Synthesis and antiviral activity of a series of...

Details Synthesis and antiviral activity of a series of... Synthesis and antiviral activity of a series of...

2000-03-23

2002-09-03

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Phosphorus esters

C560S129000, C562S024000

Reexamination Certificate

active

06444837

ABSTRACT:

BACKGROUND OF THE INVENTION
Trisodium phosphonoformate (PFA trisodium salt, Foscarnet), a pyrophosphate analogue, inhibits HIV reverse transcriptase (HIV, RT) with an IC
50
near 1 &mgr;M, and also inhibits several herpesvirus DNA polymerases including the DNA polymerase of Cytomegalovirus (CMV). In clinical trials of PFA for treatment of CMV infection in AIDS patients, the drug was efficacious but exhibited reversible nephrotoxicity. In one study, a slowed progress to death was also observed, attributed to the anti-HIV effect of the drug. A number of recent studies have suggested Foscarnet deserves consideration for use in anti-HIV combination therapy owing to its HIV resistance pattern, which differs from many clinical anti-HIV agents such as AZT. Foscarnet is broadly active against other viruses as well, including influenza and hepatitis viruses.
Foscarnet has serious disadvantages as a systemic drug. It is known to affect plasma electrolyte concentrations, intestinal phosphate transport, and bone metabolism. Furthermore, Foscarnet must be administered intravenously, owing to its low oral bioavailability. Thus antiviral pyrophosphate analogues with improved pharmacological properties are of great interest.
BRIEF SUMMARY OF THE INVENTION
The present invention solves the above-described problems by providing methods for readily synthesizing a series of pyrophosphate analogues, including sulfur-containing, polyhydroxy, and lipophilic derivatives of phosphonoformic acid. The present invention also provides compositions and methods for treating viral infections, which utilize a series of pyrophosphate analogues, including phosphonoformic, bisphosphonic, and phoshphonoacetate acid derivatives.
These and other features, aspects, and advantages of the present invention will become better understood with regard to the following detailed description and appended claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention involves the structure, synthesis, and use of a series of potent pyrophosphate analogues, which can serve as effective antiviral compounds or their intermediates. More particularly, we have identified several pyrophosphate analogues which show very high antiviral activity against human herpesvirus 8 (HHV-8).
Phosphonoformic Acid Derivatives
Thio-Analogues of PFA
Thio derivatives of organophosphorus compounds have long been of interest to chemists, not least because these compounds can be useful in agriculture or medicine, as well as in synthesis (Edmundson, R. S.,
The Chemistry of Organophosphorus Compounds;
John Wiley: New York, 1996). The replacement in a phosphate, phosphonate or phosphinate molecule of one or more oxygen atoms by sulfur may lead to significant alteration in biological activity or related properties. As a class, the sulfur containing phosphonoformate derivatives have received relatively little attention in the literature, although particular examples (chiefly triester) have been made and shown to possess a range of useful applications in synthetic chemistry [Grisley, D. W.,
J. Org. Chem.
26, 2544 (1961); Masson, S. et al.,
J. Org. Chem.
59, 4507 (1992); Masson, S. et al.,
Tetrahedron
50, 10277 (1994); Kovalenko, L. V., et al.
Russ. J. Gen. Chem.
64,1456 (1994)].
The present invention teaches the synthesis of sulfur-containing phosphonoformic acid derivatives, which are obtained by replacing one or more of the five oxygen atoms of the original phosphonoformate molecule by a sulfur atom.
The analogues have the general formula:
wherein R
1
R
2
, and R
3
are each independently selected from C
1
-C
20
alkyl, aryl, H, or cation, X
1
X
2
, X
3
, X
4
, and X
5
are O or S, provided that:
(a) at least one of X
1
-X
5
is S;
(b) when X
1
is S, then either (i) R
1
or R
2
is C
1
-C
20
alkyl, aryl, or H, or (ii) at least one of X
2
, X
3
, X
4
, and X
5
is also S.
The term “C
1
to C
20
alkyl” as used herein and in the claims (unless the context indicates otherwise) means a saturated or unsaturated, branched or straight chain hydrocarbon group having 1 to 20 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, etc. Unless otherwise specified in the particular instance, the term “aryl” includes “substituted or unsubstituted phenyl.” As used herein and in the claims, “substituted or unsubstituted phenyl” is intended to mean a phenyl group wherein an atom, element or group is regarded as having replaced a hydrogen atom.
The parent structures may also form part of a derived entity wherein R
1
, R
2
and/or R
3
are more complex groups than simple alkyl or aryl (or portions of the same molecule), with the parent incorporated via one or more esteratic or ether bonds as indicated above.
As used herein, the “cation” can be a pharmaceutically acceptable alkali metal (e.g., Li, Na, or K), ammonium cation, alkaline earth cation (e.g., Ca
2+
, Ba
2+
, Mg
2+
), higher valency cation, or polycationic counter ion (e.g., a polyammonium cation). See, Berge, et al., “Pharmaceutical Salts”,
J Pharm. Sci.
(1977) 66:1-19. It will be appreciated that the stoichiometry of an anionic compound to a salt-forming counterion (if any) will vary depending on the charge of the anionic portion of the compound (if any) will vary depending on the charge of the anionic portion of the compound (if any) and the charge of the counterion. Preferred pharmaceutically acceptable salts include a sodium, potassium or calcium salt, but other salts are also contemplated within their pharmaceutically acceptable range.
Furthermore R
1
, R
2
, and R
3
may be so designed as to create novel biologically active compounds or prodrugs, wherein one conjugating moiety may be for example a nucleoside or nucleotide with independent activity, and another moiety may be for example a diol, triol or higher polyhydroxy group conferring enhanced cell transport or other desirable properties. The term “prodrug” as used herein and in the claims (unless the context indicates otherwise) denotes a derivative of an active drug which is converted after administration back to the active drug. More particularly, it refers to derivatives of the pyrophosphate analogues of the present invention, which are capable of undergoing hydrolysis or oxidative cleavage of the ester moiety so as to release active, free drug. The physiologically hydrolyzable groups serve as prodrugs by being hydrolyzed in the body to yield the parent drug.
Note, where R
1
=R
2
, X
1
and X
2
are generally equivalent substitutions. However, compounds wherein R
1
=R
2
, such that X
1
and X
2
substitutions result in distinct isomers, are also within the scope of the invention. Furthermore, stereoisomers, including stereoisomers created by the possibility of chirality at the phosphorus atom e.g. in a structural fragment like M
+
[R
1
O(S)P(O) R
3
]
−
where M
+
is a cation are also within the scope of the invention.
We further predict an overall trend of decreasing stability as S replaces O, particularly when S≧3. Accordingly, for preferred versions of the sulfur-containing PFA derivatives of the present invention, at least two of X
1
, X
2
, X
3
, X
4
, and X
5
will be oxygen.
The most preferred sulfur containing PFA derivatives of the present invention are those which act as antiviral compounds or their intermediates. As a result of initial screening for antiviral activity against HHV-8, we have identified several candidates having a moderate to high therapeutic index for use as effective antiviral compounds. Accordingly the most preferred sulfur containing PFA derivatives of the present invention include compounds having the following structures:
General synthetic pathways as applied to examples of various thio-analogs of PFA are outlined in the following conceptual schemes:
The unique biological activities of the sulfur containing PFA derivatives disclosed herein, and their corresponding classes, derive chiefly from two factors: 1) modification of their reactivity, cell transport, cell permeation, metabolism, and enzyme or membran

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