Substituted 2′-amino and 2′-thio-bicyclic nucleosides and oligomeric compounds prepared therefrom
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/70
C07H-017/00
C07H-021/04
C07H-019/06
C07H-021/00
C12N-015/113
C07H-019/173
C07H-019/073
출원번호
US-0697970
(2011-06-02)
등록번호
US-8846637
(2014-09-30)
국제출원번호
PCT/US2011/038931
(2011-06-02)
§371/§102 date
20130207
(20130207)
국제공개번호
WO2011/156202
(2011-12-15)
발명자
/ 주소
Seth, Punit P.
Prakash, Thazha P.
Swayze, Eric E.
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Casimir Jones, S.C.
인용정보
피인용 횟수 :
2인용 특허 :
132
초록
Provided herein are 2′-amino and 2′-thio bicyclic nucleosides and oligomenc compounds prepared therefrom. The novel bicyclic nucleosides provided herein are expected to be useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as nuclease resistance.
대표청구항▼
1. A bicyclic nucleoside having Formula I: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;Q1 and Q2 are each independently, H, C1-C6 alkyl, substituted C1-C6 a
1. A bicyclic nucleoside having Formula I: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;Q1 and Q2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;G1 and G2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;Z is S or NR;R is H, C1-C6 alkyl, substituted C1-C6 alkyl or substituted acyl;each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═O)NJ1J2 and N(H)C(═S)NJ1J2;each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group; andwherein at least one of Q1, Q2, G1 and G2 is other than H. 2. The bicyclic nucleoside of claim 1 wherein Bx is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 3. The bicyclic nucleoside of claim 1 wherein T1 is 4,4′-dimethoxytrityl and T2 is diisopropylcyanoethoxy phosphoramidite. 4. The bicyclic nucleoside of claim 1 wherein Q1 and Q2 are each H. 5. The bicyclic nucleoside of claim 1 wherein one of Q1 and Q2 is H and the other of Q1 and Q2 is C1-C6 alkyl or substituted C1-C6 alkyl. 6. The bicyclic nucleoside of claim 1 wherein one of Q1 and Q2 is CH3. 7. The bicyclic nucleoside of claim 1 wherein G1 and G2 are each H. 8. The bicyclic nucleoside of claim 1 wherein one of G1 and G2 is H and the other of G1 and G2 is C1-C6 alkyl or substituted C1-C6 alky. 9. The bicyclic nucleoside of claim 1 wherein at least one of G1 and G2 is CH3. 10. The bicycle nucleoside of claim 1 wherein Z is NR wherein R is H or C1-C6 alkyl. 11. The bicyclic nucleoside of claim 10 wherein R is CH3. 12. The bicyclic nucleoside of claim 1 wherein Z is S. 13. The bicyclic nucleoside of claim 1 having Formula Ia: 14. The bicyclic nucleoside of claim 13 wherein three of Q1, Q2, G1 and G2 are H and the other one of Q1, Q2, G1 and G2 is CH3. 15. The bicyclic nucleoside of claim 13 wherein two of Q1, Q2, G1 and G2 are H and the remaining two of Q1, Q2, G1 and G2 are CH3 wherein the two that are CH3 are selected from Q1 and G1, Q1 and G2, Q2 and G1, and Q2 and G2. 16. An oligomeric compound comprising at least one bicyclic nucleoside of Formula II: wherein independently for each bicyclic nucleoside of Formula II: Bx is a heterocyclic base moiety;one of T3 and T4 is an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound and the other of T3 and T4 is H, a hydroxyl protecting group, a 5′ or 3′-terminal group or an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound;Q1 and Q2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;G1 and G2 are each independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;Z is S or NR;R is H, C1-C6 alkyl, substituted C1-C6 alkyl or substituted acyl;each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═O)NJ1J2 and N(H)C(═S)NJ1J2;each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group; andwherein at least one of Q1, Q2, G1 and G2 is other than H. 17. The oligomeric compound of claim 16 wherein Bx is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine for each bicyclic nucleoside of Formula II. 18. The oligomeric compound of claim 16 wherein at least one of T3 and T4 is a 5′ or 3′-terminal group. 19. The oligomeric compound of claim 16 wherein Q1 and Q2 are each H for each bicyclic nucleoside of Formula II. 20. The oligomeric compound of claim 16 wherein one of Q1 and Q2 is H and the other of Q1 and Q2 is C1-C6 alkyl or substituted C1-C6 alkyl for each bicyclic nucleoside of Formula II. 21. The oligomeric compound of claim 20 wherein one of Q1 and Q2 is CH3 for each bicyclic nucleoside of Formula II. 22. The oligomeric compound of claim 16 wherein G1 and G2 are each H for each bicyclic nucleoside of Formula II. 23. The oligomeric compound of claim 16 wherein one of G1 and G2 is H and the other of G1 and G2 is C1-C6 alkyl or substituted C1-C6 alkyl for each bicyclic nucleoside of Formula II. 24. The oligomeric compound of claim 23 wherein one of G1 and G2 is CH3 for each bicyclic nucleoside of Formula II. 25. The oligomeric compound of claim 16 wherein Z is NR and wherein R is H or C1-C6 alkyl for each bicyclic nucleoside of Formula II. 26. The oligomeric compound of claim 25 wherein R is CH3 for each bicycle nucleoside of Formula II. 27. The oligomeric compound of claim 16 wherein each bicyclic nucleoside has Formula IIa: 28. The oligomeric compound of claim 27 wherein three of Q1, Q2, G1 and G2 are H and the other one of Q1, Q2, G1 and G2 is CH3 for each bicyclic nucleoside of Formula IIa. 29. The oligomeric compound of claim 27 wherein two of Q1, Q2, G1 and G2 are H and the remaining two of Q1, Q2, G1 and G2 are CH3 wherein the two that are CH3 are selected from Q1 and G1, Q1 and G2, Q2 and G1, Q2 and G2 for each bicyclic nucleoside of Formula IIa. 30. The oligomeric compound of claim 16 comprising at least two regions wherein each region independently comprises from 1 to about 5 contiguous bicyclic nucleosides of Formula II and wherein the two regions are separated by an internal region comprising at least one monomer subunit different from bicycle nucleosides having Formula II and independently selected from nucleosides and modified nucleosides. 31. The oligomeric compound of claim 30 comprising a gapped oligomeric compound wherein one region of contiguous bicyclic nucleosides of Formula II is located at the 5′-end and a second region of contiguous bicyclic nucleosides of Formula II is located at the 3′-end, wherein the two regions are separated by an internal region comprising from about 6 to about 18 monomer subunits different from bicycle nucleosides having Formula II and independently selected from nucleosides and modified nucleosides. 32. The oligomeric compound of claim 16 wherein each inter-nucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group. 33. The oligomeric compound of claim 16 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group. 34. A method comprising contacting a cell with an oligomeric compound of claim 16 wherein said oligomeric compound is complementary to a target RNA. 35. The method of claim 34 wherein said cell is in an animal. 36. The method of claim 34 wherein said cell is in a human.
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이 특허에 인용된 특허 (132)
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