Gapped oligomeric compounds comprising 5′-modified deoxyribonucleosides in the gap and uses thereof
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/11
C07H-021/04
C12N-015/113
출원번호
US-0238094
(2012-08-08)
등록번호
US-9752142
(2017-09-05)
국제출원번호
PCT/US2012/049989
(2012-08-08)
§371/§102 date
20140701
(20140701)
국제공개번호
WO2013/022967
(2013-02-14)
발명자
/ 주소
Oestergaard, Michael
Prakash, Thazha P.
Seth, Punit P.
Swayze, Eric E.
출원인 / 주소
Ionis Pharmaceuticals, Inc.
인용정보
피인용 횟수 :
0인용 특허 :
51
초록▼
The present invention provides gapped oligomeric compounds comprising at least one 5′-substituted P-D-2′-deoxyribonucleoside in the gap region. Certain such gapped oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited to, nucleic acids in a cell.
The present invention provides gapped oligomeric compounds comprising at least one 5′-substituted P-D-2′-deoxyribonucleoside in the gap region. Certain such gapped oligomeric compounds are useful for hybridizing to a complementary nucleic acid, including but not limited to, nucleic acids in a cell. The oligomeric compounds provided herein have improved properties such as selectivity, potency and improved proinflammatory profile. In certain embodiments, hybridization results in modulation of the amount of activity or expression of the target nucleic acid in a cell.
대표청구항▼
1. A gapped oligomeric compound comprising a contiguous sequence of linked monomer subunits having a gap region located between a 5′-region and a 3′-region wherein the 5′ and 3′-regions each, independently, have from 2 to 8 contiguous RNA-like modified nucleosides that each adopt a 3′-endo conformat
1. A gapped oligomeric compound comprising a contiguous sequence of linked monomer subunits having a gap region located between a 5′-region and a 3′-region wherein the 5′ and 3′-regions each, independently, have from 2 to 8 contiguous RNA-like modified nucleosides that each adopt a 3′-endo conformational geometry when put into an oligomeric compound and wherein the gap region has from 6 to 14 contiguous monomer subunits selected from β-D-2′-deoxyribonucleosides and 5′-substituted β-D-2′-deoxyribonucleosides having Formula I: wherein independently for each 5′-substituted β-D-2′-deoxyribonucleoside having Formula I: T1 and T2 are each, independently, an internucleoside linking group linking the 5′-substituted β-D-2′-deoxyribonucleoside having Formula I to the remainder of the gapped oligomeric compound;Bx is a heterocyclic base moiety;R1 is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl; andwherein said gap region comprises at least one 5′-substituted β-D-2′-deoxyribonucleoside having Formula I and a plurality of β-D-2′-deoxyribonucleosides. 2. The gapped oligomeric compound of claim 1 wherein each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, NJ1J2, ═NJ1, SJ1, N3, CN, OC(=L)J1, OC(=L)NJ1J2 and NJ3C(=L)NJ1J2, wherein each J1, J2 and J3 is, independently, H, C1-C6 alkyl or a protecting group, and L is O, S or NJ1. 3. The gapped oligomeric compound of claim 1 wherein each R1 is independently selected from C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl. 4. The gapped oligomeric compound of claim 1 wherein each R1 is independently selected from CH3, CH2CH3, CH2CH2OH, CH2CHCH2 and CHCH2. 5. The gapped oligomeric compound of claim 1 wherein each R1 is CH3. 6. The gapped oligomeric compound of claim 1 having only one 5′-substituted β-D-2′-deoxyribonucleoside of Formula I. 7. The gapped oligomeric compound of claim 1 having only two 5′-substituted β-D-2′-deoxyribonucleosides of Formula I. 8. The gapped oligomeric compound of claim 1 wherein each 5′-substituted β-D-2′-deoxyribonucleoside has the configuration of Formula Ia: 9. The gapped oligomeric compound of claim 1 wherein each 5′-substituted β-D-2′-deoxyribonucleoside has the configuration of Formula Ib: 10. The gapped oligomeric compound of claim 1 wherein each internucleoside linking group that links adjacent monomer subunits is independently selected from a phosphodiester or phosphorothioate internucleoside linking group. 11. The gapped oligomeric compound of claim 1 wherein each internucleoside linking group that links adjacent monomer subunits is a phosphorothioate internucleoside linking group. 12. The gapped oligomeric compound of claim 1 wherein each monomer subunit comprises a heterocyclic base moiety independently selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. 13. The gapped oligomeric compound of claim 1 wherein each modified nucleoside in the 5′ and 3′-regions is independently selected from a bicyclic nucleoside comprising a bicyclic furanosyl sugar moiety or a modified nucleoside comprising a furanosyl sugar moiety having at least one substituent group. 14. The gapped oligomeric compound of claim 13 comprising one or more 2′-modified nucleosides that each have a 2′-substituent group independently selected from halogen, OCH3, OCH2F, OCHF2, OCF3, OCH2CH3, O(CH2)2F, OCH2CHF2, OCH2CF3, OCH2—CH═CH2, O(CH2)2—OCH3, O(CH2)2—SCH3, O(CH2)2—OCF3, O(CH2)3—N(R3)(R4), O(CH2)2—ON(R3)(R4), O(CH2)2—O(CH2)2—N(R3)(R4), OCH2C(═O)—N(R4)(R4), OCH2C(═O)—N(R5)—(CH2)2—N(R3)(R4) and O(CH2)2—N(R5)—C(═NR6)[N(R3)(R4)] wherein R3, R4, R5 and R6 are each, independently, H or C1-C6 alkyl. 15. The gapped oligomeric compound of claim 14 wherein each 2′-substituent group is independently selected from F, OCH3, O(CH2)2—OCH3 and OCH2C(═O)—N(H)CH3. 16. The gapped oligomeric compound of claim 15 wherein each 2′-substituent group is O(CH2)2—OCH3. 17. The gapped oligomeric compound of claim 13 comprising one or more bicyclic nucleosides wherein each bicyclic nucleoside has a bridging group independently selected from 4′-(CH2)—O-2′, 4′-(CH2)—S-2′, 4′-(CH2)2—O-2′, 4′-CH(CH3)—O-2′, 4′-CH(CH2OCH3)—O-2′, 4′-C(CH3)2—O-2′, 4′-CH2—N(OCH3)-2′, 4′-CH2—O—N(CH3)-2′, 4′-CH2—NCH3—O-2′, 4′-CH2—C(H)(CH3)-2′ and 4′-CH2—C(═CH2)-2′. 18. The gapped oligomeric compound of claim 17 wherein each bridging group is 4′-CH[(S)—(CH3)]—O-2′. 19. The gapped oligomeric compound of claim 1 comprising at least two different types of modified nucleosides in the 5′ and 3′-regions comprising at least two different modified ribofuranosyl sugar moieties. 20. The gapped oligomeric compound of claim 19 wherein the 5′ and 3′-regions include only 4′-CH[(S)—(CH3)]—O-2′ bicyclic nucleosides and 2′-O(CH2)2—OCH3 substituted nucleosides. 21. The gapped oligomeric compound of claim 1 wherein the modified nucleosides in the 5′ and 3′-regions each have the same modified sugar moiety. 22. The gapped oligomeric compound of claim 1 wherein the 5′ and 3′-regions each, independently, have from 3 to 6 monomer subunits and the gap region has from 6 to 10 monomer subunits. 23. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or the animal with the oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA. 24. The method of claim 23 wherein said cells are in a human. 25. The method of claim 23 wherein said target RNA is human mRNA. 26. The method of claim 23 wherein said target RNA is cleaved thereby inhibiting the function of said target RNA.
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