CROSS REFERENCE TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. § 119(e) of Provisional U.S. patent application No. 61/905,724, filed Nov. 18, 2013, the contents of which is incorporated herein by reference in its entirety.

BACKGROUND

A number of different types of nucleic acids are currently being developed as therapeutics for the treatment of a number of diseases. These nucleic acids include DNA in gene therapy, plasmids-based interfering nucleic acids, small interfering nucleic acids for use in RNA interference (RNAi), including siRNA, miRNA, antisense molecules, ribozymes and aptamers. As these molecules are being developed, there has been developed a need to produce them in a form that is stable and has a long shelf-life and that can be easily incorporated into an anhydrous organic or anhydrous polar aprotic solvent to enable encapsulations of the nucleic acids without the side-reactions that can occur in a polar aqueous solution or nonpolar solvents.

The present invention relates to novel lipid compositions that facilitate the intracellular delivery of biologically active and therapeutic molecules. The present invention relates also to pharmaceutical compositions that comprise such lipid compositions, and that are useful to deliver therapeutically effective amounts of biologically active molecules into the cells of patients.

The delivery of a therapeutic compound to a subject is important for its therapeutic effects and usually it can be impeded by limited ability of the compound to reach targeted cells and tissues. Improvement of such compounds to enter the targeted cells of tissues by a variety of the means of delivery is crucial. The present invention relates the novel lipids, incompositions and methods for preparation that facilitate the targeted intracellular delivery of biological active molecules.

Examples of biologically active molecules for which effective targeting to a patient's tissues is often not achieved include: (1) numerous proteins including immunoglobin proteins, (2) polynucleotides such as genomic DNA, cDNA, or mRNA (3) antisense polynucleotides; and (4) many low molecular weight compounds, whether synthetic or naturally occurring, such as the peptide hormones and antibiotics.

One of the fundamental challenges now facing medical practitioners is that a number of different types of nucleic acids are currently being developed as therapeutics for the treatment of a number of diseases. These nucleic acids include DNA in gene therapy, plasmids small interfering nucleic acids (iNA) for use in RNA interference (RNAi), antisense molecules, ribozymes, antagomirs, microRNA and aptamers. As these nucleic are being developed, there is a need to produce lipid formulations that are easy to make and can be readily delivered to a target tissue.

SUMMARY

What is described herein is a compound of Formula 1


in which

R1and R2are the same or different, each a linear or branched alkyl, alkenyl, or alkynyl,L1and L2are the same or different, each a linear alkyl having at least five carbon atoms, or form a heterocycle with the N,X1is a bond, or is —CO—O— whereby L2-CO—O—R2is formedX2is S or O,L3is a bond or a lower alkyl,R3is a lower alkyl,R4and R5are the same or different, each a lower alkyl.

What is also described herein is the compound of formula 1, in which L3is absent, R1and R2each consists of at least seven carbon atoms, R3is ethylene or n-propylene, R4and R5are methyl or ethyl, and L1and L2each consists of a linear alkyl having at least five carbon atoms.

What is also described herein is the compound of formula 1, in which L3is absent, R1and R2each consists of at least seven carbon atoms, R3is ethylene or n-propylene, R4and R5are methyl or ethyl, and L1and L2each consists of a linear alkyl having at least five carbon atoms.

What is also described herein is the compound of formula 1, in which L3is absent, R1and R2each consists of an alkenyl of at least nine carbon atoms, R3is ethylene or n-propylene, R4and R5are methyl or ethyl, and L1and L2each consists of a linear alkyl having at least five carbon atoms.

What is also described herein is the compound of formula 1, in which L3is methylene, R1and R2each consists of at least seven carbon atoms, R3is ethylene or n-propylene, R4and R5are methyl or ethyl, and L1and L2each consists of a linear alkyl having at least five carbon atoms.

What is also described herein is the compound of formula 1, in which L3is methylene, R1and R2each consists of at least nine carbon atoms, R3is ethylene or n-propylene, R4and R5are each methyl, L1and L2each consists of a linear alkyl having at least seven carbon atoms.

What is also described herein is the compound of formula 1, in which L3is methylene, R1consists of an alkenyl having at least nine carbon atoms and R2consists of an alkenyl having at least seven carbon atoms, R3is n-propylene, R4and R5are each methyl, L1and L2each consists of a linear alkyl having at least seven carbon atoms.

What is also described herein is the compound of formula 1, in which L3is methylene, R1and R2each consists of an alkenyl having at least nine carbon atoms, R3is ethylene, R4and R5are each methyl, L1and L2each consists of a linear alkyl having at least seven carbon atoms.

What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What is also described herein is a compound having the structure



What are also described herein are any of the compounds listed in ATX-001 to ATX-032 listed in Table 1, below or a pharmaceutically acceptable salt thereof, in a lipid composition, comprising a nanoparticle or a bilayer of lipid molecules.   The lipid bilayer preferably further comprises a neutral lipid or a polymer. The lipid composition preferably comprise a liquid medium. The composition preferably further encapsulates a nucleic acid. The nucleic acid preferably has an activity of suppressing the expression of the target gene by utilizing RNA interference (RNAi). The lipid composition preferably further comprises a nucleic acid and a neutral lipid or a polymer. The lipid composition preferably encapsulates the nucleic acid.

The nucleic acid preferably has an activity of suppressing the expression of a target gene. The target gene preferably is a gene associated with inflammation.

What is also described herein is a method for introducing a nucleic acid into a cell of a mammal by using any of the compositions, above. The cell may be in a liver, lung, kidney, brain, blood, spleen, or bone. The composition preferably is administered intravenously, subcutaneously, intraperitoneally, or intrathecally. Preferably, the compositions described herein are used in a method for treating cancer or inflammatory disease. The disease may be one selected from the group consisting of immune disorder, cancer, renal disease, fibrotic disease, genetic abnormality, inflammation, and cardiovascular disorder.

