ) n2 —CH 3 ; —(CH 2 ) n1 —O—C(O)—NH—(CH 2 ) n2 —CH 3 ; —(CH 2 ) n1 —O—(CO)—O—(CH 2 ) n2 —CH 3 or —(CH 2 ) n1 —NH—C(O)—O—(CH 2 ) n2 —CH 3 ;
R 2 is

R 3 is H or

R 4 is OH or NH—(CH 2 ) q —R 5 ;
R 5 is —N(CH 3 ) 2 , —N + (CH 3 ) 3 , —N + (CH 3 ) 2 (n-C 14 H 29 ), or

 and
R′ is diethanolamine, a monosaccharide, disaccharide, amino acid, or peptide, wherein the peptide has from 2 to 5 amino acids;
n1 is 1, 2, 3, 4 or 5;
n2 is 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;
n3 is 1, 2 or 3; and
q is 1, 2, 3, 4, or 5.

3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 3 is H.

4 . (canceled)

5 . The compound of claim 2 , wherein R 4 is OH.

6 - 23 . (canceled)

24 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —(CH 2 ) n1 —NH—C(O)—(CH 2 ) n2 —CH 3 .

25 - 26 . (canceled)

27 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —(CH 2 ) n1 —C(O)—NH—(CH 2 ) n2 —CH 3 .

28 - 33 . (canceled)

34 . The compound of claim 24 , or a pharmaceutically acceptable salt thereof, wherein n1 is 2.

35 . (canceled)

36 . The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein n1 is 2.

37 - 43 . (canceled)

44 . The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein n2 is 10.

45 . The compound of claim 36 , or a pharmaceutically acceptable salt thereof, wherein n2 is 11.

46 - 48 . (canceled)

49 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein n3 is 1.

50 - 51 . (canceled)

52 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R′ is diethanolamine.

53 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R′ is an amino acid.

54 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein R′ is a dipeptide.

55 - 58 . (canceled)

59 . The compound of claim 53 , or a pharmaceutically acceptable salt thereof, wherein the amino acid is D-alanine, β-alanine, aspartic acid, glutamic acid, iminodiacetic acid, or glycine.

60 - 66 . (canceled)

67 . A method of treating a bacterial infection in a patient in need of treatment, comprising administering to the patient a composition comprising an effective amount of compound of claim 2 , or a pharmaceutically acceptable salt thereof.

68 - 81 . (canceled)

82 . The method of claim 67 , wherein the bacterial infection is a bacterial pulmonary infection.

83 . The method of claim 82 , wherein the administering comprises administering to the lungs of the patient via a nebulizer, a metered dose inhaler, or a dry powder inhaler.

84 - 92 . (canceled)

93 . The method of claim 67 , wherein the bacterial infection is a Staphylococcus aureus ( S. aureus ) infection.

94 . The method of claim 93 , wherein the S. aureus infection is a methicillin-resistant S. aureus (MRSA) infection.

95 - 127 . (canceled)

128 . The method of claim 67 , wherein the patient is a cystic fibrosis patient.

129 - 132 . (canceled)

Assignees

• Insmed Inc

Inventors

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

Classifications

• C07K9/008 Primary

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

• A61P31/04

  Antibacterial agents · CPC title

• A61K38/14

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

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/64 Primary

  Cyclic peptides containing only normal peptide links · CPC title