Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Sulfur – selenium or tellurium compound
Reexamination Certificate
2002-11-27
2003-12-02
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Sulfur, selenium or tellurium compound
Reexamination Certificate
active
06656973
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to the field of anticancer chemotherapy, and cytoprotective agents administered before, during or after anticancer chemotherapy to protect the normal cells of the patient from the cytotoxic effects of anticancer chemotherapeutics.
BACKGROUND OF THE INVENTION
Experimental chemotherapy has been the mainstay of treatment offered to patients diagnosed with surgically unresectable advanced cancers, or cancers refractory to standard chemotherapy and radiation therapy. Of the more effective classes of drugs, curative properties are still limited. This is because of their relatively narrow therapeutic index, restricted dosage, delayed treatments and a relatively large proportion of only partial tumor reductions. This state is usually followed by recurrence, increased tumor burden, and drug resistant tumors.
Several cytoprotective agents have been proposed to enhance the therapeutic index of anticancer drugs. For methotrexate toxicity, such agents include asparaginase, leucovorum factor, thymidine, and carbipeptidase. Because of the extensive use of anthracyclines, specific and non-specific cytoprotective agents have been proposed which have varying degrees of efficacy; included are corticosteroids, desrazoxane and staurosporin. The latter is of interest in that it includes a G1/S restriction blockade in normal cells. (Chen et al.,
Proc AACR
39:4436A, 1998).
Cisplatin is widely used and has a small therapeutic index which has spurred investigation and search of cytoprotectants. Among the cytoprotectants for cisplatin with clinical potential are mesna, glutathione, Na-thiosulfate, and amifostine (Griggs,
Leuk. Res.
22 Suppl 1:S27-33, 1998; List et al.,
Semin. Oncol.
23(4 Suppl 8):58-63, 1996; Taylor et al.,
Eur. J. Cancer
33(10):1693-8, 1997). None of these or other proposed cytoprotectants such as oxonic acid for fluoropyrimidine toxicity, or prosaptide for paclitaxel PC12 cell toxicity, appears to function by a mechanism which renders normal replicating cells into a quiescent state.
What is needed are cytoprotective agents which are effective in protecting animals, inclusive of humans, from the cytotoxic side effects of chemotherapeutic agents.
Unrelated to the foregoing, styryl sulfones having pharmaceutical utility as anticancer agents have been reported in WO/99/18068, the entire disclosure of which is incorporated herein by reference. The compounds inhibit tumor cell growth by inducing tumor cell death without killing normal cells. The styryl sulfones are effective in a broad range of tumor types. Without wishing to be bound by any theory, it is believed that the styryl sulfones affect the Mitogen Activated Protein Kinase (MAPK) signal transduction pathway, thereby affecting tumor cell growth and viability.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compositions and methods for protecting animals, inclusive of humans, from the cytotoxic side effects of chemotherapeutic agents, particularly mitotic phase cell cycle inhibitors and topoisomerase inhibitors, used in the treatment of cancer and other proliferative disorders.
It is an object of the invention provide a method for treating cancer or other proliferative disorder which reduces or eliminates cytotoxic effects on normal cells.
It is an object of the invention to enhance the effects of chemotherapeutic agents, particularly mitotic phase cell cycle inhibitors and topoisomerase inhibitors, used for the treatment of cancer or other proliferative disorders.
It is an object of the present invention to provide a therapeutic program for treating cancer or other proliferative disorder which includes administration of a cytoprotective compound prior to administration of a chemotherapeutic agent, which cytoprotective compound induces a reversible cycling quiescent state in non-tumored tissues.
It is an object of the invention to provide a method for safely increasing the dosage of chemotherapeutic agents, particularly mitotic phase cell cycle inhibitors and topoisomerase inhibitors, used in the treatment of cancer and other proliferative disorders.
According to the present invention, a method for protecting an animal from cytotoxic side effects of the administration of a mitotic phase cell cycle inhibitor or a topoisomerase inhibitor comprises administering to the animal, in advance of administration of the aforesaid inhibitor, an effective amount of at least one cytoprotective &agr;,&bgr; unsaturated aryl sulfone compound. The term “animal” is meant to embrace human beings, as well as non-human animals.
By “&agr;,&bgr; unsaturated aryl sulfone compound” as used herein is meant a chemical compound containing one or more &agr;,&bgr; unsaturated aryl sulfone groups:
wherein Q
2
is substituted or unsubstituted aryl, and the hydrogen atoms attached to the &agr; and &bgr; carbons are optionally replaced by other chemical groups.
By “substituted” means that an atom or group of atoms has replaced hydrogen as the substituent attached to a ring atom. The degree of substitution in a ring system may be mono-, di-, tri- or higher substitution.
The term “aryl”, alone or in combination, means a carbocyclic aromatic system containing one, two, or more rings wherein such rings may be attached together in a pendent manner or may be fused. The term “aryl” is intended to include not only aromatic systems containing only carbon ring atoms but also systems containing one or more non-carbon atoms as ring atoms. Such systems may be known as “heteroaryl” systems. The term “aryl” is thus deemed to include “heteroaryl”. Heteroaryl groups include, for example, pyridyl, thienyl, furyl, thiazolyl, pyrrolyl, and thienyl-1,1-dioxide The heterocyclic radical may be substituted or unsubstituted. The term “aryl” is not limited to ring systems with six members.
According to one embodiment, the &agr;,&bgr; unsaturated aryl sulfone group is a styryl sulfone group:
wherein the hydrogen atoms attached to the &agr; and &bgr; carbons are optionally replaced by other chemical groups, and the phenyl ring is optionally substituted.
By “styryl sulfone” or “styryl sulfone compound” or “styryl sulfone therapeutic” as used herein is meant a chemical compound containing one or more such styryl sulfone groups.
According to another embodiment of the invention, a method of treating an individual for cancer or other proliferative disorder is provided. The method comprises administering to the animal an effective amount of at least one mitotic phase cell cycle inhibitor or topoisomerase inhibitor, and administering before the inhibitor, an effective amount of at least one cytoprotective &agr;,&bgr; unsaturated aryl sulfone compound.
By “effective amount” of the mitotic phase cell cycle inhibitor or topoisomerase inhibitor is meant an amount of said inhibitor effective in killing or reducing the proliferation of cancer cells in a host animal. By “effective amount” of the cytoprotective &agr;,&bgr; unsaturated aryl sulfone compound is meant an amount of compound effective to reduce the toxicity of the mitotic phase cell cycle inhibitor or topoisomerase inhibitor on normal cells of the animal.
The &agr;,&bgr; unsaturated aryl sulfone cytoprotective compounds are characterized by cis-trans isomerism resulting from the presence of a double bond. Stearic relations around a double bond are designated as “Z” or “E”. Both configurations are included in the scope of “&agr;,&bgr; unsaturated aryl sulfone”:
According to one embodiment, the &agr;,&bgr; unsaturated aryl sulfone compound is a compound of the formula I:
wherein:
n is one or zero;
Q
1
and Q
2
are, same or different, are substituted or unsubstituted aryl.
Preferably, n in formula I is one, that is, the compounds comprise &agr;,&bgr; unsaturated benzylsulfones, e.g. styryl benzylsulfones.
According to one sub-embodiment, n is preferably one and:
Q
1
is selected from the group consisting of substituted and unsubstituted phenyl, 1-naphthyl, 2-naphthyl, 9-anthryl and an aromatic radical of formula II:
wherein
n
1
is 1 or 2,
Y
1
and Y
2
are independ
Cosenza Stephen C.
Reddy E. Premkumar
Reddy M. V. Ramana
Bahar Mojdeh
Drinker Biddle & Reath LLP
Temple University - Of the Commonwealth System of Higher Educati
Travers Russell
LandOfFree
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