BIODEGRADABLE COMPOUND, LIPID PARTICLE, COMPOSITION CONTAINING LIPID PARTICLE, AND KIT

• US 20190076358A1
• Filed: 03/12/2018
• Published: 03/14/2019
• Est. Priority Date: 09/13/2017
• Status: Active Grant

• Current Assignee: Kabushiki Kaisha Toshiba (Toshiba Corporation)
• Original Assignee: Kabushiki Kaisha Toshiba (Toshiba Corporation)
• Inventors: ISHIHARA, Mitsuko, Akahoshi, Eiichi, Naito, Katsuyuki
• Granted Patent: US 10,639,279 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61K 47/6455 Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
• CPC Class Codes: A61K 47/6911 the form being a liposome
• CPC Class Codes: A61K 9/127 Liposomes
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/1275 Lipoproteins; Chylomicrons; Artificial HDL, LDL, VLDL, protein-free species thereof; Precursors thereof
• CPC Class Codes: C07C 229/12 to carbon atoms of acyclic carbon skeletons
• CPC Class Codes: C07C 327/32 having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 69/675 of saturated hydroxy-carboxylic acids
• CPC Class Codes: C07C 69/708 Ethers
• CPC Class Codes: C07C 69/732 of unsaturated hydroxy carboxylic acids
• CPC Class Codes: C07C 69/734 Ethers
• CPC Class Codes: C07D 307/16 Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 309/06 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 309/08 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07F 9/00 Compounds containing elements of Groups 5 or 15 of the Periodic Table
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4075 Esters with hydroxyalkyl compounds
• CPC Class Codes: C12N 15/88 using microencapsulation, e.g. using amphiphile liposome vesicle

Abstract

The compound according to the present embodiment is represented by the following formula (1):

Q-L—CHR₂   (1)

(wherein,

• Q is a non-cationic aliphatic group that does not contain nitrogen but contains oxy;
• L is a single bond or an aliphatic group containing no nitrogen; Rs are C₁₂-C₂₄ aliphatic group, the same or different; and at least one R contains, in the main chain or side chain thereof, a linking group L^R selected from the group consisting of —C(═O)—O—, —O—C(═O)—, —O—C(═O)—O—, —S—C(═O)—, —C(═O)—S—, —C(═O)—NH—, and —NH—C(═O)—).

Claims

1. A compound represented by the following formula (1):

Q-L-CHR₂ (1)

(wherein,

Q is a non-cationic aliphatic group that does not contain nitrogen but contains oxy;

L is a single bond or an aliphatic group containing no nitrogen;

Rs are C₁₂-C₂₄ aliphatic groups, the same or different; and

at least one R contains, in the main chain or side chain thereof, a linking group L^R selected from the group consisting of —

C(═

O)—

O—

, —

O—

C(═

O)—

, —

O—

C(═

O)—

O—

, —

S—

C(═

O)—

, —

C(═

O)—

S—

, —

C(═

O)—

NH—

, and —

NH—

C(═

O)—

).

2. The compound according to claim 1, wherein the L contains an ester structure selected from the group consisting of —

C(═

O)—

O—

, —

O—

C(═

O)—

O—

, —

O—

C(═

O)—

O—

, —

C(═

S)—

O—

, —

O—

C(═

S)—

, —

O—

C(═

S)—

O—

, —

S—

C(═

O)—

, —

C(═

O)—

S—

, and —

O—

P(═

O)OR′

—

O—

(wherein R′

is hydrogen, a non-cationic aliphatic group, or —

CHR₂).

3. The compound according to claim 1, wherein the L is represented by the following formula (1A):

-L^A_a-L^O-L^A_a-  

 

(1A)

(wherein

L^A is alkylene or cycloalkylene that is optionally substituted independently with oxygen;

L^O is an ester structure selected from the group consisting of —

C(═

O)—

O—

, —

O—

C(═

O)—

O—

, —

O—

C(═

O)—

O—

, —

S—

C(═

O)—

, and —

C(═

O)—

S—

, and a is independently a number from 0 to

     6).

4. The compound according to claim 3, wherein the Q is represented by the following formula (1B-1):

Q^O—

[(CH₂)_b1—

O—

]₂-  

 

(1B-1)

(wherein

Q^O is hydrogen, halogen, alkyl, or alkenyl;

b₁ is a number from 0 to 3;

b₂ is a number from 1 to 3; and

the total number of carbon atoms contained in the formula (1B) is 6 or less).

5. The compound according to claim 3, wherein the Q is represented by the following formula (1B-2):

Q¹-L^B-  

 

(1B-2)

(wherein,

Q¹ is a cyclo ether; and

L^B is alkylene.)

6. The compound according to claim 1, wherein the at least one R is represented by the following formula (1C):

—

L^C1—

C(═

O)—

O-L^C2  

 

(1C)

(wherein,

L^C1 is alkylene; and

L^C2 is alkenyl).

7. The compound according to claim 6, wherein the L^C1 and the L^C2 are represented by the following formulae (1C-1) and (1C-2) respectively:

—

(CH₂)_c1—

 

 

(1C-1)

—

CH₂—

CH═

CH—

(CH₂)_c2—

H  

 

(1C-2)

(wherein

c1 is a number from 1 to 10; and

c2 is a number from 1 to 10.)

8. The compound according to claim 7, wherein the c1 is a number from 4 to 8.

9. The compound according to claim 1, wherein the longest molecular chain contained in the R has 8 or more atoms.

10. The compound according to claim 1, presented by the following formulae (1-01) to (1-20).

11. A lipid particle comprising the compound according to claim 1.

12. The lipid particle according to claim 11, further comprising a membrane-forming lipid and an aggregation-reducing lipid.

13. The lipid particle according to claim 12, wherein the membrane-forming lipid is selected from the group consisting of

1,2-dioleoyl-sn-glycero-3-phosphoethanol amine (DOPE),

1,2-stearoyl-sn-glycero-3-phosphoethanol amine (DSPE),

1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC),

1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine (POPC),

1,2-di—

O—

octadecyl-3-trimethylammonium propane (DOTMA),

1,2-dioleoyl-3-dimethylammonium propane (DODAP),

1,2-dimyristoyl-3-di methylammonium propane (14;

0 DAP),

1,2-dipalmitoyl-3-dimethylammonium propane (16;

0 DAP),

1,2-distearoyl-3-dimethylammonium propane (18;

0 DAP),

N-(4-carboxybenzyl)-N,N-dimethyl-2,3-bis(oleoyloxy)propane (DOBAQ),

1,2-dioleoyl-3-trimethylammonium propane (DOTAP),

1,2-dioleoyl-sn-glycero-3-phosphochlorine (DOPC),

1,2-dilinoleoyl-sn-glycero-3-phosphochlorine (DLPC),

1,2-dioleoyl-sn-glycero-3-phospho-L-serine (DOPS), cholesterol, and the like; and

wherein the aggregation-reducing lipid is a polyethylene glycol (PEG)-modified lipid.

14. The lipid particle according to claim 11, further comprising an active agent.

15. The lipid particle according to claim 14, wherein the active agent is a nucleic acid selected from the group consisting of plasmids, oligonucleotides, polynucleotides, siRNAs, micro RNAs, DNAs, aptamers, and ribozymes.

16. The lipid particle according to claim 15, further comprising a compound that binds to a nucleic acid.

17. The lipid particle according to claim 16, wherein the compound that binds to a nucleic acid is a basic protein or a basic peptide.

18. The lipid particle according to claim 16, wherein the compound that binds to a nucleic acid is a protamine or a histone.

19. The lipid particle according to claim 16, further comprising a compound that regulates the expression of a nucleic acid in a cell.

20. A composition comprising the lipid particle according to claim 11 and a carrier.

21. A kit comprising the lipid particle according to claim 11 and a composition containing an incorporation agent for incorporating the lipid particle into a cell.