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

0039] In the pharmaceutical aspect according to the present invention, the compound according to the present invention is formulated preferably in admixture with a pharmaceutically acceptable carrier. In general, it is preferable to administer the pharmaceutical composition parenterally and in particular, in intravenously or intramuscular dosage form, but a number of formulations may be administered via other parenteral routes, such as transdermal, buccal, subcutaneous, suppository or other route, including via an oral route of administration. Intravenous and intramuscular formulations are preferably administered in sterile saline. Of course, one of ordinary skill in the art may modify the formulations within the teachings of the specification to provide numerous formulations for a particular route of administration without rendering the compositions of the present invention unstable or compromising their therapeutic activity. In particular, the modification of the present compounds to render them more soluble in water or other vehicle, for example, may be easily accomplished by minor modifications (such as salt formulation, etc.) which are well within the ordinary skill in the art. It is also well within the routineer's skill to modify the route of administration and dosage regimen of a particular compound in order to manage the pharmacokinetics of the present compounds for maximum beneficial effect to the patient.

0040] The routineer will take advantage of favorable pharmacokinetic parameters of the pro-drug forms of the present invention, where applicable, in delivering the present compounds to a targeted site within the host organism or patient to maximize the intended effect of the compound.

0041] The amount of compound included within therapeutically active formulations according to the present invention is an effective amount for treating the infection or condition. In its most preferred embodiment, the present compounds, and in particular, compounds where R.sub.4 is Cl or R.sub.5 is F, Cl, OCH.sub.3 or OCF.sub.3 and the remaining substituents on the benzene ring (other than the phosphate and urethane moiety) are H, preferably are used for treating neoplasia, and in particular, cancer, including, in certain instances, drug resistant cancers. In general, a therapeutically effective amount of the present preferred compound in dosage form usually ranges from slightly less than about 0.025 mg. / kg. to about 2.5 g. / kg., preferably about 2.5-5 mg / kg to about 100 mg / kg of the patient or considerably more, even more preferably about 20-50 mg / kg, more preferably about 25 mg / kg, depending upon the compound used, the condition or infection treated and the route of administration, although exceptions to this dosage range may be contemplated by the present invention. In the case of the preferred compositions according to the present invention as described above where R.sub.4 is Cl or R.sub.5 is F, Cl, OCH.sub.3 or OCF.sub.3 and the remaining substituents on the benzene (other than the phosphate and urethane moiety) are H, because the compounds exhibit enhanced anti-cancer activity, combined with reduced overall toxicity non-cancerous host cells and the bioavailability of the compounds is also high, these compounds may be administered at levels 3-10 fold higher than triapine 1A with significantly less toxicity. At these doses, the AUC (area under the curve) of triapine delivered from the prodrug form is about 5 to 25 times greater than that achieveable by the administration of triapine in non-prodrug form. The compounds according to the present invention, therefore, represent an unexpected result and are exceptional agents for the treatment of neoplasia, especially cancer. The dosage range chosen for these agents as set forth above is effective to generally produce effective blood level concentrations of active compound, which may range from less than about 0.04 to about 400 micrograms / cc or more of blood in the patient. The more favorable bioavailablility characteristics, coupled with the reduced toxicity and greater activity of the present compounds on a molar basis compared to the prior art Triapine.TM., evidences the present compounds as unexpectedly favorable compounds for use in the treatment of neoplasia, including cancer.

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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