Enzyme inhibitors, their synthesis, and methods for use

Abstract

Novel compounds are provided that are effective to inhibit the activity of DHUDase or UrdPase. Such compounds have the general formulawhere X is S or Se; Y is <INS-S DATE="20020402" ID="INS-S-00001" / >H, <INS-E ID="INS-S-00001" / >I, F, Cl, Br, methoxy, benzyl, selenenylphenyl, or thiophenyl, and R1 is <INS-S DATE="20020402" ID="INS-S-00002" / >H or <INS-E ID="INS-S-00002" / >an acyclo tail having the general formulawhere R2 is H, CH2 OH or CH2 NH2; R3 is OH, NH2, or OCOCH2CH2CO2H; and R4 is O, S, or CH2.The compounds can be used in pharmaceutical compositions, along with various chemotherapeutic agents to increase the efficacy of the treatment. These compounds can also be used in methods of treating patients by coadministering or sequentially administering the enzyme inhibiting compounds with a chemotherapeutic agent effective to treat cancers, or viral, fungal, bacterial, or parasitic infections. The compounds have further utility in enhancing imaging. Further, they can be administered alone to prevent and / or treat disorders of pyrimidine catabolism and other physiological disorders.

Description

BACKGROUND OF THE INVENTIONThe invention relates to novel enzyme inhibiting compounds, their synthesis, and their use in treating pathological and physiological conditions.Pyrimidine analogs and pyrimidine nucleosides are widely used as chemotherapeutic agents for cancer and for viral, fungal, bacterial and parasitic infections. Most pyrimidine analogs used in cancer chemotherapy must be convened to the nucleoside 5'-monophosphate level before any anticancer activity can be realized. However, all most all are administered as nucleosides or bases to facilitate transport into cells. The administered compounds are subject to catabolism and inactivation by various enzymes within a patient's body. Pyrimidines, for example, are degraded by the enzymes uridine phosphorylase (UrdPase) and dihydrouracil dehydrogenase (DHUDase). As a result, the balance between the anabolic (activation) and catabolic (inactivation) pathways must be considered when designing or choosing a chemotherapeutic regi...

AI Technical Summary

Benefits of technology

In another embodiment the invention comprises a method for administering chemotherapeutic agents while protecting and / or rescuing normal or uninfected cells from any toxicity that may result from the administration of the chemotherapeutic agent. Further, methods are provided for improving the efficacy of the chemotherapeutic agent. The methods of the invention comprise administering the chemotherapeutic agent, and coadministering or sequentially administering a DHUDase or UrdPase inhibiting compound of the type disclosed herein. The inhibition of the activity of DHUDase or UrdPase prevents or slows the degradation of the chemotherapeutic agent by these enzymes. This prevents or slows the degradation of the chemotherapeutic agent also results in lower levels of potentially toxic catabolites of the chemotherapeutic agent. These methods thus facilitate a higher concentration and / or a longer half-life of the chemotherapeutic agent, thus increasing the efficacy of the treatment regime. An additional benefit is that any toxic side effects of the chemotherapeutic regime are minimized.

The use of enzyme inhibiting compounds of the present invention are also effective to provide increased plasma levels of natural pyrimidines, such as uridine, which can help to protect and / or rescue healthy cells from toxicity induced by chemotherapeutic agents. The administration of these compounds to increase plasma levels of natural pyrimidines can also be effective to treat pathological and physiological disorders that respond to the administration of such pyrimidines. Such disorders responsive to these treatments include CNS disorders, Parkinson's disease, Alzheimer's disease, senile dimentia, sleep disorders, muscle dysfunction, long disorders, diabetes, cardiac insufficiency and myocardial infarction, liver disease and liver damage.

Problems solved by technology

Nevertheless, coadministration of known inhibitors of DHUDase with 5-FUra has not been popular due to several drawbacks associated with such previously known inhibitors.

Although the known inhibits enhanced the antitumor activity of 5-FUra, they also served as alternate substrates and caused substantial host-toxicity.

Thus, despite the potential promise of DHUDase inhibitors for chemotherapy regimes, currently known inhibitors have demonstrated several drawbacks that have discouraged their use in such treatments.

Because these compounds are subject to rapid degradation, efficacy of the compound is reduced.

Also, the catabolites of these chemotherapeutic agents (e.g., 2-fluoro-.beta.-alanine) are believed to be more toxic to a patient's healthy cells.

The utility of antiviral pyrimidine nucleosides such as AZT has been limited by the toxic effects of AZT or its catabolites such as 3' -amino-3'-deoxythymidine (AMT) on uninfected cells.

Prolonged administration of such compounds produces severe side effects including the suppression of bone marrow growth and severe anemia.

The dosage and duration of AZT therapies is limited because of such complications.

This rescuing effect of uridine, although generally beneficial, has disadvantages because of the body's rapid uridine catabolism.

Consequently, high doses are required, and high doses of uridine can cause serious toxic side effects, including phlebitis and pyrogenic reactions.

Substituted acyclouridines are good inhibitors of UrdPase, but tend to have limited water solubility and are difficult and expensive to synthesize.

Unfortunately, some acyclouridines, such as benzyl acyclouridine and its derivatives, are soluble only to about 1 mM in water at room temperature.

Administration of a physiologically useful dose would require dilution of these compounds into excessively large volumes.

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