Bicyclic nucleosides and oligomeric compounds prepared therefrom
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/70
C07H-019/06
C07H-019/073
C07H-019/173
C07H-021/04
C07H-021/00
출원번호
US-0697966
(2011-06-06)
등록번호
US-8957200
(2015-02-17)
국제출원번호
PCT/US2011/039294
(2011-06-06)
§371/§102 date
20130228
(20130228)
국제공개번호
WO2011/156278
(2011-12-15)
발명자
/ 주소
Seth, Punit P.
Swayze, Eric E.
Hanessian, Stephen
Schroeder, Benjamin R.
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Casimir Jones, S.C.
인용정보
피인용 횟수 :
1인용 특허 :
132
초록
The present invention provides novel 3′,5′-linked bicyclic nucleosides and oligomeric compounds prepared therefrom. The bicyclic nucleosides provided herein are 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;T1 is H or a hydroxyl protecting group;T2 is a phosphoramidite, H-phosphonate or phosphate triester;Q is CH═CH, CE1E2-CE3E4, CH2OCH2, CH2SCH2 or CH2N(G)CH2;E1, E2, E3 and E4 are each, independently, H, hydroxyl, ha
1. A bicyclic nucleoside having Formula I: wherein: Bx is a heterocyclic base moiety;T1 is H or a hydroxyl protecting group;T2 is a phosphoramidite, H-phosphonate or phosphate triester;Q is CH═CH, CE1E2-CE3E4, CH2OCH2, CH2SCH2 or CH2N(G)CH2;E1, E2, E3 and E4 are each, independently, H, hydroxyl, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substituted amino;G is H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or a protecting group;one of t1 and t2 is H and the other of t1 and t2 is absent;n is 0 or 1;q1 and q2 are each independently, H, hydroxyl, halogen or O-A-[(C═O)m—X]j—Z;A is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;X is O, S or N(R1);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, N(R2)(R3) or a protecting group;R1, R2 and R3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;m is 0 or 1;j is 0 or 1;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;when j is 1 then Z is other than halogen or N(R2)(R3); andwhen n is 0 and Q is CH═CH or when n is 0 or 1 and Q is-CE1E2-CE3E4 then at least one of E1 E2 E3E4, q1 and q2 is other than H. 2. The bicyclic nucleoside of claim 1 wherein n is 1. 3. The bicyclic nucleoside of claim 1 wherein n is 0. 4. The bicyclic nucleoside of claim 1 wherein Q is CE1E2-CE3E4. 5. The bicyclic nucleoside of claim 4 wherein at least one of E1, E2, E3 and E4 is C1-C6 alkyl or substituted C1-C6 alkyl. 6. The bicyclic nucleoside of claim 4 wherein E1, E2, E3 and E4 are each H. 7. The bicyclic nucleoside of claim 1 wherein Q is CH═CH, CH2OCH2, CH2SCH2 or CH2N(G)CH2 wherein G is H or CH3. 8. The bicyclic nucleoside of claim 1 wherein q1 and q2 are each independently H. 9. The bicyclic nucleoside of claim 1 wherein one of q1 and q2 is H and the other of q1 and q2 is hydroxyl, protected hydroxyl, fluoro, or substituted or unsubstituted O—C1-C6 alkyl. 10. The bicyclic nucleoside of claim 1 wherein T1 is 4,4′-dimethoxy -trityl and T2 is diisopropylaminocyanoethoxy phosphoramidite. 11. The bicyclic nucleoside of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 12. The bicyclic nucleoside of claim 1 having Formula Ia, Ib, Ic or Id: 13. The bicyclic nucleoside of claim 1 wherein t1 is H. 14. The bicyclic nucleoside of claim 1 wherein t2 is H. 15. An oligomeric compound comprising at least one bicyclic nucleoside having 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 attaching the bicyclic nucleoside of Formula II to the oligomeric compound and the other of T3 and T4 is hydroxyl, a protected hydroxyl, a terminal group or an internucleoside linking group attaching the bicyclic nucleoside of Formula II to the oligomeric compound;Q is CH═CH, CE1E2-CE3E4, CH2OCH2, CH2SCH2 or CH2N(G)CH2;E1, E2, E3 and E4 are each, independently, H, hydroxyl, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substituted amino;G is H, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl or a protecting group;one of t1 and t2 is H and the other of t1 and t2 is absent;n is 0 or 1;q1 and q2 are each independently, H, hydroxyl, halogen or O-A-[(C═O)m—X]j—Z;A is C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;X is O,S or N(R1);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, N(R2)(R3) or a protecting group;R1, R2 and R3 are each, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl;m is 0 or 1;j is 0 or 1;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;when j is 1 then Z is other than halogen or N(R2)(R3);when n is 0 and Q is CH═CH or CE1E2-CE3E4 then at least one of E1 E2 E3, E4, q1 and q2 is other than H and when n is 1 and Q is CE1E2-CE3E4 then t1 is H; andwherein said oligomeric compound comprises from 8 to 40 monomeric subunits and at least some of the heterocyclic base moieties are capable of hybridizing to a nucleic acid molecule. 16. The oligomeric compound of claim 15 wherein each n is 1. 17. The oligomeric compound of claim 15 wherein each n is 0. 18. The oligomeric compound of claim 15 wherein each Q is CE1E2-CE3E4. 19. The oligomeric compound of claim 15 wherein at least one of E1, E2, E3 and E4 is C1-C6 alkyl or substituted C1-C6 alkyl for each bicyclic nucleoside of Formula II. 20. The oligomeric compound of claim 15 wherein E1, E2, E3 and E4 are each H for each bicyclic nucleoside of Formula II. 21. The oligomeric compound of claim 15 wherein Q is CH═CH, CH2OCH2, CH2SCH2 or CH2N(G)CH2 wherein G is H or CH3 for each bicyclic nucleoside of Formula II. 22. The oligomeric compound of claim 15 wherein q1 and q2 are each H for each bicyclic nucleoside of Formula II. 23. The oligomeric compound of claim 15 wherein one of q1 and q2 is H and the other of q1 and q2 is hydroxyl, protected hydroxyl, fluoro, or substituted or unsubstituted O—C1-C6 alkyl for each bicyclic nucleoside of Formula II. 24. The oligomeric compound of claim 15 wherein each Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 25. The oligomeric compound of claim 15 wherein each bicyclic nucleoside has Formula IIa, Formula IIb, Formula IIc or Formula IId: 26. The oligomeric compound of claim 15 wherein each t1 is H. 27. The oligomeric compound of claim 15 wherein each t2 is H. 28. The oligomeric compound of claim 15 comprising at least one region of from 2 to 5 contiguous bicyclic nucleosides of said formula. 29. The oligomeric compound of claim 15 comprising from about 12 to about 20 monomer subunits in length.
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이 특허에 인용된 특허 (132)
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