Biodegradable lipids for the delivery of active agents

1. A compound of formula (I):

or a salt thereof,

wherein

with respect to R 1 and R 2 ,

(i) R 1 and R 2 are each, independently, alkyl, alkenyl, or alkynyl; or

(ii) R 1 and R 2 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocylic ring;

each occurrence of R is, independently, —(CR 3 R 4 )—;

each occurrence of R 3 and R 4 are, independently H, or alkyl;

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, selected from the group consisting of —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)NH—, —C(O)S—, —C(S)O—, —CR 5 ═NO—, —CR 5 ═N—, and —O—Si(R 6 R 6 )O—, wherein R 6 is H or C 1 -C 6 alkyl;

a is an integer between 1 and 6 inclusive;

b and c are, independently, an integer between 1 and 10 inclusive;

d, e, f, g, h, and i are each, independently, an integer between 0 and 10 inclusive;

j, k, l, and m are each, independently, an integer between 0 and 2 inclusive;

n and o are each, independently, 0 or 1, wherein at least one of n and o is 1, and

wherein the terminal —H of each chain and the tertiary carbon are separated by a chain of at least 8 atoms.

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

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

4. The compound of claim 2 , wherein M 1 and M 2 are each —C(O)O—.

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

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

7. The compound of claim 1 , wherein each instance of R is, independently, —CH 2 —, —C(CH 3 ) 2 — or —CH(iPr)-.

8. The compound of claim 1 , wherein a is 2, 3, or 4.

9. The compound of claim 1 , wherein a carbon atom alpha or beta to a biodegradable group is substituted with one or two alkyl groups.

10. The compound of claim 1 , wherein one or more of the following applies:

(i) M 1 and M 2 are both —C(O)O—;

(ii) j and k are both 1;

(iii) j and k are both 0;

(iv) b is 7;

(v) c is 7;

(vi) b and d total 7;

(vii) c and e total 7;

(viii) d and e are each 7;

(ix) n and o are both 1;

(x) f and g are both 0;

(xi) f and h total 1 or 2.

11. The compound of claim 1 , selected from:

or a salt thereof.

12. The compound of claim 1 , wherein the R 1 R 2 N—(R) a — group is (CH 3 ) 2 N—(CH 2 ) 3 —.

13. The compound of claim 1 , wherein R 1 and R 2 are each, independently, C 1 -C 4 alkyl.

14. The compound of claim 1 , wherein each occurrence of R is, independently, —CH 2 — or —CH(CH 3 )—.

15. The compound of claim 1 , wherein the sum of b+3j+d+f+3l+h is from about 8 to about 20.

16. The compound of claim 1 , wherein the sum of f+3k+e+g+3m+i is from about 8 to about 20.

17. A compound of formula TB

wherein

R 1 and R 2 are each, independently, alkyl, alkenyl, or alkynyl; or

R 1 and R 2 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocylic ring;

each occurrence of R is, independently, —(CR 3 R 4 )—;

each occurrence of R 3 and R 4 are, independently H or alkyl;

a is 1, 2, 3, 4, 5 or 6;

M 1 and M 2 are each, independently, selected from the group consisting of —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)NH—, —C(O)S—, —C(S)O—, —CR 5 ═NO—, —CR 5 ═N—, and —O—Si(R 6 R 6 )O—, wherein each occurrence of R 5 is, independently, H or alkyl, and R 6 is H or C 1 -C 6 alkyl;

each of R 9 and R 10 are independently alkylene or alkenylene; and

each of R 11 and R 12 are independently alkyl or alkenyl;

with the proviso that:

R 9 , M 1 , and R 11 are together at least 8 carbons atoms in length; and

R 10 , M 2 , and R 12 are together at least 8 carbons atoms in length.

18. The compound of claim 17 , wherein R 9 and R 10 are each independently C 4 -C 12 alkylene or C 4 -C 12 alkenylene, M 1 and M 2 are —C(O)O—, and R 11 and R 12 are C 4 -C 12 alkylene or C 4 -C 12 alkenylene.

19. The compound of claim 17 , wherein R 9 , M 1 , and R 11 are together at 12 to 24 carbons atoms in length.

20. The compound of claim 17 , wherein, R 10 , M 2 , and R 12 are together at 12 to 24 carbons atoms in length.

21. The compound of claim 17 , wherein the R 1 R 2 N—(R) a — group is (CH 3 ) 2 N—(CH 2 ) 3 —.

22. A compound of formula IC

wherein

R 1 and R 2 are each, independently, optionally substituted alkyl, alkenyl, or alkynyl; or

R 1 and R 2 , together with the nitrogen atom to which they are attached, form an optionally substituted heterocylic ring;

each occurrence of R is, independently, —(CR 3 R 4 )—;

each occurrence of R 3 and R 4 are, independently H or alkyl;

a is 1, 2, 3, 4, 5 or 6;

each of R 9 and R 10 are independently C 12 -C 24 alkyl or alkenyl substituted at its terminus with a group M selected from the group consisting of —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)NH—, —C(O)S—, —C(S)O—, —CR 5 ═NO—, —CR 5 ═N—, and —O—Si(R 6 R 6 )O—, wherein each occurrence of R 5 is, independently, H or alkyl, and R 6 is H or C 1 -C 6 alkyl.

23. The compound of claim 22 , wherein each group M is —COOR 13 wherein each R 13 is, independently, alkyl.

24. The compound of claim 22 , wherein the R 1 R 2 N—(R) a — group is (CH 3 ) 2 N—(CH 2 ) 3 —.

25. A compound selected from a compound of formulas II-XXIII:

and salts thereof,

wherein

m, n, o and p are each, individually, 1-25, with the proviso that:

(i) in Formulas (II), (IV), (VI) and (VII), m and p are both 4 or greater;

(ii) in Formulas (VIII), (X), (XII), (XIV), (XVI), (XVIII), (XXI) and (XXIII), m is 4 or greater; and

(iii) in Formulas (VIII), (IX), (XII) and (XIII), p is 8 or greater.

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

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

28. A lipid particle comprising a neutral lipid, a lipid capable of reducing aggregation, and a cationic lipid of claim 27 .

29. The lipid particle of claim 28 , 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.

30. The lipid particle of claim 28 , 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%.

31. The lipid particle of claim 28 , further comprising an active agent.

32. The lipid particle of claim 31 , 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.

33. The lipid particle of claim 28 , wherein the lipid particle has an in vivo half life (t 1/2 ) of less than about 3 hours.

34. The lipid particle of claim 28 , 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.

35. A pharmaceutical composition comprising a lipid particle of claim 28 and a pharmaceutically acceptable carrier.

36. A method of modulating the expression of a target gene in a cell, comprising providing to the cell a lipid particle of claim 28 .

37. The method of claim 26 , 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.

38. A method of inducing an immune response in a subject, comprising providing to the subject the pharmaceutical composition of claim 35 , wherein the active agent is an immunostimulatory oligonucleotide.

39. The method of claim 38 , wherein the target gene is selected from the group consisting of Factor VII, Eg5, PCSK9, TPX2, apoB, SAA, TTR, RSV, PDGF beta gene, Erb-B gene, Src gene, CRK gene, GRB2 gene, RAS gene, MEKK gene, JNK gene, RAF gene, Erk1/2 gene, PCNA(p21) gene, MYB gene, JUN gene, FOS gene, BCL-2 gene, Cyclin D gene, VEGF gene, EGFR gene, Cyclin A gene, Cyclin E gene, WNT-1 gene, beta-catenin gene, c-MET gene, PKC gene, NFKB gene, STAT3 gene, survivin gene, Her2/Neu gene, SORT1 gene, XBP1 gene, topoisomerase I gene, topoisomerase II alpha gene, p73 gene, p21(WAF1/CIP1) gene, p27(KIP1) gene, PPM1D gene, RAS gene, caveolin I gene, MIB I gene, MTAI gene, M68 gene, tumor suppressor genes, and p53 tumor suppressor gene.

40. The method of claim 39 , wherein the target gene contains one or more mutations.

41. A method of delivering a nucleic acid molecule comprising administering a lipid particle of claim 32 to a subject.