Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1999-08-20
2001-10-16
Geist, Gary (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C536S026260, C536S026700, C536S026800
Reexamination Certificate
active
06303774
ABSTRACT:
TECHNICAL FIELD
The present invention provides novel compounds that are useful as therapeutic agents, e.g., as antiviral agents, anticancer agents and metabolic moderators. The invention additionally relates to pharmaceutical compositions containing a compound of the invention as the active agent and to methods of using the novel compounds as therapeutic agents. The invention has application in the fields of biochemistry and medicinal chemistry and particularly provides nucleoside pyrophosphate and triphosphate analogs and related compounds for use in the treatment of disease.
BACKGROUND
Nucleotides are some of the most ubiquitous compounds in nature, one example of which is the adenosine triphosphate (“ATP”) molecule shown below:
The four principal ribonucleotide triphosphates may be polymerized to provide “RNA,” or “ribonucleic acid.” In addition to its role in all normal cells, RNA represents the genetic material of one major class of pathogenic viruses known as the RNA viruses, examples of which are HIV and herpes viruses. When the sugar moiety is deoxyribose, the four principal deoxyribonucleotide triphosphates are polymerized into deoxyribonucleic acid strands, or “DNA,” the genetic material of all plants and animals. There is also another class of pathogenic viruses known as DNA viruses, examples of which include measles and mumps.
Much of the cell's chemistry with regard to these various nucleotide compounds involves the addition, removal or transfer of one or more of the phosphates groups within the triphosphate moiety, as illustrated by the equilibrium transphosphorylation reaction wherein a phosphate group is transferred between uridine diphosphate (“UDP”) and ATP to give uridine triphosphate (“UIp”) and adenosine diphosphate (“ADP”):
The body triphosphorylates and dephosphorylates drug and metabolic intermediates at extremely high rates, resulting in a constant low level of triphosphorylated materials that are then used in cellular processes. Phosphates, pyrophosphates and triphosphates of antiviral drugs, nucleosides, inositol, isoprenoids, and other biochemical building blocks are critical intermediates in the biosynthesis of nucleosides, proteins and hormones.
In spite of the presence of phosphorylated compounds throughout the body, such compounds are elusive as pharmacological candidates due to the hydrolytic lability of the pyrophosphate and triphosphate groups and their short half-lives in the bloodstream. Thus, there is a need in the art for functionally equivalent compounds, i.e., compounds that are isosterically and electronically identical to the natural pyrophosphates and triphosphates, but that are hydrolytically and enzymatically more stable, and preferably have reduced toxicity as well.
The present invention is addressed to the aforementioned need in the art, and provides an unprecedented class of nucleoside-based therapeutic agents containing a functional group that is isosterically and electronically identical to a natural pyrophosphate or triphosphate group, wherein the agents are hydrolytically and enzymatically more stable than the “natural” pyrophosphate and triphosphate compounds. The therapeutic agents now provided are useful in a variety of contexts, e.g., as antiviral agents, anticancer agents, metabolic moderators, and the like. The novel compounds are also useful as starting materials or intermediates in the synthesis of other nucleoside-based therapeutic agents, as research tools for studying nucleoside triphosphates and pyrophosphates (the naturally occurring compounds hydrolyze readily, resulting in inconvenience in the laboratory), and in the sequential preparation of oligonucleotides and polynucleotides of interest.
SUMMARY OF THE INVENTION
In one aspect of the invention, novel compounds are provided having the structure of formula (I)
wherein:
x and y are integers in the range of 1 to 3 inclusive;
R
1
is a purine or pyrimidine base bound to a cyclic or acyclic sugar moiety, and may represent a single nucleoside or a nucleoside monomer contained within an oligonucleotide chain, wherein R
1
is bound through either its 3′ or 5′ position;
R
2
is selected from the group consisting of N
−
—ClO
3
, N
−
—NO
2
and N
−
—SO
2
R
3
wherein R
3
is lower alkyl, halogenated lower alkyl, halo or amino;
X is
—X
1
—X
2
— or —X
3
═N—;
X
1
and Y are independently selected from the group consisting of
wherein Z
1
is selected from the group consisting of O, S, C(CN)
2
, NClO
3
, N—NO
2
, N—SO
3
and N—SO
2
R
3
, and Z
2
is selected from the group consisting of O
−
, S
−
, lower alkyl, halogenated lower alkyl, halo, BH
3
−
, N
−
—ClO
3
, N
−
—NO
2
and N
−
—SO
2
R
3
, with the proviso that when R
2
is N
−
—ClO
3
, then Y is other than
X
2
is selected from the group consisting of O, S and N
−
;
X
3
is
wherein Z
3
and Z
4
are independently selected from the group consisting of O
−
, S
−
, lower alkyl, halogenated lower alkyl, halo, BH
3
−
, N
−
ClO
3
, N
−
—NO
2
and N
−
—SO
2
R
3
;
n is 0, 1 or 2, wherein when n is 2, the two X moieties may be the same or different; and
Cat is a cationic species.
In a related aspect of the invention, novel nucleoside based compounds are provided having the structure of formula (II)
wherein R
1
, x, y and Cat are as defined above with respect to formula (I), the X moieties may be the same or different and are as defined above with respect to formula (I), q is an optional double bond, Y
1
is P═Z
1
, As═Z
1
, S═O or Se═O, and Y
2
is N, N
−
, O or S, and further wherein (a) when y
1
is S═O or Se═O, then q is a double bond and Y
2
is N, and (b) when Y
1
is P═Z
1
or As═Z
1
, then q is absent and Y
2
is N
−
, O or S. Depending on the definition of each “X” moiety, structures of formula (II) may be represented by any of the following subgeneric formulae (IIa) through (IId)
in which X
1
, X
2
, X
3
, Y
1
, Y
2
and q are as defined previously, and wherein each structure bears a negative charge −x and is associated with x/y cationic moieties each bearing a positive charge +y.
In other aspects of the invention, novel compounds are provided that serve as starting materials or intermediates in the synthesis of compounds of formulae (I) and (II), and which are themselves useful as therapeutic agents. Such compounds have the structural formulae (III) and
wherein X, Y, Y
1
, Y
2
, R
2
, Cat, n, x, y and q are as defined earlier, and LG is a leaving group displaceable by a nucleophile. For example, LG may be halo, displaceable by an alcohol ROH in the presence of base.
Other such compounds of the invention may be more generally represented by formulae (V) and (VI)
which are identical to the compounds of formulae (III) and (IV) except that LG has been replaced with the substituent R
4
, which is a substituted or unsubstituted hydrocarbyl group of 1 to 24 carbon atoms, or, alternatively, a moiety defined as for R
2
, i.e., selected from the group consisting of N
−
—ClO
3
, N
−
—NO
2
and N
−
SO
2
R
3
, with the proviso that when R
4
is N
−
ClO
3
, Y
1
is other than S═O or Se═O.
The invention is also directed to pharmaceutical compositions containing a novel compound as provided herein, in combination with a pharmaceutically acceptable carrier. Preferably, such compositions are oral dosage forms and thus contain a carrier suitable for oral drug administration.
In addition, the invention provides methods of using a compound of the invention as a therapeutic agent. The compounds are useful as antiviral agents, anticancer agents, metabolic moderators, and the like, and can thus be administered to treat a variety of conditions, disorders and diseases. A primary use of the compounds, however, is in treating individuals suffering from a viral infection.
DETAILED DESCRPTION OF THE INVENTION
Definitions and Nomenclature
It is to be understood that unless otherwise indicated, this invention is not limit
Bottaro Jeffrey C.
Penwell Paul E.
Petrie Mark A.
Schmitt Robert J.
Crane L E
Geist Gary
Reed Dianne E.
Reed & Associates
SRI - International
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