Oligonucleotide analogs with sulfamate linkages

• US 5,470,967 A
• Filed: 04/10/1990
• Issued: 11/28/1995
• Est. Priority Date: 04/10/1990
• Status: Expired due to Term

• Current Assignee: Bristol-Myers Squibb Pharma Company (Bristol-Myers Squibb Company)
• Original Assignee: The Dupont Merck Pharmaceutical Company
• Inventors: Huie, Edward M., Trainor, George L.
• Primary Examiner(s): Robinson, Douglas W.
• Assistant Examiner(s): Kunz, Gary L.
• Application Number:
  US07/507,693
• Time in Patent Office: 2,058 Days
• Field of Search: 536/27, 536/28, 536/29, 536/23.1, 536/24.5, 536/22.1, 536/24.3
• US Class Current: 536/24.3
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: C07H 21/00 Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

Abstract

Oligonucleotides possessing at least one sulfamate or sulfamide internucleotides linkages. These compounds can be used as specific hybridization probes to detect complementary nucleic acid sequences.

Claims

1. A compound of the formula:

##STR14## wherein;

A is H, OH, OR₈, OQ or halogen;

B is a naturally occurring nucleic acid base or modified nucleic acid base;

Y is --N(R)-- or O;

Z is --N(R₇)-- or O;

wherein Y, OR₂, and A are independently bonded to the 2'"'"' or 3'"'"' position and provided further that A is bonded to a position different from that of Y or OR₂ ;

wherein each M is independently selected from ##STR15## provided at least one M is S(═

O)═

O; and

provided that when M is S(═

O)═

O, Y and Z cannot both be O;

n is 1 to 75;

R is H or alkyl of 1 to 6 carbon atoms;

R₁ is H₂ PO₃, H₃ P₂ O₅, H₄ P₃ O₇ and their suitable salts, H or an hydroxyl protecting group;

R₂ is H₂ PO₃, H₃ P₂ O₅, H₄ P₃ O₇ and their suitable salts, H or an hydroxyl protecting group;

R₃ is alkyl or cyanoethyl;

R₄ is H or alkyl of 1 to 6 carbon atoms;

R₅ is H or alkyl of 1 to 6 carbon atoms;

R₆ is H or alkyl of 1 to 6 carbon atoms;

R₇ is H or alkyl of 1 to 6 carbon atoms;

R₈ is alkyl of 1 to 6 carbon atoms;

R₉ is alkyl of 1 to 6 carbon atoms or cyanoethyl; and

Q is an hydroxyl protecting group;

provided that when each M is S(═

O)═

O, then at least one B group is not thymine.

2. The compound of claim 1 wherein when M is S(═

O)═

O, one of Y or Z is --N(R)-- or --N(R₇)-- and R or R₇ is H.

3. The compound of claim 1 wherein R is an alkyl of less than 5 carbon atoms.

4. The compound of claim 1 wherein R₃ is an alkyl of less than 5 carbon atoms.

5. The compound of claim 1 wherein R₄ is an alkyl of less than 5 carbon atoms.

6. The compound of claim 1 wherein R₅ is an alkyl of less than 5 carbon atoms.

7. The compound of claim 1 wherein R₆ is an alkyl of less than 5 carbon atoms.

8. The compound of claim 1 wherein R₇ is an alkyl of less than 5 carbon atoms.

9. The compound of claim 1 wherein R₈ is an alkyl of less than 5 carbon atoms.

10. The compound of claim 1 wherein R₉ is an alkyl of less than 5 carbon atoms.

11. The compound of claim 1 wherein the A substituent is in the 2'"'"'-position.

12. The compound of claim 1 wherein A is selected from the group consisting of H and OH.

13. The compound of claim 1 wherein B is adenine, guanine, cytosine, thymine or uracil.

14. The compound of claim 1 wherein M is S(═

O)═

O for the internucleotide linkage at the 3'"'"' terminus or 5'"'"' terminus, or both the 3'"'"' terminus and the 5'"'"' terminus of the compound.

15. The compound of claim 1 wherein M is S(═

O)═

O.

16. The compound of claim 1 wherein M is S(═

O)═

O or P(═

O)--OH.

17. The compound of claim 16 wherein Y or Z is --N(R)-- or --N(R₇)--, and R or R₇ is H.

18. A compound of the formula:

##STR16## wherein;

A is H, OH, OR₄, OQ, or halogen;

B is a naturally occurring nucleic acid base or modified nucleic acid base;

n is 1 to 75;

R₁ is alkyl of 1 to 6 carbon atoms;

R₂ is dialkylamino, morpholino, piperidino, or pyrrolidono;

R₃ is alkyl of 1 to 6 carbon atoms;

R₄ is alkyl of 1 to 6 carbon atoms;

Y is --N(R)-- or O;

Z is --N(R)-- or O;

wherein Y, OP(R₂)(OV), and A are independently bonded to the 2'"'"' or 3'"'"' position and provided further that A is bonded to a position different from that of Y or OP(R₂) (OV);

R is H or alkyl of 1 to 6 carbon atoms;

Q is an hydroxyl protecting group; and

V is an hydroxyl protecting group;

provided that at least one B group is not thymine.

19. The compound of claim 18 wherein V is cyanoethyl or methyl.

20. The compound of claim 18 wherein Q is selected from the group consisting of C₁ -C₅ trialkylsilyl, C₁ -C₅ alkyl, acyl, cyanoethyl or tetrahydropyran.

21. The compound of claim 18 wherein R is an alkyl of less than 5 carbon atoms.

22. The compound of claim 18 wherein R₁ is an alkyl of less than 5 carbon atoms.

23. The compound of claim 18 wherein R₃ is an alkyl of less than 5 carbon atoms.

24. The compound of claim 18 wherein R₄ is an alkyl or less than 5 carbon atoms.