Modified nucleosides, analogs thereof and oligomeric compounds prepared therefrom

Patent metadata

Field	Value
Publication number	US-8993738-B2
Application number	US-201113642827-A
Country	US
Kind code	B2
Filing date	Apr 26, 2011
Priority date	Apr 28, 2010
Publication date	Mar 31, 2015
Grant date	Mar 31, 2015

Abstract

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.

First claim

What is claimed is:

1. A compound having Formula Ic:

wherein:
T 1 is phosphorus moiety having the formula:

R a and R c are each, independently, protected hydroxyl, protected thiol, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, substituted C 1 -C 6 alkoxy, protected amino or substituted amino;
R b is O or S;
M 1 is H, OH or OR 1 ;
M 2 is OH, 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;
A has one of the formulas:

Q 1 and Q 2 are each, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
M 3 is O;
Bx 1 is a heterocyclic base moiety;
J 4 , J 5 , J 6 and J 7 are each, independently, H;
G is H, OH, halogen or O-[C(R 8 )(R 9 )] n -[(C═O) m -X 1 ] j -Z;
each R 8 and R 9 is, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
X 1 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 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(═X 2 )J 1 , OC(═X 2 ) -N(J 1 )(J 2 )and C(═X 2 )N(J 1 )(J 2 );
X 2 is O, S or NJ 3 ;
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl; and
when j is 1 then Z is other than halogen or N(E 2 )(E 3 ).

2. The compound of claim 1 wherein A has the formula:

wherein:
Q1 and Q2 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy.

3. The compound of claim 2 wherein Q 1 and Q 2 are each H.

4. The compound of claim 1 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 10 )(R 11 ), O(CH 2 ) 2 -ON(R 10 )(R 11 ), O(CH 2 ) 2 -O(CH 2 ) 2 -N(R 10 )(R 11 ), OCH 2 C(═O)-N(R 10 )(R 11 ), OCH 2 C(═O)-N(R 12 )-(CH 2 ) 2 -N(R 10 )(R 11 ) or O(CH 2 ) 2 -N(R 12 )-C(═NR 13 )[N(R 10 )(R 11 )] wherein R 10 , R 11 , R 12 and R 13 are each, independently, H or C 1 -C 6 alkyl.

5. The compound of claim 4 wherein said heterocyclic base moiety is a pyrimidine, substituted pyrimidine, purine or substituted purine.

6. The compound of claim 5 wherein said heterocyclic base moiety is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.

7. An oligomeric compound comprising a 5′-terminal compound having Formula IIc:

wherein:
T 1 is an optionally protected phosphorus moiety having the formula:

R a and R c are each, independently, OH, SH, 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;
R b is O or S;
T 2 is an internucleoside linking group linking the compound of Formula IIc to the oligomeric compound;
A has one of the formulas:

Q 1 and Q 2 are each, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
M 3 is O;
Bx 1 is a heterocyclic base moiety;
J 4 , J 5 , J 6 and J 7 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;
G is H, OH, halogen or O-[C(R 8 )(R 9 )] n -[(C═O) m -X 1 ] j -Z;
each R 8 and R 9 is, independently, H, halogen, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
X 1 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 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(═X 2 )J 1 , OC(═X 2 ) -N(J 1 )(J 2 ) and C(═X 2 )N(J 1 )(J 2 );
X 2 is O, S or NJ 3 ;
each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl;
when j is 1 then Z is other than halogen or N(E 2 )(E 3 ); and
wherein said oligomeric compound comprises from 8 to 40 monomeric subunits and is hybridizable to at least a portion of a target nucleic acid.

8. The oligomeric compound of claim 7 wherein A has the formula:

wherein:
Q 1 and Q2 are each, independently, H, halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 1 -C 6 alkoxy or substituted C 1 -C 6 alkoxy.

9. The oligomeric compound of claim 8 wherein Q 1 and Q 2 are each H.

10. The oligomeric compound of claim 7 wherein R b is O and R a and R c are each, independently, OCH 3 , OCH 2 CH 3 or OCH(CH 3 ) 2 .

11. The oligomeric compound of claim 7 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 10 )(R 11 ), O(CH 2 ) 2 -ON(R 10 )(R 11 ), O(CH 2 ) 2 -O(CH 2 ) 2 -N(R 10 )(R 11 ), OCH 2 C(═O)-N(R 10 )(R 11 ), OCH 2 C(═O)-N(R 12 )-(CH 2 ) 2 -N(R 10 )(R 11 ) or O(CH 2 ) 2 -N(R 12 )-C(═NR 13 )[N(R 10 )(R 11 )] wherein R 10 , R 11 , R 12 and R 13 are each, independently, H or C 1 -C 6 alkyl.

12. The oligomeric compound of claim 7 wherein said heterocyclic base moiety is a pyrimidine, substituted pyrimidine, purine or substituted purine.

13. The oligomeric compound of claim 12 wherein said heterocyclic base moiety is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.

14. The oligomeric compound of claim 7 wherein said 5′-terminal compound has Formula IIe:

wherein:
Bx 1 is uracil, thymine, cytosine, 5-methyl cytosine, adenine or guanine;
T 2 is a phosphorothioate internucleoside linking group linking the compound of Formula IIe to the oligomeric compound; and
G is halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 -CH═CH

Assignees

• Prakash Thazha P
• Seth Punit P
• Swayze Eric E
• Isis Pharmaceuticals Inc

Inventors

• Prakash Thazha P
• Seth Punit P
• Swayze Eric E

Classifications

• C12N2310/322

  2'-R Modification · CPC title

• C07H21/00 Primary

  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

• A61P31/12

  Antivirals · CPC title

• C12N2310/315

  Phosphorothioates · CPC title

• A61K31/712

  Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose · CPC title