Branched alkyl and cycloalkyl terminated biodegradable lipids for the delivery of active agents

Patent metadata

Field	Value
Publication number	US-9463247-B2
Application number	US-201214362864-A
Country	US
Kind code	B2
Filing date	Dec 7, 2012
Priority date	Dec 7, 2011
Publication date	Oct 11, 2016
Grant date	Oct 11, 2016

Abstract

The present invention relates to a cationic lipid of formula (I) having one or more biodegradable groups located in 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, heterocycle, or R 10 ;
(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 hydrogen, OH, alkyl, alkoxy, —NH 2 , R 10 , alkylamino, or dialkylamino;
each occurrence of R 10 is independently selected from PEG and polymers based on poly(oxazoline), poly(ethylene oxide), poly(vinyl alcohol), poly(glycerol), poly(N-vinylpyrrolidone), poly[N-(2-hydroxypropyl)methacrylamide] and poly(amino acid)s, wherein (i) the PEG or polymer is linear or branched, (ii) the PEG or polymer is polymerized by n subunits, (iii) n is a number-averaged degree of polymerization between 10 and 200 units, and (iv) wherein the compound of formula (I) has at most two R 10 groups;
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)—, —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;
each occurrence of R 5 is, independently, hydrogen or alkyl;
X and Y are each, independently, —(CR 6 R 7 ) c —;
each occurrence of R 6 and R 7 are, independently hydrogen, OH, alkyl, alkoxy, —NH 2 , alkylamino, or dialkylamino;
M 1 and M 2 are each, independently, a biodegradable group;
a is 1, 2, 3, 4, 5 or 6;
b is 0, 1, 2, or 3;
each occurrence of c is, independently, 2-10; and
Z 1 and Z 2 are each, independently (i) C 3 -C 10 cycloalkyl, (ii) C 3 -C 10 cycloalkyl(C 1 -C 6 alkyl), or (iii)

wherein each of R 8 and R 9 is a C 2 -C 8 alkyl.

2. The compound of claim 1 , wherein M 1 and M 2 are each, independently, —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—, or —OC(O)(CR 3 R 4 )C(O)—.

3. The compound of claim 1 , wherein M 1 and M 2 are each, independently, —OC(O)— or —C(O)O—.

4. The compound of claim 1 , wherein R 1 and R 2 are each alkyl.

5. The compound of claim 1 , wherein R 1 and R 2 are each methyl.

6. The compound of claim 1 , wherein a is 3 and b is 0.

7. The compound of claim 1 , wherein X and Y are each, independently —(CH 2 ) c —.

8. The compound of claim 1 , wherein Z 1 and Z 2 are each, independently, C 3 -C 10 cycloalkyl.

9. The compound of claim 8 , wherein Z 1 and Z 2 are each cyclohexyl or decahydronaphthalenyl.

10. The compound of claim 1 , wherein Z 1 and Z 2 are each, independently, represented by Formula II:

wherein R 8 and R 9 are each, independently, C 3 -C 8 alkyl.

11. The compound of claim 1 , selected from:

and salts thereof.

12. A compound selected from

and salts thereof.

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

14. The compound of claim 1 , wherein the compound is in the form of a cationic lipid containing a negatively charged counter ion.

15. A lipid particle comprising a neutral lipid, a lipid capable of reducing aggregation, and a cationic lipid of claim 14 .

16. The lipid particle of claim 15 , wherein the neutral lipid is selected from DSPC, DPPC, POPC, DOPE, or SM; the lipid capable of reducing aggregation is a PEG lipid; and the lipid particle further comprises a sterol.

17. The lipid particle of claim 16 , 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%.

18. The lipid particle of claim 15 , further comprising an active agent.

19. The lipid particle of claim 18 , 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.

20. The lipid particle of claim 15 , wherein the lipid particle has an in vivo half life (t 1/2 ) of less than about 3 hours.

21. The lipid particle of claim 15 , 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.

22. A pharmaceutical composition comprising a lipid particle of claim 18 and a pharmaceutically acceptable carrier.

23. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid particle of claim 18 .

24. The method of claim 23 , wherein the active agent is a nucleic acid is an siRNA.

25. A method of treating a disease or disorder characterized by the overexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of claim 22 , wherein the active agent is a nucleic acid selected from the group consisting of an siRNA, a microRNA, and an antisense oligonucleotide, and wherein the siRNA, microRNA, or antisense oligonucleotide includes a polynucleotide that specifically binds to a polynucleotide that encodes the polypeptide, or a complement thereof.

26. A method of treating a disease or disorder characterized by underexpression of a polypeptide in a subject, comprising providing to the subject the pharmaceutical composition of claim 22 , wherein the active agent is a plasmid that encodes the polypeptide or a functional variant or fragment thereof.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Ansell Steven M
• Du Xinyao

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/04

  Immunostimulants · CPC title

• C07C2601/14

  The ring being saturated · CPC title

• C07C2601/08

  the ring being saturated · CPC title

• C12N15/113

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title