Search

CN-121974814-A - Lipid compounds and lipid nanoparticle compositions

CN121974814ACN 121974814 ACN121974814 ACN 121974814ACN-121974814-A

Abstract

The present disclosure provides a lipid compound having a structure as shown in formula I and a lipid nanoparticle composition. The lipid nanoparticle provided by the disclosure has the advantages of good particle size distribution, high encapsulation efficiency, excellent delivery effect and capability of meeting the in-vivo delivery requirement.

Inventors

  • WANG ZIJUN
  • GUI YANG

Assignees

  • 上海尧唐生物科技股份有限公司

Dates

Publication Date
20260505
Application Date
20260113

Claims (20)

  1. 1. A lipid compound, or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof, wherein the lipid compound has a structure according to formula I: ; Wherein: Each L 1 、L 2 、L 5 、L 6 、L 8 、L 9 is independently selected from the group consisting of alkylene of C 1 -C 10 ; L 3 is selected from the group consisting of substituted or unsubstituted C 1 -C 10 alkylene, alkylene of C 1 -C 10 containing an olefinic bond, the substituted group being selected from the group consisting of substituents of halogen atoms; Each L 4 、L 7 、L 10 is independently selected from the group consisting of alkyl of C 5 -C 20 ; R 1 、R 2 、R 3 、R 4 、R 5 is each independently selected from a single bond, -O-C (=O) -NH-, -NH-C (=O) -, -O-C (=O) -O-, or-C (=O) -O-; G is selected from-N (R 1 ) 2 or N-containing heterocyclyl, R 1 is selected from C 1 -C 5 alkyl).
  2. 2. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein L 1 is selected from the group consisting of alkylene of C 2 -C 4 .
  3. 3. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein L 2 is selected from the group consisting of alkylene of C 1 -C 3 , optionally L 2 is selected from-CH 2 -.
  4. 4. The lipid compound according to claim 1, wherein L 3 is selected from the group consisting of C 2 -C 5 alkylene, C 2 -C 5 alkylene containing one olefinic bond, and C 2 -C 5 alkylene containing a fluorine atom substituent, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof.
  5. 5. The lipid compound of claim 1, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein each L 5 、L 6 、L 8 、L 9 is independently selected from the group consisting of alkylene of C 1 -C 5 .
  6. 6. The lipid compound according to claim 1, wherein each L 4 、L 7 、L 10 is independently selected from the group consisting of pharmaceutically acceptable salts, prodrugs, and stereoisomers thereof 、 Or (b) ,“ "Is a ligation site.
  7. 7. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein R 1 is selected from-O-C (=o) -.
  8. 8. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein each R 2 、R 4 is independently selected from a single bond, -O-C (=o) -or-C (=o) -O-.
  9. 9. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein each R 3 、R 5 is independently selected from-O-C (=o) -, -O-C (=o) -NH-, -NH-C (=o) -or-O-C (=o) -O-.
  10. 10. The lipid compound according to claim 1, wherein G is selected from -N(CH 3 ) 2 、-N(CH 2 CH 3 ) 2 、-N(CH 2 CH 2 CH 3 ) 2 or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof ,“ "Is a ligation site.
  11. 11. The lipid compound according to claim 1, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein the lipid compound has a structure as shown in formula II: ; Wherein n, a, t are each independently selected from integers from 1 to 10.
  12. 12. The lipid compound according to claim 11, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein t is selected from integers from 2 to 4.
  13. 13. The lipid compound according to claim 11, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein n, a are each independently selected from integers from 1 to 5.
  14. 14. The lipid compound of claim 11, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein the lipid compound has a structure as shown in formula II-1: ; Wherein m is selected from integers from 1 to 10.
  15. 15. The lipid compound according to claim 14, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein m is selected from integers from 2 to 5.
  16. 16. The lipid compound of claim 14, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein the lipid compound has a structure as shown in formula II-2: ; wherein x and y are each independently selected from integers from 1 to 10.
  17. 17. The lipid compound according to claim 16, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein x, y are each independently selected from integers from 1 to 5.
  18. 18. The lipid compound according to claim 16, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein a and n are the same and x and y are the same.
  19. 19. The lipid compound according to claim 18, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein the sum of a and x is an integer from 5 to 9.
  20. 20. The lipid compound of claim 11, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof, wherein the lipid compound has a structure as shown in formula II-3 or formula II-4: ; ; wherein x and y are each independently selected from integers from 1 to 10.

Description

Lipid compounds and lipid nanoparticle compositions Technical Field The present disclosure belongs to the technical field of lipid compounds, and in particular relates to a lipid compound and a lipid nanoparticle composition. Background Gene therapy has the potential to radically alter the precise medicine, nucleic acid-based gene therapy can be used to treat or prevent a number of diseases, such as cancer, bacterial infections, viral infections, genetic diseases, which often need to be protected for efficient delivery to target cells, e.g., by means of viral vectors, as nucleic acids are readily degraded in vivo, and the development of a safe and efficient delivery platform is a prerequisite for the clinical success of gene therapy. Lipid Nanoparticles (LNP) have been developed for delivery of non-viral genes. Since patisiran (patricia, onpattro ®) of LNP delivery in 2018 was used to treat hereditary transthyretin amyloidosis, the scientific research for delivering nucleic acid drugs using LNP technology has grown exponentially. LNP typically includes ionizable lipids, neutral lipids, steroids, and polymer-bound lipids, the choice of the ionized lipids among the LNP's constituents has a significant impact on LNP performance, and current LNP delivery platforms present challenges including low delivery efficiency, low cell permeability, and high susceptibility to degradation of certain nucleic acid molecules (e.g., RNA), among others. Thus, there is a need to develop new lipid compounds and lipid nanoparticles to meet the urgent need in the art. Disclosure of Invention In view of the deficiencies of the prior art, it is an object of the present disclosure to provide a lipid compound and lipid nanoparticle composition. In one aspect, the present disclosure provides a lipid compound having a structure as shown in formula I, or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof: ; Wherein: Each L 1、L2、L5、L6、L8、L9 is independently selected from the group consisting of alkylene of C 1-C10; L 3 is selected from the group consisting of substituted or unsubstituted C 1-C10 alkylene, alkylene of C 1-C10 containing an olefinic bond, the substituted group being selected from the group consisting of substituents of halogen atoms; Each L 4、L7、L10 is independently selected from the group consisting of alkyl of C 5-C20; R 1、R2、R3、R4、R5 is each independently selected from a single bond, -O-C (=O) -NH-, -NH-C (=O) -, -O-C (=O) -O-, or-C (=O) -O-; G is selected from-N (R 1)2 or N-containing heterocyclyl, R 1 is selected from C 1-C5 alkyl). In some embodiments, provided herein is a lipid compound of the structure shown in formula II, or a pharmaceutically acceptable salt, prodrug, or stereoisomer thereof: ; Wherein n, a, t are each independently selected from integers from 1 to 10. In some embodiments, provided herein is a lipid compound of the structure shown in formula III, formula IV or formula V-1, formula V-2, or a pharmaceutically acceptable salt, prodrug or stereoisomer thereof: ; ; ; ; wherein t, m, n, a, x, y are each independently selected from integers from 1 to 10. In another aspect, the present disclosure provides a composition comprising a lipid compound as described in the present disclosure, and a therapeutic and/or prophylactic agent. In another aspect, the present disclosure provides a lipid nanoparticle comprising a lipid compound or composition described in the present disclosure. In another aspect, the present disclosure provides a pharmaceutical composition comprising a lipid compound, composition or lipid nanoparticle as described in the present disclosure, and a pharmaceutically acceptable excipient. In another aspect, the present disclosure also provides the use of a lipid compound, composition, lipid nanoparticle or pharmaceutical composition described in the present disclosure in the preparation of a formulation for editing a target gene in a subject in need thereof. In another aspect, the present disclosure also provides a method of delivering a therapeutic and/or prophylactic agent to a cell in a subject, the method comprising administering to the subject a lipid compound, composition, lipid nanoparticle, or pharmaceutical composition described in the present disclosure. In another aspect, the present disclosure also provides a method of specifically delivering a therapeutic and/or prophylactic agent to an organ of a subject, the method comprising administering to the subject a lipid compound, composition, lipid nanoparticle, or pharmaceutical composition described in the present disclosure. In another aspect, the present disclosure also provides a method of producing a polypeptide of interest in a cell in a subject, the method comprising administering to the subject a lipid compound, composition, lipid nanoparticle, or pharmaceutical composition described in the present disclosure. In another aspect, the present disclosure also provides a method of editing a target gene in vivo i