Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-03-28
2003-10-07
Goldberg, Jerome D. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S086000
Reexamination Certificate
active
06630480
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for treating leukemia, and more particularly, to the use of nucleoside analogues as an effective treatment for acute or chronic myelogenous leukemia.
BACKGROUND OF THE INVENTION
Leukemia is a malignant cancer of the bone marrow and blood. It is characterized by the uncontrolled growth of blood cells. The common types of leukemia are divided into four categories: acute or chronic myelogenous, involving the myeloid elements of the bone marrow (white cells, red cells, megakaryocytes) and acute or chronic lymphocytic, involving the cells of the lymphoid lineage.
Acute leukemia is a rapidly progressing disease that results in the massive accumulation of immature, functionless cells (blasts) in the marrow and blood. The marrow often can no longer produce enough normal red and white blood cells and platelets. Anemia, a deficiency of red cells, develops in virtually all leukemia patients. The lack of normal white cells impairs the body's ability to fight infections. A shortage of platelets results in bruising and easy bleeding. In contrast, chronic leukemia progresses more slowly and leads to unregulated proliferation and hence marked overexpansion of a spectrum of mature (differentiated) cells. In general, acute leukemia, unlike the chronic form, is potentially curable by elimination of the neoplastic clone.
It is estimated that there will be 28,700 new cases of leukemia in the United States this year; about equal proportions are acute leukemia and chronic types. Most cases occur in older adults. Leukemia is expected to strike ten times as many adults as children in 1998. (About 26,500 cases compared to 2,200 in children) More than half of all cases of leukemia occur in persons over 60. The most common types of leukemia in adults are acute myelogenous leukemia (AML) with an estimated 9,400 new cases annually, chronic lymphocytic leukemia (CLL), with some 7,300 new cases this year and chronic myeloid leukemia (CML). The most common type of leukemia in children is acute lymphocytic leukemia (ALL).
Standard treatment for leukemia usually involves chemotherapy and/or bone marrow transplantation and/or radiation therapy.
The two major types of bone marrow transplants are autologus (uses the patient's own marrow) and allogeneic (uses marrow from a compatible donor). Radiation therapy, which involves the use of high-energy rays, is usually given before bone marrow transplantation to kill all leukemic cells.
Chemotherapy in leukemia usually involves a combination of two or more anti-cancer drugs. Approximately 40 different drugs are now being used in the treatment of leukemia. Some common combinations include cytarabine with either doxorubicin or daunorubicin or mitoxantrone or thioguanine, mercaptopurine with methotrexate, mitroxantrone with etoposide, asparaginase with vincristine, daunorubicin and prednisone, cyclophosphamide with vincristine, cytarabine and prednisone, cyclophosphamide with vincristine and prednisone, daunorubicin with cytarabine and thioguanine and daunorubicin with vincristine and prednisone.
New treatments for leukemia also include the reversal of multidrug resistance, involving the use of agents which decrease the mechanisms allowing the malignant cells to escape the damaging effects of the chemotherapeutic agent (and leads to refractoriness or relapses); and biological therapy, involving the use of substances known as biological response modifiers (BRMs). These substances are normally produced in small amounts as part of the body's natural response to cancer or other diseases. Types of BRMs include monoclonal antibodies, in which toxins are attached to antibodies that react with the complementary antigen carried by the malignant cells; and cytokines (e.g. interferons, interleukins, colony-stimulating factors CSFs) which are naturally occuring chemicals that stimulate blood cell production and help restore blood cell counts more rapidly after treatment. Examples of these drugs include multidrug resistance reversing agent PSC 833, the monoclonal antibody Rituxan and the following cytokines: Erythropoetin and Epoetin, which stimulate the production of red cells; G-CSF, GM-CSF, filgrastim, and Sargramostim which stimulate the production of white cells; and thrombopoietin, which stimulate the production of platelets.
Many nucleoside analogues have been found to possess anticancer cancer activity. Cytarabine, Fludarabine, Gemcitabine and Cladribine are some examples of nucleoside analogues which are currently important drugs in the treatment of leukemia.
(−)-&bgr;-L-Dioxolane-Cytidine(&bgr;-L-OddC) is also a nucleoside analogue that was first described as an antiviral agent by Belleau et al. (EP 337713) and has been shown to have potent antitumor activity (K. L. Grove et al., Cancer Res., 55(14), 3008-11, 1995; K. L. Grove et al., Cancer Res., 56(18), 4187-4191, 1996, K. L. Grove et al., Nucleosides Nucleotides, 16:1229-33, 1997; S. A Kadhim et al., Can. Cancer Res., 57(21), 4803-10, 1997).
Treatment of leukemia is very complex and depends upon the type of leukemia. Tremendous clinical variability among remissions is also observed in leukemic patients, even those that occur after one course of therapy. Patients who are resistant to therapy have very short survival times, regardless of when the resistance occurs. Despite improvements in outcome with current treatment programs, the need to discover novel agents for the treatment of all types of leukemia continues.
SUMMARY OD THE INVENTION
The present invention provides a novel method for treating leukemia in a host comprising administering a therapeutically effective amount of a compound having the formula I:
wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
6-10
aryl, and
wherein each Rc is independently selected from the group comprising H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl and an hydroxy protecting group; and
wherein said compound is substantially in the form of the (−) enantiomer.
In another embodiment, there is provided a method for treating leukemia in a host comprising administering to the host a therapeutically effective amount of at least one compound according to formula I and at least one further therapeutic agent selected from the group comprising chemotherapeutic agents; multidrug resistance reversing agents; and biological response modifiers.
Still another embodiment, there is provided a pharmaceutical composition for treating leukemia comprising at least one compound according to formula I together with at least one pharmaceutically acceptable carrier or excipient.
In another embodiment, there is provided a pharmaceutical composition for treating leukemia comprising at least one compound according to formula I and at least one further therapeutic agent selected from the group comprising chemotherapeutic agents; multidrug resistance reversing agents; and biological response modifiers.
In another embodiment of the invention is the use of a compound according to formula I for the manufacture of a medicament for treating leukemia.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a novel method for treating leukemia in a host comprising administering a therapeutically effective amount of a compound having the formula I:
wherein B is cytosine or 5-fluorocytosine and R is selected from the group comprising H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
6-10
aryl, and
wherein each Rc is independently selected from the group comprising H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl and an hydroxy protecting group; and
wherein said compound is substantially in the form of the (−) enantiomer.
In another embodiment of the invention, R is H.
In another embodiment, B is cytosine.
Alternatively, in another embodiment, B is 5-fluorocytosine.
In one embodiment, a co
Giles Francis J.
Gourdeau Henriette
Biochem Pharma Inc.
Goldberg Jerome D.
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