Organic compounds -- part of the class 532-570 series – Organic compounds – Phosphorus esters
Reexamination Certificate
2000-11-01
2001-09-04
Vollano, Jean F. (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Phosphorus esters
C558S214000
Reexamination Certificate
active
06284909
ABSTRACT:
FIELD OF INVENTION
The present invention relates to the general field of phosphorus chemistry, and is particularly directed to improved methods for large scale production of thioanalogues of phosphonoformic acid (PFA), and to the conversion of phosphonates into thiophosphonates in general, and to the conversion of phosphites into their corresponding thiophosphite derivatives.
BACKGROUND
Phosphonates play a significant role in the fields of chemistry, biology and medicine. Moreover, phosphonate analogues have been shown to possess biologically or economically important properties as pesticides, insecticides, herbicides, enzyme inhibitors and receptor antagonists. Thus, these compounds have become increasingly important in the fields of agriculture and medicine.
Due to their widespread applications, considerable activity has been devoted to developing convenient methods for synthesis of phosphonates or related compounds. However, the discovery of novel phosphonates or related compounds and new methods for synthesizing them in large quantities in a simple, fast, efficient manner with high yields remains of interest. Further, it would be advantageous to be able to synthesize these compounds in a cost-effective manner.
&agr;-Phosphonocarboxylate compounds, a class of phosphonate derivatives, are endowed with special physical, chemical and biological properties. Various uses of these derivatives, arising from the proximity of the carboxyl and phosphonyl groups, range from metal chelation to the mainfestation of biological activity. For example, phosphonocarboxylate compounds can be used as inhibitors of enzymes which catalyze reactions of biological phosphate derivatives, such as nucleoside 5′-triphosphates and oligonucleotides.
One phosphonocarboxylate derivative, phosphonoformic acid (PFA), has been found to possess antiviral properties, and in the form of its trisodium salt (foscarnet), PFA has a role in the treatment of some viral diseases, such as Cytomegalovirus (CMV) retinitis in AIDS. PFA was also shown to inhibit HIV-1, the retrovirus generally believed to cause Acquired Immune Deficiency Syndrome (AIDS).
A sulfur analogue of PFA, thiophosphonoformic acid (TPFA) in the form of a trisodium salt (Thiovir®), was found effective against HIV, the AIDS virus, in previous U.S. patents (U.S. Pat. Nos. 5,072,032 and 5,183,812, the disclosures of which are hereby incorporated by reference in their entirety, including cited references). A novel, simple synthesis of Thiovir® was reported in these patents, which teach that Thiovir® can be prepared from trimethyl phosphonoformnate via a trimethyl thiophosphonoformate intermediate. The intermediate can be formed by the action of Lawesson's Reagent (LR); [2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4disulfide] on trimethyl phosphonoformate. Thiovir® has been completely characterized by elemental analysis,
31
P,
13
C and
1
H NMR, UV, IR and X-ray crystallographic analysis.
Thiovir® and related compounds are particularly well suited for use as effective antiviral agents. Thiovir® showed unexpectedly high antiviral activity against HIV compared to its DNA polymerase inhibiting activity. Biochemical assays showed that Thiovir® selectively inhibited isolated HIV reverse transcriptase (RT) in vitro with an IC
50
of about 1 &mgr;M, but foscarnet was more inhibitory to human DNA polymerases. Both Thiovir® and foscarnet can be non-toxic to cultured H9 cells at effective antiviral doses, and showed similar inhibition dose dependencies based on a p24 antigen capture assay. Moreover, Thiovir® also exhibited antiviral activity against CMV-infected cells in culture.
Unfortunately, there are disadvantages associated with the previously developed methods and reagents used to make Thiovir® compounds. For example; the prior art method of synthesizing Thiovir® typically involves using Lawesson's reagent as a thionating reagent, which is expensive. Consequently, the cost of using this method on a large scale may be excessive.
In view of the apparent utility of these compounds, developing less expensive, and equally simple methods to produce triesters of thiophosphonoformic acid is desirable. Accordingly, it is a principal object of the present invention to disclose a new, improved method for the effective production of large quantities of trimethyl thiophosphonoformate, which is the most important intermediate in the synthesis of Thiovir®. Moreover, the costs associated with producing Thiovir®, using the methods and intermediates of the present invention, should be significantly less than those of previously reported methods.
As those skilled in the art would appreciate, it is also an object of the present invention to disclose novel, improved methods for converting the general class of phosphites and phosphonates into their corresponding thio derivatives in a simple and economical manner.
REFERENCES:
patent: 5072032 (1991-12-01), McKenna
patent: 5183812 (1993-02-01), McKenna
CA:110:114931 abs of Zh. Obshch, Khim. by Chepakova et al 57(12) pp 2716, 1987.*
CA:107:7017 abs of J Chem Soc. Perkin Trans. 1 (12) pp 2081-2090, 1986.
Li Zengmin
McKenna Charles E.
Fulbright & Jaworski L.L.P.
University of Southern California
Vollano Jean F.
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