Bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C12N-015/113
C07F-009/6512
출원번호
US-0125634
(2015-03-17)
등록번호
US-10036019
(2018-07-31)
국제출원번호
PCT/US2015/021050
(2015-03-17)
국제공개번호
WO2015/142910
(2015-09-24)
발명자
/ 주소
Seth, Punit P.
Swayze, Eric E.
출원인 / 주소
Ionis Pharmaceuticals, Inc.
대리인 / 주소
McNeill Baur PLLC
인용정보
피인용 횟수 :
0인용 특허 :
139
초록▼
The present invention provides novel bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom. Incorporation of one or more of the bicyclic carbocyclic nucleosides into an oligomeric compound is expected to enhance one or more properties of the oligomeric compound. In certain emb
The present invention provides novel bicyclic carbocyclic nucleosides and oligomeric compounds prepared therefrom. Incorporation of one or more of the bicyclic carbocyclic nucleosides into an oligomeric compound is expected to enhance one or more properties of the oligomeric compound. In certain embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in modulation of normal function of the target RNA. In certain embodiments, bicyclic carbocyclic nucleosides are provided as monomers for use as antivirals.
대표청구항▼
1. A bicyclic carbocyclic nucleoside having Formula I: wherein: Bx is an optionally protected heterocyclic base moiety;T1 is a protected hydroxyl;T2 is a reactive phosphorus group capable of forming an internucleoside linkage selected from diisopropylcyanoethoxy phosphoramidite and H-phosphonate;Q
1. A bicyclic carbocyclic nucleoside having Formula I: wherein: Bx is an optionally protected heterocyclic base moiety;T1 is a protected hydroxyl;T2 is a reactive phosphorus group capable of forming an internucleoside linkage selected from diisopropylcyanoethoxy phosphoramidite and H-phosphonate;Q is halogen or O—[C(A1)(A2)]n-[(C═O)m—X]j—Z wherein Q is other than a protected hydroxyl group;A1 and A2 are each, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;X is O, S or N(E1);Z is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or N(E2)(E3);E1, E2 and E3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;n is from 1 to about 6;m is 0 or 1;j is 0 or 1 provided that when j is 1 then Z is other than halogen or N(E2)(E3);L1 and L2 are each H or one of L1 and L2 is H and the other of L1 and L2 is C1-C6 alkyl or substituted C1-C6 alkyl;R1, R2, R3, R4, R5 and R6 are each H or one of R1, R2, R3, R4, R5 and R6 is F, CH3 or OCH3 and the remaining of R1, R2, R3, R4, R5 and R6 are each H;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, OC(=G)J1, OC(=G)N(J1)(J2) and C(=G)N(J1)(J2);G is O, S or NJ3; andeach J1, J2 and J3 is, independently, H or C1-C6 alkyl. 2. The bicyclic carbocyclic nucleoside of claim 1 wherein one of L1 and L2 is H and the other of L1 and L2 is CH3. 3. The bicyclic carbocyclic nucleoside of claim 1 wherein L1 and L2 are each H. 4. The bicyclic carbocyclic nucleoside of claim 1 wherein L1, L2, R1, R2, R3, R4, R5 and R6 are each H. 5. The bicyclic carbocyclic nucleoside claim 1 wherein Q is F. 6. The bicyclic nucleoside of claim 1 wherein Q is O(CH2)2—OCH3. 7. The bicyclic carbocyclic nucleoside of claim 1 wherein Bx is uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methylcytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyladenine, guanine or 2-N-isobutyrylguanine. 8. The bicyclic carbocyclic nucleoside of claim 1 wherein T1 is O-4,4′-dimethoxytrityl and T2 is diisopropylcyanoethoxy phosphoramidite. 9. An oligomeric compound comprising at least one bicyclic carbocyclic nucleoside having Formula II: wherein independently for each bicyclic carbocyclic nucleoside of Formula II Bx is an optionally protected heterocyclic base moiety;one of T3 and T4 is an internucleoside linking group attaching the bicyclic nucleoside to the remainder of one of the 5′ or 3′ end of the oligomeric compound and the other of T3 and T4 is hydroxyl, a protected hydroxyl, a 5′ or 3′ terminal group or an internucleoside linking group attaching the bicyclic nucleoside to the remainder of the other of the 5′ or 3′ end of the oligomeric compound;Q is halogen or O—[C(A1)(A2)]n-[(C═O)m—X]j—Z wherein Q is other than a protected hydroxyl group;A1 and A2 are each, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;X is O, S or N(E1);Z is H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or N(E2)(E3);E1, E2 and E3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;n is from 1 to about 6;m is 0 or 1;j is 0 or 1 provided that when j is 1 then Z is other than halogen or N(E2)(E3);L1 and L2 are each H or one of L1 and L2 is H and the other of L1 and L2 is C1-C6 alkyl, or substituted C1-C6 alkyl;R1, R2, R3, R4, R5 and R6 are each H or one of R1, R2, R3, R4, R5 and R6 is F, CH3 or OCH3 and the remaining of R1, R2, R3, R4, R5 and R6 are each H;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, OC(=G)J1, OC(=G)N(J1)(J2) and C(=G)N(J1)(J2);G is O, S or NJ3;each J1, J2 and J3 is, independently, H or C1-C6 alkyl; andwherein said oligomeric compound comprises from 8 to 40 monomeric subunits linked by internucleoside linking groups and wherein at least some of the heterocyclic base moieties are capable of hybridizing to a nucleic acid molecule. 10. The oligomeric compound of claim 9 wherein one of L1 and L2 is H and the other of L1 and L2 is CH3 for each bicyclic carbocyclic nucleoside having Formula II. 11. The oligomeric compound of claim 9 wherein L1 and L2 are each H for each bicyclic carbocyclic nucleoside having Formula II. 12. The oligomeric compound of claim 9 wherein L1, L2, R1, R2, R3, R4, R5 and R6 are each H for each bicyclic carbocyclic nucleoside having Formula II. 13. The oligomeric compound of claim 9 wherein Q is F for each bicyclic carbocyclic nucleoside having Formula II. 14. The oligomeric compound of claim 9 wherein Q is O(CH2)2—OCH3 for each bicyclic carbocyclic nucleoside having Formula II. 15. The oligomeric compound of claim 9 wherein each Bx is, independently, uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 16. The oligomeric compound of claim 9 wherein one T3 and or one T4 is a terminal group. 17. The oligomeric compound of claim 9 wherein one T3 or one T4 is a conjugate group that may include a bifunctional linking moiety. 18. The oligomeric compound of claim 9 comprising a first region consisting of from 2 to 5 modified nucleosides, a second region consisting of from 2 to 5 modified nucleosides and a gap region consisting of from 6 to 14 monomer subunits located between the first and second region wherein at least one of the monomer subunits in the gap region or at least one of the modified nucleosides in the first region is a bicyclic carbocyclic nucleoside having Formula II. 19. The oligomeric compound of claim 18 wherein the gap region comprises from about 8 to about 10 monomer subunits. 20. The oligomeric compound of claim 18 wherein each monomer subunit in the gap region other than bicyclic carbocyclic nucleosides of Formula II is a β-D-2′-deoxyribonucleoside. 21. The oligomeric compound of claim 18 wherein each modified nucleoside in the first and second region is, independently, a bicyclic nucleoside comprising a bicyclic furanosyl sugar moiety or a modified nucleoside comprising a furanosyl sugar moiety having at least one substituent group. 22. The oligomeric compound of claim 18 wherein each modified nucleoside in the first and second region is, independently, a bicyclic nucleoside comprising a 4′-CH((S)—CH3)—O-2′ bridge or a 2′-O-methoxyethyl substituted nucleoside. 23. The oligomeric compound of claim 18 wherein each monomer subunit in the gap region is a β-D-2′-deoxyribonucleoside. 24. The oligomeric compound of claim 9 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group. 25. A method of inhibiting gene expression comprising contacting a cell with an oligomeric compound of claim 9 wherein said oligomeric compound is complementary to a target RNA. 26. The method of claim 25 wherein said target RNA is selected from mRNA, pre-mRNA and micro RNA. 27. The method of claim 25 further comprising detecting the levels of target RNA. 28. An in vitro method of inhibiting gene expression comprising contacting one or more cells or a tissue with an oligomeric compound of claim 9.
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이 특허에 인용된 특허 (139)
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