Novel ligands for asialoglycoprotein receptor

Patent metadata

Field	Value
Publication number	US-2024092819-A1
Application number	US-202118248988-A
Country	US
Kind code	A1
Filing date	Oct 19, 2021
Priority date	Oct 20, 2020
Publication date	Mar 21, 2024
Grant date	—

Abstract

The present disclosure provides novel piperidine- and guanosine-derived ligands that bind specifically to asialoglycoprotein receptor (ASGPR) and nucleotide analogs conjugated thereto that can be incorporated into oligonucleotides, including double-stranded oligonucleotides such as siRNAs.

First claim

1 . A compound of formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
B is a heterocyclic nucleobase;
P 1 and P 2 are each, independently, H, a reactive phosphorous group, or a protecting group;
Y is NR1 or N—C(═O)—R1, wherein R1 is -L-R3, wherein
L is a C1-C25 hydrocarbon chain optionally interrupted or terminated by one or more —O—, —C(O)—, —N(Re)—, —N(Re)—C(O)—O—, —O—C(O)—N(Re)—, —N(Re)—C(O)—N(Rf)—, —C(O)—N(Re)—, —N(Re)—C(O)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; each of Re and Rf, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, hydroxyalkyl, hydroxy, or haloalkyl, the C1-C25 hydrocarbon chain being optionally substituted with one or more -L′-R3, wherein L′ is a C1-C25 hydrocarbon chain optionally interrupted by one or more —O—, —C(O)—, —N(Re)—, —N(Re)—C(O)—O—, —O—C(O)—N(Re)—, —N(Re)—C(O)—N(Rf)—, —C(O)—N(Re)—, —N(Re)—C(O)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—;
R3 is a cell targeting moiety of formula (II) or a protected derivative thereof:

wherein:
R3 targets a mammalian (optionally human) asialoglycoprotein receptor (ASGPR),
A 1 , A 2 and A 3 are, independently, H, hydroxy, alkoxy, acyloxy, aryloxy, aroyloxy, alkoxycarbonyl, aryloxycarbonyl, oxo (═O), or a (C1-C20) alkyl group, unsubstituted or optionally substituted by one or more groups selected from OH, a (C3-C8) cycloalkyl group, a (C3-C14) heterocycle, a (C6-C14) aryl group, a (C5-C14) heteroaryl group, —O—Z5, —N(Z5)(Z6), —S—Z5, —CN, —C(=M)-O—Z5, —O—C(=M)-Z5, —C(=M)-N(Z5)(Z6), and —N(Z5)-C(=M)-Z6, wherein:
M is O or S,
each of Z5 and Z6 is, independently, H, a (C1-C6) alkyl group, or a (C6-C14) aryl group, wherein both alkyl and aryl groups are either unsubstituted or optionally substituted by one or more groups selected from halogen, amino, hydroxy, thiol, cyano, alkyl, alkoxy, aryloxy, acyloxy, aroyloxy, carboxy, alkoxycarbonyl, aryloxycarbonyl and arylalkoxycarbonyl;
A4 is —N(R4) 2 , —NH—C(═O)—R4, or

wherein:
D2 and D3 are N, O, or S;
R4 is H or a (C1-C20) alkyl group, unsubstituted or optionally substituted by one or more groups selected from halogen, amino, hydroxy, thiol, cyano, alkyl, alkoxycarbonyl, aryloxycarbonyl, alkoxy, aryloxy, acyloxy, aroyloxy and carboxy; and
each of X1, X2, Ra, Rb, Rc, and Rd independently is H or a —(C1-C6) alkyl group.

2 . A compound of formula (I)

or a pharmaceutically acceptable salt thereof,
wherein:
B is a heterocyclic nucleobase;
P 1 and P 2 are each, independently, H, a reactive phosphorous group, or a protecting group;
Y is NR1 or N—C(═O)—R1, wherein R1 is -L-R3, wherein
L is a C1-C25 hydrocarbon chain optionally interrupted or terminated by one or more —O—, —C(O)—, —N(Re)—, —N(Re)—C(O)—O—, —O—C(O)—N(Re)—, —N(Re)—C(O)—N(Rf)—, —C(O)—N(Re)—, —N(Re)—C(O)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—; each of Re and Rf, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryloxy, hydroxyalkyl, hydroxy, or haloalkyl, the C1-C25 hydrocarbon chain being optionally substituted with one or more -L′-R3, wherein L′ is a C1-C25 hydrocarbon chain optionally interrupted by one or more —O—, —C(O)—, —N(Re)—, —N(Re)—C(O)—O—, —O—C(O)—N(Re)—, —N(Re)—C(O)—N(Rf)—, —C(O)—N(Re)—, —N(Re)—C(O)—, —O—C(O)—, —C(O)—O—, or —O—C(O)—O—;
R3 is a cell targeting moiety of formula (IVA) or (IVB) or a protected derivative thereof:

wherein:
R3 targets a mammalian (optionally human) asialoglycoprotein receptor (ASGPR),
R6 is H or a (C1-C6) alkyl group, unsubstituted or optionally substituted by one or more groups selected from halogen, amino, hydroxy, thiol, alkyl, alkoxy, aryloxy, carboxy, alkoxycarbonyl, and aryloxycarbonyl;
A 5 , A 6 , A 7 , and A′ 7 are independently H, hydroxy, alkoxy, acyloxy, aryloxy, aroyloxy, alkoxycarbonyl, aryloxycarbonyl, amino, or a (C1-C20) alkyl group unsubstituted or optionally substituted by one or more groups selected from OH, a (C3-C8) cycloalkyl group, a (C3-C14) heterocycle, a (C6-C14) aryl group, a (C5-C14) heteroaryl group, —O—Z7, —N(Z7)(Z8), —S—Z7, —CN, —C(=Q)-O—Z7, —O—C(=Q)-Z7, —C(=Q)-N(Z7)(Z8), and —N(Z7)-C(=Q)-Z8, wherein:
Q is O or S,
each of Z7 and Z8 independently is H, a (C1-C6) alkyl group, or a (C6-C14) aryl group, both groups unsubstituted or optionally substituted by one or more groups selected from a halogen atom and a (C1-C6) alkyl group;
each of A 8 and A 9 independently is H, halogen, OH (or its tautomeric oxo (═O)), —N(R7) 2 , —NHR7, or —NH—C(═O)—R7, wherein R7 is hydrogen or a (C1-C20) alkyl group, unsubstituted or optionally substituted by one or more groups selected from a halogen atom, alkoxy, aryloxy, a (C1-C6) alkyl group, a (C3-C8) cycloalkyl group, a (C3-C14) heterocycle, a (C6-C14) aryl group, a (C5-C14) heteroaryl group; and
each of X1, X2, Ra, Rb, Rc, and Rd independently is H or a —(C1-C6) alkyl group.

3 . The compound of formula (I) of claim 1 , wherein:
(i) L is a C1-C10 hydrocarbon chain; (ii) L is a C1-C10 hydrocarbon chain terminated by —(CO)—; or (iii) Y is NR1, wherein R1 is -L-R3, wherein L is a C1-C10 hydrocarbon chain interrupted by one or more —O—.

4 - 5 . (canceled)

6 . The compound of formula (I) of claim 1 , wherein:
(i) A1 is H, oxo (═O), or a (C1-C6) alkyl group, or a (C1-C6)-alkenyl group, both optionally substituted by hydroxy, alkoxy, or aryloxy; (ii) A1 is a (C1-C6) alkyl group optionally substituted by —O—C(=M)-Z5, wherein M is O and Z5 is a (C1-C6) alkyl group optionally substituted by an alkoxycarbonyl or arylalkoxycarbonyl group; (iii) A2 and A3 are hydroxy or acyloxy; (iv) A4 is —NH—C(═O)—R4, wherein R4 is a (C1-C6) alkyl group optionally substituted by a carboxy, alkoxycarbonyl, or aryloxycarbonyl group; or (v) A4 is

wherein D2 and D3 are N, and R4 is a (C1-C6) alkyl group, optionally substituted by an alkoxy or aryloxy group.

7 - 10 . (canceled)

11 . The compound of formula (I) of claim 2 , wherein:
(i) A6 and A7 are hydroxy or acyloxy; (ii) A′7 is H or a (C1-C6) alkyl group; (iii) A5 is H or a (C1-C6) alkyl group, optionally substituted by one or more hydroxy or acyloxy groups; (iv) A8 is H, halogen, or OH or its tautomeric oxo (═O); (v) A8 is selected in the group consisting of —N(R7) 2 , —NHR7 or —NH—C(═O)—R7, wherein R7 is H or a (C1-C6) alkyl group; (vi) A9 is H, OH or its tautomeric oxo (═O), or NH2; or (vii) R6 is a H or a (C1-C6) alkyl group.

12 - 17 . (canceled)

18 . A compound of formula (III)

or a pharmaceutically acceptable salt thereof,
wherein:
A1, A2 and A3 are, independently, H, hydroxy, alkoxy, acyloxy, aryloxy, aroyloxy, alkoxycarbonyl, aryloxycarbonyl, oxo (═O), or a (C1-C20) alkyl or alkenyl group, unsubstituted or optionally substituted by one or more groups selected from halogen, hydroxy, a (C3-C8) cycloalkyl group, a (C3-C14) heterocycle, a (C6-C14) aryl group, a (C5-C14) heteroaryl group, —O—Z5, —N(Z5)(Z6), —S—Z5, —CN, —C(=M)-O—Z5, —O—C(=M)-Z5, —C(=M)-N(Z5)(Z6), and —N(Z5)-C(=M)-Z6,

wherein:
M is O or S,
each of Z5 and Z6 is, independently, H, a (C1-C6)

Assignees

• Sanofi Sa

Inventors

• Elshorst Bettina
• Hessler Gerhard
• Hofmeister Armin
• Li Ziyu
• Pöverlein Christoph
• Schreuder Herman
• Zech Gernot

Classifications

• C07H19/16 Primary

  Purine radicals · CPC title

• C07D211/56

  Nitrogen atoms (nitro radicals C07D211/38) · CPC title

• C07H19/207

  the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide · CPC title

• C07H21/00

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C12N15/1138

  against receptors or cell surface proteins · CPC title