Modified prodrug forms of AP/AMP

Abstract

The present invention relates to compounds according to the structure: Where R is H or CH3; R2 is phosphate which can be free acid or salt; R3 is H, F, Cl, Br, I, OCH3, OCF3, CF3 or a C1-C3 alkyl group; R4 is H, F, Cl, Br, I, OCH3, OCF3 or CF3; and R5 and R6 are each independently H, F, Cl, Br, I, OCH3, OCF3 or CF3, with the proviso that when any two of R3, R4, R5 or R6 are other than H, the other two of R3, R4, R5 or R6 are H which may be used to treat neoplasia, including cancer.

Description

[0001] This application claims the benefit of priority from U.S. provisional application serial No. 60 / 240,529 of same title filed Oct. 13, 2000.[0002] The reductive conversion of ribonucleotides to deoxyribonucleotides by the enzyme Ribonucleotide Reductase (RR) is a crucial, rate-controlling step in the pathway leading to the biosynthesis of DNA. (Cory, J. G. In "Inhibitors of Ribonucleotide Diphosphate Reductase Activity", International Encyclopedia of Pharmacology and Therapeutics, Cory, J. G.; Cory, A. H, Eds.; Pergamon Press: New York, (1989); Section 128, pp 1-16). Since deoxyribonucleotides are present in extremely low levels in mammalian cells, an excellent correlation exists between tumor growth rate and specific activity of ribonucleotide reductase (Elford, et al., J. Biol. Chem. (1970), 245, 5228). Mammalian Ribonucleotide Reductase is composed of two dissimilar proteins, often referred to as R1, which binds the ribonucleotide substrate, and R2, which contains non-heme i...

AI Technical Summary

Benefits of technology

[0008] In another aspect of the invention, an object of the present invention is to provide methods of treating neoplasia utilizing compositions which exhibit favorable and enhanced characteristics of activity, pharmacokinetics, bioavailability and reduced toxicity.

[0057] While not being limited by way of theory, it is theorized that the rate-determining step in this prodrug activation process would appear to be the P--O bond cleavage step, which is catalyzed by alkaline phosphatase. The subsequent fragmentation step is usually rapid. It is possible that 3-AP prodrugs with longer half-lives in circulation, allowing them to act as a 3-AP depot; or prodrugs with a different distribution than that of the parent drug, may have desirable properties. One approach to this goal is to slow down the dephosphorylation step, the rate-limiting step in the bioactivation of 3-AP phosphate-bearing prodrugs by introducing bulky substituents at the position alpha to the phosphate group . These alkyl groups may impose steric hindrance by the close proximity to the P--O bond cleavage site, thereby slowing down the enzymatic dephosphorylation event. Another approach is to introduce electron-releasing or electron-withdrawing groups in the phenyl ring which may effect the rate of P--O bond cleavage. Similarly, the subsequent fragmentation step also may be effected by substitution at other positions with electron-releasing and electron-withdrawing groups.

Problems solved by technology

Despite the in vivo activity displayed by 3-AP, the therapeutic potential of this compound may be limited by its poor water-solubility.

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