Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-10
2001-06-05
Dentz, Bernard (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S440000, C549S035000, C549S039000, C549S040000
Reexamination Certificate
active
06242478
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to novel sulfenate esters and thiosulfinate esters containing five membered rings, and to methods of making these compounds. The invention also relates to the field of therapeutic compositions for use as anti-cancer chemotherapeutic or chemoprotective agents, and as anti-HIV agents.
BACKGROUND OF THE INVENTION
Various types of cancers occur throughout the body, and affect large numbers of people. It is postulated that many of these cancers are caused by foreign substances, also referred to as xenobiotics. One method of limiting the carcinogenic effect of various xenobiotics is by promoting steps or increasing levels of substances in the metabolic pathway that allow carcinogens to be metabolized into neutral forms that are easily excreted from the body.
A simplified description of how xenobiotics, compounds foreign to the body, are metabolized is that procarcinogens are metabolized by Phase I enzymes to either (i) electrophilic metabolites, which may cause DNA damage leading to DNA repair mechanisms or to cancer, or to (ii) nonelectrophilic metabolites that are further metabolized by Phase II enzymes to produce detoxification products. Several steps in this pathway potentially neutralize xenobiotics, and therefore could be considered as logical targets for chemoprevention of cancer. For example, the induction or inhibition of phase I enzymes might promote neutralizing metabolic steps, as could the induction of phase II enzymes. Alternatively, the promotion of DNA repair is a potentially promising means of preventing the carcinogenic effect of xenobiotics that are metabolized through Phase I enzymes to produce electrophilic metabolites which damage nucleic acid structures.
The prevention of the development of cancer by administering drugs prophylactically has been termed chemoprevention. Chemoprevention is an emerging concept that envisages the active prevention of malignant processes. Chemoprevention involves the “use of specific natural or synthetic substances with the objective of reversing, suppressing or preventing carcinogenic progression . . . ” (Singh and Lippman, 1998). A number of such chemopreventive agents are currently in development for undergoing clinical trials.
Chemopreventive agents can be conceptually classified as “blocking” or “suppressive” agents. Blocking agents prevent cancer-producing compounds from reaching or reacting with their critical target sites; suppressive agents prevent the evolution of the neoplastic process in cells already altered by carcinogens (see Singh and Lippman, 1998 for review). Thus, chemopreventive agents can be provided either to high risk groups or to the population at large.
Oltipraz can be considered to have both blocking and suppressive activities, and is being investigated for chemopreventive activity in a number of cancers, including those of the bladder, prostate, breast, skin, lung, colon, and liver (Wattenberg, 1997). A large scale clinical trial of the ability of oltipraz to prevent aflatoxin F1-related hepatocellular carcinoma is currently underway in the People's Republic of China. However, oltipraz has been associated with some toxicities, including photosensitivity/heat intolerance, GI effects, and neurologic toxicities (Dimitrov et al., 1992). Thus, the continued search for improved chemopreventive agents is clearly warranted.
Phase II enzymes are responsible for the detoxification of reactive electrophilic and nucleophilic metabolites. Phase II enzymes include NAD(PH):quinone oxidoreductase (facilitates metabolism of carcinogens through two electron reduction), glutathione S transferase (mediates deactivation of carcinogens through conjugation to reduced glutathione), manganese superoxide dismutase (reduces levels of superoxide anion) ferritin (reduces oxygen free radical formation by sequestering iron), and others (Talalay, 1989). Glutathione S-transferases (GST) are phase II enzymes that catalyze the reaction of glutathione, a tripeptide, with electrophiles such as epoxides, alkyl and aryl halides and &agr;,&bgr;-unsaturated ketones. Glutathione conjugation serves to deactivate electrophiles, therefore making them less toxic and carcinogenic and more easily excreted by the body.
In the reaction between glutathione and an electrophile, the first step involves the binding of glutathione (GSH) to the glutathione-S-transferase enzyme (GST). The enzyme is known to lower the pKa of the thiol from 9.0 to ~6.5. The thiolate ion of glutathione then reacts with electrophiles to produce the less toxic glutathione conjugates.
Several sulfur-containing compounds are known to elevate levels of GST in rats and mice. These include allicin (Talalay, et al.), a natural product found in garlic, and Oltipraz 10, which is undergoing clinical trials at the time of the present disclosure.
Oltipraz and its derivatives (1,2-dithiole-3-thiones) are particularly attractive because of two important characteristics. First, 1,2-dithiole-3-thiones are monofunctional inducers. They only induce phase II enzymes and not phase I enzymes. Induction of phase I enzymes could enhance the production of activated carcinogens, therefore complicating any increased activity of phase II enzymes. Secondly, 1,2-dithiole-3-thiones can induce higher levels of GSTs in several organs, providing possible protection against several types of cancer.
Because of this selective usefulness of sulfur-containing compounds that display an ability to induce high levels of GST in particular, industry is constantly seeking additional forms of such compounds, as well as reliable methods for their synthesis. As a result, several syntheses have been reported for unsaturated five-membered cyclic sulfenate esters or &ggr;-sultines (Bondarenko, et al.); however, none of the reported syntheses to date are very general. In 1970, King and co-workers reported that thermolysis of thiete 1,1-dioxide and 2-phenylthiete 1,1-dioxide produced unsaturated sultines (King et al.) Thermolysis of other substituted thiete 1,1-dioxides resulted in sulfur dioxide extrusion to yield various alkenes.
Braverman and co-workers have studied the electrophilic fragmentation and cyclization of allenic sulfones to unsaturated &ggr;-sultines (Braverman and Duar). Allenyl sulfone when reacted with bromine produced a bromonium ion intermediate which cyclized to produce sultine. This reaction is unfavorably limited, however, because only bromine substituted sultines can be synthesized.
Another synthesis of unsaturated sultines reported by Duboudin and co-workers required Grignard reagents formed from propargyl alcohols (Thomazeau et al.). The resulting Grignards reacted with sulfur dioxide by insertion into the carbon-metal bond. The sultines were obtained, however, in poor to moderate yields.
Accordingly, novel compounds that can induce GST and other enzymes of the Phase II response, and a method of reliably synthesizing such compounds in various forms while resulting in useful levels of the desired product is still sought.
The tendency of HIV-1 to mutate to viral strains that are resistant to existing therapeutic regimens is now well documented (Cohen, 1997). This resistance has fueled the search for antiviral drug targets that are conserved through mutations. The zinc finger containing nucleocapsid proteins of retroviruses would appear to be such a therapeutic target since they are conserved through mutations, are involved in early and late phases of the viral replication cycle, and are chemically reactive toward soft electrophilic reagents that can be prepared via rational synthetic structure-activity modification schemes (Rice and Turpin, 1996). The structure of the HIV-1 nucleocapsid protein (NCp7) was determined in the early 1990's (South et al., 1990; Chance, et al., 1992; Summers et al., 1992) and found to have the Cys-Xaa
2
-Cys-Xaa
4
-His-Xaa
4
-Cys zinc coordination sphere sequence with the short tether links that are now sometimes referred to as a “zinc knuckle”. At that same time Rice and co-workers first postulated that the Cys res
Hurley Allison L.
Pietsch Eva
Torti Frank M.
Torti Suzy V.
Townsend Alan J.
Corder Timothy S.
Dentz Bernard
Vinson & Elkins LLP
Wake Forest University
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