Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Utility Patent
1998-03-25
2001-01-02
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
Utility Patent
active
06169104
ABSTRACT:
BACKGROUND OF THE INVENTION
Cell mitosis is a multi-step process that includes cell division and replication (Alberts, B., et al., In The Cell, pp. 652-661 (1989); Stryer, E. Biochemistry (1988)). Mitosis is characterized by the intracellular movement and segregation of organelles, including mitotic spindles and chromosomes. Organelle movement and segregation are facilitated by the polymerization of the cell protein tubulin. Microtubules are formed from alpha and beta tubulin polymerization and the hydrolysis of guanosine triphosphate (GTP). Microtubule formation is important for cell mitosis, cell locomotion and the movement of highly specialized cell structures such as cilia and flagella.
Unfortunately, numerous diseases are characterized by abnormal cell mitosis. For example, uncontrolled cell mitosis is a hallmark of cancer. Cancer is the leading cause of death, second only to heart disease, of both men and women. In the fight against cancer, numerous techniques have been developed and are the subject of current research directed to understanding the nature and cause of the disease and to providing methods for the control or cure thereof.
To date, three major families of antitumor agents are known. Each of the families of agents is associated with a recognized mechanism of action. First, antitumor agents may be alkylating agents, which generally bind in a covalent manner with DNA to form bifunctional lesions. The bifunctional lesions involve adjacent or nearby bases of the same strand or, alternatively, involve bases on opposite strands forming interstrand crosslinks. Examples of alkylating agents include nitrogen mustard, cyclophosphamide and chlorambucil. Toxicities associated with the use of alkylating agents include nausea, vomiting, alopecia, hemorrhagic cystitis, pulmonary fibrosis, etc. Second, antitumor agents may be antimetabolites, which generally inhibit enzymes involved in the synthesis or assembly of DNA. Alternatively, an antimetabolite may serve as a fraudulent or analog substrate of DNA processes. Examples of antimetabolites include purine, pyrimidine and folate antagonists and plant alkaloids such as vincristine and vinblastine. Toxicities associated with the use of antimetabolites include alopecia, myelosuppression, vomiting, nausea, peripheral neuropathy, etc. Third, antitumor agents may be antibiotics, which work by intercalating into the DNA helix or introducing strand breaks into DNA. Examples of antibiotics include doxorubicin, daunorubicin and actinomycin. Toxicities associated with the use of antibiotics include myelosuppression, anaphylactic reactions, anorexia, cardiotoxicity, pulmonary fibrosis, etc.
Ionizing radiation is a well established treatment for malignant disease and is of proven benefit for both curative and palliative purposes. However, radiotherapy can have several undesirable complications, such as mucositis, leukopenia, desquamation, spinal cord necrosis, and obliterative endarteritis. These complications frequently limit the ability to deliver a full therapeutic dose of radiation or cause significant morbidity following treatment. Many chemotherapy agents are also toxic to cells of normal tissue, and, thus, the side-effects of chemotherapy are sometimes almost as devastating to the patient as the tumor burden itself. One approach to reducing the side effects of chemotherapy has been to attempt to target chemotherapeutic agents, including radioisotopes and various plant and bacterial toxins, to tumor cells by attaching the agents to antibodies that are specific for antigens present on a tumor cell. See, e.g., U.S. Pat. Nos. 4,348,376 and 4,460,559 which describe radioimmunotherapy of solid tumors (carcinomas) using an anti-carcinoembryonic antigen antibody, and U.S. Pat. No. 5,595,721 which is directed to radioimmunotherapy of lymphoma, a more disseminated tumor. However, while there are several reports of individual successes, the results of therapy using antibody conjugates has generally been disappointing. Remission rates have been low and generally non-reproducible.
Although thousands of potential anticancer agents have been evaluated, the treatment of human cancer remains fraught with complications which often present an array of suboptimnal treatment choices. As such, chemotherapeutic agents which possess little or no toxicity, which are inexpensive to obtain or manufacture, which are well tolerated by the patient, and which are easily administered would be a desirable addition to the therapeutic modalities currently available to the oncologist. Agents that will selectively sensitize malignant tissue to allow lower doses of radiation or therapy to achieve the same therapeutic effect with less damage to healthy tissues are also desirable. Similarly, agents that prevent cancer from occurring or reoccurring are also desirable. The present invention remedies these needs by providing such chemotherapeutic and sensitizing agents.
SUMMARY OF THE INVENTION
The present invention relates to (i) compounds that bind tubulin and exhibit anti-mitotic properties, (ii) methods of using such compounds to inhibit abnormal cell mitosis and, in particular, to inhibit tumor cell growth, (ii) compounds that inhibit angeogenesis and the vascularization of endothelial cells, (iv) methods of using such compounds to inhibit angiogenesis and the vascularization of endothelial cells, (v) compounds that reduce the level of tumor necrosis factor &agr; (TNF-&agr;) produced by a cell; (vi) methods of using such compounds to reduce TNF-&agr; production and to treat inflammatory diseases; and (vii) pharmaceutical compositions comprising such compounds.
In one embodiment, the present invention provides compounds having the general formula:
or a pharmaceutically acceptable salt thereof.
In Formula I, R
1
, R
2
, R
3
and R
4
are each independently selected and are functional groups including, but not limited to, H, alkyl, S-alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy, halogen, NO
2
and NH
2
. R
5
, R
6
, R
7
and R
8
are each independently selected and are functional groups including, but not limited to, H, S-alkyl, alkyl, alkenyl, alkynyl, aryl, hydroxyl, alkoxy and halogen.
In Formula I, X, if present, is a group including, but not limited to, the following:
A, in the above formula, together with the carbons to which it is bound, forms an optionally substituted 3, 4, 5 or 6 membered carbocylic or heterocyclic ring. R
9
and R
10
in the above formula are independently hydrogen, alkyl and halogen. Y, in Formula I, is a functional group including, but not limited to, H, alkyl and alkoxy. Z is a functional group including, but not limited to, the following:
Q, in the above formula Z, is a functional group including, but not limited to, H, alkyl and S-alkyl. Z, Q and Y are selected such that if Z is
and Q is methyl, then Y is other than methoxy and ethoxy.
Within the scope of Formula I, certain embodiments are preferred. Examples of particularly preferred compounds include, but are not limited to, those compounds set forth below. The compounds set forth below and throughout this specification are referred to by code numbers, which are used for convenience only, and are strictly arbitrary for purposes of this invention.
The compounds of the present invention can be used either in vivo or in vitro to inhibit the growth of a tumor cell. The compounds of the present invention are also useful because they bind tublin and exhibit antimitotic properties and, thus, can be used either in vivo or in vitro to inhibit abnormal cell mitosis. Moreover, the compounds of the present invention are useful because they inhibit angiogenesis and the vascularization of endothelial cells. In addition, the compounds of the recent invention are useful because they reduce (e.g., downregulate) the level of TNF-&agr; produced by a cell.
The compounds of the present invention also are useful in conjunction with other cancer therapies, including radiation therapy, chemotherapy, and immunotherapy (including radioimmunotherapy). Within these embodiments, the compounds of the presen
Chen Xiaoying
Hiebert Charles K.
Knapp A. Merrill
Laderoute Keith
Olsen Cris M.
Large Scale Biology Corporation
Townsend and Townsend / and Crew LLP
Weddington Kevin E.
LandOfFree
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