8-Substituted cyclic nucleotides by free radical alkylation and acylation

• US 3,968,101 A
• Filed: 12/20/1974
• Issued: 07/06/1976
• Est. Priority Date: 12/20/1974
• Status: Expired due to Term

• Current Assignee: Viratek, Inc. (Bausch Health Cos., Inc.)
• Original Assignee: ICN Pharmaceuticals, Inc (Bausch Health Cos., Inc.)
• Inventors: Robins, Roland K., Christensen, Leon F.
• Primary Examiner(s): Brown, Johnnie R.
• Application Number:
  US05/534,750
• Time in Patent Office: 564 Days
• Field of Search: 260/211.5 R
• US Class Current: 536/26.12
• CPC Class Codes: C07H 19/20 with the saccharide radical esterified by phosphoric or polyphosphoric acids

Abstract

Novel compounds of the general formula ##SPC1##

Wherein X is H or NH₂ ; R'"'"' is C₁ to C₈ alkyl, C₁ to C₈ substituted alkyl, benzyl, C₁ to C₈ acyl, benzoyl, carbamoyl, are disclosed as well as a novel free radial alkylation and acylation process for making such compounds. The compounds of the invention display activity comparable to or superior to their naturally occurring analogue while resisting phosphodiesterase degradation. In some cases the compounds of this invention actually inhibit enzymatic degradation of the natural analogue.

Claims

1. The compound of the structure:

##SPC4##

wherein X is H or NH₂ ; and

R'"'"' is iso-propyl;

neo-pentyl;

C₁ to C₈ substituted alkyl wherein the alkyl is substituted at the 1-alkyl position and the substituents are selected from the group consisting of hydroxyl, phenyl, semicarbazone, thiosemicarbazone, 4-phenyl semicarbazone, and phenyl hydrazone;

benzyl;

C₁ to C₈ acyl;

or carbamoyl.

2. The compound of the structure:

##SPC5##

wherein R'"'"' is iso-propyl;

neo-pentyl;

C₁ to C₈ substituted alkyl wherein the alkyl is substituted at the 1-alkyl position and the substituents are selected from the group consisting of hydroxyl, phenyl, semicarbazone, thiosemicarbazone, 4-phenyl semicarbazone, and phenyl hydrazone;

benzyl;

C₁ to C₈ acyl;

or carbamoyl.

3. The compound 8-butyrylguanosine 3'"'"',5'"'"'-cyclic phosphate.

4. The compound 8-benzoylguanosine 3'"'"',5'"'"'-cyclic phosphate.

5. The compound 8-carbamoylguanosine 3'"'"',5'"'"'-cyclic phosphate.

6. The compound 8-(1-hydroxyethyl)guanosine 3'"'"',5'"'"'-cyclic phosphate.

7. The compound 8-(α

-hydroxybenzyl)guanosine 3'"'"',5'"'"'-cyclic phosphate.

8. The compound of the structure:

##SPC6##

wherein R'"'"' is C₁ to C₈ alkyl;

C₁ to C₈ substituted alkyl wherein the alkyl is substituted at the 1-alkyl position and the substituents are selected from the group consisting of hydroxyl, phenyl, semicarbazone, thiosemicarbazone, 4-phenyl semicarbazone and phenyl hydrazone;

benzyl;

C₁ to C₈ acyl;

or carbamoyl.

9. The compound 8-acetylinosine 3'"'"',5'"'"'-cyclic phosphate.

10. The compound 8-Benzoylinosine 3'"'"',5'"'"'-cyclic phosphate.

11. A process of synthesizing 8-substituted 3'"'"',5'"'"'-cyclic phosphate nucleotides of the general formula:

##SPC7##

wherein X is H or NH₂ and R'"'"' is iso-propyl, neo-pentyl, benzyl, C₁ to C₈ acyl or carbamoyl comprising reacting the corresponding 8 unsubstituted nucleotide with a free radical corresponding to R'"'"' generated in situ from an alkyl peroxide, an aldehyde, formamide or toluene in the presence of Fe⁺⁺ and either a persulfate or alkyl peroxide free radical initiator with the proviso that when R'"'"' is generated from the alkyl peroxide the alkyl peroxide can serve as both the R'"'"' source and the free radical initiator.

12. The process of claim 11 wherein the iso-propyl and neo-pentyl free radicals are generated in situ with the nucleotide via reaction between Fe⁺⁺ and the corresponding alkyl peroxide.

13. The process of claim 12 wherein the alkyl peroxide is t-butyl peroxide or trimethylhydroperoxypentane.

14. The process of claim 11 wherein the benzyl free radical is generated in situ with the nucleotide via reaction between Fe⁺⁺, toluene and a free radical initiator.

15. The process of claim 11 wherein the C₁ to C₈ acyl free radical is generated in situ with the nucleotide via hydrogen abstraction of the carbonyl carbon of an aldehyde by a free radical source.

16. The process of claim 15 wherein the free radical source is generated via the reaction between Fe⁺⁺ and a free radical initiator selected from the group consisting of t-butyl peroxide and ammonium persulfate.

17. A process of synthesizing 8-(1-substituted)purine of the general formula:

##SPC8##

wherein X is H or NH₂ ;

Z is selected from the group consisting of 9-β

-D-ribofuranosyl, 9-β

-D-ribofuranosyl 3'"'"',5'"'"'-cyclic phosphate, and 9-β

-D-ribofuranosyl 5'"'"'-phosphate;

R is selected from the group consisting of C₁ to C₈ alkyl, phenyl, and benzyl; and

Y is selected from the group consisting of hydroxy, semicarbazone, thiosemicarbazome, 4-phenyl semicarbazone, and phenyl hydrazone comprising reacting a compound of the structure;

##SPC9##

wherein X, Z, and R are the same as above with NaBH₄, hydrazine, semicarbazide, thiosemicarbazide, 4-phenyl semicarbazide, or phenyl hydrazine.