Nucleoside analogs and uses in treating disease

Details Nucleoside analogs and uses in treating disease Nucleoside analogs and uses in treating disease

1998-12-23

2001-03-27

Wilson, James O. (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C536S023100, C536S025600, C536S026230, C536S026240, C536S026250, C536S026260, C536S115000, C536S116000, C536S117000, C536S118000, C536S120000

Reexamination Certificate

active

06207649

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of Invention
This invention relates to novel nucleosides and dinucleoside dimers and derivatives of these compounds, including, L-deoxyribofuranosyl nucleoside phosphodiester dimers in which the sugar moiety of at least one of the nucleosides has an L-configuration. These compounds are highly effective in the treatment of various diseases. They may be used to treat parasitic infections. They may also be used to treat bacterial, viral, and fungal infections, and may also be used to treat cancer.
2. Prior Art
Modified nucleoside analogs are an important class of antineoplastic and antiviral drugs. The present application discloses novel compounds for of this type for use in the treatment of parasitic infections. Due to the extraordinary morbidity and mortality associated with parasitic infections, related research has intensified during the past decade in a desperate search for effective treatments. A safe and effective vaccine still does not exist. Instead, victims must depend upon chemotherapy.
Furthermore, these modified nucleoside analogs may be used to treat bacterial infections, fungal infections, viral infections, and cancer.
These chemotherapeutic agents can be classified into two groups: those that act post-translationally, and those that act by interfering with nucleic acid synthesis.
Most drugs are in the first group, which means that they exert their therapeutic effect by interfering with a cell's protein synthesis, and hence its metabolism (rather than its nucleic acid synthesis). Examples of drugs in this group include: the antifolate compounds (which inhibit dihyrdofolate reductase), and sulfonamide drugs (which inhibit dihydropteroate synthetase. Yet these drugs have serious drawbacks. For example, the protozoan responsible for malaria very quickly develops resistance to these drugs. The reason is that, since resistance occurs through adaptive mutations in successive generations of the parasite, a one or two point mutation is often sufficient to confer resistance. Bacterial, viral, and fungal infections are frequently also susceptible to these types of resistance mutations.
The second group of compounds includes the nucleic acid intercalators such as acridines, phenanthrenes and quinolines. These intercalators partially mimic the biochemical activity of nucleic acids, and therefore are incorporated into a cell's nucleic acid (DNA and RNA), though once incorporated, do not allow further nucleic acid synthesis, hence their effectiveness. At the same time, these intercalators interfere with host nucleic acid synthesis as well, and thus give rise to toxic side effects. Because of the potential for toxic side effects, these drugs can quite often be given only in very small doses. Once again, a resistance pattern may develop. For example, some protozoans are known to develop “cross-resistance,” which means that the parasites develop resistance to other classes of drugs even though they were exposed on a different class of drug.
Indeed, all of the currently known drugs or drug candidates utilizing the delivery of cytotoxic pyrimidine or purine biosynthesis inhibitors to invading cells are extremely toxic. Therefore, while drugs of this type—i.e., those that interfere with nucleic acid synthesis-are effective, they lack selectivity. It is this latter parameter that must be maximized in the development of a safe and effective drug. In other words, such a drug would target host tissues that are infected, or cancerous, yet leave the host tissue unchanged.
Recent advances in our understanding of the biochemistry of parasite cells serves as a valuable example regarding the design of effective therapies. One investigator (H. Ginsburg, Biochem. Pharmacol. 48, 1847-1856 (1994)) observed that normal and parasite-infected erythrocytes exhibit significant differences with respect to purine and pyrimidine metabolism in single enzymes, as well as in whole branches of related pathways. The parasite satisfies all of its purine requirements through scavenger pathways; meanwhile, the host cell lacks the enzymes necessary to exploit this pathway, and so therefore must meet its pyrimidine requirements largely through de novo synthesis. Put another way, the parasite is more efficient than normal or host cells since it can synthesize the nucleic acid building blocks.
Other investigators (G. Beaton, D. Pellinqer, W. S. Marshall & M. H. Caruthers, In:
Oligonucleotides and Analogues: A Practical Approach
, F. Eckstein Ed., IRL Press, Oxford, 109-136 (1991)) have established that a malaria-infected erythrocyte is capable of effectively transporting the non-naturally occurring “L-nucleosides” (in contrast to the “D-nucleosides” which are the naturally occurring form) for use in nucleic acid synthesis. Yet, normal mammalian cells are nonpermeable to this class of compounds, which suggests that the L-nucleosides are non-toxic to normal mammalian or host cells. Thus, derivatives of these compounds may be used as highly selective drugs against parasite infection, or against any other type of cell or organism utilizing the L-nucleosides. The chemical modification of the L-nucleosides consists generally of modifying the nucleosides so that they are still recognized by the invading cell or organism's nucleic acid synthetic machinery, and therefore incorporated into a nucleic acid chain, but yet once this incorporation occurs, no further synthesis will take place.
Currently, there are no therapeutic compounds in use that are based on dimers of these nucleoside analogs. While dimers of the naturally occurring D-deoxyribofuranosyl nucleosides are well known, dimers in which one or both nucleosides are of the unnatural L-configuration are much less known, and their use in therapy of neoplastic and viral diseases is unknown.
In the synthesis of DNA-related oligomers, types of nucleoside dimers are synthesized as part of the overall process. These dimers usually include bases from naturally occurring DNA or RNA sequences. There is much known in the art about nucleoside monophosphate dimers. Many of these compounds have been synthesized and are available commercially.
However, these dimers are made from nucleosides containing a sugar moiety in D-configuration.
Reese, C. B., Tetrahedron 34 (1978) 3143 describes the synthesis of fully-protected dinucleoside monophosphates by means of the phosphotriester approach.
Littauer, U. Z., and Soreg, H. (1982) in
The Enzymes
, Vol. XV, Academic Press, NY, p. 517 is a standard reference which describes the enzymatic synthesis of dinucleotides.
Heikkilö, J., Stridh, S., Oberg, B. and Chattopodhyaya, J., Acta Chem. Scand. B 39 (1985) 657-669, provides an example of the methodology used in the synthesis of a variety of ApG nucleoside phosphate dimers. Included are references and methods for synthesis of 3′→5′ phosphates and 2′→5′ phosphates by solution phase chemistry.
Gait, M., “Oligonucleotide Synthesis”, IRL Press, Ltd., Oxford, England, 1984, is a general reference and a useful overview for oligonucleotide synthesis. The methods are applicable to synthesis of dimers, both by solution phase and solid phase methods. Both phosphitetriester and phosphotriester methods of coupling nucleosides are described. The solid phase method is useful for synthesizing dimers.
Gulyawa, V. and Holy, A., Coll. Czec. Chem. Commun 44 613 (1979), describe the enzymatic synthesis of a series of dimers by reaction of 2′,-3′ cyclic phosphate donors with ribonucleoside acceptors. The reaction was catalyzed by non-specific RNases. The donors are phosphorylated in the 5′-position, yielding the following compounds: donor nucleoside-(3′→5′) acceptor nucleoside. Dimers were made with acceptors, &bgr;-L-cytidine, &bgr;-L-adenosine, and 9(&agr;-L-lyxofuranosyl) adenine. Also, a large number of dimers with D-nucleosides in the acceptor 5′-position were made.
Holy, A., Sorm, F., Collect. Czech. Chem. Commun., 34, 3383 (1969), describe an enzymatic synthesis of &bgr;-D-guanylyl-(3

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