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EP-3630154-B1 - LIPO-GLYCOPEPTIDE CLEAVABLE DERIVATIVES AND USES THEREOF

EP3630154B1EP 3630154 B1EP3630154 B1EP 3630154B1EP-3630154-B1

Inventors

  • HECKLER, Ryan
  • KONICEK, Donna
  • PLAUNT, Adam
  • MALININ, VLADIMIR
  • PERKINS, WALTER

Dates

Publication Date
20260513
Application Date
20180522

Claims (17)

  1. A pharmaceutical composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, for use in treating a Gram positive pulmonary bacterial infection in a patient in need thereof, wherein the pharmaceutical composition is administered to the lungs of the patient via a nebulizer, dry powder inhaler (DPI) or metered dose inhaler (MDI): 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 pharmaceutical composition for use of claim 1, wherein R 2 is OH, R 3 is H and R 4 is H.
  3. The pharmaceutical composition for use of claim 1, wherein R 2 is OH, R 3 is and R 4 is H.
  4. The pharmaceutical composition for use of claim 1, wherein R 2 is OH, R 3 is H and R 4 is CH 2 -NH-CH 2 -PO 3 H 2 .
  5. The pharmaceutical composition for use of any one of claims 1-4, wherein R 1 is - (CH 2 ) n1 -NH-C(O)-(CH 2 ) n2 -CH 3 .
  6. The pharmaceutical composition for use of any one of claims 1-4, wherein R 1 is - (CH 2 ) n1 -O-C(O)-(CH 2 ) n2 -CH 3 .
  7. The pharmaceutical composition for use of any one of claims 1-4, wherein R 1 is - (CH 2 ) n1 -C(O)-NH-(CH 2 ) n2 -CH 3 .
  8. The pharmaceutical composition for use of any one of claims 1-7, wherein n1 is 1.
  9. The pharmaceutical composition for use of any one of claims 1-8, wherein n2 is 9, 10, 11, 12, 13, or 14.
  10. The pharmaceutical composition for use 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.
  11. The pharmaceutical composition for use of claim 1, wherein R 1 is -(CH 2 ) n1 -O-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 12.
  12. The pharmaceutical composition for use of any one of claims 1-11, wherein the pharmaceutical composition is administered to the lungs of the patient via a dry powder inhaler.
  13. The pharmaceutical composition for use of any one of claims 1-12, wherein the Gram-positive pulmonary bacterial infection is a Gram-positive cocci infection.
  14. The pharmaceutical composition for use of claim 13, wherein the Gram-positive cocci infection is a Staphylococcus, an Enterococcus, or a Streptococcus infection.
  15. The pharmaceutical composition for use of claim 14, wherein the Gram-positive cocci infection is a Staphylococcus infection and the Staphylococcus infection is a Staphylococcus aureus (S. aureus) infection.
  16. The pharmaceutical composition for use of claim 15, wherein the S. aureus infection is a methicillin-resistant S. aureus (MRSA) infection.
  17. The pharmaceutical composition for use of any one of claims 1-16, wherein the patient is a cystic fibrosis patient.

Description

BACKGROUND OF THE INVENTION The high frequency of multidrug resistant bacteria, and in particular, Gram-positive bacteria, both in the hospital setting and the community present a significant challenge for the management of infections (Krause et al. (2008). Antimicrobial Agents and Chemotherapy 52(7), pp. 2647-2652). The treatment of invasive Staphylococcus aureus (S. aureus) infections has relied significantly on vancomycin. However, the treatment and management of such infections is a therapeutic challenge because certain S. aureus isolates, and in particular, methicillin-resistant S. aureus isolates, have been shown to be resistant to vancomycin (Shaw et al. (2005). Antimicrobial Agents and Chemotherapy 49(1), pp. 195-201; Mendes et al. (2015). Antimicrobial Agents and Chemotherapy 59(3), pp. 1811-1814). Chinese Patent Application Publication No. CN 105085636A describes vancomycin derivatives and their use in treating and/or preventing diseases related to gram negative bacterial infections. International Patent Application Publication No. WO 2009/042187 A1 describes systems and methods for the pulmonary delivery of a glycopeptide, such as vancomycin. de Jesús Valle MJ et al., "Pulmonary versus systemic delivery of antibiotics: comparison of vancomycin dispositions in the isolated rat lung," Antimicrob Agents Chemother. 51(10):3771-4 (2007) compares vancomycin dispositions in the respiratory system after systemic and inhalatory administration under two respiratory conditions using the isolated-lung model. Because of the resistance displayed by many Gram-positive organisms to antibiotics, and the general lack of susceptibility to existing antibiotics, there is a need for new therapeutic strategies to combat infections due to these bacteria. The present invention addresses this and other needs. SUMMARY OF THE INVENTION The invention is set out in the claims. The references to the methods of treatment by therapy of this description are to be interpreted as references to compounds, pharmaceutical compositions and medicaments of the present invention for use in those methods. The present invention addresses the need for new antibiotics by providing certain glycopeptides containing a primary amino conjugated lipophilic moiety that is cleavable by enzymatic hydrolysis for use. The lipophilic moiety is conjugated to the primary amino group via a functional group that can undergo enzymatic hydrolysis. Glycopeptides for use in the present invention are referred to herein in various embodiments, as lipo-glycopeptide cleavable (LGPC) derivatives. Without being bound by any particular theory or mechanism, it is believed that the cleavage of the lipophilic moiety promotes clearance of the glycopeptide from the site of administration. The LGPC derivative may clear more rapidly from the site of administration (the lung) as compared to a structurally similar glycopeptide having a non-cleavable lipophilic moiety conjugated to the counterpart primary amino group. In the present invention, a compound for use in the invention is represented by Formula (II), or a pharmaceutically acceptable salt thereof: wherein, R1 is -(CH2)n1-C(O)-NH-(CH2)n2-CH3; -(CH2)n1-NH-C(O)-(CH2)n2-CH3; or -(CH2)n1-O-C(O)-(CH2)n2-CH3;n1 is 1, 2, 3 ,4 or 5;n2 is 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15;R2 is OH or NH-(CH2)q-R5;q is 1, 2, 3, 4, or 5;R3 is H or R4 is H or CH2-NH-CH2-PO3H2; andR5 is -N(CH3)2, -N+(CH3)3, -N+(CH3)2(n-C14H29), or In one embodiment, n1 is 1 or 2, and n2 is 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15. In a further embodiment, R2 is OH or NH-(CH2)3-N(CH3)2; and R3 is H. In a further embodiment, n2 is 6, 7, 8, 9, 10, 11, 12, or 14. In one embodiment, R1 is -(CH2)n1-NH-C(O)-(CH2)n2-CH3 or -(CH2)n1-O-C(O)-(CH2)n2-CH3. In a further embodiment, n1 is 1, 2, 3 or 4, and n2 is 9, 10 or 11. In even a further embodiment, n1 is 2 and n2 is 10. In still even a further embodiment, R2 is OH, R3 is H and R4 is H. In one embodiment, R1 is -(CH2)n1-NH-C(O)-(CH2)n2-CH3. In a further embodiment, n1 is 1, 2, 3 or 4, and n2 is 9, 10 or 11. In even a further embodiment, n1 is 2 and n2 is 10. In still even a further embodiment, R2 is OH, R3 is H and R4 is H. In one embodiment, R1 is-(CH2)n1-O-C(O)-(CH2)n2-CH3. In a further embodiment, n1 is 1, 2, 3 or 4, and n2 is 9, 10 or 11. In even a further embodiment, n1 is 2 and n2 is 10. In still even a further embodiment, R2 is OH, R3 is H and R4 is H. In another embodiment, R2 is -NH-(CH2)q-R5. In a further embodiment, q is 3 and R5 is -N(CH3)2. In even a further embodiment, n1 is 1, 2, 3 or 4 and n2 is 9, 10 or 11. In still even a further embodiment, R3 is H and R4 is H. In even a further embodiment, R1 includes an amide group. In another embodiment, R2 is -NH-(CH2)q-R5. In a further embodiment, q is 3 and R5 is -N(CH3)2. In even a further embodiment, n1 is 1, 2, 3 or 4 and n2 is 9, 10 or 11. In still even a further embodiment, R3 is H and R4 is H. In even a further embodiment, R1 includes an ester group. In another e