Biodegradable lipids for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-9682922-B2
Application number	US-201514661945-A
Country	US
Kind code	B2
Filing date	Mar 18, 2015
Priority date	Jun 3, 2010
Publication date	Jun 20, 2017
Grant date	Jun 20, 2017

Abstract

The present invention relates to a cationic lipid having one or more biodegradable groups located in the mid- or distal section of a lipidic moiety (e.g., a hydrophobic chain) of the cationic lipid. These cationic lipids may be incorporated into a lipid particle for delivering an active agent, such as a nucleic acid. The invention also relates to lipid particles comprising a neutral lipid, a lipid capable of reducing aggregation, a cationic lipid of the present invention, and optionally, a sterol. The lipid particle may further include a therapeutic agent such as a nucleic acid.

First claim

What is claimed is:

1. A compound of Formula (I)

or a salt thereof;
wherein
R′ is absent, hydrogen, or alkyl;

with respect to R 1 and R 2 ,
(i) R 1 and R 2 are each, independently, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or heterocycle;
(ii) R 1 and R 2 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocylic ring; or
(iii) one of R 1 and R 2 is optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or heterocycle, and the other forms a 4-10 member heterocyclic ring or heteroaryl with (a) the adjacent nitrogen atom and (b) the (R) a group adjacent to the nitrogen atom;
each occurrence of R is, independently, —(CR 3 R 4 )—;
each occurrence of R 3 and R 4 are, independently H, OH, alkyl, alkoxy, —NH 2 , alkylamino, or dialkylamino;
or R 3 and R 4 , together with the carbon atom to which they are directly attached, form a cycloalkyl group, wherein no more than three R groups in each chain attached to the carbon C* are cycloalkyl;
the dashed line to Q is absent or a bond;
when the dashed line to Q is absent then Q is absent or is —O—, —NH—, —S—, —C(O)O—, —OC(O)—, —C(O)N(R 4 )—, —N(R 5 )C(O)—, —S—S—, —OC(O)O—, —O—N═C(R 5 )—, —C(R 5 )═N—O—, —OC(O)N(R 5 )—, —N(R 5 )C(O)N(R 5 )—, —N(R 5 )C(O)O—, —C(O)S—, —C(S)O— or —C(R 5 )═N—O—C(O)—; or
when the dashed line to Q is a bond then (i) b is 0 and (ii) Q and the tertiary carbon adjacent to it (C*) form a substituted or unsubstituted, mono- or bi-cyclic heterocyclic group having from 5 to 10 ring atoms;
Q 1 and Q 2 are each, independently, absent, —O—, —S—, —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —C(S)O—, —S—S—, —C(O)(NR 5 )—, —N(R 5 )C(O)—, —C(S)(NR 5 )—, —N(R 5 )C(O)—, —N(R 5 )C(O)N(R 5 )—, or —OC(O)O—;
Q 3 and Q 4 are each, independently, H, —(CR 3 R 4 )—, aryl, or a cholesterol moiety;
each occurrence of A 1 , A 2 , A 3 and A 4 is, independently, —(CR 5 R 5 —CR 5 ═CR 5 )—;
each occurrence of R 5 is, independently, H or alkyl;
M 1 and M 2 are each, independently, a biodegradable group;
Z is absent, alkylene or —O—P(O)(OH)—O—;
each ------ attached to Z is an optional bond, such that when Z is absent, Q 3 and Q 4 are not directly covalently bound together;
a is 1, 2, 3, 4, 5 or 6;
b is 0, 1, 2, or 3;
c, d, e, f, i, j, m, n, q and r are each, independently, 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;
g and h are each, independently, 0, 1 or 2;
k and l are each, independently, 0 or 1, where at least one of k and 1 is 1; and
o and p are each, independently, 0, 1 or 2,

wherein
(i) the compound does not contain the following moiety:

wherein ---- is an optional bond; and
Q 3 and Q 4 are each, independently, separated from the tertiary carbon atom marked with an asterisk (*) by a chain of 8 or more atoms.

2. The compound of claim 1 , wherein the biodegradable group is selected from —OC(O)—, —C(O)O—, —SC(O)—, —C(O)S—, —OC(S)—, —C(S)O—, —S—S—, —C(R 5 )═N—, —N═C(R 5 )—, —C(R 5 )═N—O—, —O—N═C(R 5 )—, —C(O)(NR 5 )—, —N(R 5 )C(O)—, —C(S)(NR 5 )—, —N(R 5 )C(O)—, —N(R 5 )C(O)N(R 5 )—, —OC(O)O—, —OSi(R 5 ) 2 O—, —C(O)(CR 3 R 4 )C(O)O—, and —OC(O)(CR 3 R 4 )C(O)—.

3. The compound of claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.

4. The compound of claim 1 , wherein the compound is in the form of a cationic lipid.

5. A lipid particle comprising a neutral lipid selected from DSPC, DPPC, POPC, DOPE, or SM, a lipid capable of reducing aggregation, wherein the lipid capable of reducing aggregation is a PEG lipid, and a cationic lipid of claim 4 .

6. The lipid particle of claim 5 , wherein the lipid particle further comprises a sterol.

7. The lipid particle of claim 6 , wherein the cationic lipid is present in a mole percentage of about 20% and about 60%; the neutral lipid is present in a mole percentage of about 5% to about 25%; the sterol is present in a mole percentage of about 25% to about 55%; and the PEG lipid is PEG-DMA, PEG-DMG, or a combination thereof, and is present in a mole percentage of about 0.5% to about 15%.

8. The lipid particle of claim 5 , further comprising an active agent.

9. The lipid particle of claim 8 , wherein the active agent is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

10. The lipid particle of claim 5 , wherein the lipid particle has an in vivo half life (t 1/2 ) of less than about 3 hours.

11. The lipid particle of claim 5 , wherein the lipid particle has an in vivo half life (t 1/2 ) of less than about 10% of that for a lipid particle containing the same cationic lipid without a biodegrable group.

12. A pharmaceutical composition comprising a lipid particle of claim 5 and a pharmaceutically acceptable carrier.

13. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid particle of claim 5 .

14. The method of claim 13 , wherein the active agent is a nucleic acid selected from a plasmid, an immunostimulatory oligonucleotide, an siRNA, an antisense oligonucleotide, a microRNA, an antagomir, an aptamer, and a ribozyme.

15. The compound of claim 1 , wherein (i) R 1 and R 2 are each, independently, optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or heterocycle; or (ii) R 1 and R 2 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocylic ring.

16. The compound of claim 1 , wherein
(a) when Q 1 is a biodegradable group (e.g., —C(O)O—), then c is at least 4;
(b) when Q 2 is a biodegradable group, then d is at least 4; and
(c) Q 3 and Q 4 are each, independently, separated from the tertiary carbon atom marked with an asterisk (*) by a chain of 10 or more atoms.

17. The compound of claim 1 , wherein a carbon atom alpha or beta to a biodegradable group in formula (I) is substituted with one or two alkyl groups.

18. The compound of claim 1 , wherein the M 1 or M 2 group and neighboring variable(s) form the group:

wherein n is 4-6.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Manoharan Muthiah
• Maier Martin
• Jayaraman Muthusamy
• Matsuda Shigeo
• Nair Jayaprakash K
• Rajeev Kallanthottathil G
• Akinc Akin
• Baillie Thomas A

Classifications

• A61P37/04

  Immunostimulants · CPC title

• A61P31/18

  for HIV · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C12N15/88

  using microencapsulation, e.g. using {amphiphile} liposome vesicle · CPC title