8-Substituted cyclic nucleotides by free radical alkylation and acylation
First Claim
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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.
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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.
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Citations
17 Claims
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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.
- ##SPC4##
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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.
- ##SPC5##
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3. The compound 8-butyrylguanosine 3'"'"',5'"'"'-cyclic phosphate.
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4. The compound 8-benzoylguanosine 3'"'"',5'"'"'-cyclic phosphate.
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5. The compound 8-carbamoylguanosine 3'"'"',5'"'"'-cyclic phosphate.
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6. The compound 8-(1-hydroxyethyl)guanosine 3'"'"',5'"'"'-cyclic phosphate.
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7. The compound 8-(α
- -hydroxybenzyl)guanosine 3'"'"',5'"'"'-cyclic phosphate.
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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.
- ##SPC6##
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9. The compound 8-acetylinosine 3'"'"',5'"'"'-cyclic phosphate.
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10. The compound 8-Benzoylinosine 3'"'"',5'"'"'-cyclic phosphate.
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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. - View Dependent Claims (12, 13, 14, 15, 16)
- ##SPC7##
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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.
- ##SPC8##
Specification