5′ modified nucleosides and oligomeric compounds prepared therefrom

1. A 5′ modified nucleoside having the formula:

wherein:

Bx is a heterocyclic base moiety;

M 1 is H, hydroxyl or OR 1 ;

M 2 is hydroxyl, OR 1 or N(R 1 )(R 2 );

each R 1 and R 2 is, independently, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;

r is 0 or 1;

q 5 and q 7 are each, independently, hydroxyl, protected hydroxyl, thiol, protected thiol, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, amino or substituted amino;

q 6 is O or S;

G is H, protected hydroxyl, halogen or O—[C(R 4 )(R 5 )] n —[(C═O) m —X] j —Z;

each R 4 and R 5 is, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;

X is O, S or N(E 1 );

Z is H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl or N(E 2 )(E 3 );

E 1 , E 2 and E 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;

n is from 1 to about 6;

m is 0 or 1;

j is 0 or 1;

each substituted group has 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 ), OC(=L)J 1 , C(=L)N(J 1 )(J 2 ), C(=L)O(J 1 ), C(=L)N(H)—(CH 2 ) 2 N(J 1 )(J 2 ), a heterocyclic radical, and an aryl group;

L is O, S or NJ 3 ;

each J 1 , J 2 and J 3 is, independently, H, C 1 -C 6 alkyl or a protecting group; and

when j is 1 then Z is other than halogen or N(E 2 )(E 3 ).

2. The 5′ modified nucleoside of claim 1 wherein Bx is uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl or guaninyl.

3. The 5′ modified nucleoside of claim 1 wherein q 5 and q 7 are each, independently, OCH 3 , OCH 2 CH 3 or OC(H)(CH 3 ) 2 and q 6 is O.

4. The 5′ modified nucleoside of claim 1 wherein r is 1, M 1 is H and M 2 is hydroxyl or r is 0, M 1 is O(CH 2 ) 2 CN and M 2 is N[CH(CH 3 ) 2 ] 2 .

5. The 5′ modified nucleoside of claim 4 wherein G is halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 6 )(R 7 ), O(CH 2 ) 2 —ON(R 6 )(R 7 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 6 )(R 7 ), OCH 2 C(═O)—N(R 6 )(R 7 ), OCH 2 C(═O)—N(R 5 )—(CH 2 ) 2 —N(R 6 )(R 7 ) or O(CH 2 ) 2 —N(R 8 )—C(═NR 9 )[N(R 6 )(R 7 )] wherein R 6 , R 7 , R 5 and R 9 are each, independently, H or C 1 -C 6 alkyl.

6. The 5′ modified nucleoside of claim 5 wherein G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 .

7. The 5′ modified nucleoside of claim 1 having the configuration of the formula below:

8. The 5′ modified nucleoside of claim 7 wherein:

r is 0;

M 1 is O(CH 2 ) 2 CN;

M 2 is N[CH(CH 3 ) 2 ] 2 ;

G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 ;

q 5 and q 7 are each, independently, OCH 3 , OCH 2 CH 3 or OC(H)(CH 3 ) 2 ; and

q 6 is O or S.

9. The 5′ modified nucleoside of claim 7 wherein:

r is 0;

M 1 is O(CH 2 ) 2 CN;

M 2 is N[CH(CH 3 ) 2 ] 2 ;

G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 ;

q5 and q7 are each OCH 2 CH 3 , and

q6 is O.

10. An oligomeric compound comprising a 5′ modified nucleoside having the formula below:

Bx is a heterocyclic base moiety;

T 2 is a phosphodiester or phosphorothioate internucleoside linking group linking the 5′ modified nucleoside to the remainder of the oligonucleotide;

q 5 and q 7 are each, independently, hydroxyl, protected hydroxyl, thiol, protected thiol, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, amino or substituted amino;

q 6 is O or S;

G is H, protected hydroxyl, halogen or O—[C(R 4 )(R 5 )] n —[(C═O) m —X] j —Z;

each R 4 and R 5 is, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;

X is O, S or N(E 1 );

Z is H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl or N(E 2 )(E 3 );

E 1 , E 2 and E 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;

n is from 1 to about 6;

m is 0 or 1;

j is 0 or 1;

each substituted group has 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 ), OC(=L)J 1 , C(=L)N(J 1 )(J 2 ), C(=L)O(J 1 ), C(=L)N(H)—(CH 2 ) 2 N(J 1 )(J 2 ), a heterocyclic radical, and an aryl group;

L is O, S or NJ 3 ;

each J 1 , J 2 and J 3 is, independently, H, C 1 -C 6 alkyl or a protecting group; and

when j is 1 then Z is other than halogen or N(E 2 )(E 3 ).

11. The oligomeric compound of claim 10 wherein Bx is uracilyl, thyminyl, cytosinyl, 5-methylcytosinyl, adeninyl or guaninyl.

12. The oligomeric compound of claim 10 wherein q 5 and q 7 are each, independently, OCH 3 , OCH 2 CH 3 or OC(H)(CH 3 ) 2 and q 6 is O.

13. The oligomeric compound of claim 10 , wherein G is halogen, OCH 3 , OCH 2 F, OCHF 2 , OCF 3 , OCH 2 CH 3 , O(CH 2 ) 2 F, OCH 2 CHF 2 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —SCH 3 , O(CH 2 ) 2 —OCF 3 , O(CH 2 ) 3 —N(R 6 )(R 7 ), O(CH 2 ) 2 —ON(R 6 )(R 7 ), O(CH 2 ) 2 —O(CH 2 ) 2 —N(R 6 )(R 7 ), OCH 2 C(═O)—N(R 6 )(R 7 ), OCH 2 C(═O)—N(R 5 )—(CH 2 ) 2 —N(R 6 )(R 7 ) or O(CH 2 ) 2 —N(R 8 )—C(═NR 9 )[N(R 6 )(R 7 )] wherein R 6 , R 7 , R 5 and R 9 are each, independently, H or C 1 -C 6 alkyl.

14. The oligomeric compound of claim 13 , wherein G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 .

15. The oligomeric compound of claim 10 , wherein the 5′-nucleoside has the configuration of the formula below:

16. The oligomeric compound of claim 15 , wherein:

G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 ;

q 5 and q 7 are each, independently, OCH 3 , OCH 2 CH 3 or OC(H)(CH 3 ) 2 ; and

q 6 is O or S.

17. The oligomeric compound of claim 15 wherein:

G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 ;

q 5 and q 7 are each OCH 2 CH 3 , and

q 6 is O.

18. A double stranded nucleic acid comprising:

a first oligonucleotide and a second oligonucleotide wherein the first oligonucleotide is complementary to the second oligonucleotide and each of said first and second oligonucleotides independently consist of 18 to 23 linked nucleosides; at least one of the first and second oligonucleotides comprises a 5′ modified nucleoside having the formula below:

wherein:

Bx is a heterocyclic base moiety;

q 5 and q 7 are each, independently, hydroxyl, protected hydroxyl, thiol, protected thiol, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy, substituted C 1 -C 6 alkoxy, amino or substituted amino;

q 6 is O or S;

G is H, protected hydroxyl, halogen or O—[C(R 4 )(R 5 )] n —[(C═O) m —X] j —Z;

each R 4 and R 5 is, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;

X is O, S or N(E 1 );

Z is H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl or N(E 2 )(E 3 );

E 1 , E 2 and E 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;

n is from 1 to about 6;

m is 0 or 1;

j is 0 or 1;

each substituted group has 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 ), OC(=L)J 1 , C(=L)N(J 1 )(J 2 ), C(=L)O(J 1 ), C(=L)N(H)—(CH 2 ) 2 N(J 1 )(J 2 ), a heterocyclic radical, and an aryl group;

L is O, S or NJ 3 ;

each J 1 , J 2 and J 3 is, independently, H, C 1 -C 6 alkyl or a protecting group; and

when j is 1 then Z is other than halogen or N(E 2 )(E 3 ).

19. The double-stranded nucleic acid of claim 18 , wherein:

G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 ;

q 5 and q 7 are each, independently, OCH 3 , OCH 2 CH 3 or OC(H)(CH 3 ) 2 ; and

q 6 is O or S.

20. The double-stranded nucleic acid of claim 18 , wherein:

G is F, OCH 3 , O(CH 2 ) 2 —OCH 3 , OCH 2 C(═O)—N(H)CH 3 or OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 ;

q 5 and q 7 are each OCH 2 CH 3 , and

q 6 is O.