Targeting aminoacid lipids

Patent metadata

Field	Value
Publication number	US-11510988-B2
Application number	US-201815867985-A
Country	US
Kind code	B2
Filing date	Jan 11, 2018
Priority date	Mar 16, 2012
Publication date	Nov 29, 2022
Grant date	Nov 29, 2022

Abstract

The present invention is directed to carrier systems comprising ether-lipids conjugated to one or more bioactive ligands and exposed on the surface of the carrier system for use in targeted delivery and/or antigen display systems. Optionally one or more further bioactive agents may be encapsulated or embedded within or attached to or adsorbed onto the carrier system. The present invention is further directed to methods of their preparation and their uses in medical applications, such as targeted delivery of bioactive agents to specific tissues or cells and antigen display systems for the study, diagnosis, and treatment of traits, diseases and conditions that respond to said bioactive agents.

First claim

The invention claimed is:

1. A carrier system comprising a compound of formula I

wherein
Y represents O, N, S or a covalent bond,
S 1 , S 2 , S 3 represent independently of each other a covalent bond or a spacer group,
X 1 , X 2 , X 3 represent independently of each other H or a ligand group or any two of X 1 , X 2 , X 3 may together form a ligand group, wherein at least one of X 1 , X 2 , X 3 is a legumain targeting ligand group,
L is a group of formula (a)

wherein the dashed line represents the linkage to N,
R 1 represents H or a group of formula —(CH 2 ) 2 —OR b1 ,
R 1 ′ represents H or a group of formula —(CH 2 ) 2 —OR b2 ,
R 2 represents H or a group of formula —CH 2 —OR c ,
R 2 ′ represents H or a group of formula —OR d or —CH 2 —OR d ,
R 3 represents H or a group of formula —(CH 2 ) 2 —OR e or —(CH 2 ) 3 —OR e ,
R a , R b1 , R b2 ,
R c , R d , R e represent independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain,
m is 1, 2 or 3,
with the proviso that at least one of R 1 , R 1 ′, R 2 , R 2 ′, R 3 is not H,
and
wherein at least one of the following conditions is satisfied:
the carrier system comprises a pharmaceutically active agent in a solvated form;
or
the carrier system comprises one or more pteroyl derivatives and/or aza-peptide derivatives;
or
the carrier system has been lyophilized or freeze-dried and therefore has enhanced stability;
or
wherein at least one of X 1 , X 2 , X 3 is a ligand that is capable of binding to an antibody, antibody fragment, engineered antibody or an antibody mimic.

2. The carrier system according to claim 1 , which comprises a pharmaceutically active agent in a solvated form.

3. The carrier system according to claim 1 , which comprises one or more pteroyl derivatives and/or aza-peptide derivatives.

4. The carrier system according to claim 1 , which has been lyophilized or freeze-dried and therefore has enhanced stability.

5. The carrier system according to claim 1 , wherein at least one of X 1 , X 2 , X 3 is a ligand that is capable of binding to an antibody, antibody fragment, engineered antibody or an antibody mimic.

6. The carrier system according to claim 1 , wherein R 3 is H, and L is a group of formulas (b) or (c)

wherein the dashed line represents the linkage to N, and
S 1 , S 2 , S 3 , X 1 , X 2 , X 3 , Y, R a , and m are defined as for formula I,
with the proviso that in formula (b) one of R 2 and R 2 ′ is not H, and in formula (c) one of R 1 and R 1 ′ is not H, and at least one of X 1 , X 2 , X 3 is a legumain targeting ligand group.

7. The carrier system according to claim 6 , wherein L is a group of formula (b1), (b2), (b3) or (b4):

wherein the dashed line represents the linkage to N, and
wherein R a , R c and R d are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain.

8. The carrier system according to claim 6 , wherein L is a group of formula (c1) or (c2):

wherein the dashed line represents the linkage to N, and
wherein R a , R b1 , R b2 are independently of each other a saturated or unsaturated, straight or branched hydrocarbon chain.

9. The carrier system according to claim 1 , wherein R 1 , R 1 ′, R 2 , R 2 ′ are H, R 3 is a group of formula —(CH 2 ) 2 —OR e or —(CH 2 ) 3 —OR e , and S 1 , S 2 , S 3 , X 1 , X 2 , X 3 , Y, R a , and m are defined as for formula I.

10. The carrier system according to claim 1 , wherein R a , R b1 , R b2 , R c , R d , R e are independently of each other straight or branched C(10-22)alkyl, C(10-22)alkenyl or C(10-22)alkynyl.

11. The carrier system according to claim 10 , wherein C(10-22)alkenyl and C(10-22)alkynyl have 1, 2, 3 or 4 unsaturated bonds.

12. The carrier system according to claim 10 , wherein C(10-22)alkenyl and C(10-22)alkynyl have 1 or 2 unsaturated bonds.

13. The carrier system according to claim 1 , wherein the carrier system is a microparticulate or a nanoparticulate material.

14. The carrier system according to claim 13 , wherein the microparticulate or a nanoparticulate material is a liposome or a micelle, comprising at least one compound of formula I and optionally one or more other co-lipids.

15. The carrier system according to claim 13 , wherein the microparticulate or a nanoparticulate material is a lipid vesicle, a nanoparticle, a nanosphere and/or a nanorod, comprising at least one compound of formula I and optionally one or more other co-lipids.

16. The carrier system according to claim 15 , wherein the lipid vesicle further contains at least one bioactive agent enclosed or embedded within its internal void or adsorbed onto or attached to its surface.

17. The carrier system according to claim 1 , wherein the spacer group is polyethylene glycol or an end-capped polyethylene glycol.

18. The carrier system according to claim 1 , wherein the at least one of X 1 , X 2 , X 3 that is a legumain targeting ligand group is RR11a.

19. The carrier system according to claim 1 , wherein the carrier system is a liposome, and the at least one of X 1 , X 2 , X 3 that is a legumain targeting ligand group is RR11a.

20. The carrier system according to claim 1 , wherein, in addition to at least one of X 1 , X 2 , X 3 being a legumain targeting ligand group, at least one further of X 1 , X 2 , X 3 or two of X 1 , X 2 , X 3 together is a targeting ligand or an antigenic ligand or a therapeutic or diagnostic ligand or a combination thereof.

21. A pharmaceutical composition comprising the carrier system according to claim 1 and a pharmaceutically acceptable carrier.

22. A drug delivery system, diagnostic system or as an antigen display system, said system comprising the carrier system according to claim 1 and a pharmaceutically acceptable carrier.

23. A method for the diagnosis of a disease by a disease specific diagnostic agent containing a legumain targeting ligand group, comprising administering to a host in need thereof a carrier system comprising a compound of formula I

wherein
Y represents O, N, S or a covalent bond,
S 1 , S 2 , S 3 represent independently of each other a covalent bond or a spacer group,
X 1 , X 2 , X 3 represent independently of each other H or a ligand group or any two of X 1 , X 2 , X 3 may together form a ligand group, wherein at least one of X 1 , X 2 , X 3 is a legumain targeting ligand group,
L is a group of formula (a)

wherein the dashed line represents the linkage to N,

R 1 represents H or a group of formula —(CH 2 ) 2 —OR b1 ,
R 1′ represents H or a group of formula —(CH 2 ) 2 —OR

Assignees

• Merck Patent Gmbh

Inventors

• Platscher Michael
• Behrendt Raymond
• Groehn Viola
• Hoertner Simone
• Passafaro Marco
• Bauer Finn

Classifications

• A61K47/6911 Primary

  the form being a liposome · CPC title

• C07C237/06

  having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07K7/08

  having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68) · CPC title

• C07C237/30

  having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms · CPC title