Compounds and compositions for intracellular delivery of therapeutic agents

Patent metadata

Field	Value
Publication number	US-12263248-B2
Application number	US-201917278040-A
Country	US
Kind code	B2
Filing date	Sep 19, 2019
Priority date	Sep 19, 2018
Publication date	Apr 1, 2025
Grant date	Apr 1, 2025

Abstract

The disclosure features novel lipids and compositions involving the same. Nanoparticle compositions include a novel lipid as well as additional lipids such as phospholipids, structural lipids, and PEG lipids. Nanoparticle compositions further including therapeutic and/or prophylactics such as RNA are useful in the delivery of therapeutic and/or prophylactics to mammalian cells or organs to, for example, regulate polypeptide, protein, or gene expression.

First claim

The invention claimed is:

1. A compound, selected from the group consisting of:

and salts thereof.

2. A 1nanoparticle composition comprising a lipid component comprising a compound of claim 1 , wherein the lipid component further comprises (i) a phospholipid; (ii) a structural lipid; and/or (iii) a PEG lipid.

3. The nanoparticle composition of claim 2 , wherein the phospholipid is selected from the group consisting of 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC), 1,2-dimyristoyl-sn-glycero-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-diundecanoyl-sn-glycero-phosphocholine (DUPC), 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC), 1,2-di-O-octadecenyl-sn-glycero-3-phosphocholine (18:0 Diether PC), 1-oleoyl-2-cholesterylhemisuccinoyl-sn-glycero-3-phosphocholine (OChemsPC), 1-hexadecyl-sn-glycero-3-phosphocholine (C16 Lyso PC), 1,2-dilinolenoyl-sn-glycero-3-phosphocholine, 1,2-diarachidonoyl-sn-glycero-3-phosphocholine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphocholine, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE), 1,2-diphytanoyl-sn-glycero-3-phosphoethanolamine (ME 16.0 PE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dilinolenoyl-sn-glycero-3-phosphoethanolamine, 1,2-diarachidonoyl-sn-glycero-3-phosphoethanolamine, 1,2-didocosahexaenoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt (DOPG), dipalmitoylphosphatidylglycerol (DPPG), palmitoyloleoylphosphatidylethanolamine (POPE), distearoyl-phosphatidyl-ethanolamine (DSPE), dipalmitoyl phosphatidyl ethanolamine (DPPE), dimyristoylphosphoethanolamine (DMPE), 1-stearoyl-2-oleoyl-phosphatidyethanolamine (SOPE), 1-stearoyl-2-oleoyl-phosphatidylcholine (SOPC), sphingomyelin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, phosphatidic acid, palmitoyloleoyl phosphatidylcholine, lysophosphatidylcholine, lysophosphatidylethanolamine (LPE), and mixtures thereof.

4. The nanoparticle composition of claim 2 , wherein the structural lipid is selected from the group consisting of cholesterol, fecosterol, sitosterol, ergosterol, campesterol, stigmasterol, brassicasterol, tomatidine, ursolic acid, alpha-tocopherol, and mixtures thereof.

5. The nanoparticle composition of claim 2 , wherein the PEG lipid is selected from the group consisting of a PEG-modified phosphatidylethanolamine, a PEG-modified phosphatidic acid, a PEG-modified ceramide, a PEG-modified dialkylamine, a PEG-modified diacylglycerol, a PEG-modified dialkylglycerol, and mixtures thereof, or the PEG lipid is a compound of Formula (V):

or a salt or isomer thereof, wherein:
R 3PEG is-ORO;
R O is hydrogen, C 1-5 alkyl or an oxygen protecting group;
r PEG is an integer between 1 and 100;
R 5PEG is C 10-40 alkyl, C 10-40 alkenyl, or C 10-40 alkynyl; and optionally one or more methylene groups of R 5PEG are independently replaced with C 3-10 carbocyclylene, 4 to 10 membered heterocyclylene, C 6-10 arylene, 4 to 10 membered heteroarylene, —N(R N )—, —O—, —S—, —C(O)—, —C(O)N(R N )—, —NR N C(O)—, —NR N C(O)N(R N )—, —C(O)O—, —OC(O)—, —OC(O)O—, —OC(O)N(R N )—, —NR N C(O)O—, —C(O)S—, —SC(O)—, —C(═NR N )—, —C(═NR N )N(R N )—, —NR N C(═NR N )—, —NR N C(═NR N )N(R N )—, —C(S)—, —C(S)N(R N )—, —NR N C(S)—, —NR N C(S)N(R N )—, —S(O)—, —OS(O)—, —S(O)O—, —OS(O)O—, —OS(O) 2 —, —S(O) 2 O—, —OS(O) 2 O—, —N(R N )S(O)—, —S(O)N(R N )—, —N(R N )S(O)N(R N )—, —OS(O)N(R N )—, —N(R N )S(O)O—, —S(O) 2 —, —N(R N )S(O) 2 —, —S(O) 2 N(R N )—, —N(R N )S(O) 2 N(R N )—, —OS(O) 2 N(R N )—, or —N(R N )S(O) 2 O—; and
each instance of R N is independently hydrogen, C 1-6 alkyl, or a nitrogen protecting group.

6. The nanoparticle composition of claim 2 , further comprising a therapeutic and/or prophylactic agent.

7. The nanoparticle composition of claim 6 , wherein the therapeutic and/or prophylactic agent is a vaccine or a compound capable of eliciting an immune response.

8. The nanoparticle composition of claim 6 , wherein the therapeutic and/or prophylactic agent is a nucleic acid.

9. The nanoparticle composition of claim 8 , wherein the nucleic acid is an mRNA.

10. A method of delivering a therapeutic and/or prophylactic agent to a mammalian cell, the method comprising administering to a subject the nanoparticle composition of claim 6 , said administering comprising contacting the cell with the nanoparticle composition, whereby the therapeutic and/or prophylactic agent is delivered to the cell.

11. A method of producing a polypeptide of interest in a mammalian cell, the method comprising contacting the cell with the nanoparticle composition of claim 6 , wherein the therapeutic and/or prophylactic agent is an mRNA, and wherein the mRNA encodes the polypeptide of interest, whereby the mRNA is capable of being translated in the cell to produce the polypeptide of interest.

12. The compound of claim 1 , wherein the compound is compound 347:

or a salt thereof.

13. The compound of claim 1 , wherein the compound is compound 348:

or a salt thereof.

14. The compound of claim 1 , wherein the compound is compound 384:

or a salt thereof.

15. The compound of claim 1 , wherein the compound is compound 385:

or a salt thereof.

Assignees

• Modernatx Inc

Inventors

• Benenato Kerry E
• Cornebise Mark
• Hennessy Edward

Classifications

• C07F9/091

  with hydroxyalkyl compounds with further substituents on alkyl · CPC title

• C07D473/34

  attached in position 6, e.g. adenine · CPC title

• C07D473/18

  one oxygen and one nitrogen atom, e.g. guanine · CPC title

• C07D295/13

  to an acyclic saturated chain · CPC title

• C07D249/04

  1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles · CPC title