Amine-containing lipidoids and uses thereof

• US 9,227,917 B2
• Filed: 11/25/2013
• Issued: 01/05/2016
• Est. Priority Date: 08/13/2012
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Anderson, Daniel Griffith, Whitehead, Kathryn Ann, Dorkin, Joseph R., Vegas, Arturo Jose, Zhang, Yunlong, Langer, Robert S.
• Primary Examiner(s): HEARD, THOMAS SWEENEY
• Application Number:
  US14/089,603
• Publication Number:
  US 20140161830A1
• Time in Patent Office: 771 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/225 Polycarboxylic acids
• CPC Class Codes: A61K 31/357 having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/4985 Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/713 Double-stranded nucleic acids or oligonucleotides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/543 Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
• CPC Class Codes: A61K 47/6925 the form being a microcapsule, nanocapsule, microbubble or nanobubble
• CPC Class Codes: A61K 9/1272 with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids with cholesterol as the only non-phosphatidyl surfactant A61K9/127; lipids as modifying agent A61K47/543
• CPC Class Codes: A61K 9/5123 Organic compounds, e.g. fats, sugars
• CPC Class Codes: C07C 225/06 and acyclic
• CPC Class Codes: C07C 229/12 to carbon atoms of acyclic carbon skeletons
• CPC Class Codes: C07C 229/14 : to carbon atoms of carbon skeletons containing rings
• CPC Class Codes: C07C 229/24 : having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
• CPC Class Codes: C07C 229/26 : having more than one amino group bound to the carbon skeleton, e.g. lysine
• CPC Class Codes: C07C 229/28 : the carbon skeleton being saturated and containing rings
• CPC Class Codes: C07C 229/34 : the carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/26 : with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 211/34 : with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 241/04 : having no double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/15 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/16 : acylated on ring nitrogen atoms
• CPC Class Codes: C07D 319/16 : condensed with one six-membered ring
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems
• CPC Class Codes: C12N 15/111 : General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 15/1137 : against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 15/88 : using microencapsulation, e.g. using amphiphile liposome vesicle
• CPC Class Codes: C12N 2310/14 : interfering N.A.
• CPC Class Codes: C12N 2320/32 : Special delivery means, e.g. tissue-specific

Abstract

Provided herein are lipidoids that may be prepared from the conjugate addition of alkylamines to acrylates. In some embodiments, provided lipidoids are biodegradable and may be used in a variety of drug delivery systems. Given the amino moiety of the lipidoids, they are well-suited for the delivery of polynucleotides, in addition to other agents. Nanoparticles containing the inventive lipidoids and polynucleotides have been prepared and have been shown to be effective in delivering siRNA.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein the compound is of the Formula (I-a):

3. The compound of claim 1, wherein L is unbranched C_1-6 alkylene.

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

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

6. The compound of claim 1, wherein all R groups are —

CH₂CH₂C(═

O)OR^B.

7. The compound of claim 1, wherein all R^B groups are the same.

8. The compound of claim 1, wherein R^B is C₁₀ alkyl, C₁₁ alkyl, C₁₂ alkyl, C₁₃ alkyl, or C₁₄ alkyl.

10. A nanoparticle comprising a compound of claim 1 and one or more agents to be delivered.

11. The nanoparticle of claim 10, wherein the one or more agents is a polynucleotide, drug, protein, peptide, a small molecule, or gas.

12. A composition comprising one or more compounds of claim 1, and an excipient.

13. The composition of claim 12, wherein the composition further comprises an agent selected from the group consisting of an organic molecule, inorganic molecule, nucleic acid, protein, peptide, polynucleotide, targeting agent, an isotopically labeled chemical compound, vaccine, and an immunological agent.

14. A method of administering an agent, the method comprising:

administering to a subject in need thereof a therapeutically effective amount of a composition comprising a compound of claim 1 and an agent to be delivered.

15. The compound of claim 1, wherein L is ethylene.

16. The compound of claim 1, wherein L is propylene.

17. The compound of claim 1, wherein q is 1.

18. The compound of claim 1, wherein q is 2.

19. The compound of claim 1, wherein q is 3.

20. The compound of claim 1, wherein R^A is branched or unbranched C_1-6 alkyl.

21. The compound of claim 1, wherein R^A is methyl, ethyl, or propyl.

22. The compound of claim 1, wherein R^A is C_3-7 cycloalkyl.

23. The nanoparticle of claim 11, wherein the one or more agents is a polynucleotide, and the polynucleotide is RNA.

24. The composition of claim 13, wherein the agent is a polynucleotide, and the polynucleotide is DNA.

25. The composition of claim 13, wherein the agent is a polynucleotide, and the polynucleotide is RNA.

26. The composition of claim 25, wherein the RNA is mRNA, dsRNA, siRNA, shRNA, miRNA, or antisense RNA.

27. The composition of claim 13, wherein the agent is a polynucleotide, and the polynucleotide encodes a protein or peptide.

9. A compound selected from the group consisting of: