Amine Cationic Lipids and Uses Thereof

Patent metadata

Field	Value
Publication number	US-2017137409-A1
Application number	US-201715407512-A
Country	US
Kind code	A1
Filing date	Jan 17, 2017
Priority date	Oct 18, 2011
Publication date	May 18, 2017
Grant date	—

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, C 11-24 alkynyl, C 11-24 heteroalkyl, C 11-24 heteroalkenyl, or C 11-24 heteroalkynyl;
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 the compound is selected from the group consisting of L-2, L-5, L-6, L-22, L-23, L-24, L-25, L-26, L-28, L-29, L-45, and L-48 as follows:

3 . A compound having the formula:

4 . A compound having the formula:

5 . The compound of claim 1 , wherein each R 1 and R 2 is, independently, substituted C 11-24 alkyl, substituted C 11-24 alkenyl, substituted C 11-24 alkynyl, substituted C 11-24 heteroalkyl, substituted C 11-24 heteroalkenyl, or substituted C 11-24 heteroalkynyl.

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

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

8 . The formulation of claim 7 , 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).

9 . The formulation of claim 7 , wherein the cationic lipid is DODMA and the neutral lipid is DSPC.

10 . The formulation of claim 7 , wherein the formulation further comprises a PEG-lipid conjugate.

11 . The formulation of claim 10 , 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).

12 . The formulation of claim 10 , wherein the PEG-lipid conjugate is PEG-DMPE or PEG-DSPE.

13 . The formulation of claim 7 , 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-(((3S,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)-((3S,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((3S,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-(((3S,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).

14 . The formulation of claim 8 , wherein the sterol derivative is cholesterol.

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

16 . A formulation of claim 10 , comprising 22 mol % of a compound of claim 1 , 26 mol % of the cationic lipid, 5 mol % to 9 mol % of the PEG-lipid conjugate, 14 mol % of the neutral lipid, and 29 mol % to 33 mol % of the sterol derivative

17 . The formulation of claim 5 , further comprising a lipid particle comprising a transfection lipid.

18 . The formulation of claim 7 , 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.

19 . The formulation of claim 17 , 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.

20 . The formulation of claim 7 , 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.

21 . The formulation of claim 7 , 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.

22 . The formulation claim 7 , further comprising a liposome, a lipoplex, or a micelle.

23 . The formulation of claim 22 , wherein the liposome is a lipid nanoparticle.

24 . 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.

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

26 . 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.

27 . 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, S

Assignees

• Dicerna Pharmaceuticals Inc

Inventors

• Brown Bob Dale

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K9/1272

  comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543}) · CPC title

• A61K9/146

  with organic macromolecular compounds · CPC title

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C12Y204/02008

  Hypoxanthine phosphoribosyltransferase (2.4.2.8) · CPC title