5′ and 2′ BIS-substituted nucleosides and oligomeric compounds prepared therefrom
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A01N-043/04
A61K-031/70
A61K-048/00
C07H-021/00
A61K-031/00
출원번호
US-0125557
(2009-10-23)
등록번호
US-8883752
(2014-11-11)
국제출원번호
PCT/US2009/061913
(2009-10-23)
§371/§102 date
20110712
(20110712)
국제공개번호
WO2010/048549
(2010-04-29)
발명자
/ 주소
Swayze, Eric E.
Prakash, Thazha P.
출원인 / 주소
Isis Pharmaceuticals, Inc.
대리인 / 주소
Casimir Jones, S.C.
인용정보
피인용 횟수 :
5인용 특허 :
128
초록▼
The present invention provides modified nucleosides and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides having at least one 5′-substituent and a 2′-O-substituent, oligomeric compounds comprising at least one of these modified nucleoside
The present invention provides modified nucleosides and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides having at least one 5′-substituent and a 2′-O-substituent, oligomeric compounds comprising at least one of these modified nucleosides and methods of using the oligomeric compounds. In some embodiments, the oligomeric compounds provided herein are expected to hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
대표청구항▼
1. An oligomeric compound comprising one monomer of Formula IV: wherein: Bx is a heterocyclic base moiety;T7 is a phosphorus moiety having the formula: wherein: Ra and Rc are each, independently, OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substitu
1. An oligomeric compound comprising one monomer of Formula IV: wherein: Bx is a heterocyclic base moiety;T7 is a phosphorus moiety having the formula: wherein: Ra and Rc are each, independently, OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substituted amino; andRb is O or S;T8 is an internucleoside linking group linking the monomer of Formula IV to the oligomeric compound;Q1, Q2, Q3 and Q4 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;G1 is O—[C(R2)(R3)]n—[(C═O)m—X]j—Z or halogen;each R2 and R3 is, independently, H or halogen;X is O, S or N(E1);Z is H, 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;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=L)J1, OC(=L)N(J1)(J2) and C(=L)N(J1)(J2);L is O, S or NJ3;each J1, J2 and J3 is, independently, H or C1-C6 alkyl;provided that when j is 1 then Z is other than N(E2)(E3);provided that when Q1, Q2, Q3 and Q4 are each H then G1 is other than H or OH; andwherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is complementary to at least a portion of a nucleic acid target. 2. The oligomeric compound of claim 1 wherein Bx is uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl, or guaninyl. 3. The oligomeric compound of claim 1 wherein G1 is 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(R4)(R5), O(CH2)2—ON(R4)(R5), O(CH2)2—O(CH2)2—N(R4)(R5), OCH2C(═O)—N(R4)(R5), OCH2C(═O)—N(R6)—(CH2)2—N(R4)(R5) or O(CH2)2—N(R6)—C(═NR7)[N(R4)(R5)] wherein R4, R5, R6 and R7 are each, independently, H or C1-C6 alkyl. 4. The oligomeric compound of claim 1 wherein G1 is F, OCH3, O(CH2)2—OCH3, OCH2C(═O)—N(H)CH3 or OCH2C(═O)—N(H)—(CH2)2—N(CH3)2. 5. The oligomeric compound of claim 1 wherein Q1, Q2, Q3 and Q4 are each H. 6. The oligomeric compound of claim 1 wherein one of Q1, Q2, Q3 and Q4 is F or C1-C6 alkyl and the other three of Q1, Q2, Q3 and Q4 are each H. 7. The oligomeric compound of claim 1 wherein two of Q1, Q2, Q3 and Q4 are F. 8. The oligomeric compound of claim 7 wherein Q3 and Q4 are each F and Q1 and Q2 are each H. 9. The oligomeric compound of claim 1 wherein Q1 is CH3 and Q2, Q3 and Q4 are each H or Q2 is CH3 and Q1, Q3 and Q4 are each H. 10. The oligomeric compound of claim 1 wherein each monomer of Formula IV has the configuration: 11. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group. 12. The oligomeric compound of claim 1 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group. 13. A double stranded composition comprising: a first oligomeric compound and a second oligomeric compound wherein the first oligomeric compound is complementary to the second oligomeric compound and the second oligomeric compound is complementary to a nucleic acid target;at least one of the first and second oligomeric compounds is an oligomeric compound according to claim 1; andwherein said composition optionally comprises one or more 5′ or 3′ terminal groups. 14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an oligomeric compound comprising one monomer of Formula IV: wherein: Bx is a heterocyclic base moiety;T7 is a phosphorus moiety having the formula: wherein: Ra and Rc are each, independently, OH, SH, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, amino or substituted amino; andRb is O or S;T8 is an internucleoside linking group linking the monomer of Formula IV to the oligomeric compound;Q1, Q2, Q3 and Q4 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;G1 is O—[C(R2)(R3)]n—[(C═O)m—X]j—Z or halogen;each R2 and R3 is, independently, H or halogen;X is O, S or N(E1);Z is H, 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;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), =NJ1, SJ1, N3, CN, OC(=L)J1, OC(=L)N(J1)(J2) and C(=L)N(J1)(J2);L is O, S or NJ3;each J1, J2 and J3 is, independently, H or C1-C6 alkyl;provided that when j is 1 then Z is other than N(E2)(E3);provided that when Q1, Q2, Q3 and Q4 are each H then G1 is other than H or OH; andwherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is complementary to at least a portion of a nucleic acid target. 15. The pharmaceutical composition of claim 14 wherein Bx is uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl, or guaninyl. 16. The pharmaceutical composition of claim 14 wherein G1 is 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(R4)(R5), O(CH2)2—ON(R4)(R5), O(CH2)2—O(CH2)2—N(R4)(R5), OCH2C(═O)—N(R4)(R5), OCH2C(═O)—N(R6)—(CH2)2—N(R4)(R5) or O(CH2)2—N(R6)—C(═NR7)[N(R4)(R5)] wherein R4, R5, R6 and R7 are each, independently, H or C1-C6 alkyl. 17. The pharmaceutical composition of claim 14 wherein G1 is F, OCH3, O(CH2)2—OCH3, OCH2C(═O)—N(H)CH3 or OCH2C(═O)—N(H)—(CH2)2—N(CH3)2. 18. The pharmaceutical composition of claim 14 wherein: a) Q1, Q2, Q3 and Q4 are each H, b) wherein one of Q1, Q2, Q3 and Q4 is F or C1-C6 alkyl and the other three of Q1, Q2, Q3 and Q4 are each H, or c) wherein two of Q1, Q2, Q3 and Q4 are F. 19. The pharmaceutical composition of claim 14 wherein Q3 and Q4 are each F and Q1 and Q2 are each H. 20. The pharmaceutical composition of claim 14 wherein Q1 is CH3 and Q2, Q3 and Q4 are each H or Q2 is CH3 and Q1, Q3 and Q4 are each H. 21. The pharmaceutical composition of claim 14 wherein each monomer of Formula IV has the configuration: 22. The pharmaceutical composition of claim 14 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphoro-thioate internucleoside linking group. 23. The pharmaceutical composition of claim 14 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group.
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이 특허에 인용된 특허 (128)
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