Multi-tailed lipids and uses thereof

Patent metadata

Field	Value
Publication number	US-9895443-B2
Application number	US-201414900869-A
Country	US
Kind code	B2
Filing date	Jun 26, 2014
Priority date	Jun 26, 2013
Publication date	Feb 20, 2018
Grant date	Feb 20, 2018

Abstract

The present invention provides multi-tailed lipid compounds, and salts and stereoisomers thereof, and methods of preparing the compounds. Also provided are compositions including a compound of the invention and an agent (e.g., an siRNA, mRNA, plasmid DNA, small molecule, protein, peptide). The present invention also provides methods, and kits using the compositions for delivering an agent to a subject (e.g., to the liver, spleen, or lung of the subject) or cell and for treating and/or preventing a range of diseases, such as genetic diseases, proliferative diseases, hematological diseases, neurological diseases, immunological diseases, gastrointestinal diseases (e.g., liver diseases), respiratory diseases (e.g., lung diseases), painful conditions, psychiatric disorders, metabolic disorders, and spleen diseases.

First claim

What is claimed is:

1. A compound of Formula (I):

or a salt or stereoisomer thereof;
wherein:
each instance of R A is independently substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group;
each instance of R B is independently substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R C is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R D is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R E is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
each instance of R F is independently hydrogen, halogen, or substituted or unsubstituted C 1-6 alkyl;
k is 0 or 1;
m is 2, 3, 4, 5, or 6; and
each instance of n is independently 1, 2, 3, 4, 5, or 6.

2. The compound of claim 1 , wherein the compound is of the formula:

or a salt or stereoisomer thereof.

3. The compound of claim 1 , wherein the compound is of the formula:

or a salt or stereoisomer thereof.

4. The compound of claim 1 , wherein the compound is of the formula:

or a salt or stereoisomer thereof.

5. The compound of claim 1 , wherein the compound is of the formula:

or a salt or stereoisomer thereof.

6. The compound of claim 1 , wherein at least one instance of R A is substituted or unsubstituted alkyl.

7. The compound of claim 1 , wherein:
at least one instance of R A is C 1-6 alkyl substituted with one or more substituents R A1 ;
each instance of R A1 is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or —N(R A1a ) 2 ; and
each instance of R A1a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a nitrogen protecting group, or two instances of R A1a are joined to form a substituted or unsubstituted heterocyclic ring.

8. The compound of claim 7 , wherein at least one instance of R A is C 1-6 alkyl substituted with one or more substituents R A1 , wherein at least one instance of R A1 is substituted or unsubstituted, 3- to 9-membered, monocyclic carbocyclyl including zero, one, or two double bonds in the carbocyclic ring.

9. The compound of claim 7 , wherein at least one instance of R A is C 1-6 alkyl substituted with one or more substituents R A1 , wherein at least one instance of R A1 is substituted or unsubstituted, 3- to 9-membered, monocyclic heterocyclyl, wherein one, two, or three atoms in the heterocyclic ring is independently selected from the group consisting of nitrogen, oxygen, or sulfur.

10. The compound of claim 7 , wherein at least one instance of R A is C 1-6 alkyl substituted with one or more substituents R A1 , wherein at least one instance of R A1 is substituted or unsubstituted, 5- to 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring is independently selected from the group consisting of nitrogen, oxygen, or sulfur.

11. The compound of claim 7 , wherein at least one instance of R A is C 1-6 alkyl substituted with one or more substituents R A1 , wherein at least one instance of R A1 is substituted or unsubstituted, 9- to 10-membered, bicyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring is independently selected from the group consisting of nitrogen, oxygen, or sulfur.

12. The compound of claim 7 , wherein at least one instance of R A is C 1-6 alkyl substituted with one or more substituents R A1 , wherein at least one instance of R A1 is —N(R A1a ) 2 .

13. The compound of claim 1 , wherein at least one instance of R A is substituted or unsubstituted, 3- to 9-membered, monocyclic heterocyclyl including zero, one, or two double bonds in the heterocyclic ring, wherein one, two, or three atoms in the heterocyclic ring are independently selected from the group consisting of nitrogen, oxygen, and sulfur.

14. The compound of claim 1 , wherein at least one instance of R A is unsubstituted C 1-6 alkyl.

15. The compound of claim 1 , wherein at least one instance of R B is substituted or unsubstituted alkyl.

16. The compound of claim 1 , wherein all instances of R C are hydrogen.

17. A method of preparing a compound of claim 1 , or a salt or stereoisomer thereof, the method comprising:
(a) reacting a compound of Formula (A), or a salt thereof, with a compound of Formula (B), or a salt thereof, to provide a compound of Formula (C), or a salt thereof:

and
(b) reacting the compound of Formula (C), or a salt thereof, with a compound of Formula (D), or a salt thereof, to provide the compound of claim 1 , or the salt or stereoisomer thereof:
R B —SH  (D).

18. A composition comprising:
a compound of claim 1 , or a salt thereof;
an agent; and
optionally an excipient.

19. A method of delivering an agent to a subject or cell, the method comprising administering to the subject or contacting the cell with a composition of claim 18 .

20. The compound of claim 1 , wherein the compound of Formula (I) is a compound of Formula (I-B-3) or Formula (I-C-3):

or a salt or stereoisomer thereof.

21. The The compound of claim 1 , wherein at least one instance of R A is of the formula:

22. The compound of claim 1 , wherein at least one instance of R B is unsubstituted or substituted C 6-18 alkyl.

23. The compound of claim 1 , wherein at least one instance of R B is unsubstituted C 6-12 alkyl.

24

Assignees

• Massachusetts Inst Technology

Inventors

• Alabi Akinleye C
• Love Kevin Thomas
• Anderson Daniel Griffith
• Langer Robert S

Classifications

• A61K9/127

  Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant · 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

• C12N2310/14

  interfering nucleic acids [NA] · CPC title

• C07C323/12 Primary

  the carbon skeleton being acyclic and saturated · CPC title

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title