Targeting aminoacid lipids

Patent metadata

Field	Value
Publication number	US-9878044-B2
Application number	US-201314384702-A
Country	US
Kind code	B2
Filing date	Mar 11, 2013
Priority date	Mar 16, 2012
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

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,
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 at least one of X 1 , X 2 , X 3 is a ligand group.

2. A 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 ligand group.

3. A carrier system according to claim 2 , 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.

4. A carrier system according to claim 2 , 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.

5. A 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.

6. A 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.

7. A carrier system according to claim 6 , wherein C(10-22)alkenyl and C(10-22)alkynyl have 1, 2, 3 or 4 unsaturated bonds.

8. A carrier system according to claim 1 wherein the carrier system is a microparticulate or a nanoparticulate material.

9. A carrier system according to claim 8 , 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.

10. A carrier system according to claim 1 wherein at least one 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.

11. A carrier system according to claim 1 wherein the spacer group is polyethylene glycol or an end-capped polyethylene glycol.

12. A carrier system according to claim 9 , 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.

13. Pharmaceutical composition comprising a carrier system according to claim 1 and a pharmaceutically acceptable carrier.

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

15. 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
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 at least one of X 1 , X 2 , X 3 is a ligand group.

16. A method for the treatment of a disease which responds to a therapeutic agent, comprising administering to a host in need thereof a carrier system according to claim 1 , wherein at least one of X 1 , X 2 , X 3 is said therapeutic agent.

17. A method for the diagnosis of a disease using a disease specific diagnostic agent, comprising administering to a host in need thereof a carrier system according to claim 1 , wherein at least one of X 1 , X 2 , X 3 is said diagnostic agent.

18. A method for modulating an immune response, comprising administering to a host in need thereof a carrier system according to claim 1 , wherein at least one of X 1 , X 2 , X 3 is an antigenic agent.

19. A carrier system according to claim 6 , wherein C(10-22)alkenyl and C(10-22)alkynyl have 1 or 2 unsaturated bonds.

20. A carrier system according to claim 8 , 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.

Assignees

• Merck Patent Gmbh

Inventors

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

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P37/02

  Immunomodulators · CPC title

• C07C237/06

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

• A61K47/60 Primary

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• C07D475/04

  with a nitrogen atom directly attached in position 2 · CPC title