초록 ▼

This invention relates to antisense oligonucleotides comprising at least one N3′→P5′ phosphorodiamidate linkage (NPN) in the backbone, and kits and pharmaceutical compositions thereof, useful for modulating gene expression involved in the pathogenesis of a disease. Also included are compounds useful

This invention relates to antisense oligonucleotides comprising at least one N3′→P5′ phosphorodiamidate linkage (NPN) in the backbone, and kits and pharmaceutical compositions thereof, useful for modulating gene expression involved in the pathogenesis of a disease. Also included are compounds useful as building blocks of said antisense oligonucleotides and methods of preparing said antisense oligonucleotides and building block compounds including NPN linkages.

대표청구항 ▼

1. A compound of formula (I): whereinR1 is hydrogen, an amino protecting group, or an oligonucleotide;R2 is hydrogen, a hydroxyl protecting group, solid support, or an oligonucleotide;each R3 is independently selected from hydrogen, hydroxyl, and —O—R3a; wherein each R3a is C1-6 alkyl or C1-6 alkyl

1. A compound of formula (I): whereinR1 is hydrogen, an amino protecting group, or an oligonucleotide;R2 is hydrogen, a hydroxyl protecting group, solid support, or an oligonucleotide;each R3 is independently selected from hydrogen, hydroxyl, and —O—R3a; wherein each R3a is C1-6 alkyl or C1-6 alkyl substituted with —NR3bR3c, imidazolyl, —(CH2)aO(CH2)bNR3bR3c, or —(CH2)aONR3d(CH2)bNR3bR3c; wherein each R3b is hydrogen or C1-2 alkyl;each R3c is hydrogen or C1-2 alkyl;each R3d is hydrogen or C1-2 alkyl;each a is an integer selected from one to 4;each b is an integer selected from one to 4;each R4 is independently C1-6 alkyl or C1-6 alkyl substituted with —NR4aR4b; wherein R4a is hydrogen or C1-2 alkyl and R4b is hydrogen or C1-2 alkyl;each R5 is independently C1-6 alkyl or C1-6 alkyl substituted with —NR5aR5b; wherein R5a is hydrogen or C1-2 alkyl and R5b is hydrogen or C1-2 alkyl; orR4 and R5 taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl or a monocyclic heterocyclyl substituted with C1-6 alkyl, sperminyl, or spermidinyl;each W is independently selected from O, S, and Se;each B1 is independently selected from a heterocyclic base moiety or a protected heterocyclic base moiety; andn is an integer selected from one to 50;or a salt thereof. 2. The compound of claim 1, or a salt thereof, wherein each W is O. 3. The compound of claim 1, or a salt thereof, wherein each B1 is independently selected from purinyl and pyrimidinyl. 4. The compound of claim 1, or a salt thereof, wherein each B1 is independently selected from 4-benzoyl-1-cytosinyl, 6-benzoyl-9-adeninyl, 6-dimethylformamidino-9-adeninyl, 2-isobutyryl-9-guaninyl, 2-dimethylformamidino-9-guaninyl, 9-adeninyl, 9-guaninyl, 1-cytosinyl, 1-thyminyl and 1-uracilyl. 5. The compound of claim 1, or a salt thereof, wherein n is an integer from 2 to 30. 6. A compound of claim 1, wherein the compound comprises a sequence which includes a region that is complementary to any portion of a sequence of a telomerase RNA (SEQ ID NO:1). 7. The compound of claim 1, or a salt thereof, wherein n is an integer from 6 to 30. 8. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 9. A kit comprising a compound of claim 1, or a salt thereof. 10. A compound of formula (III) whereinR1 is hydrogen or an amino protecting group;R2 is hydrogen, a hydroxyl protecting group, or solid support;each R3 is independently selected from hydrogen, hydroxyl, and —O—R3a; wherein each R3a is C1-6 alkyl or C1-6 alkyl substituted with —NR3bR3c, imidazolyl, —(CH2)aO(CH2)bNR3bR3c, or —(CH2)aONR3d(CH2)bNR3bR3c; wherein each R3b is hydrogen or C1-2 alkyl;each R3c is hydrogen or C1-2 alkyl;each R3d is hydrogen or C1-2 alkyl;each a is an integer selected from one to 4;each b is an integer selected from one to 4;each R4 is C1-6 alkyl or C1-6 alkyl substituted with —NR4aR4b; wherein R4a is hydrogen or C1-2 alkyl and R4b is hydrogen or C1-2 alkyl;each R5 is C1-6 alkyl or C1-6 alkyl substituted with —NR5aR5b; wherein R5a is hydrogen or C1-2 alkyl and R5b is hydrogen or C1-2 alkyl; orR4 and R5 taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl or a monocyclic heterocyclyl substituted with C1-6 alkyl, sperminyl or spermidinyl;each W is independently selected from O, S, and Se; andeach B1 is independently selected from a heterocyclic base moiety and a protected heterocyclic base moiety;or a salt thereof. 11. The compound of claim 10, or a salt thereof, wherein W is O. 12. The compound of claim 10, or a salt thereof, wherein each B1 is independently selected from purinyl and pyrimidinyl. 13. The compound of claim 10, or a salt thereof, wherein each B1 is independently selected from 4-benzoyl-1-cytosinyl, 6-benzoyl-9-adeninyl, 6-dimethylformamidino-9-adeninyl, 2-isobutyryl-9-guaninyl, 2-dimethylformamidino-9-guaninyl, 9-adeninyl, 9-guaninyl, 1-cytosinyl, 1-thyminyl and 1-uracilyl. 14. The compound of claim 10, or a salt thereof, wherein R2 is a hydroxyl protecting group or a solid support. 15. The compound of claim 10, or a salt thereof, wherein the compound is selected from: 16. An oligonucleotide, wherein the nucleoside subunits of the oligonucleotide are joined by intersubunit linkages, wherein at least one of the intersubunit linkages is a phosphorothioate or phosphate diester linkage, andwherein the oligonucleotide has formula (I) whereinR1 is selected from hydrogen and an oligonucleotide;R2 is selected from hydrogen and an oligonucleotide;each R3 is independently selected from hydrogen, hydroxyl, and —O—R3a; wherein each R3a is C1-6 alkyl or C1-6 alkyl substituted with —NR3bR3c, imidazolyl, —(CH2)aO(CH2)bNR3bR3c, or —(CH2)aONR3d (CH2)bNR3bR3c; wherein each R3b is hydrogen or C1-2 alkyl;each R3c is hydrogen or C1-2 alkyl;each R3d is hydrogen or C1-2 alkyl;each a is an integer selected from one to 4;each b is an integer selected from one to 4;each R4 is independently C1-6 alkyl or C1-6 alkyl substituted with —NR4aR4b; wherein R4a is hydrogen or C1-2 alkyl and R4b is hydrogen or C1-2 alkyl;each R5 is independently C1-6 alkyl or C1-6 alkyl substituted with —NR5aR5b; wherein R5a is hydrogen or C1-2 alkyl and R5b is hydrogen or C1-2 alkyl; orR4 and R5 taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl or a monocyclic heterocyclyl substituted with C1-6 alkyl, sperminyl or spermidinyl;each W is independently selected from O, S, and Se;each B1 is independently selected from a heterocyclic base moiety or a protected heterocyclic base moiety; andn is an integer selected from one to 25;or a salt thereof. 17. The oligonucleotide of claim 16, or a salt thereof, wherein: R1 is H; andR2 is an oligonucleotide which comprises a central region comprising intersubunit linkages independently selected from phosphorothioate and phosphate diester linkages joined to a terminal 5′-flanking region having the formula: wherein each n is independently an integer selected from one to 25. 18. The oligonucleotide of claim 16, or a salt thereof, wherein: R1 is an oligonucleotide comprising intersubunit linkages independently selected from phosphorothioate and phosphate esters; andR2 is an oligonucleotide comprising intersubunit linkages independently selected from phosphorothioate and phosphate esters. 19. The oligonucleotide of claim 16, or a salt thereof, wherein the oligonucleotide prevents translation of the mRNA by steric hindrance. 20. The oligonucleotide of claim 16, or a salt thereof, wherein the oligonucleotide is a substrate for RNase-H-mediated degradation of the mRNA from a gene. 21. An oligonucleotide of claim 16, wherein the oligonucleotide comprises a sequence which includes a region that is complementary to any portion of a sequence of a telomerase RNA (SEQ ID NO:1). 22. A pharmaceutical composition comprising an oligonucleotide of claim 16, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 23. A kit comprising an oligonucleotide of claim 16, or a salt thereof. 24. A method of preparing a compound of formula (I): whereinR1 is hydrogen or an amino protecting group;R2 is hydrogen or a hydroxyl protecting group;each R3 is independently selected from hydrogen, hydroxyl, and —O—R3a; wherein each R3a is C1-6 alkyl or a C1-6 alkyl substituted with —NR3bR3c, imidazolyl, —(CH2)aO(CH2)bNR3bR3c, or —(CH2)aONR3d(CH2)bNR3bR3c; wherein each R3b is hydrogen or C1-2 alkyl;each R3c is hydrogen or C1-2 alkyl;each R3d is hydrogen or C1-2 alkyl;each a is an integer selected from one to 4;each b is an integer selected from one to 4;each W is independently selected from O, S, and Se;each B1 is independently selected from a heterocyclic base moiety and a protected heterocyclic base moiety;each R4 is independently C1-6 alkyl or a C1-6 alkyl substituted with —NR4aR4b; wherein R4a is hydrogen or C1-2 alkyl and R4b is hydrogen or C1-2 alkyl;each R5 is independently C1-6 alkyl or a C1-6 alkyl substituted with —NR5aR5b; wherein R5a is hydrogen or C1-2 alkyl and R5b is hydrogen or C1-2 alkyl; orR4 and R5 taken together with the nitrogen to which they are attached form a monocyclic heterocyclyl or a monocyclic heterocyclyl substituted with C1-6 alkyl, sperminyl, or spermidinyl; andn is an integer selected from one to 50;or a salt thereof;wherein the method comprises:a) contacting a compound of formula (II) with a compound of formula (B):