Enzyme inhibitors, their synthesis, and methods for use

Details Enzyme inhibitors, their synthesis, and methods for use Enzyme inhibitors, their synthesis, and methods for use

1997-12-01

2002-04-02

Ford, John M. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S270000, C544S302000, C544S314000

Reissue Patent

active

RE037623

ABSTRACT:

BACKGROUND OF THE INVENTION
The 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 regime for treating various malignancies, or for treating viral, fungal, bacterial or parasitic infections.
Until recently, most studies of pyrimidine analog metabolism have focused on anabolism, with little attention devoted to catabolism. Pyrimidine bases and nucleoside analogs can be anabolized within a patient's body to the nucleoside 5′-monophosphate, or catabolized to &bgr;-amino acids. The catabolism of nucleosides to bases proceeds by nucleoside phosphonilases. The resulting bases are then convened to their respective &bgr;-amino acids by a chain of three reactions, catalyzed by DHUDase, dihydropyrimidinase and &bgr;-ureidopropionase. Wastemack, Pharmac. Ther., 8:629-651 (1981); Naguib, et al, Cancer Res., 45:5405-5412 (1985). Cytidine, cytosine and their analogs must be deaminated before they can be catabolized.
The importance of DHUDase as a target Ibr chemotherapy has been established by several recent studies. For example, patients receiving continuous infusion of 5-fluorouracil (5-FUra) at a constant rate were found to have plasma concentrations of 5-FUra that varied significantly during treatment. This variation followed a circadian rhythm which was the inverse of that observed for DHUDase activity. Harris et al, Biochem. Pharmac., 37: 759-4762 (1988); Harris et al, Cancer Res., 49:6610-6614 (1989); Petit E., et al Cancer Res., 48:1676-1679 (1988); Naguib et al, Biochem. Pharmac., 45: 667-673. (1993). That is, high plasma concentration of 5-FUra was associated with low DHUDase activity and vice versa. A significant correlation between the circadian rhythm of DHUDase activity and that of the anticancer efficacy of 5-FUra and 5-fluoro-2′-deoxyuridine (5-FdUrd) has also been reported. Petit et al. Cancer Res., 48:1676-1679 (1988); von Roemeling et al, Advances in Chronobiology, Part B, 357-373 (1987). Thus it is clear that a strong association exists between the level of DHUDase activity and the bioavailability and efficacy of fluoropyrimidines for chemotherapy.
The importance of DHUDase in cancer chemotherapy is further emphasized by studies with inhibitors of DHUDase, where the inhibitors were found to increase the concentration and half life of 5-FUra in plasma and to dramatically enhance the chemotherapeutic efficacy of 5-FUra in vitro and in vivo. 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. Cooper et al, Cancer Res., 32:390-397 (1972); Gentry et al, Cancer Res., 31:909-912 (1971). It was also believed that DHUDase inhibition would mimic the genetic deficiency of this enzyme which is known to be accompanied by neurological disorders. Bakkeren et al, Clinica Chimica Acta, 140:246-247 (1984); Tuchman et al N. Engl. J. Med, 313:245-249 (1985); Diasio et al, J. Clin. Invest., 81:47-51 (1988); Wadman et al, Adv. Exp. Med. Biol., 165A: 109-114 (1984). Finally, it was generally believed that tumors lack or possess very little DHUDase activity. Chaudhury et al, Cancer Res., 18:318-328 (1958); Heidelberger et al, Cancer, Res., 30:1549-1569 (1970); Mukherjee et al, Biol. Chem., 235:433-437 (1960).
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.
UrdPase inhibitors are also known to possess a number of clinically useful attributes. For example, UrdPase Inhibitors have been proposed to increase the selectivity and efficacy of various uracil and uridine derivatives in cancer chemotherapy. U.S. Pat. No. 5,077,280 (Sommadossi et al) discloses that UrdPase inhibitors can be used as rescue agents to reduce the toxicity of antiviral agents such as 3′-azido-3′-deoxythymidine (AZT), Ideal UrdPase inhibitors are those that are potent, specific, and non toxic. Moreover, useful UrdPase inhibitors should be readily soluble in aqueous solutions buffered within the physiological pH range.
As noted above halogenated pyrimidine bases such as 5-FUra and halogenated pyrimidine nucleosides such as 5-FdUrd have been used as chemotherapeutic agents in cancer 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-&bgr;-alanine) are believed to be more toxic to a patient's healthy cells.
Halogenated pyrimidine nucleosides, for example, are known to share the same catabolic pathway as uridine. Because there is little functional thymidine phosphorylase in many tumor cells, the first step in the catabolic pathway in tumor cells relies primarily on UrdPase. The inhibition of this enzyme in tumor cells serves to inhibit the catabolism of the chemotherapeutic agents in tumor tissue, thereby increasing their effectiveness. In healthy host tissue, the halogenated pyrimidine nucleosides can still be catabolized to their pyrimidine counterparts by the action of thymidine phosphorylase.
Similarly, halogenated pyrimidine bases such as 5-FUra can compete with cellular pyrimidines and their nucleotides for incorporation into RNA and DNA. However, UrdPase inhibitors increase the plasma and uridine concentration (Monks et al, Biochem. Pharmac., 32, 2003-2009) (1983); Darnowski et al, Cancer Res., 45:5364-5368 (1985)) and the availability of uridine for salvage of host healthy tissue. The increase in plasma uridine concentration also increases the pool of uracil nucleosides in tissue. The increased intracellular uridine concentration can thus reduce the toxicity of halogenated compounds in host tissue. Moreover, it has been shown that the addition of a phosphorylase inhibitor selectively increases the ability of host tissue to salvage uridine. Darnowski et al, Cancer Res., 45:5364-5368 (1985). This tissue specific enhancement of uridine utilization is of particular importance for chemotherapy regimes using 5-fluorouracil.
Another application of UrdPase inhibitors lies in their use in the protection against host toxicity of various antiviral agents. For example, viral therapies for patients infected with the human immunodeficiency virus (HIV) and/or those suffering from Acquired Immune Deficiency Syndrome (AIDS) have typically involved the administration of an antiviral pyrimidine nucleoside such as AZT. Such an antiviral agent functions by inhibiting the reverse transcriptase enzyme of the HIV to reduce the cytopathic effects of the virus.
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. Cretton et al, Molec., Pharmac., 39:258-266 (1991). 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 t

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