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JP-2026076156-A - Nucleic acid and compounds containing half-life motifs

JP2026076156AJP 2026076156 AJP2026076156 AJP 2026076156AJP-2026076156-A

Abstract

[Problem] To provide improved nucleic acid compounds and methods for introducing such compounds into cells. [Solution] A compound is provided that contains nucleic acid (A) covalently bonded to a half-life extension motif (HLEM). [Selection Diagram] None

Inventors

  • ズッコー，アーサー・ティー
  • アラーソン，チャールズ
  • トゥッチ，ファビオ・シー

Assignees

  • ノバルティス アーゲー

Dates

Publication Date
20260511
Application Date
20251224
Priority Date
20191126

Claims (20)

  1. A compound containing a nucleic acid (A) covalently bonded to a half-life extension motif (HLEM).
  2. The aforementioned compound has formula (I), (HLEM)z-A (I), The compound according to claim 1, wherein z is an integer from 1 to 5.
  3. The compound according to claim 1, wherein the nucleic acid is covalently bonded to an incorporation motif (UM).
  4. The aforementioned compound has formula (II), (HLEM)z-A-(UM)t (II), The compound according to claim 3, wherein t is an integer from 1 to 5 in the formula.
  5. The aforementioned half-life extension motif has the following structure: During the ceremony, L1 is an independent covalent linker, L2 is independently an unsubstituted alkylene. The compound according to claim 1, wherein k is an integer from 1 to 5.
  6. L1 is L1A-L1B-L1C-L1D-L1E, L2 is an unsubstituted C2-C22 alkylene. L1A, L1B, L1C, L1D, and L1E are independently coupled, -N(R20)- , -O-, -S-, -C(O)-, -N(R20)C(O)-, -C(O)N(R21) -, -N(R20)C(O)N(R21)-, -C(O)O-, -OC(O)-, -N( R20)C(O)O-, -OC(O)N(R21)-, -OPO2-O-, -OP(O )(S)-O-, -O-P(O)(R22)-O-, -O-P(S)(R22)-O-, -OP(O)(NR20R21)-N-, -OP(S)(NR20R21)-N-, -OP(O)(NR20R21)-O-, -OP(S)(NR20R21)-O-, -P(O)(NR20R21)-N-, -P(S)(NR20R21)-N-, -P(O )(NR20R21)-O-,-P(S)(NR20R21)-O-,-S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene, The compound according to claim 5, wherein each of R20, R21, and R22 is independently hydrogen or an unsubstituted C1-C10 alkyl group.
  7. The compound according to claim 5, wherein the maximum dimension of L1 is less than 200 angstroms.
  8. The compound according to claim 5, wherein the longest linear atomic path L1 has a length of 1 to 60 atoms.
  9. The maximum dimensions of each of L1A, L1B, L1C, L1D, and L1E are independent of each other, The compound according to claim 6, wherein the angstrom is less than 0 angstroms.
  10. The compound according to claim 6, wherein each of L1A, L1B, L1C, L1D, and L1E is independently 1 to 20 atoms long.
  11. The compound according to claim 1, wherein each of R20, R21, and R22 is independently hydrogen or an unsubstituted C1-C3 alkyl group.
  12. The compound according to claim 1, wherein the nucleic acid is an oligonucleotide.
  13. The compound according to claim 12, wherein one L1A is bonded to the 3' carbon of the oligonucleotide.
  14. The compound according to claim 12, wherein one L1A is bonded to the 3' nitrogen of the oligonucleotide.
  15. The compound according to claim 12, wherein one L1A is bonded to the 5' carbon of the oligonucleotide.
  16. The compound according to claim 12, wherein one L1A is bonded to the 6' carbon of the oligonucleotide.
  17. The compound according to claim 12, wherein one L1A is bonded to the 2' carbon of the oligonucleotide.
  18. The compound according to claim 12, wherein one L1A is bound to a nucleic acid base of the oligonucleotide.
  19. L1A independently produces -O-, -C(O)-, -C(O)O-, -OC(O)-, -OP O2-O-, -O-P(O)(S)-O-, -O-P(O)(CH3)-O-, -O-P (S)(CH3)-O-, -O-P(O)(N(CH3)2)-N-, -O-P(O)( N(CH3)2)-O-, -O-P(S)(N(CH3)2)-N-, -O-P(S)( N(CH3)2)-O-, -P(O)(N(CH3)2)-N-, -P(O)(N(CH 3) 2) -O-, -P(S) (N(CH3)2) -N-, -P(S) (N(CH3)2) The compound according to claim 6, which is -O-, a substituted or unsubstituted alkylene, or a substituted or unsubstituted heteroalkylene.
  20. L1A became independent, The compound according to claim 6.

Description

Cross-reference of related applications This application is a U.S. Provisional Patent Application No. 62/940,83 filed on November 26, 2019. The interests of Article 5 are asserted, and the entirety of which is incorporated herein for all purposes. The sequence listings, tables, or computer program listings appendix documents submitted as ASCII files, are incorporated herein by reference. Specifically, the sequence listings described in the file DTX-003-01WO_ST25.TXT (created November 23, 2020, 1,174 bytes in size, machine format IBM-PC, MS Windows operating system) are incorporated herein by reference. This disclosure relates to the field of biologically active compounds, including nucleic acids. More specifically, this disclosure relates to compounds, their preparation, and their use. Delivering therapeutic nucleic acids to cells remains a challenging area of research. Therefore, There is a need for improved nucleic acid compounds and strategies for introducing such compounds into cells. Provided herein, among other things, are compounds, or half-life extension motifs (HLEM It is a compound containing nucleic acid (A) covalently bonded to ). In one embodiment, a compound having formula (I) is provided (HLEM)z-A(I), where z is an integer from 1 to 5. In this embodiment, the half-life extension motif has the following structure k is an integer between 1 and 5. L1 is independently a covalent linker. L2 is independently an unsubstituted alkylene. In this embodiment, the nucleic acid covalently binds to the incorporation motif (UM). In the embodiment, the compound is (HLEM)z-A-(UM)t(II), where t is an integer from 1 to 5. In this embodiment, the incorporated motif independently has the following structure L3 and L4 independently bond, -N(R23)-, -O-, -S-, -C(O)- , -N(R23)C(O)-, -C(O)N(R24)-, -N(R23)C(O)N( R24)-, -C(O)O-, -OC(O)-, -N(R23)C(O)O-, -OC( O)N(R24)-, -OPO2-O-, -OP(O)(S)-O-, -OP(O) (R25) -O-, -O-P(S) (R25) -O-, -O-P(O) (NR23R24 ) -N-, -O-P(S) (NR23R24) -N-, -O-P(O) (NR23R24 ) -O-, -O-P(S) (NR23R24) -O-, -P(O) (NR23R24)- N-, -P(S)(NR23R24)-N-, -P(O)(NR23R24)-O-, - P(S)(NR23R24)-O-, -S-S-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene. Each of R23, R24, and R25 is independently hydrogen or an unsubstituted C1-C10 alkyl. L5 is -L5A-L5B-L5C-L5D-L5E-. L6 is -L6A-L 6B-L6C-L6D-L6E-. L5A, L5B, L5C, L5D, L5E, L 6A, L6B, L6C, L6D, and L6E are independently bonded, -NH-, -O-, - S-, -C(O)-, -NHC(O)-, -NHC(O)NH-, -C(O)O-, -O These are C(O)-, -C(O)NH-, substituted or unsubstituted alkylenes, substituted or unsubstituted heteroalkylenes, substituted or unsubstituted cycloalkylenes, substituted or unsubstituted heterocycloalkylenes, substituted or unsubstituted arylenes, or substituted or unsubstituted heteroarylenes. R1 and R2 are independently unsubstituted C1-C25 alkyl groups, and at least one of R1 and R2 is an unsubstituted C9-C19 alkyl group. R3 is hydrogen, -NH2, -OH, -SH, -C(O)H, -C(O)NH2, -NHC(O)H, -NHC(O) These are OH, -NHC(O)NH2, -C(O)OH, -OC(O)H, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In one embodiment, a method is provided, as described herein, which includes contacting cells with a compound or a compound comprising nucleic acid (A). In one embodiment, a method is provided which involves administering a compound described herein or a compound containing nucleic acid (A) to a target. In one embodiment, a compound for therapeutic use, or a compound comprising nucleic acid (A) as described herein, is provided. In one embodiment, a method is provided for introducing nucleic acids into cells within a subject. The method includes administering a compound containing nucleic acid (A) as described herein to the subject. In one embodiment, cells comprising a compound containing nucleic acid (A) as described herein are provided. In one embodiment, as described herein, a pharmaceutically acceptable excipient and nucleic acid (A) A compound containing and a pharmaceutical composition containing are provided. Other embodiments are disclosed below. The structure of DT-000137 according to an exemplary embodiment is shown.The structure of DT-000146 according to an exemplary embodiment is shown.The structure of DT-000347 according to an exemplary embodiment is shown.The structure of DT-000155 according to an exemplary embodiment is shown.The structure of DT-000156 according to an exemplary embodiment is shown.The structure of DT-000157 according to an exemplary embodiment is shown.The structure of DT-000272 according to an exemplary embodiment is shown.The structure of DT-000273 according to an exemplary em