Derivatives and analogs

Details Derivatives and analogs Derivatives and analogs

1999-07-13

2002-08-27

Vollano, Jean F. (Department: 1621)

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

Organic compounds

Phosphorus esters

C562S024000

Reexamination Certificate

active

06441214

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates generally to the field of phosphorus chemistry, and is particularly concerned with a novel method for the production of sulfur-containing phosphonoformates and their derivatives. An additional aspect of the present invention relates to the use of these compounds as antiviral agents, including: Human Immunodeficiency Virus (HIV); herpes viruses including, Herpes Simplex Virus (HSV), Ebstein-Barr Virus (EBV), Varicella Zoster Virus (VZV), Cytomegalovirus (CMV), HSV-6, and HSV-8 (Kaposi's sarcoma); Human Papilloma Virus (HPV); rhinoviruses; and hepatitis-linked viruses.
2. Description of Related Art
A retrovirus designated HIV is believed to be the causative agent of the complex disease termed Acquired Immune Deficiency Syndrome (AIDS). The complex disease AIDS includes progressive destruction of the immune system and degeneration of the central and peripheral nervous system. The HIV virus appears to preferentially attack helper T-cells (T-lymphocytes or OKT4-bearing T-cells) and also other human cells, e.g., certain cells within the brain. The helper T-cells are invaded by the virus and the T-cells become an HIV virus producer. The helper T-cells are quickly destroyed and their number in the human being is depleted to such an extent that the body's B-cells as well as other T-cells normally stimulated by the helper T-cells no longer function normally or produce sufficient lymphokines and antibodies to destroy the invading virus or other invading microbes.
While the HIV virus does not necessarily cause death per se, it does cause severe damage to the human immune system resulting in the onset of various other opportunistic diseases such as, herpes, toxoplasmosis, cytomegalovirus (CMV), Kaposi's sarcoma, and EBV related lymphomas, among others, (AIDS). HIV virus infected individuals, at first, experience few or no symptoms. Later in the disease, the onset of immune system dysfunction occurs, leading to various symptoms such as weight loss, malaise, fever, and swollen lymph nodes (AIDS related complex). The disease further progresses to full blown AIDS, leading usually to death. Those infected with the HIV virus are persistently infective to others.
Unfortunately, the present state of the art is such that antiviral drugs are only capable of attacking such viruses when they are replicating. Attacking a latent virus such as HIV, which does not reproduce itself following infection until reactivated by presently unknown factors would require distinguishing the viral genetic material from the surrounding host genetic material and selectively destroying it. Thus, the current generation of antiviral drugs is only effective against replicating viruses. Considerable efforts are being directed toward the control of HIV by means of inhibition of the reverse transcriptase of HIV and of other targets of viral functions, required for replication of the virus. Unfortunately, many of the known compounds suffer from toxicity problems, lack of bioavailability or are short-lived in vivo, viral resistance, or combinations thereof. Particularly important is combined therapy agents targeting more than one viral function. The requirement for development of new drugs able to be used in combination with other types of drugs is important in continued HIV therapy.
Several researchers have indicated that the pyrophosphonate analogues, such as phosphonoformic acid (PFA) and its analogues and derivatives possess antiviral properties in that they inhibit the replication of several viruses. (See, U.S. Pat. Nos. 5,072,032 and 5,183,812 to McKenna; D. W. Hutchinson, et al., Synthesis and Biochemical Properties of Some Pyrophosphate Analogues,
Biophosphates and Their Analogues-Synthesis, Structure, Metabolism and Activity,
K. S. Bruzik and W. J. Stec (Eds.), Elsevier Science Publishers, B. V., 1987, 441-450;. and Helgstrands, et al.,
Science,
201:819-821 (1978)). Trisodium phosphonoformate (PFA, Foscarnet), a pyrophosphate analog, has been reported to inhibit HIV reverse transcriptase (HIV, RT) with an ID
50
near 1 &mgr;m, and has also been reported to inhibit several herpes virus DNA polymerases, including the DNA polymerase of CMV. See, U.S. Pat. No. 5,072,032 to McKenna.
Previous studies reported the addition of nucleophiles to the thiocarbonyl group. (See, J. Levillain, et al.,
J. Am. Chem. Soc.
115, 8444-8446, 1993; and L. V. Kovalenko, et al.,
Russian J. General Chemistry
64, Part 1, 1456-1459, 1994). Preparations of thiocaibonyl and dithiocarboxyl derivatives have been demonstrated in the reaction of trialkyl phosphate and chlorothioformate. (See, D. W. Grisley, Jr.,
J. Org. Chem.
26, 2544-2546, 1961.) However, trimethyl phosphonoformate thio derivatives have not been previously reported, except trimethyl thiophosphonoformate, U.S. Pat. No.5,072,032 to C. E. McKenna, et al., and trimethyl phosphonothionoformate, Kovalenko et al., supra. Corresponding monosodium salts and trisodium salts are, disclosed for the first time, except for the monosodium and trisodium salts of thiophosphonoformate which were previously disclosed McKenna, et al, supra.
BRIEF SUMMARY OF THE INVENTION
The present invention solves the above-described problems by providing methods for readily synthesizing sulfur-containing phosphonoformic acid derivatives and the use of such derivatives as chemotherapeutic agents. In one embodiment of the invention, sulfur-containing phosphonoformate derivatives are obtained formally by replacing one or more of the five oxygen atoms of the original phosphonoformate molecule by a sulfur atom. Another embodiment of the present invention is a method for synthesizing polyhydroxy derivatives of such analogs. The method uses the base compound (foscarnet), but can be extended to prepare similar derivatives based on the thio analogues of foscarnet. An additional aspect of the present invention relates to the use of these compounds as antiviral agents, including: HIV and herpes viruses.
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 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, see TABLE I. CAS is the Chemical Abstract Service.
TABLE I
Selected Phosphonoformate Thio-Analogues
Name
Structure
Na
3
TPFA,
1

NaTPFA,
6

NaPTNFA,
7

NaPTLFA,
8

NaPDTFA,
9

NaTPTNFA,
10

NaTPTLFA,
11

NaTPDTFA,
12

Me
3
TPFA,
13

Me
3
PTNFA,
14

Me
3
PTLFA,
15

Me
3
PDTFA,
16

Me
3
TPTLFA,
17

Me
3
TPTNFA,
18

Me
3
TPDTFA,
19
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 compounds disclosed herein, and their corresponding classes, derive chiefly from two factors: 1) modification of their reactivity, cell transport, cell permeation, metabolism, and enzyme or membrane receptor site binding properties due to the different chemical and physical properties of sulfur relative to oxygen; and 2) potential in situ physiological conversion of S to O, creating the possibility of prodrugs for which the actual drug has one or more S converted to O after administration. Another factor is the modified properties of prodrugs or other analogues in which the sulfur-containing function is derivatized, e.g. as an ester, ether, etc., relative to metabolic activation in vivo.
Thio-Analogues of PFA
The analogues have the general structure:
R
1
and R
2
are each independently selected from alkyl, aryl, H, or cation, R
3
is independently selected from 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 alkyl, aryl, or H, or (ii) at least o

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