Analogs of indole-3-carbinol metabolites as chemotherapeutic...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

Reexamination Certificate

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C548S418000

Reexamination Certificate

active

06800655

ABSTRACT:

TECHNICAL FIELD
This invention relates generally to compounds and compositions for the treatment of cancer and other hyperproliferative diseases. More particularly, the invention pertains to novel dietary indole analogs that are useful in treating a range of cancers, including estrogen-related cancers such as breast, uterine, cervical, ovarian, and endometrial cancers, and non-estrogen-related cancers such as prostate, colon, liver and lung cancers.
BACKGROUND
Cancer is the second leading cause of death in the United States, exceeded only by heart disease. Drugs that are used to treat cancer tend to be toxic at their therapeutic dose levels, commonly causing severe and even life-threatening adverse effects. Current anticancer drugs must also be administered intravenously. Consequently, nearly all cancer chemotherapy must be administered in a hospital or clinic. An additional problem with most current cancer chemotherapy is that cancers frequently develop resistance to the drugs, so that recurrence of disease is common.
For patients who have been diagnosed with cancer, cytotoxic chemotherapy is considered an essential part of the management of the disease, but resistance to chemotherapeutic drugs is unfortunately a common development in cancer. Although the mechanisms of resistance to chemotherapy are not fully understood, the cellular mechanisms thus far implicated in the development of drug resistance are the same as those that protect normal tissues from toxicity. Furthermore, the efficacy of cytotoxic chemotherapeutics is ultimately limited by their narrow therapeutic index. Therefore, it is unlikely that any breakthrough in the treatment of cancer will come about as a result of a cytotoxic approach. There is accordingly an urgent need for new noncytotoxic therapies that are safer and more effective than those currently available, and that, furthermore, will improve both survival rate and the quality of life for cancer survivors.
Recurrence is a potential threat for anyone who is diagnosed and treated with cancer, and up to 50% of patients with recurrent cancer will eventually have metastatic disease, which is often fatal. Therefore, for patients who have been treated for early stage cancer, once stabilization of the disease has been achieved, consideration must be given to adjuvant chemopreventive therapy to suppress disease for as long as possible. Since chemopreventive therapeutics are used on a long-term basis, there is a serious need for agents with three key characteristics: good tolerability, oral bioavailability, and long-term safety.
Furthermore, primary prevention is the optimal way to address any disease, and this is particularly true of cancer. Continuing advances in identification and validation of intermediate biomarkers, along with risk factors (e.g., genetic susceptibility or life-style) and exposure biomarkers, offer opportunities to more accurately assess the risk that any given individual may develop cancer. The aforementioned advances also enable a more precise identification of patient groups at an elevated risk for development of cancer, e.g., patients who may be in an otherwise undiagnosed phase of a carcinogenic process that could ultimately be fatal. Accordingly, the development of an effective cancer preventive (“chemopreventive”) agent for high risk individuals is of utmost importance. Since chemopreventive agents may be given to relatively healthy subjects for extended time periods, the long-term safety of such drugs is essential.
Currently, none of the available methods for treating cancer, such as breast cancer, ovarian cancer and prostate cancer, meet all of these important criteria.
Breast cancer is one of the most prevalent types of cancer. Although breast cancer research has developed at a rapid pace over the last decade, breast cancer remains a common and devastating disease and the second leading cause of cancer-related deaths in women in the United States. Many breast tumors appear to follow a predictable clinical pattern, initially being responsive to endocrine therapy and cytotoxic chemotherapy but ultimately exhibiting a phenotype resistant to both modalities. Although the mechanisms responsible for hormone resistance of tumors remain unclear, experiments revealed that when a tumor composed of mixed populations of cells with different sensitivities to hormones was deprived of hormones, the autonomous cell types could keep growing, and inevitably the tumor growth progressed from hormone sensitive to hormone independent. Since cellular heterogeneity of estrogen receptor (ER) distribution is seen in most cases of ER-positive breast cancer, the promising treatment strategy and drugs should achieve maximal growth inhibition of both estrogen-dependent and estrogen-independent breast tumor cells at the same time.
New therapeutic agents are also needed for the treatment of ovarian cancer. Ovarian cancer has a high mortality-to-incidence ratio, is usually asymptomatic until it is diagnosed in advanced stages, and quickly develops resistance to existing chemotherapeutics. The advent of paclitaxel (Taxol) as a component of first-line and salvage therapies has further improved response rates and prolonged survival, but resistance to chemotherapeutic drugs is a common development in ovarian cancer. These chemoresistant tumor cells frequently develop a broad cross-resistance to multiple drugs, and virtually all patients in whom multiple drug resistance has developed do not survive.
With the advent of prostate-specific antigen (PSA) testing and increased public awareness, approximately 75% of prostate cancer patients now present with clinically localized disease at the time of initial diagnosis. Although detection of organ-confined disease provides the most realistic opportunity for cure, the curative potential of all presently accepted local therapies (i.e., surgery and radiation therapy) remains disappointing, while treatment-associated side effects have been shown to seriously impair sexual, urinary, and bowel function for most patients. As diagnostic modalities and screening advance, continued increases in the incidence of prostate cancer and the shift to an earlier patient age and tumor stage at diagnosis are expected in the years to come. Clearly, there is an urgent need to identify and implement novel therapeutic agents to improve cancer control while minimizing associated morbidity.
It is, therefore, of utmost importance to develop new anticancer agents that are not only effective in treating a range of cancers, but also exhibit low toxicity and have a wide therapeutic window, such that an agent allow long-term treatment to maximize disease control. An ideal anticancer agent would also be easily administrable outside of a clinical setting; orally active compounds would be particularly attractive in this regard. Ideal agents would also be useful prophylactically in patients at risk of developing cancer, or at risk of cancer recurrence, in addition to their utility in therapeutic methods.
One route to discovering safe anticancer agents is to search for dietary compounds that have anticancer properties, then to modify them to enhance their anticancer effects while retaining their safe biological profile. Known dietary compounds with anticancer activity include certain indoles, particularly indole-3-carbinol (I3C), that are found abundantly in cruciferous vegetables such as broccoli, cabbage, cauliflower, and Brussels sprouts. I3C is highly acid sensitive and it can be converted by gastric acid to form several metabolites in stomach. The four I3C metabolites shown below—3,3′-diindolylmethane (3,3′-DIM), indolo[3,2-b]carbazole (ICZ), 2-(indol-3-ylmethyl)-3,3′-diindolyl-methane (LT), and 5,6,11,12,17,18-hexahydro-cyclonona [1,2-b:4,5-b′:7,8-b″]triindole (CT)—have been identified as having antitumor activity:
A number of in vitro and in vivo studies have shown I3C and its metabolites to have significant activity in preventing and treating estrogen-related cancers, including cancers of the breast (

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