Heavily fluorinated sugar analogs

Details Heavily fluorinated sugar analogs Heavily fluorinated sugar analogs

1999-09-02

2002-05-21

Wilson, James O. (Department: 1623)

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

C536S018400, C536S018500, C536S022100, C536S028530, C536S028540, C536S028550, C536S027140

Reexamination Certificate

active

06392032

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to heavily fluorinated sugar molecules, a method for the preparation thereof, and their use as antiviral and antineoplastic agents, glycosidase inhibitors, plant growth regulators and herbicides, and as intermediates for the preparation of heavily fluorinated oligo- and polysaccharides. The present invention also relates to a new starting material for the preparation of the heavily fluorinated sugar analogs of the present invention.
2. Description of the Prior Art
Nucleotides perform a large number of functions for living organisms. For example, nucleotides serve as the basic building blocks for RNA and DNA, store and transfer the essential chemical energy that propels metabolism, activate chemical bonds for enzymatic reactions, control glycolysis, regulate the process of cell to cell communication, and perform a large number of other essential tasks. Because they are crucial to such a wide variety of essential biochemical tasks, nature has designed exquisitely selective enzymes for this class of compounds.
Neoplastic or viral diseases, in contrast to bacterial diseases, have proved difficult to treat. While bacterial diseases have a number of biochemical processes that are distinct to the organism, viruses use the cellular machinery of the infected host cell, and there are relatively few virus specific processes that can be inhibited selectively. Similarly, tumor cells are mutated variants of normal cells and rely on many of the same biochemical pathways. Therefore, chemotherapies targeted for these diseases are often highly toxic due to the lack of selectivity of the compound for diseased cells. One characteristic that marks both virally infected cells and tumor cells is their propensity for rapid growth. Since growth involves synthesis of DNA and RNA, these cells require a greater flux of nucleotides in comparison to normal cells, and often the diseased cell contains enzymes which are less selective for nucleotides than their counterparts in normal cells. Therefore, nucleotide analogs may act as substrates for the disease state enzymes, while they are virtually ignored by normal enzymes. This is the rationale for design of therapeutic nucleotide or nucleoside analogs, such as IUDR, trifluorothymidine, AZT, Ara-A, ribavirin, acyclovir, ganciclovir, gemcitabine, MDL-101,731. Research on derivatives of nucleoside and nucleotide analogs continues to be intense. As the above examples show, modification on the base and sugar moieties is possible and in some case, desirable. Recently, there has been a great deal of interest in fluorinated derivatives in which fluorine is incorporated into the sugar nucleus. Gemcitabine (Eli Lilly) is now heading to market as an antiviral as well as a treatment for non small cell lung cancer. Pancreatic cancer studies are also underway. The fluorine substituents help stabilize the sugar against glycolysis and improve the oral bioavailability of the drug. MDL 101,731 is active against breast, prostate, and colon cancers. Although nucleoside analogs containing fluorine in the sugar nucleus are known in the art, such as gemcitabine and MDL-101,731, the prior art compounds only contain one or two fluorine substituents. See also U.S. Pat. No. 4,963,662 (Matthes et al.), U.S. Pat. No. 5,153,180 (Matthes et al.), and U.S. Pat. No. 4,762,823 (Watannabe et al.).
SUMMARY OF THE INVENTION
It is an object of the present invention to provide heavily fluorinated sugar analogs containing a tetrafluoroethylene unit (—CF
2
CF
2
—) in the sugar nucleus of ribose based nucleoside analogs and a hexafluorotrimethylene unit (—CF
2
CF
2
CF
2
—) in the sugar nucleus of hexose based nucleoside analogs.
Another object of the present invention is to provide a synthetic method for easily obtaining the heavily fluorinated sugar analogs which provides for a higher degree of fluorination than is obtainable in the prior art methods, and which does not require a fluorination step at or near the end of the synthesis.
Another object of the present invention is to provide a novel starting material for the production of heavily fluorinated sugars.
Yet another object of the present invention is to provide a method for the treatment of viral and neoplastic diseases by administering a pharmaceutically effective amount of the heavily fluorinated nucleoside analogs according to the present invention to a patient in need thereof.
A further object of the present invention is to provide for a method of inhibiting glycosidases by administering a pharmaceutically effective amount of the heavily fluorinated nucleoside analogs according to the present invention to a patient in need thereof, such as a patient with diabetes mellitus.


REFERENCES:
patent: 6013790 (2000-01-01), Dimagno

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