Bicyclic morpholino compounds and oligomeric compounds prepared therefrom

Patent metadata

Field	Value
Publication number	US-2016186175-A1
Application number	US-201514983907-A
Country	US
Kind code	A1
Filing date	Dec 30, 2015
Priority date	Dec 30, 2014
Publication date	Jun 30, 2016
Grant date	—

Abstract

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.

First claim

What is claimed is:

1 . A compound having Formula Ia:

wherein:
Bx is a heterocyclic base moiety;
one of T 1 and T 2 is a reactive phosphorus group and the other of T 1 and T 2 is a protecting group;
R 1 and R 2 are each, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
two of E 1 , E 2 , E 3 , E 4 , E 5 and E 6 form a bridge between two carbon atoms comprising from 1 to 3 linked biradical groups selected from O, S, NR 3 , C(R 4 )(R 5 ), C═O, C(R 4 )═C(R 5 ) and C[═C(R 4 )(R 5 )];
each R 3 , R 4 and R 5 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, amino, substituted amino, thiol or substituted thiol;
the other four of E 1 , E 2 , E 3 , E 4 , E 5 and E 6 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , N(J 1 )(J 2 ), =NJ 1 , SJ 1 , N 3 , CN, OC(=L)J 1 , OC(=L)N(J 1 )(J 2 ) and C(=L)N(J 1 )(J 2 );
L is O, S or NJ 3 ; and
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 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 E 1 forms a bridge with one of E 4 and E 5 .

4 . The compound of claim 1 wherein one of E 2 and E 3 forms a bridge with one of E 4 and E 5 .

5 . The compound of claim 1 wherein said bridge is C(R 4 )(R 5 ), C═O, C(R 4 )(R 5 )C(R 4 )(R 5 ), C(R 4 )(R 5 )C(R 4 )(R 5 )C(R 4 )(R 5 ), C(R 4 )(R 5 )C[═C(R 4 )(R 5 )], C(R 4 )(R 5 )C(R 4 )(R 5 )C[═C(R 4 )(R 5 )], C(R 4 )(R 5 )OC(R 4 )(R 5 ) or C(R 4 )(R 5 )N(R 3 )C(R 4 )(R 5 ) wherein R 3 is H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy and each R 4 and R 5 is, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.

6 . The compound of claim 1 wherein said bridge is CH 2 , CHNH 2 , C(H)(N(H)CH 3 ), C(H)—(N(CH 3 ) 2 ), C═O, (CH 2 ) 2 , (CH 2 ) 3 , CH 2 C(═CH 2 ), CH 2 CH 2 C(═CH 2 ) or CH 2 OCH 2 .

7 . The compound of claim 1 wherein each of E 1 , E 2 , E 3 , E 4 , E 5 and E 6 not forming said bridge is H.

8 . The compound of claim 1 wherein one of R 1 and R 2 is H and the other of R 1 and R 2 is CH 3 .

9 . The compound of claim 1 wherein R 1 and R 2 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 T 3 and T 4 is a an internucleoside linking group linking the compound of Formula IIa to the oligomeric compound and the other of T 3 and T 4 is H, a protecting group, a terminal group, a phosphorus moiety or an internucleoside linking group;
R 1 and R 2 are each, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
two of E 1 , E 2 , E 3 , E 4 , E 5 and E 6 form a bridge between two carbon atoms comprising from 1 to 3 linked biradical groups selected from O, S, NR 3 , C(R 4 )(R 5 ), C═O, C(R 4 )═C(R 5 ) and C[═C(R 4 )(R 5 )];
each R 3 , R 4 and R 5 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, amino, substituted amino, thiol or substituted thiol;
the other four of E 1 , E 2 , E 3 , E 4 , E 5 and E 6 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or substituted C 2 -C 6 alkynyl;
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 1 , N(J 1 )(J 2 ), =NJ 1 , SJ 1 , N 3 , CN, OC(=L)J 1 , OC(=L)N(J 1 )(J 2 ) and C(=L)N(J 1 )(J 2 );
L is O, S or NJ 3 ;
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl; and
wherein 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 E 1 forms a bridge with E 4 or for each compound of Formula IIa E 1 forms a bridge with E 5 .

13 . The oligomeric compound of claim 10 wherein for each compound of Formula IIa one of E 2 and E 3 forms a bridge with one of E 4 and E 5 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(R 4 )(R 5 ), C═O, C(R 4 )(R 5 )C—(R 4 )(R 5 ), C(R 4 )(R 5 )C(R 4 )(R 5 )C(R 4 )(R 5 ), C(R 4 )(R 5 )C[═C(R 4 )(R 5 )], C(R 4 )(R 5 )C(R 4 )(R 5 )C[═C(R 4 )—(R 5 )], C(R 4 )(R 5 )OC(R 4 )(R 5 ) or C(R 4 )(R 5 )N(R 3 )C(R 4 )(R 5 ) wherein R 3 is H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy and each R 4 and R 5 is, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl for each compound of Formula IIa.

15 . The oligomeric compound of claim 10 wherein said bridge is CH 2 , CHNH 2 , C(H)—(N(H)CH 3 ), C(H)(N(CH 3 ) 2 ), C═O, (CH 2 ) 2 , (CH 2 ) 3 , CH 2 C(═CH 2 ), CH 2 CH 2 C(═CH 2 ) or CH 2 OCH 2 for each compound of Formula IIa.

16 . The oligomeric compound of claim 10 wherein each of E 1 , E 2 , E 3 , E 4 , E 5 and E 6 not forming said bridge is H for each compound of Formula IIa.

17 . The oligomeric compound of claim 10 wherein one of R 1 and R 2 is H and the other of R 1 and R 2 is C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy for each compound of Formula IIa.

18 . The oligomeric compound of claim 10 wherein R 1 and R 2 are each H for each compound of Formula IIa.

19 . The oligomeric compound of claim 10 wherein one T 3 and or one T 4 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 and wherein said composition optionally comprises one or more terminal groups.

Assignees

• Ionis Pharmaceuticals Inc

Inventors

• Seth Punit P
• Swayze Eric E

Classifications

• C07H21/00

  Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids · CPC title

• C07F9/6561 Primary

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• C12N2310/141

  MicroRNAs, miRNAs · CPC title

• C12N15/113 Primary

  Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)} · CPC title

• C12N2310/3233

  Morpholino-type ring · CPC title