Phosphorodiamidate morpholino oligomers
Inventors
CAI, Baozhong • MARTINI, Mitchell • THOMAS, Katie • SHIMABUKU, Ross
Assignees
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Publication Number
US-12297219-B2
Publication Date
2025-05-13
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 oligomer synthesis while maintaining overall yield and purity of a synthesized oligomer.
Core Innovation
The invention relates to a compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R1 is a support-medium. R2 is independently selected at each occurrence from a defined group and is specified at each position from 1 to 25 and 5′ to 3′ by a position-by-position assignment, including DPG, T, PC, and PA.
The disclosed compounds are characterized by an R1-linked support-medium framework and a position-dependent sequence of R2-bearing units across defined positions. Multiple formula variants, including Formula (IXa), Formula (A9), Formula (A9a), Formula (X), Formula (Xa), and Formula (A10), are presented as illustrative embodiments within the same general framework.
Additional embodiments describe an oligomeric framework with an integer n from 10 to 40, together with variable substituents R3 and R4 or R2/R4. R3 is identified with trityl-type groups, including trityl, mono-methoxytrityl, dimethoxytrityl, and trimethoxytrityl, and the R4 substituent set includes PC, DPG, T, PA, and additional options shown in the structures.
Claims Coverage
The consolidated claims coverage contains one independent claim directed to a compound of Formula (X) or a pharmaceutically acceptable salt thereof. The claim specifies two core inventive features: R1 is a support-medium, and R2 is independently selected at each occurrence and assigned by position across positions 1 to 25 and 5′ to 3′. A dependent claim refines the framework to Formula (Xa) while preserving the same R1/R2 positional constraints.
Compound of Formula (X) with a support-medium R1
A compound of Formula (X), or a pharmaceutically acceptable salt thereof, wherein R1 is a support-medium.
Position-dependent R2 assignment across positions 1 to 25 and 5′ to 3′
R2 is independently selected at each occurrence from a defined group and is assigned at each position from 1 to 25 and 5′ to 3′, including DPG, T, PC, and PA.
Specific embodiment defined as Formula (Xa)
A dependent refinement narrows the compound to Formula (Xa) while preserving the same R1 support-medium and position-specific R2 framework.
Overall, the claim coverage centers on Formula (X) compounds in which R1 is a support-medium and R2 is defined by independent selection plus explicit position-by-position assignment across positions 1 to 25 and 5′ to 3′. The dependent claim narrows this framework to Formula (Xa) without changing the core positional substitution concept.
Stated Advantages
Resistance to RNase degradation.
Resistance to RNase H heteroduplex.
Cellular transport.
Enables scale-up while maintaining yield and purity.
Documented Applications
Hybridization to complementary nucleic acids including RNA hybridization.
Antisense applications, including splice switching oligonucleotides for dystrophin-related exon skipping, exemplified by DMD exon skipping using Golodirsen.
Solid-phase oligomer synthesis of Golodirsen.
Preparation of an anchor-loaded resin and an activated EG3 tail within a described linker/anchor system.
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