Bicyclic morpholino compounds and oligomeric compounds prepared therefrom
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07F-009/6561
C07H-021/00
출원번호
US-0983907
(2015-12-30)
등록번호
US-9688707
(2017-06-27)
발명자
/ 주소
Seth, Punit P.
Swayze, Eric E.
출원인 / 주소
Ionis Pharmaceuticals, Inc.
대리인 / 주소
Ionis Pharmaceuticals, Inc. Patent Dept.
인용정보
피인용 횟수 :
0인용 특허 :
134
초록▼
The present invention provides bicyclic morpholino compounds and oligomeric compounds prepared therefrom. More particularly, incorporation of one or more of the bicyclic morpholino compounds into an oligomeric compound is expected to enhance one or more properties of the oligomeric compound. Such ol
The present invention provides bicyclic morpholino compounds and oligomeric compounds prepared therefrom. More particularly, incorporation of one or more of the bicyclic morpholino compounds into an oligomeric compound is expected to enhance one or more properties of the oligomeric compound. Such oligomeric compounds can also be included in a double stranded composition. In certain 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 Ia: wherein: Bx is a heterocyclic base moiety;T1 is a protecting group;T2 is a reactive phosphorus group;R1 and R2 are each, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 a
1. A compound having Formula Ia: wherein: Bx is a heterocyclic base moiety;T1 is a protecting group;T2 is a reactive phosphorus group;R1 and R2 are each, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;one of E1, E2 and E3, and one of E4 and E5 form a bridge comprising from 1 to 3 linked biradical groups selected from O, S, NR3, C(R4)(R5), C═O, C(R4)═C(R5) and C[═C(R4)(R5)];each R3, R4 and R5 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, amino, substituted amino, thiol or substituted thiol;the other four of E1, E2, E3, E4, E5 and E6 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;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; andeach J1, J2 and J3 is, independently, H or C1-C6 alkyl. 2. The compound of claim 1 wherein Bx is a pyrimidine, substituted pyrimidine, purine or substituted purine. 3. The compound of claim 1 wherein E1 forms a bridge with one of E4 and E5. 4. The compound of claim 1 wherein one of E2 and E3 forms a bridge with one of E4 and E5. 5. The compound of claim 1 wherein said bridge is C(R4)(R5), C═O, C(R4)(R5)C—(R4)(R5), C(R4)(R5)C(R4)(R5)C(R4)(R5), C(R4)(R5)C[═C(R4)(R5)], C(R4)(R5)C(R4)(R5)C[═C(R4)—(R5)], C(R4)(R5)OC(R4)(R5) or C(R4)(R5)N(R3)C(R4)(R5) wherein R3 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy or substituted C1-C6 alkoxy and each R4 and R5 is, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl. 6. The compound of claim 1 wherein said bridge is CH2, CHNH2, C(H)—(N(H)CH3), C(H)(N(CH3)2), C═O, (CH2)2, (CH2)3, CH2C(═CH2), CH2CH2C(═CH2) or CH2OCH2. 7. The compound of claim 1 wherein each of E1, E2, E3, E4, E5 and E6 not forming said bridge is H. 8. The compound of claim 1 wherein one of R1 and R2 is H and the other of R1 and R2 is CH3. 9. The compound of claim 1 wherein R1 and R2 are each H. 10. An oligomeric compound comprising at least one compound of Formula IIa: wherein independently for each compound of Formula IIa: Bx is a heterocyclic base moiety;one of T3 and T4 is a an internucleoside linking group linking the compound of Formula IIa to the oligomeric compound and the other of T3 and T4 is H, a protecting group, a terminal group, a phosphorus moiety or an internucleoside linking group;R1 and R2 are each, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;one of E1, E2 and E3, and one of E4 and E5 form a bridge comprising from 1 to 3 linked biradical groups selected from O, S, NR3, C(R4)(R5), C═O, C(R4)═C(R5) and C[═C(R4)(R5)];each R3, R4 and R5 is, independently, H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl, substituted C2-C6 alkynyl, amino, substituted amino, thiol or substituted thiol;the other four of E1, E2, E3, E4, E5 and E6 are each, independently, H, halogen, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy, substituted C1-C6 alkoxy, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C6 alkynyl or substituted C2-C6 alkynyl;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; andwherein said oligomeric compound comprises from 8 to about 40 monomeric subunits and is capable of hybridizing to a nucleic acid target. 11. The oligomeric compound of claim 10 wherein each Bx is, independently, a pyrimidine, substituted pyrimidine, purine or substituted purine. 12. The oligomeric compound of claim 10 wherein for each compound of Formula IIa E1 forms a bridge with E4 or for each compound of Formula IIa E1 forms a bridge with E5. 13. The oligomeric compound of claim 10 wherein for each compound of Formula IIa one of E2 and E3 forms a bridge with one of E4 and E5 and wherein said bridge has the same configuration for each compound of Formula IIa. 14. The oligomeric compound of claim 10 wherein said bridge is C(R4)(R5), C═O, C(R4)(R5)C(R4)(R5), C(R4)(R5)C(R4)(R5)C(R4)(R5), C(R4)(R5)C[═C(R4)(R5)], C(R4)(R5)C(R4)—(R5)C[═C(R4)(R5)], C(R4)(R5)OC(R4)(R5) or C(R4)(R5)N(R3)C(R4)(R5) wherein R3 is H, C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy or substituted C1-C6 alkoxy and each R4 and R5 is, independently, H, C1-C6 alkyl or substituted C1-C6 alkyl for each compound of Formula IIa. 15. The oligomeric compound of claim 10 wherein said bridge is CH2, CHNH2, C(H)(N(H)CH3), C(H)(N(CH3)2), C═O, (CH2)2, (CH2)3, CH2C(═CH2), CH2CH2C(═CH2) or CH2OCH2 for each compound of Formula IIa. 16. The oligomeric compound of claim 10 wherein each of E1, E2, E3, E4, E5 and E6 not forming said bridge is H for each compound of Formula IIa. 17. The oligomeric compound of claim 10 wherein one of R1 and R2 is H and the other of R1 and R2 is C1-C6 alkyl, substituted C1-C6 alkyl, C1-C6 alkoxy or substituted C1-C6 alkoxy for each compound of Formula IIa. 18. The oligomeric compound of claim 10 wherein R1 and R2 are each H for each compound of Formula IIa. 19. The oligomeric compound of claim 10 wherein one T3 and or one T4 is a terminal group. 20. 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 10 andwherein said composition optionally comprises one or more terminal groups.
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이 특허에 인용된 특허 (134)
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