Processes for preparing phosphorodiamidate morpholino oligomers
Inventors
CAI, Baozhong • MARTINI, Mitchell • SHIMABUKU, Ross • THOMAS, Katie
Assignees
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Publication Number
US-12258362-B2
Publication Date
2025-03-25
Expiration Date
Abstract
Provided herein are processes for preparing an oligomer (e.g., a morpholino oligomer). The synthetic processes described herein may be advantageous to scaling up oligomersynthesis while maintaining overall yield and purity of a synthesized oligomer.
Core Innovation
The disclosure describes compounds of Formula (A9), Formula (A9a), Formula (IX), Formula (IXa), Formula (Xa), Formula (A10), and related oligomeric structures, including pharmaceutically acceptable salts. The compounds define R1 as a support-medium, R3 as hydrogen or trityl-type groups including trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl, and R4 as independently selected at each occurrence from the group specified in the claim.
The document further defines position-specific substituent rules for R2 at positions 1 to 30 and 5′ to 3′, with selectable substituent types including PC, T, PA, and DPG. Named embodiments further refine these positional assignments while maintaining the support-medium constraint for R1 and the selected trityl-type groups for R3.
The disclosed work also describes iterative synthesis of oligomeric compounds through deblocking, coupling, and cleavage operations on a support-medium, including iterative construction of Formula (IX) and conversion through related formula intermediates. The preparation of the oligomeric compound eteplirsen is mentioned, and the document includes formula schemes for multiple A-series and related variants.
Claims Coverage
The claim coverage centers on a compound of Formula (A9) or a pharmaceutically acceptable salt thereof. Four inventive feature areas are consistently present: n from 10 to 40, R1 as a support-medium, R3 limited to hydrogen or trityl-type groups, and independently selected R4 at each occurrence. Dependent claims narrow the scope with named formula embodiments and position-specific R2 assignments over defined ranges.
Compound of Formula (A9) with support-medium R1
A compound of Formula (A9) or a pharmaceutically acceptable salt thereof, wherein n is an integer from 10 to 40 and R1 is a support-medium.
Trityl-type selection for R3
R3 is selected from hydrogen, trityl, monomethoxytrityl, dimethoxytrityl, and trimethoxytrityl.
Independently selected R4 at each occurrence
R4 is independently selected at each occurrence from the group recited in the claim.
Position-specific R2 assignments across 1 to 30 and 5′ to 3′
Named embodiments such as Formula (A9a), Formula (IX), Formula (IXa), and Formula (Xa) assign R2 independently at positions 1 to 30 and 5′ to 3′ from a set including PC, T, PA, and DPG.
Overall, the claims cover Formula (A9) compounds and salts defined by n, support-medium R1, trityl-type R3 selection, and independently selected R4, with dependent embodiments further narrowing the structure through named formulas and position-by-position R2 selection across defined indices.
Stated Advantages
Stronger DNA/RNA affinity.
Sequence selectivity not compromised.
Reduced or prevented RNase H cleavage.
Ability to produce PMO quantities at large scale (kg range).
Documented Applications
Antisense technology for splice switching oligonucleotides (SSO).
Duchenne muscular dystrophy (DMD).
The PMO drug eteplirsen (AVI-4658).
Processes for preparing the oligomeric compound eteplirsen are mentioned.
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