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

• US 10,639,279 B2
• Filed: 03/12/2018
• Issued: 05/05/2020
• 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
• Primary Examiner(s): Rozof, Timothy R
• Application Number:
  US15/918,397
• Publication Number:
  US 20190076358A1
• Time in Patent Office: 785 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 which is represented by the following formula (1B-1);

Q⁰-[(CH₂)_b1—

O-]_b2- 

 

(1B-1)

wherein

Q⁰ 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-1) is 6 or less;

L is an aliphatic group which is represented by the following formula (1A);

-L^A_a-L⁰-L^A_a- 

 

(1A)

wherein

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

L⁰ is an ester structure selected from the group consisting of —

C(═

O)—

O—

, —

O—

C(═

O)—

, —

O—

C(═

O)—

O—

, —

S—

C(═

O)—

, and —

C(═

O)—

S—

, and a is independently a number from 0 to

     6);

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—

C(═

O)—

O—

, —

C(═

S)—

O—

, —

O—

C(═

S)—

, —

O—

C(═

S)—

O—

, —

S—

C(═

O)—

, and —

C(═

O) S—

.

3. The compound according to claim 1, 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.

4. 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.

5. The compound according to claim 4, 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.

6. The compound according to claim 5, wherein the c1 is a number from 4 to 8.

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

8. The compound according to claim 1, wherein is said compound is a compound presented by one of the following formulae (1-01), (1-02), (1-05) to (1-12), and (1-14) to (1-20)

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

10. The lipid particle according to claim 9, further comprising a membrane-forming lipid and an aggregation-reducing lipid.

11. The lipid particle according to claim 10, 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.

12. The lipid particle according to claim 9, further comprising an active agent.

13. The lipid particle according to claim 12, wherein the active agent is a nucleic acid selected from the group consisting of plasmids, oligonucleotides, polynucleotides, siRNAs, micro RNAs, DNAs, aptamers, and ribozymes.

14. The lipid particle according to claim 13, further comprising a compound that binds to a nucleic acid.

15. The lipid particle according to claim 14, wherein the compound that binds to a nucleic acid is a basic protein or a basic peptide.

16. The lipid particle according to claim 14, wherein the compound that binds to a nucleic acid is a protamine or a histone.

17. The lipid particle according to claim 14, further comprising a compound that regulates the expression of a nucleic acid in a cell.

18. A composition comprising the lipid particle according to claim 9 and a carrier.

19. A kit comprising the lipid particle according to claim 9 and a composition containing an incorporation agent for incorporating the lipid particle into a cell.

20. 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 is represented by the following formula (1C);

—

(CH₂)_c1—

C(═

O)—

O—

CH₂—

CH═

CH—

(CH₂)_c2—

H 

 

(1C)

wherein,

c1 is a number from 1 to 10; and

c2 is a number from 1 to 10.

21. The compound according to claim 20, wherein the L contains an ester structure selected from the group consisting of —

C(═

O)—

O—

, —

O—

C(═

O)—

, —

O—

C(═

O)—

O—

, —

C(═

S)—

O—

, —

O—

C(═

S)—

, —

O—

C(═

S)—

O—

, —

S—

C(═

O)—

, and —

C(═

O) S—

.

22. The compound according to claim 20, wherein the L is represented by the following formula (1A):

-L^A_a-L⁰-L^A_a- 

 

(1A)

wherein

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

L⁰ is an ester structure selected from the group consisting of —

C(═

O)—

O—

, —

O—

C(═

O)—

, —

O—

C(═

O)—

O—

, —

S—

C(═

O)—

, and —

C(═

O)—

S—

, and a is independently a number from 0 to 6.

23. The compound according to claim 22, wherein the Q is represented by the following formula (1B-1):

Q⁰-[(CH₂)_b1—

O—

]_b2- 

 

(1B-1)

wherein

Q⁰ 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-1) is 6 or less.

24. The compound according to claim 22, 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.

25. The compound according to claim 20, wherein the c1 is a number from 4 to 8.

26. The compound according to claim 20, wherein the longest molecular chain contained in the R has 8 or more atoms.

27. The compound according to claim 20, wherein said compound is a compound presented by one of the following formulae (1-01) to (1-12) and (1-14) to (1-20)

28. A lipid particle comprising the compound according to claim 20.

29. The lipid particle according to claim 28, further comprising a membrane-forming lipid and an aggregation-reducing lipid.

30. The lipid particle according to claim 29, 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.

31. The lipid particle according to claim 28, further comprising an active agent.

32. The lipid particle according to claim 31, wherein the active agent is a nucleic acid selected from the group consisting of plasmids, oligonucleotides, polynucleotides, siRNAs, micro RNAs, DNAs, aptamers, and ribozymes.

33. The lipid particle according to claim 32, further comprising a compound that binds to a nucleic acid.

34. The lipid particle according to claim 33, wherein the compound that binds to a nucleic acid is a basic protein or a basic peptide.

35. The lipid particle according to claim 33, wherein the compound that binds to a nucleic acid is a protamine or a histone.

36. The lipid particle according to claim 33, further comprising a compound that regulates the expression of a nucleic acid in a cell.

45. A composition comprising the lipid particle according to claim 28 and a carrier.

46. A kit comprising the lipid particle according to claim 28 and a composition containing an incorporation agent for incorporating the lipid particle into a cell.

37. A lipid particle comprising the compound which 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 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)—

,

a membrane-forming lipid, and

an aggregation-reducing lipid.

38. The lipid particle according to claim 37, 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.

39. The lipid particle according to claim 37, further comprising an active agent.

40. The lipid particle according to claim 39, wherein the active agent is a nucleic acid selected from the group consisting of plasmids, oligonucleotides, polynucleotides, siRNAs, micro RNAs, DNAs, aptamers, and ribozymes.

41. The lipid particle according to claim 40, further comprising a compound that binds to a nucleic acid.

42. The lipid particle according to claim 41, wherein the compound that binds to a nucleic acid is a basic protein or a basic peptide.

43. The lipid particle according to claim 41, wherein the compound that binds to a nucleic acid is a protamine or a histone.

44. The lipid particle according to claim 41, further comprising a compound that regulates the expression of a nucleic acid in a cell.

47. A composition comprising the lipid particle according to claim 37 and a carrier.

48. A kit comprising the lipid particle according to claim 37 and a composition containing an incorporation agent for incorporating the lipid particle into a cell.