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CN-122029176-A - Containing a plurality of oligonucleotides modified oligonucleotides

CN122029176ACN 122029176 ACN122029176 ACN 122029176ACN-122029176-A

Abstract

The present disclosure provides oligonucleotides comprising at least two oligonucleotide strands conjugated together by a linker and modified with at least one instance of a central nervous system receptor ligand. The disclosure also provides pharmaceutical compositions and kits comprising the oligonucleotides, methods of delivering the oligonucleotides, methods of modulating protein activity using the oligonucleotides, and methods of treating, preventing, or diagnosing a disease (e.g., central nervous system disease, neurodegenerative disease, and neurocognitive disease) in a subject in need thereof using the oligonucleotides or pharmaceutical compositions thereof.

Inventors

  • LI ZHEN
  • ZHU RUI
  • Chandra Munli Cheruta
  • CHENG BO

Assignees

  • 阿达尔克斯制药有限公司

Dates

Publication Date
20260512
Application Date
20240816
Priority Date
20230817

Claims (20)

  1. 1. An oligonucleotide comprising a modified oligonucleotide strand of formula I: , (I) Or a pharmaceutically acceptable salt or prodrug thereof, wherein: Independently a divalent group of an oligonucleotide chain; S1 instances of the nucleobase-sugar moiety at the internal position of each instance of (a) are independently replaced by a moiety of formula a: (A); s1 is 0,1, 2, 3, 4, 5 or 6; when s1 is 1, 2, 3, 4, 5 or 6: Each instance of N 1 is independently a nucleobase group; Each instance of t1 is independently 1,2, or 3; each instance of y1 and y2 is independently 0,1, 2,3, 4, 5, or 6, provided that at least one instance of y1 and y2 is 1,2,3, 4, 5, or 6; When present, each instance of a 1 and a 2 is independently a group of a ligand or lipid; When (when) When y1 of examples of (1) is 0, L 1 is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heteroalkenyl, substituted OR unsubstituted heteroalkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl 、–CN、–OR b 、–SCN、–SR b 、–SSR b 、–N 3 、–NO、–N(R b ) 2 、–NO 2 、–C(=O)R b 、–C(=O)OR b 、–C(=O)SR b 、–C(=O)N(R b ) 2 、–S(=O)R b 、–S(=O)OR b 、–S(=O)SR b 、–S(=O)N(R b ) 2 、–S(=O) 2 R b 、–S(=O) 2 OR b 、–S(=O) 2 SR b 、–S(=O) 2 N(R b ) 2 、–OC(=O)R b 、–OC(=O)OR b 、–OC(=O)SR b 、–OC(=O)N(R b ) 2 、–OS(=O)R b 、–OS(=O)OR b 、–OS(=O)SR b 、–OS(=O)N(R b ) 2 、–OS(=O) 2 R b 、–OS(=O) 2 OR b 、–OS(=O) 2 SR b 、–OS(=O) 2 N(R b ) 2 、–ON(R b ) 2 、–SC(=O)R b 、–SC(=O)OR b 、–SC(=O)SR b 、–SC(=O)N(R b ) 2 、–NR b C(=O)R b 、–NR b C(=O)OR b 、–NR b C(=O)SR b 、–NR b C(=O)N(R b ) 2 、–NR b S(=O)R b 、–NR b S(=O)OR b 、–NR b S(=O)SR b 、–NR b S(=O)N(R b ) 2 、–NR b S(=O) 2 R b 、–NR b S(=O) 2 OR b 、–NR b S(=O) 2 SR b 、–NR b S(=O) 2 N(R b ) 2 、–Si(R b ) 3 、–Si(R b ) 2 OR b 、–Si(R b )(OR b ) 2 、–Si(OR b ) 3 、–OSi(R b ) 3 、–OSi(R b ) 2 OR b 、–OSi(R b )(OR b ) 2 OR-OSi (OR b ) 3 ; OR when When y1 of an example of (1), 2, 3, 4, 5 or 6, L 1 is a linker; Each instance of R b is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroalkenyl, substituted or unsubstituted heteroalkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R b attached to the same intervening atom are joined together by an intervening atom to form a substituted or unsubstituted monocyclic, heterocyclic, or heteroaryl ring; When (when) When y2 of an example of (C) is 0, L 2 is-OH, -OR c , halogen, -CN OR-N 3 , OR when When y2 of examples of (2) is 1,2, 3, 4, 5 or 6, L 2 thereof is a linker, and Each instance of R c is independently a substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group; v1 examples of internucleoside linkers of each example of (2) are independently Replacement; v1 is 0, 1,2, 3, 4, 5 or 6; When present, each instance of L A and L 4 is independently a linker; when present, each instance of y4 is independently 1,2, 3, 4, 5, or 6; When present, each instance of a 4 is independently a group of a ligand or lipid; each instance of y5 and y6 is independently 0,1, 2, 3, 4, 5, or 6; L 5 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when y5 is 0, or L 5 is a linker when y5 is 1, 2, 3, 4,5 or 6; L 6 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group when y6 is 0, or L 6 is a linker when y6 is 1, 2, 3, 4,5 or 6; When present, each instance of a 5 and a 6 is independently a group of a ligand or lipid; u1 is 1, 2, 3, 4, 5 or 6; Each instance of L B is independently a linker; Each instance of y7 is independently 0,1,2, 3, 4, 5, or 6; When (when) Examples of (2) are When L 7 is hydrogen, substituted or unsubstituted C 1-6 alkyl or an oxygen protecting group, or when Examples of (2) are When it is a linker, L 7 is a linker, and When present, each instance of a 7 is independently a group of a ligand or lipid; With the proviso that at least one example of y1, y2, y4, y5, y6 and y7 is 1,2, 3,4, 5 or 6 and at least one example of a 1 、A 2 、A 4 、A 5 、A 6 and a 7 is a group of a central nervous system receptor ligand.
  2. 2. The oligonucleotide of claim 1, wherein the oligonucleotide is a single stranded oligonucleotide.
  3. 3. The oligonucleotide of claim 1, wherein the oligonucleotide is a double-stranded oligonucleotide comprising a sense oligonucleotide strand and an antisense oligonucleotide strand.
  4. 4. The oligonucleotide of any one of claims 1-3, wherein Is a sense oligonucleotide strand, and the oligonucleotide further comprises an antisense oligonucleotide strand of the sense oligonucleotide strand.
  5. 5. The oligonucleotide of any one of claims 1-4, wherein Is an antisense oligonucleotide strand, and the oligonucleotide further comprises a sense oligonucleotide strand.
  6. 6. The oligonucleotide of any one of claims 1-5, wherein the nucleobases of the antisense oligonucleotide strand are complementary to the nucleobases of the sense oligonucleotide strand.
  7. 7. The oligonucleotide of any one of claims 1-6, wherein the oligonucleotide comprises RNA.
  8. 8. The oligonucleotide of any one of claims 1-7, wherein the oligonucleotide is RNA.
  9. 9. The oligonucleotide of any one of claims 1-8, wherein Is siRNA.
  10. 10. The oligonucleotide of any one of claims 1-9, wherein Independently comprising between 6 and 100 nucleosides (inclusive).
  11. 11. The oligonucleotide of any one of claims 1-10, wherein Independently comprising between 10 and 30 nucleosides (inclusive).
  12. 12. The oligonucleotide of any one of claims 1-11, wherein Independently comprising between 14 and 23 nucleosides (inclusive).
  13. 13. The oligonucleotide of any one of claims 1-12, wherein At least one example of (a) is 。
  14. 14. The oligonucleotide of any one of claims 1-13, wherein At least one example of (a) is 。
  15. 15. The oligonucleotide of any one of claims 1-14, wherein At least one example of (a) is 。
  16. 16. The oligonucleotide of any one of claims 1-15, wherein At least one example of (a) is 。
  17. 17. The oligonucleotide of any one of claims 1-16, wherein: each instance of s1, v1 and y7 is 0, and Each of y5 and y6 is 1.
  18. 18. The oligonucleotide of any one of claims 1-17, wherein: Each instance of s1, v1, y5 and y6 is 0, and Y7 is 1.
  19. 19. The oligonucleotide of any one of claims 1-18, wherein: At least one example of s1 and v1 is 1; Each of y5 and y6 is 0, and Y7 is 1.
  20. 20. The oligonucleotide of any one of claims 1-19, wherein: s1 and v1 are each 0, and Each of y5, y6, and y7 is 1.

Description

Containing a plurality of oligonucleotides modified oligonucleotides RELATED APPLICATIONS The present application claims priority from U.S. s.n. 63/520,092 to U.S. s.n. 63/520, filed on day 17 of 2023, 8, 119 (e), the contents of which are incorporated herein by reference. Background In therapeutic, prophylactic or diagnostic applications using compounds (e.g., oligonucleotides), it is often desirable to deliver the compound to a particular location (e.g., to a desired cell, to a desired organ or tissue, or to a particular location in a subject) to enhance therapeutic or prophylactic effects or to facilitate diagnostic purposes. This is often the case when attempting to deliver therapeutic compounds in vivo. Furthermore, being able to effectively deliver a compound to a particular location may limit or potentially eliminate unexpected consequences (such as off-target effects) that may result from administration of the compound. One strategy that facilitates the in vivo delivery of a compound (such as a therapeutic, prophylactic or diagnostic compound) to a desired location is to link or attach the compound to a targeting ligand. One class of compounds that can be targeted using targeting ligands are oligomeric compounds, such as, for example, proteins, peptides, antibodies, and oligonucleotides. Oligomeric compounds (e.g., oligonucleotides) comprising nucleotide sequences at least partially complementary to a target nucleic acid have been demonstrated to alter the function and activity of the target in vitro and in vivo. Oligonucleotides have been demonstrated to modulate expression or activity of a target nucleic acid when delivered to cells containing the target nucleic acid, such as mRNA or pre-mRNA. In some cases, the oligonucleotides can reduce expression of a gene by inhibiting translation of a nucleic acid target and/or triggering degradation of the target nucleic acid. If the target nucleic acid is mRNA, one mechanism by which the oligonucleotide can modulate mRNA target expression is by RNA interference. RNA interference is a biological process by which RNA or RNA-like compounds, such as chemically modified RNA compounds, can be used to silence gene expression at least in part through the RNA-induced silencing complex (RISC) pathway. In addition, oligonucleotides can modulate expression of a target nucleic acid (such as a target mRNA) by an rnase recruitment mechanism, a microrna mechanism, an occupancy-based mechanism, and an editing mechanism. The oligonucleotides may be single-stranded or double-stranded. Oligonucleotides may include DNA, RNA, and RNA-like compounds, which may also comprise modified nucleosides that include one or more modified sugars, modified nucleobases, and modified internucleoside linkages. There is a need for new compounds for delivering agents (e.g., therapeutic, prophylactic, and diagnostic agents) to a subject. Disclosure of Invention In one aspect, the present disclosure provides an oligonucleotide comprising at least two oligonucleotide strands conjugated together by a linker and modified with at least one instance of a central nervous system receptor ligand. In one aspect, the disclosure relates to an oligonucleotide comprising a modified oligonucleotide chain of formula I: , (I) Or a pharmaceutically acceptable salt or prodrug thereof, wherein: Independently a divalent group of an oligonucleotide chain; S1 instances of the nucleobase-sugar moiety at the internal position of each instance of (a) are independently replaced by a moiety of formula a: ; s1 is 0,1, 2, 3, 4, 5 or 6; when s1 is 1, 2, 3, 4, 5 or 6: Each instance of N 1 is independently a nucleobase group; Each instance of t1 is independently 1,2, or 3; each instance of y1 and y2 is independently 0,1, 2,3, 4, 5, or 6, provided that at least one instance of y1 and y2 is 1,2,3, 4, 5, or 6; When present, each instance of a 1 and a 2 is independently a group of a ligand or lipid; When (when) When y1 of examples of (1) is 0, L 1 is hydrogen, halogen, substituted OR unsubstituted alkyl, substituted OR unsubstituted alkenyl, substituted OR unsubstituted alkynyl, substituted OR unsubstituted heteroalkyl, substituted OR unsubstituted heteroalkenyl, substituted OR unsubstituted heteroalkynyl, substituted OR unsubstituted carbocyclyl, substituted OR unsubstituted heterocyclyl, substituted OR unsubstituted aryl, substituted OR unsubstituted heteroaryl 、–CN、–ORb、–SCN、–SRb、–SSRb、–N3、–NO、–N(Rb)2、–NO2、–C(=O)Rb、–C(=O)ORb、–C(=O)SRb、–C(=O)N(Rb)2、–S(=O)Rb、–S(=O)ORb、–S(=O)SRb、–S(=O)N(Rb)2、–S(=O)2Rb、–S(=O)2ORb、–S(=O)2SRb、–S(=O)2N(Rb)2、–OC(=O)Rb、–OC(=O)ORb、–OC(=O)SRb、–OC(=O)N(Rb)2、–OS(=O)Rb、–OS(=O)ORb、–OS(=O)SRb、–OS(=O)N(Rb)2、–OS(=O)2Rb、–OS(=O)2ORb、–OS(=O)2SRb、–OS(=O)2N(Rb)2、–ON(Rb)2、–SC(=O)Rb、–SC(=O)ORb、–SC(=O)SRb、–SC(=O)N(Rb)2、–NRbC(=O)Rb、–NRbC(=O)ORb、–NRbC(=O)SRb、–NRbC(=O)N(Rb)2、–NRbS(=O)Rb、–NRbS(=O)ORb、–NRbS(=O)SRb、–NRbS(=O)N(Rb)2、–NRbS(=O)2Rb、–NRbS(=O)2ORb、–NRbS(=O)2SRb、–NRbS(=O)2N(Rb)2、–Si(Rb)3、–Si(Rb)2ORb、–Si(Rb)(ORb)2、–Si(O