US 2014/0235872 A1Published application

Novel low molecular weight cationic lipids for oligonucleotide delivery

AssigneeSirna Therapeutics, Inc.

InventorsBrian W. BUDZIK, Steven L. COLLETTI, Jennifer R. DAVIS, Ivory D. HILLS, Darla Danile SEIFRIED, Matthew G. STANTON

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Abstract

The instant invention provides for novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy along with lower liver toxicity as a result of lower lipid levels in the liver. The present invention employs low molecular weight cationic lipids with one short lipid chain to enhance the efficiency and tolerability of in vivo delivery of siRNA.

Claims7

Dependent claims

A cationic lipid of Formula A:

wherein:
R1 and R2 are independently selected from H, (C1-C6)alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three substituents selected from R′, or R1 and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocycle with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocycle is optionally substituted with one to three substituents selected from R′;
R′ is independently selected from halogen, R″, OR″, SR″, CN, CO2R″ or CON(R″)2;
R″ is independently selected from H and (C1-C6)alkyl, wherein said alkyl is optionally substituted with halogen and OH;
L1 is selected from C4-C22 alkyl and C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R′;
and
L2 is selected from C3-C13 alkyl and C3-C13 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R′;
or any pharmaceutically acceptable salt or stereoisomer thereof.

5 more elements

A cationic lipid which is selected from:

R—N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-amine (Compound 2);
S—N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-amine (Compound 1);
1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-[(octyloxy)methyl]ethyl}pyrrolidine (Compound 3);
(2S)—N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-[(5Z)-oct-5-en-1-yloxy]propan-2-amine (Compound 4);
1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-[(octyloxy)methyl]ethyl}azetidine (Compound 5);
(2S)-1-(hexyloxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 6);
(2S)-1-(heptyloxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 7);
N,N-dimethyl-1-(nonyloxy)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 8);
N,N-dimethyl-1-[(9Z)-octadec-9-en-1-yloxy]-3-(octyloxy)propan-2-amine (Compound 9);
(2S)—N,N-dimethyl-1-[(6Z,9Z,12Z)-octadeca-6,9,12-trien-1-yloxy]-3-(octyloxy)propan-2-amine (Compound 10);
(2S)-1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(pentyloxy)propan-2-amine (Compound 11);
(2S)-1-(hexyloxy)-3-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethylpropan-2-amine (Compound 12);
1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(oetyloxy)propan-2-amine (Compound 13);
1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine (Compound 14);
(2S)-1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-3-(hexyloxy)-N,N-dimethylpropan-2-amine (Compound 15);
(2S)-1-[(13Z)-docos-13-en-1-yloxy]-3-(hexyloxy)-N,N-dimethylpropan-2-amine (Compound 16);
1-[(13Z)-docos-13-en-1-yloxy]-N,N-dimethyl-3-(oetyloxy)propan-2-amine (Compound 17);
1-[(9Z)-hexadec-9-en-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine (Compound 18);
(2R)—N,N-dimethyl-1-[(1-methyloctyl)oxy]-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 19);
(2R)-1-[(3,7-dimethyloctyl)oxy]-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine (Compound 20);
N,N-dimethyl-1-(octyloxy)-34 {8-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl}cyclopropyl]octyl}oxy)propan-2-amine (Compound 21);
and
N,N-dimethyl-1-{[R-(2-octylcyclopropyl)octyl]oxy}-3-(octyloxy)propan-2-amine (Compound 22);
or any pharmaceutically acceptable salt or stereoisomer thereof.

21 more elements

Dependencies are inferred from the claim text.

Facts

Application: 14/265,029Filed 29 Apr 2014
Priority: 4 Jun 2010
Published: 21 Aug 2014
Term ends: Not estimatedThe source records don’t support an estimate.

Classification14 codes

C07C 217/46
Having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton: the carbon skeleton being acyclic and…
A61K 9/1272
Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers: comprising non-phosphatidyl surfactants as…
A61K 47/18
Containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates: amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids;…
C07C 43/15
Unsaturated ethers: containing only non-aromatic carbon-to-carbon double bonds

Family

Application61/351,373Us provisional application · filed 4 Jun 2010
Application61/382,067Us provisional application · filed 13 Sep 2010
Application13/701,636Continuation · filed 3 Dec 2012
Application14/265,029Continuation
US 2013/0090372 A1Published application
US 8,748,667 B2Related patent
US 9,062,021 B2Related patent
US 2014/0235872 A1This patent

From the US filing history. Foreign family members aren’t listed.