Diester and triester based low molecular weight, biodegradeable cationic lipids for oligonucleotide delivery

Patent metadata

Field	Value
Publication number	US-9402816-B2
Application number	US-201314395267-A
Country	US
Kind code	B2
Filing date	Apr 16, 2013
Priority date	Apr 19, 2012
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

The instant invention provides for novel cationic lipids of Formula A 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 coupled with inclusion of hydrolysable functionality in the lipid chains to enhance the efficiency and tolerability of in vivo delivery of siRNA.

First claim

What is claimed is:

1. A cationic lipid of Formula A:

wherein:
R 1 and R 2 are each independently selected from the group consisting of H, (C 1 -C 6 )alkyl, heterocyclyl, and polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one to three R′;
or R 1 and R 2 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 R′;
R 3 is selected from the group consisting of (C 4 -C 20 )alkylene and (C 4 -C 20 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R′;
R 4 is selected from the group consisting of (C 1 -C 16 )alkyl and (C 2 -C 16 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 5 is selected from the group consisting of (C 4 -C 8 )alkylene and (C 4 -C 8 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R′;
R 6 is (C 1 -C 2 )alkyl;
Q 1 and Q 2 are each, independently, selected from the group consisting of a bond, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —S—S—, —C(R″)═N—, —N═C(R″)—, —C(R″)═N—O—, —O—N═C(R″)—, —C(O)(NR″)—, —N(R″)C(O)—, C(S)(NR″)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″) 2 O—, —C(O)(CR″ 2 )C(O)O— and —OC(O)(CR″2)C(O)—), with the proviso that when either Q 1 or Q 2 is a bond then the other is not a bond;
X is selected from the group consisting of —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —S—S—, —C(R″)═N—, —N═C(R″)—, —C(R″)═N—O—, —O—N═C(R″)—, —C(O)(NR″)—, —N(R″)C(O)—, C(S)(NR″)—, —N(R″)C(O)N(R″)—, —OC(O)O—, OSi(R″) 2 O—, —C(O)(CR″ 2 )C(O)O— and —OC(O)(CR″ 2 )C(O)—),
each occurrence of R′ is independently selected from the group consisting of halogen, R″, OR″, SR″, CN, CO 2 R″ and CON(R″) 2 ;
each occurrence of R″ is independently selected from the group consisting of H and (C 1 -C 6 )alkyl, wherein said alkyl is optionally substituted with halogen and OH; and
n is 1, 2, 3, 4 or 5;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A cationic lipid of Formula A according to claim 1 , wherein:
R 1 and R 2 are each methyl;
n is 3;
R 3 is selected from (C 4 -C 20 )alkylene and (C 4 -C 20 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R;
R 4 is selected from (C 1 -C 16 )alkyl and (C 2 -C 16 )alkenyl, said alkyl or alkenyl is optionally substituted with one to three R′;
R 5 is selected from (C 4 -C 8 )alkylene and (C 4 -C 8 )alkenylene, said alkylene or alkenylene is optionally substituted with one to three R;
R 6 is (C 1 -C 2 )alkyl;
Q 1 and Q 2 are each, independently, a bond or —C(O)O—, with the proviso that when either Q 1 or Q 2 is a bond then the other is not a bond; and
X is —C(O)O—;

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. A cationic lipid which is selected from:
methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}octacos-9-enoate (Compound 1);
methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]octanoate (Compound 2);
methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}heptacos-9-enoate (Compound 3);
methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}hexacos-9-enoate (Compound 4);
methyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}pentacos-9-enoate (Compound 5);
methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}triacont-9-enoate (Compound 6);
methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}nonacos-9-enoate (Compound 7);
methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}octacos-9-enoate (Compound 8);
methyl (9Z)-21-{[4-(dimethylamino)butanoyl]oxy}heptacos-9-enoate (Compound 9);
methyl (11Z)-19-{[4-(dimethylamino)butanoyl]oxy}octacos-11-enoate (Compound 10);
methyl (7Z)-19-{[4-(dimethylamino)butanoyl]oxy}octacos-7-enoate (Compound 11);
methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}heptadecyl)cyclopropyl]octanoate (Compound 12);
methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}hexadecyl)cyclopropyl]octanoate (Compound 13);
methyl 8-[2-(9-{[4-(dimethylamino)butanoyl]oxy}pentadecyl)cyclopropyl]octanoate (Compound 14);
methyl 8-[2-(11-{[4-(dimethylamino)butanoyl]oxy}icosyl)cyclopropyl]octanoate (Compound 15);
methyl 8-[2-(11-{[4-(dimethylamino)butanoyl]oxy}nonadecyl)cyclopropyl]octanoate (Compound 16);
methyl 8-{2-[11-(dimethylamino)octadecyl]cyclopropyl}octanoate (Compound 17);
methyl 8-[2-(11-{[4-(dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]octanoate (Compound 18);
methyl 10-[2-(7-{[4-(dimethylamino)butanoyl]oxy}hexadecyl)cyclopropyl]decanoate (Compound 19);
methyl 6-[2-(11-{[4-(dimethylamino)butanoyl]oxy}icosyl)cyclopropyl]hexanoate (Compound 20);
ethyl (7Z)-17-{[4-(dimethylamino)butanoyl]oxy}hexacos-7-enoate (Compound 21);
ethyl 6-[2-(9-{[4-(dimethylamino)butanoyl]oxy}octadecyl)cyclopropyl]hexanoate (Compound 22);
(2Z)-non-2-en-1-yl 10-{[4-(dimethylamino)butanoyl]oxy}nonadecanoate (Compound 23); (2-hexylcyclopropyl)methyl 10-{[4-(dimethylamino)butanoyl]oxy}nonadecanoate (Compound 24);
(2Z)-undec-2-en-1-yl 8-{[4-(dimethylamino)butanoyl]oxy}heptadecanoate (Compound 25);
(2Z)-hept-2-en-1-yl 12-{[4-(dimethylamino)butanoyl]oxy}henicosanoate (Compound 26);
(2-octylcyclopropyl)methyl 8-{[4-(dimethylamino)butanoyl]oxy}heptadecanoate (Compound 27);
(2-butylcyclopropyl)methyl 12-{[4-(dimethylamino)butanoyl]oxy}henicosanoate (Compound 28);
methyl (19Z,22Z)-9-{[4-(dimethylamino)butanoyl]oxy}octacosa-19,22-dienoate (Compound 29);
ethyl (18Z,21Z)-8-{[4-(dimethylamino)butanoyl]oxy}heptacosa-18,21-dienoate (Compound 30);
methyl 9-{[4-(dimethylamino)butanoyl]oxy}-16-(2-octylcyclopropyl)hexadecanoate (Compound 31);
ethyl 8-{[4-(dimethylamino)butanoyl]oxy}-15-(2-octylcyclopropyl)pentadecanoate (Compound 32);
dimethyl (9Z)-19-{[4-(dimethylamino)butanoyl]oxy}heptacos-9-enedioate (Compound 33); and
1-methyl 18-[(2Z)-non-2-en-1-yl] 9-{[4-(dimethylamino)butanoyl]oxy}octadecanedioate (Compound 34);

or a pharmaceutically acceptable salt or stereoisomer thereof.

4. An LNP composition which comprises a cationic lipid of Formula A according to claim 1 , cholesterol, DSPC and PEG-DMG.

5. A lipid nanoparticle comprising a cationic lipid according to claim 1 .

6. The lipid nanoparticle according to claim 5 , wherein the nanoparticle comprises an oligonucleotide.

7. The lipid nanoparticle according to claim 6 wherein the oligonucleotide is siRNA.

Assignees

• Sirna Therapeutics Inc
• Sima Therapeutics Inc

Inventors

• Colletti Steven L
• Stanton Matthew G

Classifications

• C07C229/12 Primary

  to carbon atoms of acyclic carbon skeletons · CPC title

• A61K47/60

  the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol · CPC title

• A61K9/5123 Primary

  Organic compounds, e.g. fats, sugars · CPC title

• C07C229/28

  the carbon skeleton being saturated and containing rings · CPC title

• C07C2601/02

  with a three-membered ring · CPC title