# US 2016/0354476 A1 · Targeted therapeutic nucleosides and their use

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- Number: US 2016/0354476 A1
- Document ID: US20160354476A1
- Status: Published application
- Kind: A1
- Application number: 15/021,995
- Filed: 2014-09-19
- Published: 2016-12-08
- Earliest claimed: 2013-09-20
- Assignees: Ionis Pharmaceuticals, Inc.
- Applicants: Ionis Pharmaceuticals, Inc.
- Inventors: Punit P. Seth; Thazha P. Prakash
- Web page: https://patentgrep.com/patent/US20160354476A1

## CPC

- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61K 31/7072: having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
- A61K 31/711: Natural deoxyribonucleic acids, i.e. containing only 2'-deoxyriboses attached to adenine, guanine, cytosine or thymine and having 3'-5' phosphodiester links
- A61K 31/7115: Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/549: {Sugars, nucleosides, nucleotides or nucleic acids}
- C07H 19/10: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H 19/20: with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- A61K 31/7008: Compounds having an amino group directly attached to a carbon atom of the saccharide radical, e.g. D-galactosamine, ranimustine
- A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 31/7064: containing condensed or non-condensed pyrimidines
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- C12N 2310/11: Antisense
- C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/351: Conjugate
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- 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)
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Provided herein are compounds comprising one or more therapeutic nucleosides and one or more targeting groups. In certain embodiments, the compounds further comprise one or more oligonucleotides. In certain embodiments, a targeting group comprises one or more N-Acetylgalactosamine.

## Claims

### Claim at position 1

1-235. (canceled)

### Claim 236

A compound comprising a targeting group and at least one therapeutic nucleoside, wherein the targeting group comprises at least one cell-targeting ligand.

### Claim 237 (depends on 236)

The compound of claim 236, wherein the targeting group comprises 3 cell-targeting ligands.

### Claim 238 (depends on 236)

The compound of claim 236, wherein each cell-targeting ligand is N-acetylgalactosamine.

### Claim 239 (depends on 236)

The compound of claim 236, wherein the targeting group comprises a cleavable moiety.

### Claim 240 (depends on 236)

The compound of claim 236, wherein the targeting group comprises a structure represented by formula I below:
wherein:
A is a cell-targeting ligand;
B is a tether;
C is a branching group;
D is a targeting group linker;
E is a cleavable moiety;
n is 1, 2, 3, 4, or 5; and
m is 0 or 1.

### Claim 241 (depends on 236)

The compound of claim 236, wherein at least one therapeutic nucleoside comprises a modified furanosyl ring.

### Claim 242 (depends on 241)

The compound of claim 241, wherein the modified furanosyl ring of the at least one therapeutic nucleoside comprises a 2′ or 3′ substituent independently selected from hydrogen, halogen, hydroxyl, amino, alkyl, alkenyl, alkynyl, alkoxy, CF3, and ester.

### Claim 243 (depends on 236)

The compound of claim 236, wherein at least one therapeutic nucleoside comprises the following structure:
wherein R3 is hydroxyl or the targeting group; and
R4 and R5 are each independently selected from phenoxy, NHCH(CH3)C(O)OiPr, alkoxy, alkylamino, hydroxyl, an internucleoside linking group linking the therapeutic nucleoside to another nucleoside or to an oligomeric compound, and the targeting group;
provided that at least one of R3, R4, and R5 is a targeting group.

### Claim 244 (depends on 236)

The compound of claim 236, wherein at least one therapeutic nucleoside comprises the following structure:
wherein B is a modified or unmodified nucleobase;
X is O or CCH2;
Y is S or CR6R7; and
R6 and R7 are each independently selected from hydrogen, hydroxyl, O-L-valinyl ester, and the targeting group.

### Claim 245 (depends on 236)

The compound of claim 236, wherein at least one therapeutic nucleoside is an antiviral nucleoside.

### Claim 246 (depends on 245)

The compound of claim 245, wherein the at least one antiviral nucleoside inhibits a viral polymerase.

### Claim 247 (depends on 245)

The compound of claim 245, wherein at least one antiviral nucleoside is selected from among an anti-HCV nucleoside and an anti-HBV nucleoside.

### Claim 248 (depends on 236)

The compound of claim 236, wherein the compound comprises one therapeutic nucleoside.

### Claim 249 (depends on 236)

The compound of claim 236, wherein the compound comprises 2-50 therapeutic nucleosides.

### Claim 250 (depends on 236)

The compound of claim 236 comprising an oligomeric compound.

### Claim 251 (depends on 250)

The compound of claim 250, wherein the oligomeric compound is complementary to a target viral RNA or a target human RNA that is involved in virus pathogenicity.

### Claim 252 (depends on 250)

The compound of claim 250, wherein the oligomeric compound is complementary to a target microRNA.

### Claim 253 (depends on 252)

The compound of claim 252, wherein the target microRNA is miR-122, miR-221 or miR-21.

### Claim 254 (depends on 236)

A pharmaceutical composition comprising a compound of claim 236 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

### Claim 255 (depends on 245)

A method of treating an RNA-dependent virus infection comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of claim 245.