6-Substituted purine nucleotides

• US 3,915,958 A
• Filed: 05/22/1972
• Issued: 10/28/1975
• Est. Priority Date: 05/22/1972
• Status: Expired due to Term

• Current Assignee: Viratek, Inc. (Bausch Health Cos., Inc.)
• Original Assignee: Dennis A. Shuman, Rich B. Meyer
• Inventors: Shuman, Dennis A., Meyer, Rich B.
• Primary Examiner(s): Brown, Johnnie R.
• Application Number:
  US05/255,804
• Time in Patent Office: 1,254 Days
• Field of Search: 260/211.5R
• US Class Current: 536/26.13
• CPC Class Codes: C07H 19/052 Imidazole radicals
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

A process of synthesizing 6-substituted purine nucleotides is disclosed, as are certain such compounds produced during synthesis which have exhibited the ability to inhibit the enzyme phosphodiesterase, to activate adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphatedependent protein kinase, and, in one instance, antiviral activity and high cytotoxicity for KB and HeLa Carcinomas. As is apparent from the description which follows, such compounds also serve as intermediates in the described synthesis process.

Claims

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE STRUCTURE:

2. The compound of claim 1 in which X is N, Y is C-NH-OR2, and R is OH.

3. The compound of claim 2 in wHich R2 is H.

4. The compound of claim 2 in which R2 is CH3.

5. The compound of claim 2 in which R2 is C2H5.

6. 6-Hydroxylamino-9- Beta -D-ribofuranosylpurine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate.

7. 6-Methoxyamino-9- Beta -D-ribofuranosylpurine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate.

8. 6-Ethoxyamino-9- Beta -D-ribofuranosylpurine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate.

9. A process of synthesizing 6-substituted purine nucleotides comprising alkylating the N1 oxide function of adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate 1-N-oxide with a compound selected from the group consisting of C1 to C8 alkyl or C7 to C10 aralkyl to provide the corresponding O-alkylated adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate 1-N-oxide, subjecting said O-alkylated adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate 1-N-oxide to base catalyzed rearrangement at pH greater than 7 to afford N6-alkoxy adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate, and reacting said N6 -alkoxy compound with hydrogen sulfide causing it to undergo nucleophillic displacement to yeild the corresponding 6-thione substituted compound.

10. A process of synthesizing 6-substituted purine nucleotides comprising subjecting adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate-1-N-oxide to base catalyzed rearrangement at pH greater than 7 to afford 6-hydroxylamino-9- Beta -D-ribofuranoxylpurine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate, and thereafter causing said 6-hydroxylamino derivative to undergo nucleophillic displacement by reacting itt with hydrogen sulfide to yield the corresponding 6-thione substituted compound.

11. The process of claim 9 in which said 6-thione substituted compound is thereafter alkylated to afford 6-alkylthio-9- Beta -D-ribofuranosylpurine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate, wherein the alkyl group is from C1 to C6.

12. The process of claim 9 in which said base catalyzed rearrangement is carried out in a refluxing solution having a pH of between about 7.0 and 9.0.

13. The process of claim 10 in which said base catalyzed rearrangement is carried out in a solution having a pH of at least 10.

14. The process of claim 9 in which said nucleophillic displacement is carried out in a closed container in the presence of an aqueous solution of pyridine containing a molar excess of hydrogen sulfide with respect to said pyridine.

15. A process of synthesizing 6-substituted purine nucleotides comprising alkylating adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate 1-N-oxide with a compound selected from the group consisting of C1 to C8 alkyl or C7 to C10 aralkyl to provide the corresponding O-alkylated adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate 1-N-oxide, subjecting said O-alkylated adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate 1-N-oxide to a refluxing solution having a pH of between about 7.0 and 9.0 at a temperature between 0* and 100*C to cause base catalyzed rearrangement and to afford N6-alkoxy adenosine 3'"'"''"'"',5'"'"''"'"'-cyclic phosphate, and reacting said N6-alkoxy compound in a closed container in the presence of an aqueous solution of pyridine containing a molar excess of hydrogen sulfide with respect to said pyridine to cause said N6 -alkoxy compound to undergo nucleophillic displacement to yield the corresponding 6-thione substituted compound.