Amine cationic lipids and uses thereof

Patent metadata

Field	Value
Publication number	US-11059807-B2
Application number	US-201816204053-A
Country	US
Kind code	B2
Filing date	Nov 29, 2018
Priority date	Oct 18, 2011
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The present invention relates to lipid compounds and uses thereof. In particular, the compounds include a class of cationic lipids having an amine moiety, such as an amino-amine or an amino-amide moiety. The lipid compounds are useful for in vivo or in vitro delivery of one or more agents (e.g., a polyanionic payload or an antisense payload, such as an RNAi agent).

First claim

What is claimed is:

1. A compound having the formula:

wherein each R 1 and R 2 is, independently, C 11-24 alkyl, C 11-24 alkenyl, or C 11-24 alkynyl;
each n1 and n2 is, independently, an integer from 1 to 2; and
R 5 is selected from the group consisting of H, C 1-6 alkyl, and heterocyclyl.

2. The compound of claim 1 , wherein each R 1 and R 2 is C 11-24 alkenyl.

3. The formulation of claim 2 , further comprising a lipid particle comprising a transfection lipid.

4. The formulation of claim 3 , wherein the one or more transfection lipid, comprises from 5 mol % to 20 mol % of the neutral lipid, from 0.5 mol % to 10 mol % of the PEG-lipid conjugate, and from 20 mol % to 40 mol % of the sterol derivative.

5. The compound of claim 1 , wherein R 5 is C 1-6 alkyl.

6. The compound of claim 5 , wherein each R 1 and R 2 is C 11-24 alkenyl.

7. The formulation compound of claim 6 , wherein the C 1-6 alkyl is a methyl.

8. A formulation comprising a compound of claim 1 , the formulation further comprising a cationic lipid, a neutral lipid, a sterol derivative and a dsRNA.

9. The formulation of claim 8 , wherein the cationic lipid is selected from the group consisting of N,N-dimethyl-(2,3-dioleyloxy) propylamine (DODMA), 1,2-di-O-octadecenyl-3-trimethylammonium propane (DOTMA), 1,2-dipalmitoyl-sn-glycero-O-ethyl-3-phosphocholine (DPePC), 1,2-dioleoyl-3-dimethylammonium propane (DODAP), and 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP); and the neutral lipid is selected from the group consisting of 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-dioleoyl-glycero-sn-3-phosphoethanolamine (DOPE), and sphingomyelin (SM).

10. The formulation of claim 9 , wherein the sterol derivative is cholesterol.

11. The formulation of claim 8 , wherein the cationic lipid is DODMA and the neutral lipid is DSPC.

12. The formulation of claim 8 , wherein the formulation further comprises a PEG-lipid conjugate.

13. The formulation of claim 12 , wherein the PEG-lipid conjugate is selected from the group consisting of 1,2-dimyristoyl-sn-glycerol-3-(methoxy-polyethylene glycol) (PEG-DMG), 1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine-N-(carbonyl-methoxy-polyethylene glycol) (PEG-DMPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-(carbonyl-methoxy-polyethylene glycol) (PEG-DSPE), 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N-(carbonyl-methoxy-polyethylene glycol) (PEG-DPPE), 1,2-dipalmitoyl-sn-glycerol-3-(methoxy-polyethylene glycol) (PEG-DPG), 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-(carbonyl-methoxy-polyethylene glycol) (PEG-DOPE), and 1,2-dioleoyl-sn-glycerol-3-(methoxy-polyethylene glycol) (PEG-DOG).

14. The formulation of claim 12 , wherein the PEG-lipid conjugate is PEG-DMPE or PEG-DSPE.

15. The formulation of claim 8 , wherein the sterol derivative is selected from the group consisting of cholesterol; cholestanone; cholestenone; coprostanol; 3β-[-(N—(N′,N′-dimethylaminoethane)-carbamoyl]cholesterol (DC-cholesterol); bis-guanidium-tren-cholesterol (BGTC); (2S,3S)-2-(((3 S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)carbonylamino)ethyl 2,3,4,4-tetrahydroxybutanoate (DPC-1); (2S,3S)-((3 S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2,3,4,4-tetrahydroxybutanoate (DPC-2); bis((3 S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2,3,4-trihydroxypentanedioate (DPC-3); and 6-(((3 S,10R,13R,17R)-10,13-dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,7,8,9,10,11,12,13,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yloxy)oxidophosphoryloxy)-2,3,4,5-tetrahydroxyhexanoate (DPC-4).

16. The formulation of claim 8 , wherein the dsRNA comprises from 10 mol % to 40 mol % of one or more cationic lipids and from about 0.5 mol % to 10 mol % of one or more PEG-lipids.

17. The formulation of claim 8 , wherein the dsRNA has a length selected from the group consisting of 10 to 40 nucleotides, 16 to 30 nucleotides, 19 to 29 nucleotides, 25 to 35 nucleotides and 8-50 nucleotides.

18. The formulation of claim 8 , wherein the formulation, comprises from 1:10 (w/w) to about 1:100 (w/w) ratio of the dsRNA to the total lipid present in the formulation.

19. The formulation claim 8 , further comprising a liposome, a lipoplex, or a micelle.

20. The formulation of claim 19 , wherein the liposome is a lipid nanoparticle.

21. A formulation comprising from 20 mol % to 25 mol % of the compound of claim 1 , from 20 mol % to 30 mol % of a cationic lipid, from 2 mol % to 8 mol % of a PEG-lipid conjugate, from 10 mol % to 20 mol % of a neutral lipid, and from 25 mol % to 35 mol % of a sterol derivative.

22. A formulation comprising 22 mol % of the compound of claim 1 , 26 mol % of a cationic lipid, 5 mol % to 9 mol % of a PEG-lipid conjugate, 14 mol % of a neutral lipid, and 29 mol % to 33 mol % of a sterol derivative.

23. A formulation comprising a compound of claim 1 , wherein the formulation further comprises one or more components selected from a group consisting of a cationic lipid, a neutral lipid, a sterol derivative, a PEG-lipid conjugate, lipid particles comprising one or more RNA-binding agents, transfection lipids, a dsRNA, a liposome, a lipoplex, and a micelle.

24. A pharmaceutical composition comprising the compound of claim 1 , and a pharmaceutically acceptable excipient.

25. A method of treating or preventing a disease in a subject, the method comprising administering to the subject the compound of claim 1 , in an amount sufficient to treat the disease, wherein the disease is selected from the group consisting of hepatocellular carcinoma, lung cancer, prostate cancer, or neuroblastoma.

26. A method of modulating the expression of a target nucleic acid in a subject, the method comprising administering to the subject the compound of claim 1 , in an amount sufficient to reduce the expression of the target gene in the subject,
wherein the target gene is, selected from the group consisting of ABL1, AR, β-Catenin, BCL1, BCL2, BCL6, CBFA2, CBL, CSF1R, ERBA1, ERBA2, ERBB1, ERBB2, ERBB3, ERBB4, ETS1, ETS2, ETV6, FGR, FOS, FYN, HCR, HRAS, JUN, KRAS, LCK, LYN, MET, MDM2, MLL1, MLL2, MLL3, MYB, MYC, MYCL1, MYCN, NRAS, PIM1, PML, RET, SRC, TAL1, TAL2, TCL3, TCL5, YES, BRCA1, BRCA2, MADH4, MCC, NF1, NF2, RB1, TP53, WT1, ApoB100, CSN5, CDK6, ITGB1, TGFβ1, Cyclin D1, PLK1, and KIF1-binding protein; and wherein expression of the target gene is reduced in the subject.

27. A method of modulating the expression of a target nucleic acid in a subject, the method comprising administering the compound of claim 1 in an amount sufficient to reduce the expression of the target gene in the subject,
wherein the target gene is, selected from the group consisting of ABL1, AR, β-Catenin, BCL1, BCL2, BCL6, CBFA2, CBL, CSF1R, ERBA1, ERBA2, ERBB1, ERBB2, ERBB3, ERBB4, ETS1, ETS2, ETV6, FGR, FOS, FYN, HCR, HRAS, JUN, KRAS, LCK, LYN, MET, MDM2, MLL1, MLL2, MLL3, MYB, MYC, MYCL1, MYCN, NRAS, PIM1, PML, RET, SRC, TAL1, TAL2, TCL3, TCL5, YES, BRCA1, BRCA2, MADH4, MCC, NF1

Assignees

• Dicerna Pharmaceuticals Inc

Inventors

• Brown Bob Dale

Classifications

• A61K31/713

  Double-stranded nucleic acids or oligonucleotides · CPC title

• C07D211/36

  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 title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title