Monomers and oligonucleotides comprising cycloaddition adduct(s)

Patent metadata

Field	Value
Publication number	US-10550386-B2
Application number	US-201615395221-A
Country	US
Kind code	B2
Filing date	Dec 30, 2016
Priority date	Jan 28, 2010
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

In one embodiment, the invention relates compounds and processes for conjugating ligand to oligonucleotide. The invention further relates to methods for treating various disorders and diseases such as viral infections, bacterial infections, parasitic infections, cancers, allergies, autoimmune diseases, immunodeficiencies and immunosuppression.

First claim

We claim:

1. A compound of formula XIIa or pharmaceutically acceptable salts thereof:

wherein:
R a and R b are independently hydrogen, an activated phosphate group, an activated phosphite group, a phosphoramidite, a solid support, —P(Z 1 )(Z 2 )-OH, —P(Z 1 )(Z 2 )—O-nucleoside, or —P(Z′)(Z 2 )—O-oligonucleotide;
Y 1 -Y 6 are each independently O, S, NR N , or CR P 2 ;
each linker can be the same or different;
J is independently for each occurrence absent, O, S, NR N , OC(O)NH, NHC(O)O, C(O)NH, NHC(O), NHSO, NHSO 2 , NHSO 2 NH, OC(O), C(O)O, OC(O)O, NHC(O)NH, NHC(S)NH, OC(S)NH, O-N═CH, OP(N(R N ) 2 )O, or OP(N(R N ) 2 );
X is O, S, NR N or CR P 2 ;
E is absent or C(O), C(O)O, C(O)NH, C(S), C(S)NH, SO, SO 2 , or SO 2 NH;
R L is hydrogen or a ligand;
R N is independently for each occurrence H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted heteroaryl or an amino protecting group;
R P is independently for each occurrence H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heteroaryl; and
Z 1 and Z 2 are each independently for each occurrence O, S or optionally substituted alkyl.

2. The compound of claim 1 , where R L is selected from the group consisting of:

3. The compound of claim 1 , wherein each linker is represented by structure
[P-Q 1 -R] q -T-,

wherein:
P, R and T are each independently for each occurrence absent, CO, NH, O, S, S-S, OC(O), NHC(O), CH 2 , CH 2 NH, CH 2 O, NHCH(R a )C(O), —C(O)—CH(R a )—NH-, —C(O)-(optionally substituted alkyl)-NH-, CH═N-O,

acetal, ketal,

Q 1 is independently for each occurrence absent, -(CH 2 ) n -, -C(R 100 )(R 200 )(CH 2 ) n —, —(CH 2 ) n C(R 100 )(R 200 )—, —(CH 2 CH 2 O) m CH 2 CH 2 —, or -(CH 2 CH 2 O) m CH 2 CH 2 NH-; provided that at least one of Q 1 , P, R, and T is not absent;
R a is H or an amino acid side chain;
R 100 and R 200 are each independently for each occurrence H, CH 3 , OH, SH or N(R X ) 2 ;
R X is independently for each occurrence H, methyl, ethyl, propyl, isopropyl, butyl or benzyl;
q is independently for each occurrence 0-20;
n is independently for each occurrence 1-20; and
m is independently for each occurrence 0-50.

4. The compound of claim 1 , wherein R a or R b contains an oligonucleotide.

5. The compound of claim 4 , wherein the oligonucleotide is a single-stranded oligonucleotide.

6. The compound of claim 4 , wherein the oligonucleotide is a double-stranded oligonucleotide.

Assignees

• Alnylam Pharmaceuticals Inc

Inventors

• Manoharan Muthiah
• Nair Jayaprakash K
• Rajeev Kallanthottahil G
• Jung Michael E

Classifications

• A61K47/56

  the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P33/00

  Antiparasitic agents · CPC title