Modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-019/00
C07H-021/02
C07H-019/10
C07H-019/067
C07H-019/167
C07H-019/20
C07H-021/00
C12N-015/113
출원번호
US-0627960
(2015-02-20)
등록번호
US-9321799
(2016-04-26)
발명자
/ 주소
Prakash, Thazha P.
Seth, Punit P.
Swayze, Eric E.
출원인 / 주소
Ionis Pharmaceuticals, Inc.
대리인 / 주소
McNeill Baur PLLC
인용정보
피인용 횟수 :
2인용 특허 :
130
초록▼
The present invention provides modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides and analogs thereof that are useful for incorporation at the terminus of an oligomeric compound. Such oligomeric co
The present invention provides modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom. More particularly, the present invention provides modified nucleosides and analogs thereof that are useful for incorporation at the terminus of an oligomeric compound. Such oligomeric compounds can also be included in a double stranded composition. 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. A compound having Formula If: wherein: T1 is a phosphorus moiety having the formula: Ra and Rc are each, independently, protected hydroxyl, protected thiol, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, protected amino or substituted amino;Rb is O or S;M1 is H, OH
1. A compound having Formula If: wherein: T1 is a phosphorus moiety having the formula: Ra and Rc are each, independently, protected hydroxyl, protected thiol, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, protected amino or substituted amino;Rb is O or S;M1 is H, OH or OR1;M2 is OH, OR1 or N(R1)(R2);each R1 and R2 is, independently, C1-C6 alkyl or substituted C1-C6 alkyl;r is 0 or 1;A has one of the formulas: Q1 and Q2 are each, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;Q3 is O, S, N(R5) or C(R6)(R7); each R5, R6 and R7 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl or C1-C6 alkoxy; Bx1 is a heterocyclic base moiety;G is H, OH, halogen or O—[C(R8)(R9)n]—[(C═O)m—X1]j—Z;each R8 and R9 is, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;X1 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;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, CN, OC(═X2)J1, OC(═X2)N(J1)(J2) and C(═X2)N(J1)(J2);X2 is O, S or NJ3;each J1, J2 and J3 is, independently, H or C1-C6 alkyl; andwhen j is 1 then Z is other than halogen or N(E2)(E3). 2. The compound of claim 1 wherein Q3 is C(R6)(R7). 3. The compound of claim 2 wherein R6 and R7 are each, independently, H or C1-C6 alkyl. 4. The compound of claim 2 wherein R6 and R7 are each H. 5. The compound of claim 1 wherein Q3 is O, S or N(R5) wherein R5 is H or C1-C6 alkyl. 6. The compound of claim 1 wherein Q1 and Q2 are each, independently, H or C1-C6 alkyl. 7. The compound of claim 1 wherein Q1 and Q2 are each H. 8. The compound of claim 1 wherein G is 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(R10)(R11), O(CH2)2—ON(R10)(R11), O(CH2)2—O(CH2)2—N(R10)(R11), OCH2C(═O)—N(R10)(R11), OCH2C(═O)—N(R12)—(CH2)2—N(R10)(R11) or O(CH2)2—N(R12)—C(═NR13)[N(R10)(R11)] wherein R10, R11, R12 and R13 are each, independently, H or C1-C6 alkyl. 9. The compound of claim 1 wherein said heterocyclic base moiety is a pyrimidine, substituted pyrimidine, purine or substituted purine. 10. The compound of claim 9 wherein said heterocyclic base moiety is an optionally protected uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 11. An oligomeric compound comprising a 5′-terminal compound having Formula IIf: wherein: T1 is an optionally protected phosphorus moiety having the formula: 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;Rb is O or S;T2 is an internucleoside linking group linking the compound of Formula IIc to the remainder of the oligomeric compound;A has one of the formulas: Q1 and Q2 are each, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;Q3 is O, S, N(R5) or C(R6)(R7);each R5, R6 and R7 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl or C1-C6 alkoxy;Bx1 is a heterocyclic base moiety;G is H, OH, halogen or O—[C(R8)(R9)]n—[(C═O)m—X1]j—Z;each R8 and R9 is, independently, H, halogen, C1-C6 alkyl or substituted C1-C6 alkyl;X1 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;each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ1, N(J1)(J2), ═NJ1, SJ1, N3, CN, OC(═X2)J1, OC(═X2)N(J1)(J2) and C(═X2)N(J1)(J2);X2 is O, S or NJ3;each J1, J2 and J3 is, independently, H or C1-C6 alkyl;when j is 1 then Z is other than halogen or N(E2)(E3); andwherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is hybridizable to at least a portion of a target nucleic acid. 12. The oligomeric compound of claim 11 wherein Q3 is C(R6)(R7). 13. The oligomeric compound of claim 12 wherein R6 and R7 are each, independently, H or C1-C6 alkyl. 14. The oligomeric compound of claim 12 wherein R6 and R7 are each H. 15. The oligomeric compound of claim 11 wherein Q3 is O, S or N(R5) wherein R5 is H or C1-C6 alkyl. 16. The oligomeric compound of claim 11 wherein Q1 and Q2 are each, independently, H or C1-C6 alkyl. 17. The oligomeric compound of claim 11 wherein Q1 and Q2 are each H. 18. The oligomeric compound of claim 11 wherein Rb is O and Ra and Rc are each, independently, OCH3, OCH2CH3 or OCH(CH3)2. 19. The oligomeric compound of claim 11 wherein Rb is O and Ra and Rc are each OH or OCH3. 20. The oligomeric compound of claim 11 wherein G is 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(R10)(R11), O(CH2)2—ON(R10)(R11), O(CH2)2—O(CH2)2—N(R10)(R11), OCH2C(═O)—N(R10)(R11), OCH2C(═O)—N(R12)—(CH2)2—N(R10)(R11) or O(CH2)2—N(R12)—C(═NR13)[N(R10)(R11)] wherein R10, R11, R12 and R13 are each, independently, H or C1-C6 alkyl. 21. The oligomeric compound of claim 11 said heterocyclic base moiety is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine. 22. The oligomeric compound of claim 11 wherein said 5′-terminal compound has one of the formulas: wherein: Bx1 is uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine;T2 is a phosphorothioate internucleoside linking group linking said 5′-terminal compound having one of said formulas to the remainder of the oligomeric compound; andG is halogen, OCH3, OCF3, OCH2CH3, OCH2CF3, OCH2—CH═CH2, O(CH2)2—OCH3, O(CH2)2—O(CH2)2—N(CH3)2, OCH2C(═O)—N(H)CH3, OCH2C(═O)—N(H)—(CH2)2—N(CH3)2 or OCH2—N(H)—C(═NH)NH2. 23. The oligomeric compound of claim 11 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group. 24. 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 11; andwherein said composition optionally comprises one or more 5′ and or 3′ terminal groups.
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