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EP-4739651-A1 - LIPID COMPOUNDS FOR DELIVERY OF THERAPEUTIC AGENTS AND PREPARATION METHOD AND ITS USE THEREOF

EP4739651A1EP 4739651 A1EP4739651 A1EP 4739651A1EP-4739651-A1

Abstract

The present invention discloses lipid compounds for delivery of therapeutic agents and preparation method and its use thereof, specifically, the present invention discloses a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof, the ionizable lipid compounds of the present invention can effectively deliver nucleic acid molecules, small molecule compounds and other drugs, and by comparison, the lipid nanoparticles of the present invention have better particle size distribution, high encapsulation efficiency, and the delivery effect can be significantly better than the comparison lipid nanoparticles, which can meet the demand for in vivo delivery.

Inventors

  • WANG, ZIJUN
  • GUI, Yang

Assignees

  • Yoltech Therapeutics Co., Ltd

Dates

Publication Date
20260513
Application Date
20240708

Claims (20)

  1. A compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof, having the following structure: wherein R 1 is selected from -OH and R a (R b ) N-, wherein R a and R b are each independently hydrogen, C 1 -C 10 alkyl or C 1 -C 10 haloalkyl; R 2 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 3 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, or R c - (CH 2 ) n-, wherein n is a positive integer of 1-20, preferably, a positive integer of 1-14, more preferably a positive integer of 1-10; R c is selected from the structure as shown below: wherein represents a connection bond; L1, L2, L3, L4, L5 are absent or each independently selected from the group consisting of: X is absent or -CH-or N; R 4 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 5 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 6 is C 1 -C 30 alkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl; R 7 is C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl; R 8 , R 9 are absent or is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; R 10 , R 11 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl, or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S.
  2. The compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of claim 1, wherein the compound of Formula I has a structure of Formula I-1 as follows: wherein R 1 -R 2 , R 6 -R 11 , L 2 -L 5 are defined as above; R 3 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl.
  3. The compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of claim 1, wherein the compound of Formula I has a structure of Formula I-2 as follows: wherein R 1 -R 2 , R 6 -R 7 , R 10 -R 11 , L 1 -L 5 are defined as above; R 3 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, or R c - (CH 2 ) n-, wherein n is a positive integer of 1-20, preferably, a positive integer of 1-14, more preferably a positive integer of 1-10, R c is defined as above; R 5 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 8 , R 9 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl.
  4. The compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of claim 1, wherein the compound of Formula I has a structure of Formula I-3 as follows: Wherein R 1 -R 3 , R 6 , R 7 , R 10 , R 11 , L 1 -L 5 are defined as above; R 4 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 5 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 8 , R 9 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl.
  5. The compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of claim 1, wherein the compound of Formula I has a structure of Formula I-4 as follows: Wherein R 1 -R 7 , R 10 -R 11 , L 1 -L 3 , L 5 are defined as above.
  6. A compound of Formula II or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof, having the following structure: wherein R 1 is selected from -OH and R a (R b ) N-, wherein R a and R b are each independently hydrogen, C1-C 6 alkyl or C1-C 6 haloalkyl; R 3 is C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl, or R c - (CH 2 ) n-, wherein n is a positive integer of 1-20, preferably, a positive integer of 1-14, more preferably a positive integer of 1-10, more preferably a positive integer of 1-6; R c is selected from the structure as shown below: wherein represents a connection bond; L1, L2, L3, L4, L5 are absent or each independently selected from the group consisting of: R 4 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 5 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 8 , R 9 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl or - R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; R 10 , R 11 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl, or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; r is 2 or 3; u is a positive integer of 1-10; t is a positive integer of 1-10; in addition, when R 1 is selected from R a (R b ) N-, r is 2.
  7. A compound of Formula III or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof, having the following structure: wherein R a and R b are each independently hydrogen, C1-C 6 alkyl or C1-C 6 haloalkyl; R c is selected from the structure as shown below: wherein represents a connection bond; s is a positive integer of 1-10; L1, L2, L3, L4, L5 are absent or each independently selected from the group consisting of: R 4 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 5 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 8 , R 9 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; R 10 , R 11 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl, or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; r is a positive integer of at least 3; u is a positive integer of 1-10; t is a positive integer of 1-10.
  8. A compound of Formula IV or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof, having the following structure: wherein R a and R b are each independently hydrogen, C1-C 6 alkyl or C1-C 6 haloalkyl; R 3 is C 1 -C 15 alkyl, C 2 -C 15 alkenyl, C 2 -C 15 alkynyl, or R c - (CH 2 ) n-, wherein n is a positive integer of 1-20, preferably, a positive integer of 1-14, more preferably a positive integer of 1-10; R c is selected from the structure as shown below: wherein represents a connection bond; L1, L2, L3, L4, L5 are absent or each independently selected from the group consisting of: R 4 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 5 is absent or C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 8 , R 9 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; R 10 , R 11 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl, or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; r is a positive integer of at least 3; u is a positive integer of 1-10; t is a positive integer of 1-10.
  9. A compound of Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof, having the following structure: wherein R a and R b are each independently hydrogen, C1-C 6 alkyl or C1-C 6 haloalkyl; R c is selected from the structure as shown below: wherein represents a connection bond; L1, L2, L3, L5 are absent or each independently selected from the group consisting of: R 4 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 5 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl; R 6 is C 1 -C 30 alkyl, C 2 -C 30 alkenyl, C 2 -C 30 alkynyl; R 10 , R 11 is each independently C 1 -C 14 alkyl, C 2 -C 14 alkenyl, C 2 -C 14 alkynyl, or -R h -C 1 -C 14 alkyl, -R h -C 2 -C 14 alkenyl, -R h -C 2 -C 14 alkynyl, wherein R h is O or S; r is a positive integer of at least 3; t is a positive integer of 1-10.
  10. The compound of Formula I or Formula II or Formula IIII or Formula IV or Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of any of claims 1-9, the compound is selected from the group consisting of (Table 1) : Table 1
  11. The compound of claim 10, wherein the compound has the structure as shown below:
  12. A lipid carrier, comprising a compound of Formula I or Formula II or Formula IIII or Formula IV or Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of any of claims 1-11.
  13. A lipid nanoparticle (LNP) , comprising a compound of Formula I or Formula II or Formula IIII or Formula IV or Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of any of claims 1-11.
  14. A lipid nanoparticle composition comprising a lipid carrier of claim 12 or a lipid nanoparticle of claim 13, and a bioactive substance encapsulated in the lipid carrier or the lipid nanoparticle.
  15. A pharmaceutical composition comprising a lipid carrier of claim 12 or a lipid nanoparticle of claim 13, and a bioactive substance encapsulated in the lipid carrier or the lipid nanoparticle, and a pharmaceutically acceptable excipient, carrier or diluent.
  16. A pharmaceutical formulation comprising a lipid carrier of claim 12 or a lipid nanoparticle of claim 13, and a bioactive substance encapsulated in the lipid carrier or the lipid nanoparticle, and a pharmaceutically acceptable excipient, carrier or diluent; or the pharmaceutical formulation comprising a lipid nanoparticle composition of claim 14, and a pharmaceutically acceptable excipient, carrier or diluent.
  17. Use of a compound of Formula I or Formula II or Formula IIII or Formula IV or Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of any of claims 1-11 in the preparation of a lipid nanoparticle.
  18. Use of a compound of Formula I or Formula II or Formula IIII or Formula IV or Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of any of claims 1-11 or a lipid carrier of claim 12 or a lipid nanoparticle of claim 13 or a lipid nanoparticle composition of claim 14 or a pharmaceutical composition of claim 15 or a pharmaceutical formulation of claim 16 in the preparation of a nucleic acid drug, a genetic vaccine, a small molecule drug, a polypeptide or a protein drug.
  19. A method for preparing a lipid nanoparticle composition of claim 14, comprising: (a) Mixing a compound of Formula I or Formula II or Formula IIII or Formula IV or Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of any of claims 1-11 with an optionally auxiliary lipid and an organic solvent, thereby obtaining a lipid organic phase; (b) Mixing the bioactive substance with an aqueous solvent, thereby obtaining an aqueous phase containing the bioactive substance; (c) Mixing the lipid organic phase in step (a) with the aqueous phase in step (b) , thereby obtaining the lipid nanoparticle composition.
  20. Use of a compound of Formula I or Formula II or Formula IIII or Formula IV or Formula V or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof of any of claims 1-11 for the preparation of a drug delivery system.

Description

Lipid compounds for delivery of therapeutic agents and preparation method and its use thereof The present invention belongs to the field of biopharmaceuticals and, specifically, relates to lipid compounds for delivery of therapeutic agents and preparation method and its use thereof. Background Gene therapy technology is a hot topic of research in modern biomedical field, and the nucleic acid drugs can prevent and treat cancer, bacterial and viral infections, and treat diseases with inherited pathogenic factor, etc. Since nucleic acid drugs are easily degradable and difficult to enter cells, they usually need to be encapsulated and delivered to target cells with the help of carriers, therefore, the development of safe and efficient delivery carriers is a precondition for the clinical application of gene therapy. Lipid nanoparticle (LNP) is currently a hot research topic in the field of non-viral gene vectors. In 2018, FDA approved LNP delivery of patisiran (onpattro) for the treatment of hereditary transthyretin familial amyloidosis, and since then the research on the delivery of nucleic acid drugs using LNP technology has shown a burst of growth. In particular, in the end of 2020, the FDA approved Moderna and BioNtech &Pfizer's novel coronavirus vaccine for COVID 19, respectively, both of which use LNP technology to deliver mRNA drugs for the prevention of SARS-CoV-2. LNPs usually contain ionizable lipids which have an impact on the effectiveness of LNP delivery. There is still a need to develop new lipid compounds to facilitate the in vitro or in vivo delivery of nucleic acid molecules for therapeutic and/or prophylactic purposes. Summary of the invention It is an object of the present invention to provide novel lipid compounds to facilitate the in vitro or in vivo delivery of nucleic acid molecules for therapeutic and/or prophylactic purposes. It is also an object of the present invention to provide a lipid compound or a pharmaceutically acceptable form thereof (e.g., salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor drug, etc. ) that can be used with other lipid compounds (e.g., neutral lipids, charged lipids, steroids) to prepare lipid nanoparticles for delivery of therapeutic agents (e.g., nucleic acid molecules, specifically also including mRNA) to enhance the delivery efficiency of nucleic acid drugs in vivo, and lipid compounds with specific structures can be used as lipid carriers depending on the organ where the nucleic acid drug needs to be enriched. It is a further object of the present invention to provide lipid carriers comprising the above compounds or a pharmaceutically acceptable form thereof. It is a further object of the present invention to provide nucleic acid lipid nanoparticle compositions comprising the above compounds or pharmaceutically acceptable forms thereof or the above lipid carriers. It is a further object of the present invention to provide pharmaceutical formulations comprising the above compounds or pharmaceutically acceptable forms thereof, or the above lipid carriers, or the above nucleic acid lipid nanoparticle compositions. It is a further object of the present invention to provide a method of delivering  a therapeutic or prophylactic agent to a subject cell. It is a further object of the present invention to provide a method for producing a target protein or target polypeptide in a subject cell. It is a further object of the present invention to provide a use of the above compounds or pharmaceutically acceptable forms thereof or the above lipid carriers or the above nucleic acid lipid nanoparticle compositions or the above pharmaceutical formulations in the preparation of nucleic acid drugs, gene vaccines, small molecule drugs, polypeptides or protein drugs. It is a further object of the present invention to provide a method for delivering nucleic acid drugs in vivo, comprising administering the above nucleic acid lipid nanoparticle compositions or the above pharmaceutical formulations to a subject in need thereof. In a first aspect of the invention, it provides a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, solvate, chelate, non-covalent complex, or precursor thereof, having the following structure: wherein R1 is absent or selected from -OH and Ra (Rb) N-, wherein Ra and Rb are each independently hydrogen, C1-C10 alkyl or C1-C10 haloalkyl; R2 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl; R3 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl, or Rc- (CH2) n-, wherein n is a positive integer of 1-20, preferably, a positive integer of 1-14, more preferably a positive integer of 1-10; Rc is selected from the structure as shown below: whereinrepresents a connection bond; L1, L2, L3, L4, L5 are absent or each independently selected from the group consisting of: X is absent or -CH-or N; R4 is absent or C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl; R5 is absent or C1-C20 alkyl, C2-C20 alkenyl,