Novel ionizable cationic lipids containing thioether linkage

Abstract

The invention relates to novel ionizable amine lipids incorporating one or more sulphur atoms in the tail section. These lipids can be used in combination with other components to form lipid nanoparticles with oligonucleotides. The invention describes the synthesis of the lipids of formula (I), formation and characterization of nanoparticles and biological experiments demonstrating that the lipid nanoparticles prepared with these novel lipids can efficiently deliver their cargo (e.g. RNA, DNA, mRNA, siRNA, miRNA, pDNA, circular DNA, dsRNA, small biologically active molecules) into the cells.

Description

Abstract This invention relates to novel ionizable amine lipids with one or more sulfur atoms introduced into the tail. These lipids can be used in combination with other components to form lipid nanoparticles with oligonucleotides. This invention describes the synthesis of lipids of formula (I), the formation and characterization of nanoparticles, and biological experiments demonstrating that lipid nanoparticles prepared from these novel lipids can efficiently deliver their carriers (e.g., RNA, DNA, mRNA, siRNA, miRNA, pDNA, circular DNA, dsRNA, small bioactive molecules) into cells.

Claims

Claims1. Compound of formula (I)or its salt or stereoisomer, whereinG1is unsubstituted C4-C9 alkylene,-(CH2)X-CH=CH-(CH2)y-, wherein x is an integer selected from 1 to 6, y is an integer selected from 1 to 6, and the sum of x+y is an integer selected from 2 to 7, or-(CH2)W-X-(CH2) z-, wherein w is an integer selected from 1 to 7, z is an integer selected from 2 to 7, the sum of w+z is an integer selected from 3 to 8, wherein -(CH2)Z- is attached to N, and X is selected from O, S;T1iswherein b1is a bond to G1,Xi and X2are the same or different and each independently represents O or S,R2is linear C1-C12 alkyl, branched C5-C11 alkyl, in both cases containing one S at any position in the carbon chain with the proviso that the heteroatom is not in the alpha or omega position of the carbon chain, orR2is linear C5-C11 alkenyl, branched C5-C11 alkenyl containing one or more double bonds with the proviso that there is at least one -CH2- group between the double bond and the carbon linking Xi and X2and in both cases containing one S at any position in the carbon chain with the proviso that the heteroatom is not in the alpha or omega position of the carbon chain and with the further proviso that there is at least one -CH2- is between the heteroatom and the adjacent carbon atom of the double bond;G2is defined as G1above, where G1and G2may be identical or different;T2is defined as T1above, wherein b1is a bond to G2, and where T1and T2may be identical or different;D1is selected fromwhereinRs is Ci-Ce alkyl, cyclopentyl, cyclohexyl, hydroxyl, hydroxymethyl, hydroxyethyl, phenyl, benzyl, 4-hydroxy benzyl,R4 and R5 are independently selected from H and Ci-Ce alkyl, m is an integer selected from 1 to 6, n is an integer selected from 0 to 6,0 is an integer selected from 0 to 6, p is an integer selected from 2 to 6, q is an integer selected from 0 to 6, j is an integer selected from 1 to 4,Cyi is a Ci-Ce cycloalkyl optionally substituted by one or more -OH, orCyi is a pyranose, furanose ring, which can be linked via any of its OH group, wherein the pyranose or furanose ring is optionally substituted by a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine, a mono- or oligosaccharide, or by a 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from N, O or S; orCyi is a 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, N or S, wherein the heterocyclic ring is optionally substituted by Re, whereinRe is Ci-Ce alkyl, an arginine containing peptide, a pyranose or furanose ring attached by any of their ring-carbon atoms to the 4-, 5-, 6- or 7-membered heterocyclic ring, wherein the pyranose or furanose ring is optionally substituted by a -NH-CO-CH3 group, adenine, guanine, uracil, cytosine, thymine or a mono- or oligosaccharide, or Re is a group selected from (c), (d), (e) or (g), wherein, m, n, 0, p, j, R3, 1 and R5 are as defined above, orgroup wherein r is an integer selected from 1 to 4, and Cy2 is a 4-, 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 heteroatoms selected from O, N and S, optionally substituted by Ci-Ce alkyl.

2. Compound according to claim 1, wherein G1and G2are the same or different and each is independently linear C4-C9 alkylene, preferably C5-C9 alkylene, or, alternatively, each is independently linear C5, Ce, C7, or C9 alkylene.

3. Compound according to claim 1 or 2 wherein G'-T1and G2-T2are identical.

4. Compound according to claim 1 wherein the sulphur in the -position in R25. Compound according to any of claims 1 to 3 wherein T1and / or T2is selected from the following:

6. Compound according to claim 5 wherein in R2the heteroatom S is in the beta position of the carbon chain.

7. Compound according to any of claims 1 to 6 wherein R2is selected from the following:

8. Compound according to any of claims 1 to 7 wherein D1is selected from the following:wherein q is an integer selected from 1 to 4 and b4is a bond to the nitrogen.

9. Compound according to claim 8 wherein D1is10. Compound according to claim 1 which is selected from the following:

11. A compound according to any of claims 1 to 10 for use in the preparation of a lipid nanoparticle.

12. A lipid nanoparticle comprising a therapeutic agent and a compound according to any of claims 1 to 10.