# US 2018/0023084 A1 · Disulfide-Containing Alkyne Linking Agents

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- Number: US 2018/0023084 A1
- Document ID: US20180023084A1
- Status: Published application
- Kind: A1
- Application number: 15/716,809
- Filed: 2017-09-27
- Published: 2018-01-25
- Earliest claimed: 2015-03-17
- Assignees: Arrowhead Pharmaceuticals, Inc.
- Applicants: Arrowhead Pharmaceuticals, Inc.
- Inventors: Aaron Almeida; Andrei V. Blokhin; Darren H. Wakefield; Jonathan D. Benson; David B. Rozema
- Web page: https://patentgrep.com/patent/US20180023084A1

## CPC

- 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)}
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/315: Phosphorothioates
- C12N 2310/321: 2'-O-R Modification
- C12N 2310/322: 2'-R Modification
- C12N 2310/351: Conjugate
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2310/3521: Methyl
- C12N 2310/3533: Halogen
- C12N 2320/50: Methods for regulating/modulating their activity
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

Described are improved disulfide-containing alkyne linking agents having have branched disulfides. The improved linking agents exhibit improved stability. The linking agents are useful for attachment of oligonucleotides to targeting groups or delivery agents.

## Claims

### Claim 1

An RNAi agent-containing composition for inhibiting the expression of a target gene in a cell in vitro or in vivo, the RNAi agent-containing composition comprising an RNAi agent covalently linked to an cyclooctyne-alkyl disulfide compound having the structure represented by:
wherein
R1 is an alkyl group and R2 is hydrogen, or R1 is hydrogen and R2 is an alkyl group,
L1 and L2 are linkers,
X comprises a cyclooctyne, and
Y comprises a reactive group.

### Claim 2 (depends on 1)

The RNAi agent-containing composition of claim 1, wherein the alkyl group is a methyl group.

### Claim 3 (depends on 1)

The RNAi agent-containing composition of claim 1, wherein X is diarylcyclooctyne, DBCO, Azadibenzocyclooctyne (DIBAC or ADIBO), a cyclooctyne moiety fused to aryl groups,
wherein X═C or N,

### Claim 4 (depends on 1)

The RNAi agent-containing composition of claim 1, further including one or more pharmaceutically acceptable excipients.

### Claim 5 (depends on 1)

The RNAi agent-containing composition of claim 1, wherein the RNAi agent is an siRNA.

### Claim 6

An RNAi agent-containing composition for inhibiting the expression of a target gene in a cell in vitro or in vivo, the RNAi agent-containing composition comprising an RNAi agent covalently linked to an cyclooctyne-alkyl disulfide compound having the structure represented by:
wherein
R1 and R1′ are each alkyl groups and R2 and R2′ are each hydrogen, or R1 and R1′ are each hydrogen and R2 and R2′ are each alkyl groups,
L1 and L2 are linkers,
X comprises a cyclooctyne, and
Y comprises a reactive group.

### Claim 7 (depends on 6)

The compound of claim 6, wherein the alkyl groups are methyl groups.

### Claim 8 (depends on 6)

The RNAi agent-containing composition of claim 6, wherein X is diarylcyclooctyne, DBCO, Azadibenzocyclooctyne (DIBAC or ADIBO), a cyclooctyne moiety fused to aryl groups,
wherein X═C or N,

### Claim 9 (depends on 6)

The RNAi agent-containing composition of claim 6, further including one or more pharmaceutically acceptable excipients.

### Claim 10 (depends on 6)

The RNAi agent-containing composition of claim 6, wherein the RNAi agent is an siRNA.

### Claim 11 (depends on 1)

A method of inhibiting the expression of a target gene in a cell, the method comprising delivering to the cell an effective amount of the composition of claim 1.

### Claim 12 (depends on 6)

A method of inhibiting the expression of a target gene in a cell, the method comprising delivering to the cell an effective amount of the composition of claim 6.