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CN-122028908-A - Compositions and compounds for delivery of therapeutic agents

CN122028908ACN 122028908 ACN122028908 ACN 122028908ACN-122028908-A

Abstract

A lipid nanoparticle composition for delivery of a therapeutic agent comprising a compound of formula I or formula I and formula II or a salt thereof.

Inventors

  • LIU CHONGYI
  • JIANG JUN
  • HUANG JIAN
  • ZHU LINGJIAN
  • KUANG JINGWEN
  • ZOU YANG
  • NING WEI
  • LIAO CHENG

Assignees

  • 上海瑞宏迪医药有限公司

Dates

Publication Date
20260512
Application Date
20241213
Priority Date
20231213

Claims (20)

  1. A lipid nanoparticle composition comprising: 1) A compound of formula I or a salt thereof, or 2) A compound shown in a formula I or a salt thereof, a compound shown in a formula II or a salt thereof, Wherein, the L a and L b are each independently selected from the group consisting of-O-; -C (O) -, -OC (O) -, -C (O) O-, -OC (O) O-, -O-C 1-6 alkylene-C (O) O- -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-; h a 、H b and H c are each independently selected from C 1-10 alkylene; R a and R b are each independently selected from C 1-24 alkyl and C 2-24 alkenyl; R c is selected from NR c1 R c2 and N + R c3 R c4 R c5 ; R c1 and R c2 are each independently selected from hydrogen and C 1-6 alkyl; R c3 、R c4 and R c5 are each independently selected from C 1-6 alkyl; L 1 and L 2 are each independently selected from the group consisting of-O-, -C (O) -, -OC (O) -, -C (O) O-, -OC (O) O-, -O-C 1-6 alkylene-C (O) O- -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-, and at least one of L 1 and L 2 is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-, -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-; H 1 、H 2 and H 3 are each independently selected from C 1-10 alkylene; R 1 and R 2 are each independently selected from C 1-24 alkyl and C 2-24 alkenyl; R 3 is selected from hydroxy.
  2. The lipid nanoparticle composition of claim 1, wherein L a and L b are each independently selected from the group consisting of-OC (O) -, -C (O) O-, -O-C 1-6 alkylene-C (O) O-, -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-; L 1 and L 2 are each independently selected from the group consisting of-OC (O) -, -C (O) O-, -O-C 1-6 alkylene-C (O) O-; -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-; Preferably, the method comprises the steps of, at least one of L a and L b is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-; -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-; Further preferably, L a and L b are each independently selected from -OC(O)-、-C(O)O-、-OCH 2 C(O)O-、-OC(O)CH 2 O-、-OCH 2 OC(O)-、-C(O)OCH 2 O-、-O(CH 2 ) 2 OC(O)- and-C (O) O (CH 2 ) 2 O-, and at least one of L a and L b is selected from -OCH 2 C(O)O-、-OC(O)CH 2 O-、-OCH 2 OC(O)-、-C(O)OCH 2 O-、-O(CH 2 ) 2 OC(O)- or-C (O) O (CH 2 ) 2 O-; L 1 and L 2 are each independently selected from -OC(O)-、-C(O)O-、-OCH 2 C(O)O-、-OC(O)CH 2 O-、-OCH(CH 3 )C(O)O-、-OC(O)CH(CH 3 )O-、-OC(CH 3 ) 2 C(O)O-、-OC(O)C(CH 3 ) 2 O-、-OCH 2 OC(O)-、-C(O)OCH 2 O-、-O(CH 2 ) 2 OC(O)-、-C(O)O(CH 2 ) 2 O-、-O(CH 2 ) 4 OC(O)- and-C (O) O (CH 2 ) 4 O-, and at least one of L 1 and L 2 is selected from -OCH 2 C(O)O-、-OC(O)CH 2 O-、-OCH(CH 3 )C(O)O-、-OC(O)CH(CH 3 )O-、-OC(CH 3 ) 2 C(O)O-、-OC(O)C(CH 3 ) 2 O-、-OCH 2 OC(O)-、-C(O)OCH 2 O-、-O(CH 2 ) 2 OC(O)-、-C(O)O(CH 2 ) 2 O-、-O(CH 2 ) 4 OC(O)- and-C (O) O (CH 2 ) 4 O-).
  3. The lipid nanoparticle composition of claim 1 or 2, wherein H a is selected from the group consisting of linear or branched C 1-10 alkylene, H b is selected from the group consisting of linear or branched C 1-10 alkylene, H c is selected from the group consisting of linear or branched C 1-10 alkylene, H 1 is selected from the group consisting of linear or branched C 1-10 alkylene, H 2 is selected from the group consisting of linear or branched C 1-10 alkylene, and H 3 is selected from the group consisting of linear or branched C 1-10 alkylene; Preferably, H a is selected from the group consisting of linear or branched C 3-8 alkylene, H b is selected from the group consisting of linear or branched C 3-8 alkylene, H c is selected from the group consisting of linear or branched C 1-6 alkylene, H 1 is selected from the group consisting of linear or branched C 3-8 alkylene, H 2 is selected from the group consisting of linear or branched C 3-8 alkylene, and H 3 is selected from the group consisting of linear or branched C 1-6 alkylene; More preferably, the process is carried out, H a is selected from -(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 - and- (CH 2 ) 8 -;H b is selected from -(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 - and- (CH 2 ) 8 -;H c is selected from the group consisting of-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -and- (CH 2 ) 4 -; H 1 is selected from -(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 - and- (CH 2 ) 8 -;H 2 is selected from -(CH 2 ) 3 -、-(CH 2 ) 4 -、-(CH 2 ) 5 -、-(CH 2 ) 6 -、-(CH 2 ) 7 - and- (CH 2 ) 8 -;H 3 ) is selected from the group consisting of-CH 2 -、-(CH 2 ) 2 -、-(CH 2 ) 3 -and- (CH 2 ) 4 -.
  4. The lipid nanoparticle composition of any one of claims 1-3, wherein R a and R b are each independently selected from linear or branched C 1-24 alkyl, R 1 and R 2 are each independently selected from linear or branched C 1-24 alkyl; Preferably, R a and R b are each independently selected from linear or branched C 4-18 alkyl, R 1 and R 2 are each independently selected from linear or branched C 4-18 alkyl; More preferably, R a is selected from straight chain C 4-18 alkyl, R b is selected from branched C 4-18 alkyl, or R a is selected from branched C 4-18 alkyl, R b is selected from branched C 4-18 alkyl; R 1 is selected from straight-chain C 4-18 alkyl, R 2 is selected from branched-chain C 4-18 alkyl, or R 1 is selected from branched-chain C 4-18 alkyl, R 2 is selected from branched-chain C 4-18 alkyl; Further preferably, R a 、R b 、R 1 and R 2 are each independently selected from:
  5. The lipid nanoparticle composition according to any one of claims 1 to 4, wherein the compound of formula I or a salt thereof is a compound of formula Ia or a salt thereof, Wherein L a 、L b 、H a 、H b 、H c 、R a and R b are as defined in any one of claims 1 to 4.
  6. The lipid nanoparticle composition according to any one of claims 1-5, wherein the compound of formula I or salt thereof is selected from the group consisting of compounds of formulas IA, IB, IC, ID, IE and IF or salts thereof, Wherein H c 、R a 、R b and R c are as defined in any one of claims 1 to 5; R d1 、R d2 、R d3 、R d4 、R d5 、R d6 、R e1 、R e2 、R e3 、R e4 、R e5 、R e6 、R f1 、R f2 、R f3 、R f4 、R f5 、R f6 、R g1 、R g2 、R g3 、R g4 、R g5 、R g6 、R h3 、R h4 、R h5 、R h6 、R i3 、R i4 、R i5 And R i6 are each independently selected from hydrogen and C 1-6 alkyl; n1, n2, n3, n4, n5, n6, n8, n9, n11, n12, n14 and n15 are each independently selected from 1, 2, 3,4, 5, 6, 7, 8, 9 and 10; n7, n10, n13 and n16 are each independently selected from 0, 1, 2, 3, 4, 5 and 6.
  7. The lipid nanoparticle composition according to any one of claims 1-6, wherein the compound of formula I is selected from the group consisting of, And/or the compound shown in the formula II is selected from the compound II-1,
  8. The lipid nanoparticle composition of any one of claims 1-7, wherein the compound of formula I or salt thereof comprises 10% to 80%, preferably 10% to 60% by mole of the lipid nanoparticle composition; and/or, the compound represented by formula II or a salt thereof accounts for 5% to 50%, preferably 10% to 45% of the lipid nanoparticle composition by mole.
  9. A lipid nanoparticle composition comprising: 1) Primary amine lipids, or 2) Primary amine lipids, and a compound represented by formula II or a salt thereof according to any one of claims 1 to 7, Wherein L 1 、L 2 、H 1 、H 2 、H 3 、R 1 、R 2 and R 3 are as defined in any one of claims 1 to 4; Preferably, the primary amine lipid is a compound represented by formula Ia or a salt thereof according to claim 5, Wherein L a 、L b 、H a 、H b 、H c 、R a and R b are as defined in any one of claims 1 to 4.
  10. The lipid nanoparticle composition of claim 9, wherein the primary amine lipid comprises 10% to 80%, preferably 10% to 60% by mole of the lipid nanoparticle composition; and/or, the compound represented by formula II or a salt thereof accounts for 5% to 50%, preferably 10% to 45% of the lipid nanoparticle composition by mole.
  11. The lipid nanoparticle composition of any one of claims 1-10, wherein the lipid nanoparticle composition comprises a phospholipid; Preferably, the phospholipid is selected from DGTS, DOPE and DSPC, and/or the phospholipid comprises 1 to 25% by mole of the lipid nanoparticle composition; More preferably, DSPC, and/or the phospholipids comprise from 1% to 15% by mole of the lipid nanoparticle composition.
  12. The lipid nanoparticle composition of any one of claims 1-11, wherein the lipid nanoparticle composition further comprises a steroid; Preferably, the steroid is selected from cholesterol, and/or the steroid comprises 10 to 50 mole percent of the lipid nanoparticle composition; More preferably, the steroid comprises from 10% to 45% by mole of the lipid nanoparticle composition.
  13. The lipid nanoparticle composition of any one of claims 1-12, wherein the lipid nanoparticle composition further comprises a pegylated lipid; Preferably, the pegylated lipid is selected from the group consisting of pegylated diacylglycerols, and/or the pegylated lipid comprises 0.5% to 10% by mole of the lipid nanoparticle composition; More preferably, the pegylated lipid is selected from DMG-PEG and/or the pegylated lipid comprises 0.5% to 5% by mole of the lipid nanoparticle composition.
  14. The lipid nanoparticle composition of any one of claims 1-13, wherein the composition preferentially delivers a therapeutic agent to a target organ selected from the group consisting of lung, heart, liver, spleen, or stomach; Preferably, the target organ is a lung.
  15. The lipid nanoparticle composition of any one of claims 1-14 further comprising a therapeutic agent selected from the group consisting of a small molecule, a protein, and a nucleic acid; Preferably, the therapeutic agent is selected from the group consisting of nucleic acids; more preferably, the nucleic acid is selected from mRNA.
  16. A compound of formula III or a salt thereof, Wherein, the L A and L B are each independently selected from the group consisting of-O-, -C (O) -, -OC (O) -, -C (O) O-, -OC (O) O-, -O-C 1-6 alkylene-C (O) O- -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-, and at least one of L A and L B is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-, -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-, wherein C 1-6 alkylene is not n-propylene; H a 、H b 、H c 、R a 、R b and R c are as defined in any one of claims 1 to 7.
  17. The compound of claim 16, wherein L A and L B are each independently selected from-OC (O) -, -C (O) O-, -O-C 1-6 alkylene-C (O) O-, -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-, wherein C 1-6 alkylene is not n-propylene; Preferably, the method comprises the steps of, at least one of L A and L B is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-; -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-; More preferably, L A and L B are each independently selected from -OC(O)-、-C(O)O-、-OCH 2 C(O)O-、-OC(O)CH 2 O-、-OCH 2 OC(O)-、-C(O)OCH 2 O-、-O(CH 2 ) 2 OC(O)- and-C (O) O (CH 2 ) 2 O-, and at least one of L A and L B is selected from -OCH 2 C(O)O-、-OC(O)CH 2 O-、-OCH 2 OC(O)-、-C(O)OCH 2 O-、-O(CH 2 ) 2 OC(O)- or-C (O) O (CH 2 ) 2 O-).
  18. The compound or salt thereof according to claim 16 or 17, wherein the compound of formula III or salt thereof is selected from compounds of formulas IIIA, IIIB, IIIC and IIID or salts thereof, Wherein H c 、R a 、R b and R c are as defined in any one of claims 1 to 7; R d3 、R d4 、R d5 、R d6 、R e3 、R e4 、R e5 、R e6 、R f3 、R f4 、R f5 、R f6 、R g3 、R g4 、R g5 、R g6 、R h3 、R h4 、R h5 、R h6 、R i3 、R i4 、R i5 、R i6 As defined in claim 6; n5, n6, n7, n8, n9, n10, n11, n12, n13, n14, n15 and n16 are as defined in claim 6; preferably, the compound shown in the formula III or the salt thereof is a compound with the following structure or the salt thereof,
  19. A pharmaceutical composition comprising the lipid nanoparticle composition of any one of claims 1-15 or the compound or salt thereof of any one of claims 16-18, and a pharmaceutically acceptable excipient.
  20. Use of a lipid nanoparticle composition according to any one of claims 1-15 or a compound or salt thereof according to any one of claims 16-18 or a pharmaceutical composition according to claim 19 in the manufacture of a medicament for the prevention and/or treatment of cancer, infections, autoimmune diseases, neurodegenerative diseases and inflammation.

Description

Compositions and compounds for delivery of therapeutic agents Technical Field The present disclosure is in the field of medicine, and relates to a composition and compound for delivering a therapeutic agent. Background Nucleic acid-based drugs, such as messenger RNAs (mrnas), antisense oligonucleotides, small interfering RNAs (sirnas), plasmids, etc., have broad application prospects, and how to safely and effectively deliver them to target organs and target cells in vivo is a difficult problem restricting the development of the technology. Currently nucleic acid drug delivery systems can be divided into viral vector systems and non-viral systems, lipid nanoparticle mediated nucleic acid drug delivery is the primary method of non-viral delivery systems. In gene therapy and vaccine applications, lipid Nanoparticles (LNP) have proven to be excellent vectors for nucleic acids for the treatment of various diseases. Lipid nanoparticles formed from cationic lipids and other helper lipids, such as cholesterol, phospholipids, and pegylated lipids encapsulate nucleic acids, protecting them from degradation and promoting cellular uptake, reducing immune responses. In addition, the lipid nanoparticle has other advantages such as good targeting, small side effects, good stability, higher transfection efficiency and the like in cell transfer of bioactive components. Historically, effective LNPs consist of 4 components, ionizable cationic lipids, zwitterionic phospholipids, cholesterol, and lipidic poly (ethylene glycol) (PEG). However, these LNPs only result in general delivery of nucleic acids, not targeted to organs or tissues. LNP typically delivers RNA only to the liver. CN112930198a discloses a new class of LNP, which is prepared by adding DOTAP (permanent cation) on the basis of 5A2-SC8 (ionizable cation), DOPE (zwitterionic), cholesterol, DMG-PEG to achieve spleen and lung targeting. The application proves that DOTAP has specificity, and the corresponding effect can not be realized by replacing DOTAP with other lipid. The rapid development of nucleic acid molecule-based therapeutic fields has placed greater demands on the delivery of nucleic acid drugs, and therefore the development of efficient, safe nucleic acid delivery vehicles is needed. Lipid compositions for delivering nucleic acid drugs which are clinically marketed at present can only be targeted to liver tissues or locally administered, so that the development of a novel nucleic acid drug delivery carrier capable of achieving targeted delivery of other organs has great significance for expanding the application of nucleic acid drugs. Disclosure of Invention The present disclosure provides a lipid nanoparticle composition comprising a compound of formula I or a salt thereof, Wherein, the L a and L b are each independently selected from the group consisting of-O-; -C (O) -, -OC (O) -, -C (O) O-, -OC (O) O-, -O-C 1-6 alkylene-C (O) O- -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-; h a、Hb and H c are each independently selected from C 1-10 alkylene; R a and R b are each independently selected from C 1-24 alkyl and C 2-24 alkenyl; R c is selected from NR c1Rc2 and N +Rc3Rc4Rc5; R c1 and R c2 are each independently selected from hydrogen and C 1-6 alkyl; r c3、Rc4 and R c5 are each independently selected from C 1-6 alkyl. In some embodiments, only substituents or groups are defined below, the definitions of the non-mentioned substituents or groups being the same as in any other embodiment (hereinafter "in some embodiments"), L a and L b are each independently selected from the group consisting of-OC (O) -, -C (O) O-, -O-C 1-6 alkylene-C (O) O- -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-. In some embodiments of the present invention, in some embodiments, at least one (e.g., one) of L a and L b is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-; -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-. In some embodiments, at least one (e.g., one) of L a and L b is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-, -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-, wherein C 1-6 alkylene is not n-propylene. In some embodiments of the present invention, in some embodiments, L a is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-, -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-, L b is selected from the group consisting of-OC (O) -and-C (O) O-. In some embodiments of the present invention, in some embodiments, L b is selected from the group consisting of-O-C 1-6 alkylene-C (O) O-, -OC (O) -C 1-6 alkylene-O-, -O-C 1-6 alkylene-OC (O) -and-C (O) O-C 1-6 alkylene-O-, L a is selected from the group consisting of-OC (O) -and-C (O) O-. In some embodiments, L a and L b are each independently selected from -OC(O)-、-C(O)O-、-OCH2C(O)O-、-OC(O)CH2O-、-OCH2OC(O)