Biodegradable compound, lipid particle, composition comprising lipid particle, and kit

Patent metadata

Field	Value
Publication number	US-11548857-B2
Application number	US-202016812625-A
Country	US
Kind code	B2
Filing date	Mar 9, 2020
Priority date	Aug 21, 2018
Publication date	Jan 10, 2023
Grant date	Jan 10, 2023

Abstract

The present embodiment provides a compound represented by the formula (1):

Q-CHR 2   (1)

(Q is a nitrogen-containing aliphatic group containing two or more tertiary nitrogens but no oxygen, and R is an aliphatic group containing a biodegradable group). From the compound in combination with other lipids such as a lipid capable of reducing aggregation, lipid particles can be formed. Further, the compound can be used for a pharmaceutical composition to deliver an activator into cells.

First claim

The invention claimed is:

1. A compound represented by the formula (1):
Q-CHR 2   (1)

wherein
Q is a nitrogen-containing aliphatic group containing two or more tertiary nitrogens but no oxygen, and
each R is independently an aliphatic group of C 12 to C 24 , and is represented by the following formula (1-R):
-L R1 -C(═O)—O-L R2   (1-R)

wherein
L R1 is alkylene, and
L R2 is represented by the following formula (1-R2);
−CH 2 -CH=CH−(CH 2 ) r2 −H  (1-R2)

wherein r2 is an integer of 1 to 10.

2. The compound according to claim 1 , wherein said Q is represented by the following formula (1-Q):
R Q1 2 N—(CR Q2 2 ) q1 —NR Q1 —(CR Q2 2 ) q2 —*  (1-Q)

wherein
each R Q1 is independently an alkyl,
each R Q2 is independently hydrogen or an alkyl,
any two of R Q1 s and R Q2 s may link together to form a nitrogen-containing alicyclic ring,
q1 is an integer of 1 to 4,
q2 is an integer of 0 to 4, and
the mark * indicates the position bonding to —CHR 2 .

3. The compound according to claim 1 , wherein said Q has any of the following structures:

wherein the mark * indicates the position bonding, to —CHR 2 .

4. The compound according to claim 1 , wherein said L R1 is represented by the following formula (1-R1):
—(CH 2 ) r1 —  (1-R1)

wherein
r1 is an integer of 1 to 10.

5. The compound according to claim 4 , wherein said r1 is an integer of 4 to 8.

6. The compound according to claim 1 , wherein the longest molecular chain contained in said R consists of 8 or more atoms.

7. The compound according to claim 1 , which is represented by any of the following formulas (1-01), (1-02), (1-04) to (1-14), (1-16), and (1-19)to (1-21):

8. Lipid particles containing the compound according to claim 1 .

9. The lipid particles according to claim 8 , which further contain a compound represented by the following formula (2):
P—[X—W—Y—W′—Z] 2   (2)

wherein
P is an alkyleneoxy having one or more ether bonds in the main chain,
each X is independently a divalent linking group having a tertiary amine structure,
each W is independently a C 1 to C 6 alkylene,
each Y is independently a divalent linking group selected from the group consisting of single bond, ether bond, carboxylic ester bond, thiocarboxylic ester bond, thioester bond, amide bond, carbamate bond, and urea bond
each W′ is independently a single bond or a C 1 to C 6 alkylene, and
each Z is independently a liposoluble vitamin residue, a sterol residue, or a C 12 to C 22 aliphatic hydrocarbon group;

provided that
the structure further contains at least one biodegradable group selected from the group consisting of carboxylic ester bond, thiocarboxylic ester bond, dithiocarboxylic bond, amide bond, carbamate bond, carboxydioxy bond, and urea bond.

10. The lipid particles according to claim 9 , wherein said P contains 3 to 8 carbons and 1 to 2 oxygens.

11. The lipid particles according to claim 9 , wherein said each X is independently selected from the group consisting of methylimino, 1,2-pyrrolidinediyl and 1,3-pyrrolidinediyl.

12. The lipid particles according to claim 9 , wherein said each Z is a liposoluble vitamin residue or a sterol residue.

13. The lipid particles according to claim 8 , which further contain a lipid forming a membrane and a lipid capable of reducing aggregation.

14. The lipid particles according to claim 13 , wherein said lipid forming a membrane is selected from the group consisting of:
1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE),
1,2-stearoyl-sn-glycero-3-phosphoethanolamine (DSPE),
1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC),
1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC),
1,2-di-o-octadecyl-3-trimethylammoniumpropane (DOTMA),
1, 2-dioleoyl-3-dimethylammoniumpropane (DODAP),
1,2-dimyristoyl-3-dimethylammoniumpropane (14:0 DAP),
1,2-dipalmitoyl-3-dimethylammoniumpropane (16:0 DAP),
1,2-distearoyl-3-dimethylammoniumpropane (18:0 DAP),
N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)-propane (DOBAQ),
1, 2-dioleoyl-3-trimethylammoniumpropane (DOTAP),
1,2-dioleoyl-sn-glycero-3-phosphochlorin (DOPC),
1,2-dilinoleoyl-sn-glycero-3-phosphochlorin (DLPC),
1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), and
cholesterol:
and
said lipid capable of reducing aggregation is a polyethylene glycol (PEG)-modified lipid.

15. The lipid particles according to claim 8 , which furthermore contain an activator.

16. The lipid particles according to claim 15 , wherein said activator is a nucleic acid selected from the group consisting of plasmid, oligonucleotide, polynucleotide, siRNA, microRNA, DNA, mRNA, aptamer, and ribozyme.

17. The lipid particles according to claim 15 , wherein said activator contains a combination of at least one DNA and at least one RNA.

18. The lipid particles according to claim 16 , which further contain a compound combinable with the nucleic acid.

19. The lipid particles according to claim 18 , wherein said compound combinable with the nucleic acid is a basic protein or a basic peptide.

20. The lipid particles according to claim 18 , wherein said compound combinable with the nucleic acid is protamine or histone.

21. The lipid particles according to claim 18 , which further contain a compound controlling expression of the nucleic acid in cells.

22. A composition characterized by comprising the lipid particles according to claim 8 and a medium.

23. A composition for delivering, activators to cells, comprising the lipid particles according to claim 8 and a medium.

24. The composition according to claim 23 , wherein said lipid particles contain both the compounds of the formulas (1) and (2).

25. The composition according to claim 24 , wherein the mole ratio of the content of the compound of the formula (2) to that of the compound of the formula (1) is less than 1.

26. The composition according to claim 23 , wherein said cells are tumor cells.

27. The lipid particles according to claim 8 , which are used for delivering activators to cells.

28. The lipid particles according to claim 27 , which contain both the compounds of the formulas (1) and (2).

29. The lipid particles according to claim 28 , wherein the mole ratio of the content of the compound of the formula (2) to that of the compound of the formula (1) is less than 1.

30. The lipid particles according to claim 27 , wherein said cells are tumor cells.

31. A method for delivering activators to cells, wherein the activator-containing lipid particles according to claim 8 are brought into contact with the cells.

32. The method according to claim 31 , wherein said lipid particles are administered to the subject.

33. The method according to claim 31 , wherein said lipid particles contain both the compounds of the formulas (1) and (2).

Assignees

• Toshiba Kk

Inventors

• Ishihara Mitsuko
• Akahoshi Eiichi
• Naito Katsuyuki
• Nozaki Emi
• Saruwatari Saeko

Classifications

• C07C229/30

  the carbon skeleton being acyclic and unsaturated · CPC title

• A61K47/18

  Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids · CPC title

• A61K9/1271

  Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911}) · CPC title

• A61K31/7088

  Compounds having three or more nucleosides or nucleotides · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title