Targeted therapeutic nucleosides and their use

Patent metadata

Field	Value
Publication number	US-2018296684-A1
Application number	US-201815907119-A
Country	US
Kind code	A1
Filing date	Feb 27, 2018
Priority date	Sep 20, 2013
Publication date	Oct 18, 2018
Grant date	—

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.

First claim

1 .- 235 . (canceled)

236 . A compound consisting of a targeting group and 2-50 linked therapeutic nucleosides, wherein the targeting group comprises at least one cell-targeting ligand.

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

238 . The compound of claim 236 or 237 , wherein each cell-targeting ligand is N-acetylgalactosamine.

239 . 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.

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

241 . The compound of claim 236 , wherein at least one therapeutic nucleoside comprises the following structure:

wherein R 3 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 therapeutic nucleoside, and the targeting group;
provided that exactly one of R3, R4, and R5 is the targeting group.

242 . The compound of claim 236 , wherein one terminal therapeutic nucleoside comprises the following structure:

wherein B is a modified or unmodified nucleobase;
X is O or CCH2;
Y is CR 6 R 7 ; and
R 6 is the targeting group, hydrogen, hydroxyl, or O-L-valinyl ester; R 7 is hydrogen, hydroxyl, or O-L-valinyl ester; and
wherein if R 6 is not the targeting group, the terminal therapeutic nucleoside is linked to a compound comprising a targeting group.

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

244 . The compound of claim 243 , wherein at least one antiviral nucleoside inhibits a viral polymerase.

245 . The compound of claim 243 , wherein at least one antiviral nucleoside is selected from among an anti-HCV nucleoside and an anti-HBV nucleoside.

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

247 . A compound consisting of a targeting group, 1-50 linked therapeutic nucleosides, and an antisense compound; wherein the targeting group comprises at least one cell-targeting ligand; wherein the therapeutic nucleosides are linked by cleavable bonds to each other and to the antisense compound; wherein said therapeutic nucleosides are cleaved from each other and from the antisense compound upon cellular uptake; and wherein the antisense compound consists of 8-30 linked nucleosides.

248 . The compound of claim 247 , wherein the cell-targeting ligand is N-acetylgalactosamine.

249 . The compound of claim 247 , wherein the cleavable bond is selected from among an amide, a polyamide, an ester, an ether, a phosphodiester, a phosphate ester, a phosphonate, a phosphoramidate, a carbamate, a disulfide, or a peptide.

250 . The compound of claim 247 , wherein the antisense compound comprises at least one modified nucleoside comprising a modification at the 2′ position selected from MOE, OMe, cEt, and LNA.

251 . The compound of claim 247 , wherein the antisense oligomeric compound is complementary to a target viral RNA or a target human RNA that is involved in virus pathogenicity.

252 . The compound of claim 247 , wherein at least one therapeutic nucleoside(s) comprises the following structure:

wherein for each therapeutic nucleoside with this structure, R3 is hydroxyl or a targeting group; and R4 and R5 are each phenoxy, NHCH(CH3)C(O)OiPr, alkoxy, alkylamino, hydroxyl, a targeting group, or an internucleoside linking group linking the therapeutic nucleoside to another therapeutic nucleoside or to the antisense compound;
with the proviso that the compound has exactly one targeting group.

253 . The compound of claim 247 , wherein each internucleoside linkage linking two therapeutic nucleosides to one another is an unmodified phosphodiester internucleoside linkage.

254 . A pharmaceutical composition comprising a compound of claim 247 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Seth Punit P
• Prakash Thazha P

Classifications

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• A61K31/7072

  having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine · CPC title

• A61K31/7064

  containing condensed or non-condensed pyrimidines · CPC title

• C12N2310/351

  Conjugate · CPC title

• A61K31/7068

  having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid · CPC title