US 9,809,824 B2
CpG oligonucleotide prodrugs, compositions thereof and associated therapeutic methods
Daniela Verthelyi, Potomac, MD (US); Serge L. Beaucage, Silver Spring, MD (US); and Andrzej Grajkowski, Kensington, MD (US)
Assigned to The United States of America, Represented by the Secretary, Department of Health and Human Services, Washington, DC (US)
Appl. No. 11/721,409
Filed by Daniela Verthelyi, Potomac, MD (US); Serge L. Beaucage, Silver Spring, MD (US); and Andrzej Grajkowski, Kensington, MD (US)
PCT Filed Dec. 13, 2005, PCT No. PCT/US2005/044935
§ 371(c)(1), (2), (4) Date Aug. 2, 2007,
PCT Pub. No. WO2006/065751, PCT Pub. Date Jun. 22, 2006.
Claims priority of provisional application 60/635,744, filed on Dec. 13, 2004.
Prior Publication US 2009/0263405 A1, Oct. 22, 2009
Int. Cl. C07H 21/00 (2006.01); C12N 15/117 (2010.01)
CPC C12N 15/117 (2013.01) [C07H 21/00 (2013.01); C12N 2310/17 (2013.01); C12N 2310/315 (2013.01); C12N 2310/351 (2013.01)] 25 Claims
 
1. A CpG oligonucleotide prodrug comprising a CpG oligonucleotide that has a poly-G tail at the 3′-end of the oligonucleotide and a thermolabile substituent bonded thereto, wherein the thermolabile substituent is bonded to the non-bridging oxygen atom of a deoxyguanosine phosphate, phosphorothioate, or phosphoroselenoate diester present in the poly-G tail in an amount sufficient to inhibit G-tetrad formation, wherein the CpG oligonucleotide that has a poly-G tail forms a tetraplex in the absence of the thermolabile substituent, and, wherein the thermolabile substituent is of the formula:

OG Complex Work Unit Drawing
wherein:
R2, R2′, R3 and R3′are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl, or R2 or R2′, in combination with R3 or R3′, together with the carbon atoms to which they are bonded, comprise a cyclic substituent of the formula:

OG Complex Work Unit Drawing
wherein p is an integer from 0-6 and a-d are the same or different and each is selected from the group consisting of H, an alkyl, a nitro, a dialkylamino, an alkoxy, an alkylthio, a cyano and a halogen;
Z is O, S, NR4a, CR4aR4a′or CR4aR4a′CR4bR4b′, wherein R4a, R4a′, R4b and R4b′ are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl; and
Y is CH2R1 or C(X)H wherein X is O or S, and R1 is H, R1a, OR1a, SR1a or NR1aR1a′, wherein R1a and R1a′are the same or different and each is H, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, an aryl, or an aralkyl;
wherein R1a, R1a′, R2, R2′,R3, R3′, R4a, R4a′,R4b and R4b′ are unsubstituted or substituted with one or more substituents, which are the same or different, selected from the group consisting of OR5, SR5, CN, NO2, N3, and a halogen, wherein R5 is H or an alkyl.