Phosphoramidite nucleoside compounds

• US 4,668,777 A
• Filed: 08/06/1984
• Issued: 05/26/1987
• Est. Priority Date: 03/27/1981
• Status: Expired due to Term

• Current Assignee: University Patents, Inc.
• Original Assignee: University Patents, Inc.
• Inventors: Caruthers, Marvin H., Beaucage, Serge L.
• Primary Examiner(s): Brown, Johnnie R.
• Assistant Examiner(s): Peselev, Elli
• Application Number:
  US06/637,927
• Time in Patent Office: 1,023 Days
• Field of Search: 536/27, 536/28, 536/29
• US Class Current: 536/26.5
• 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

A new class of nucleoside phosphoramidites which are relatively stable to permit isolation thereof and storage at room temperature. The phosphoramidites are derivatives of saturated secondary amines.

Claims

1. A compound represented by one of the formulae:

##STR11## wherein B is a nucleoside or deoxynucleoside base;

A is H, OH or OR₄ in which R₄ is a blocking group;

R'"'"'₁ is a hydrocarbyl radical containing up to 10 carbon atoms;

X is NR'"'"'₂ R'"'"'₃ wherein R'"'"'₂ and R'"'"'₃ taken separately each represents alkyl, aryl, aralkyl, cycloalkyl and cycloakylalkyl containing up to 10 carbon atoms;

R'"'"'₂ and R'"'"'₃ when taken together form an alkylene chain containing up to 5 carbon atoms in the principal chain and a total of up to 10 carbon atoms with both terminal valence bonds of said chain being attached to the nitrogen atom to which R'"'"'₂ and R'"'"'₃ are attached; and

R'"'"'₂ and R'"'"'₃ when taken together with the nitrogen atom to which they are attached form a saturated nitrogen heterocycle including at least one additional heteroatom from the group consisting of nitrogen, oxygen and sulfur; and

R is a triarylmethyl blocking group selected from p-anisy-1-1-naphthylphenylmethyl, di-O-anisyl-1-naphthylmethyl, and p-tolyldiphenylmethyl.

23. A compound according to claim 1 wherein said triarylmethyl blocking group is p-anisyl-1-naphthylphenylmethyl.

24. A compound according to claim 1 wherein said triarylmethyl blocking group is di-O-anisyl-1-naphthylmethyl.

25. A compound according to claim 1 wherein said triarylmethyl blocking group is p-tolyldiphenylmethyl.

2. A compound selected from the group consisting of:

5'"'"'-O-di-p-Anisylphenylmethyl-N-isobutyryl-deoxyguanosine-3'"'"'-N,N-dimethylaminomethoxyphosphine;

5'"'"'-O-p-Anisyl-1-naphthylphenylmethyldeoxythymidine-3'"'"'-N,N-dimethylaminomethxyphosphine;

5'"'"'-O-di-o-Anisyl-1-napthylmethyl-N-benzoyldeoxcytidine-3'"'"'-N,N-dimethylaminomethyoxyphosphine,

5'"'"'-O-p-Tolydiphenylmethyl-N-benzoyldeoxyadenosine-3'"'"'-N,N-dimethylaminomethyoxyphosphine;

5-O-di-p-Anisylphenylmethyl-N-isobutyryldeoxyguanosine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'-O-p-Anisyl-1-naphthylphenylmethyldeoxythymidine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-benzoyldeoxycytidine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'-O-p-Tolydiphenylmethyl-N-benzoyldeoxyadenosine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'-O-di-p-Anisylphenylmethyl-N-acetyldeoxyguanosine-3'"'"'-N,N-dimethylaminomethoxyphosphine;

5'"'"'-O-di-p-Anisylphenylmethyl-N-benzoyldeoxyguanosine-3'"'"'-N,N-dimethylaminomethoxyphosphine;

5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-acetyldeoxycytidine-3'"'"'-N,N-dimethylaminomethoxyphosphine;

5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-isobutyryldeoxycytidine-3'"'"'-N,N-dimethylaminomethoxyphosphine;

5'"'"'-O-p-Tolydiphenylmethyl-N-acetyldeoxyadenosine-3'"'"'-N,N-dimethylaminomethoxyphosphine;

5'"'"'-O-p-Tolydiphenylmethyl-N-isobutyryladenosine-3'"'"'-N,N-dimethylaminomethoxyphosphine;

'"'"' -O-di-p-Anisylphenylmethyl-N-acetyldeoxyguansine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'-O-di-p-Anisylphenylmethyl-N-benzoyl-deoxyguanosine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-isobutyryldeoxycytidine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'-O-di-o-Anisyl-1-napthylmethyl-N-acetyldeoxycytidine-3'"'"'-N,N-morpholinomethoxyphosphine;

5'"'"'O-p-Tolydiphenylmethyl-N-acetyldeoxyadenosine-3'"'"'-N,N-morpholinomethoxyphosphine; and

5'"'"'-O-p-Tolydiphenylmethyl-N-isobutyryldeoxyadenosine-3'"'"'-N,N-morpholinomethoxyphosphine.

3. The compound according to claim 2 which is 5'"'"'-O-di-p-Anisylphenylmethyl-N-isobutyryl-deoxyguanosine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

4. The compound according to claim 2 which is 5'"'"'-O-p-Anisyl-1-naphthylphenylmethydeoxythymidine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

5. The compound according to claim 2 which is 5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-benzoyl-deoxcytidine-3'"'"'-N,N-dimethylaminomethyloxyphosphine.

6. The compound according to claim 2 which is 5'"'"'-O-p-Tolydiphenylmethyl-N-benzoyldenoxyadenosine-3'"'"'-N,N-dimethylaminemethoxyphosphine.

7. The compound according to claim 2 which is 5'"'"'-O-di-p-Anisylphenylmethyl-N-isobutyryldeoxyguanosine-3'"'"'-N,N-morpholinomethoxyphosphine.

8. The compound according to claim 2 which is 5'"'"'-O-p-Anisyl-1-naphthylphenylmethyldeoxythymidine-3'"'"'-N,N-morpholinomethoxyphosphine.

9. The compound according to claim 2 which is 5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-benzoyldeoxycytidine-3'"'"'-N,N-morpholinomethoxyphosphine.

10. The compound according to claim 2 which is 5'"'"'-O-p-Tolydiphenylmethyl-N-benzoyldeoxyadenosine-3'"'"'-N,N-morpholinomethoxyphosphine.

11. The compound according to claim 2 which is 5'"'"'-O-di-p-Anisylphenylmethyl-N-acetyldeoxyguanosine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

12. The compound according to claim 2 which is 5'"'"'-O-di-p-Anisylphenylmethyl-N-benzoyldeoxyguanosine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

13. The compound according to claim 2 which is 5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-acetyldeoxycytidine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

14. The compound according to claim 2 which is 5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-isobutyryldeoxycytidine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

15. The compound according to claim 2 which is 5'"'"'-O-p-Tolydiphenylmethyl-N-acetyldeoxyadenosine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

16. The compound according to claim 2 which is 5'"'"'-O-p-Tolydiphenylmethyl-N-isobutyryladenosine-3'"'"'-N,N-dimethylaminomethoxyphosphine.

17. The compound according to claim 2 which is 5'"'"'-O-di-p-Anisylphenylmethyl-N-acetyldeoxyguanosine-3'"'"'-N,N-morpholinomethoxyphosphine.

18. The compound according to claim 2 which is 5'"'"'-O-di-p-Anisylphenylmethyl-N-benzoyldeoxyguanosine-3'"'"'-N,N-morpholinomethoxyphosphine.

19. The compound according to claim 2 which is 5'"'"'-O-di-o-Anisyl-1-naphthylmethyl-N-isobutyryldeoxycytidine-3'"'"'-N,N-morpholinomethoxyphosphine.

20. The compound according to claim 2 which is 5'"'"'-O-di-o-Anisyl-1-napthylmethyl-N-acetyldeoxycytidine-3'"'"'-N,N-morpholinomethoxyphosphine.

21. The compound according to claim 2 which is 5'"'"'-O-p-Tolydiphenylmethyl-N-acetyldeoxyadenosine-3'"'"'-N,N-morpholinomethyphosphine.

22. The compound according to claim 2 which is 5'"'"'-O-p-Tolydiphenylmethyl-N-isobutyryldeoxyadenosine-3'"'"'-N,N-morpholinomethoxyphosphine.