# US 11,028,117 B2 · Bicyclic nucleosides and oligomers prepared therefrom

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- Number: US 11,028,117 B2
- Document ID: US11028117B2
- Status: Granted
- Kind: B2
- Application number: 16/465,127
- Filed: 2017-11-29
- Published: 2019-11-14
- Granted: 2021-06-08
- Earliest claimed: 2016-11-30
- Assignees: UniversitäT Bern
- Applicants: UniversitäT Bern
- Inventors: Christian Leumann; Damien Evéquoz
- Web page: https://patentgrep.com/patent/US11028117B2

## CPC

- C07H 19/048: Pyridine radicals
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 473/18: one oxygen and one nitrogen atom, e.g. guanine
- C07D 473/34: attached in position 6, e.g. adenine
- C07D 473/40: with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- C07F 9/65586: {at least one of the hetero rings does not contain nitrogen as ring hetero atom}
- C07F 9/65616: {containing the ring system [IMAGE cpc-sch-C07F-1006.gif] having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs}
- C07H 19/06: Pyrimidine radicals
- C07H 19/16: Purine radicals
- C07H 21/00: Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
- C07H 21/02: with ribosyl as saccharide radical
- C07H 21/04: with deoxyribosyl as saccharide radical
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 2310/11: Antisense
- C12N 2310/315: Phosphorothioates
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2320/33: Alteration of splicing
- Y02P 20/55: Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02P: CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS

## Abstract

Oligomers can be prepared from bicyclic nucleosides. The nucleosides can be a compound of formula (I) in which each of T1 and T2 is independently OR1 or OR2; R1 is H or a hydroxyl protecting group, R2 is a phosphorus moiety; and Bx is a nucleobase. The compounds, bicyclic nucleosides and oligomers are useful for the prevention, treatment or diagnosis of muscular dystrophy.

## Claims

### Claim 1

A compound of formula (I):
wherein T1 and T2 are each independently selected from the group consisting of OR1 and OR2;
and; wherein
R1 is H or a hydroxyl protecting group, and
R2 is a phosphorus moiety; and wherein
Bx is a nucleobase.

### Claim 2 (depends on 1)

The compound of claim 1, having the structure of formula (II)
wherein T1 and T2 are each independently selected from the group consisting of OR1 and OR2.

### Claim 3 (depends on 1)

The compound of claim 1, having the structure of formula (III)
wherein T1 and T2 are each independently selected from the group consisting of OR1 and OR2.

### Claim 4 (depends on 1)

The compound of claim 1, wherein said phosphorus moiety R2 is selected from the group consisting of a phosphate moiety, a phosphoramidate moiety and a phosphoramidite moiety.

### Claim 5 (depends on 1)

The compound of claim 1, having the structure selected from the group consisting of:

### Claim 6 (depends on 1)

The compound of claim 1, wherein the nucleobase is selected from the group consisting of a purine base and a pyrimidine base.

### Claim 7

An oligomer comprising at least one monomer subunit as a compound of formula (IV)
wherein either T3 or T4 are independently a nucleosidic linkage group; and
when T3 is a nucleosidic linkage group;
T4 is selected from the group consisting of OR1, OR2, a 5′ terminal group, a 7′ terminal group and a nucleosidic linkage group, and
when T4 is a nucleosidic linkage group;
T3 is selected from the group consisting of OR1, OR2, a 5′ terminal group, a 7′ terminal group and a nucleosidic linkage group, and;
wherein R1 is selected from H and a hydroxyl protecting group, and R2 is a phosphorus moiety; and
Bx is a nucleobase.

### Claim 8 (depends on 7)

The oligomer of claim 7, having the structure of formula (V):
wherein:
(i) when T3 is a nucleosidic linkage group, T4 is selected from the group consisting of a 7′ terminal group, OR1,and OR2; or
(ii) when T3 is selected from the group consisting of a 5′ terminal group, OR1, and OR2, T4 is a nucleosidic linkage group; or
(iii) T3 and T4 are independently of each other a nucleosidic linkage group.

### Claim 9 (depends on 7)

The oligomer of claim 7, having the structure of formula (VI):
wherein:
(i) when T3 is a nucleosidic linkage group, T4 is selected from the group consisting of a 7′ terminal group, OR1,and OR2; or
(ii) when T3 is selected from the group consisting of a 5′ terminal group, OR1, and OR2, T4 is a nucleosidic linkage group; or
(iii) T3 and T4 are independently of each other a nucleosidic linkage group.

### Claim 10 (depends on 7)

The oligomer of claim 7, wherein each nucleosidic linkage group is independently selected from the group consisting of a phosphodiester linkage group, a phosphotriester linkage group, a phosphorothioate linkage group, a phosphorodithioate linkage group, a phosphonate linkage group, a phosphonothioate linkage group, a phosphinate linkage group, a phosphorthioamidate linkage and a phosphoramidate linkage group.

### Claim 11 (depends on 10)

The oligomer of claim 10 wherein each nucleosidic linkage group is independently selected from the group consisting of a phosphodiester linkage group and a phosphorothioate linkage group.

### Claim 12 (depends on 11)

The oligomer of claim 11 wherein each nucleosidic linkage group is a phosphorothioate linkage group.

### Claim 13 (depends on 11)

The oligomer of claim 11, wherein each nucleosidic linkage group is a phosphodiester linkage group.

### Claim 14 (depends on 7)

The oligomer of claim 7, comprising at least two contiguous monomer subunits of compounds of formula (IV), wherein each of the contiguous subunit of compound of formula (IV) is independently linked to the adjacent contiguous subunit of compound of formula (IV) by the nucleosidic linkage group, wherein the nucleosidic linkage group links a 5′ terminus and a 7′ terminus of the two contiguous subunits of compounds of formula (IV).

### Claim 15 (depends on 7)

The oligomer of claim 7, wherein said oligomer comprises at least one nucleic acid sequence, wherein said nucleic acid sequence comprises said at least one monomer subunit of compound of formula (IV), and wherein said nucleic acid sequence is selected from the group consisting of the SEQ ID NO: 1 to 24.

### Claim 16 (depends on 15)

The oligomer of claim 15, wherein the nucleic acid sequence is SEQ ID NO: 24.

### Claim 17 (depends on 7)

The oligomer of claim 7, wherein the oligomer comprises a nucleic acid sequence, wherein said nucleic acid sequence consists of at least two contiguous monomer subunits of compounds of formula (V), wherein said nucleic acid sequence is flanked on its 5′ terminus and on its 7′ terminus by at least one nucleotide or nucleoside that is different from the compound of formula (IV),
wherein the 5′ terminus of said nucleic acid sequence is linked to a 5′ terminus of the nucleotide or nucleoside that is different from the compound of formula (IV), and wherein the 7′ terminus of said nucleic acid sequence is linked to a 3′ terminus of the nucleotide or nucleoside that is different from the compound of formula (IV).

### Claim 18 (depends on 7)

The oligomer of claim 7, wherein the oligomer comprises a nucleic acid sequence, wherein said nucleic acid sequence consists of at least two contiguous monomer subunits of compounds of formula (VI), wherein said nucleic acid sequence is flanked on its 5′ terminus and on its 7′ terminus each by at least one nucleotide or nucleoside that is different from the compound of formula (IV),
wherein the 5′ terminus of said nucleic acid sequence is linked to a 3′ terminus of the nucleotide or nucleoside that is different from the compound of formula (IV), and wherein the 7′ terminus of said nucleic acid sequence is linked to a 5′ terminus of the nucleotide or nucleoside that is different from the compound of formula (IV).

### Claim 19 (depends on 7)

The oligomer of claim 7, wherein said monomer subunit of compound of formula (IV) is selected from the group consisting of:

### Claim 20 (depends on 7)

The oligomer of claim 7, wherein the nucleobase is selected from the group consisting of a purine base and a pyrimidine base.