Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-03-21
2004-06-08
Rotman, Alan L. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C549S496000
Reexamination Certificate
active
06747061
ABSTRACT:
FIELD OF THE INVENTION
The present invention describes N-substituted dithiocarbamate esters and their use in the treatment of biological disorders. The N-substituted dithiocarbamate esters are particularly useful in the treatment of hyperproliferative conditions such as cancer. They can also be used in the treatment of VCAM-1 mediated conditions such as cardiovascular disorders and inflammatory diseases.
BACKGROUND OF THE INVENTION
A wide range of disorders involve the hyperproliferation of cells, ranging from psoriasis to benign and malignant tumors. These disorders are generally caused by a loss of control over normal cell growth, differentiation, or the process of programmed cell death (apoptosis). Many of the abnormalities that underlie these disorders, particularly cancer, occur at the genetic level. Antineoplastic agents (also known as cytotoxic agents) are often used in the treatment of hyperproliferative conditions. Therapy with antineoplastic agents is successful in the treatment of a number of malignant conditions; however, in most it is used to palliate the symptoms and to prolong life in patients with advanced disease.
Cancer is a class of tumors that is characterized by invasiveness and metastasis. It is possible to recur after attempted removal, and causes death unless adequately treated.
Stedman's Medical Dictionary,
25th Edition Illustrated, Williams & Wilkins, 1990. Approximately 1.2 million Americans are diagnosed with cancer each year, 8,000 of which are children. In addition, 500,000 Americans die from cancer each year in the United States alone. Specifically, lung and prostate cancer are the top cancer killers for men while lung and breast cancer are the top cancer killers for women. It is estimated that cancer-related costs account for about 10 percent of the total amount spent on disease treatment in the United States.
CNN Cancer Facts,
http://www.cnn.com/HEALTH/9511/conquer_cancer/facts/index.html, page 2 of 2, Jul. 18, 1999.
Although a variety of approaches to cancer therapy (e.g., surgical resection, radiation therapy, and chemotherapy) are available and have been used for many years, cancer remains one of the leading causes of death in the world. This is due in part to the fact that the therapies themselves cause significant toxic side-effects and re-emergence is common.
Antineoplastic agents have been described extensively in a number of texts, including Martindale,
The Extra Pharmacopoeia,
31
st
Edition, Royal Pharmaceutical Society (1996).
Antineoplastic agents include:
(i) antifolates;
(ii) antimetabolites (including purine antimetabolites, cytarabine, fudarabine, floxuridine, 6-mercaptopurine, methotrexate, 5-fluoropyrimidine, including 5-fluorouracil, cytidine analogues such as &bgr;-L-1,3-dioxolanyl cytidine and 6-thioguanine);
(iii) hydroxyurea;
(iv) mitotic inhibitors (including CPT-11, Etoposide(VP-21)), taxol, and vincristine,
(v) alkylating agents (including but not limited to busulfan, chlorambucil, cyclophosphamide, ifofamide, mechlorethamine, melphalan, and thiotepa);
(vi) nonclassical alkylating agents, platinum containing compounds, bleomycin, anti-tumor antibiotics, anthracycline, anthracenedione, topoisomerase 11 inhibitors, hormonal agents (including but not limited to corticosteroids (dexamethasone, prednisone, and methylprednisone); and
(v) androgens such as fluoxymesterone and methyltestosterone, estrogens such as diethylstilbesterol, antiestrogens such as tamoxifen, LHRH analogues such as leuprolide, antiandrogens such as flutamide, aminoglutethimide, megestrol acetate, and medroxyprogesterone), asparaginase, carmustine, lomustine, hexamethyl-melamine, dacarbazine, mitotane, streptozocin, cisplatin, carboplatin, levamasole, and leucovorin.
A more comprehensive list of antineoplastic agents includes Aceglatone; Aclarubicin; Altretamine; Aminoglutethimide; 5-Aminogleavulinic Acid; Amsacrine; Anastrozole; Ancitabine Hydrochloride; 17-1A Antibody; Antilymphocyte Immunoglobulins; Antineoplaston A10; Asparaginase; Pegaspargase; Azacitidine; Azathioprine; Batimastat; Benzoporphyrin Derivative; Bicalutamide; Bisantrene Hydrochloride; Bleomycin Sulphate; Brequinar Sodium; Broxuridine; Busulphan; Campath-IH; Caracemide; Carbetimer; Carboplatin; Carboquone; Carmofur; Carmustine; Chlorambucil; Chlorozotocin; Chromomycin; Cisplatin; Cladribine; Corynebacterium parvum; Cyclophosphamide; Cyclosporin; Cytarabine; Dacarbazine; Dactinomycin; Daunorubicin Hydrochloride; Decitabine; Diaziquone; Dichlorodiethylsulphide; Didemnin B.; Docetaxel; Doxifluridine; Doxorubicin Hychloride; Droloxifene; Echinomycin; Edatrexate; Elliptinium; Elmustine; Enloplatin; Enocitabine; Epirubicin Hydrochloride; Estramustine Sodium Phosphate; Etanidazole; Ethoglucid; Etoposide; Fadrozole Hydrochloride; Fazarabine; Fenretinide; Floxuridine; Fludarabine Phosphate; Fluorouracil; Flutamide; Formestane; Fotemustine; Gallium Nitrate; Gencitabine; Gusperimus; Homoharringtonine; Hydroxyurea; Idarubicin Hydrochloride; Ifosfamide; Ilmofosine; Improsulfan Tosylate; Inolimomab; Interleukin-2; Irinotecan; JM-216; Letrozole; Lithium Gamolenate; Lobaplatin; Lomustine; Lonidamine; Mafosfamide; Melphalan; Menogaril; Mercaptopurine; Methotrexate; Methotrexate Sodium; Miboplatin; Miltefosine; Misonidazole; Mitobronitol; Mitoguazone Dihydrochloride; Mitolactol; Mitomycin; Mitotane; Mitozanetrone Hydrochloride; Mizoribine; Mopidamol; Multialchilpeptide; Muromonab-CD3; Mustine Hydrochloride; Mycophenolic Acid; Mycophenolate Mofetil; Nedaplatin; Nilutamide; Nimustine Hydrochloride; Oxaliplatin; Paclitaxel; PCNU; Penostatin; Peplomycin Sulphate; Pipobroman; Pirarubicin; Piritrexim Isethionate; Piroxantrone Hydrochloride; Plicamycin; porfimer Sodium; Prednimustine; Procarbazine Hydrochloride; Raltitrexed; Ranimustine; Razoxane; Rogletimide; Roquinimex; Sebriplatin; Semustine; Sirolimus; Sizofiran; Sobuzoxane; Sodium Bromebrate; Sparfosic Acid; Sparfosate Sodium; Sreptozocin; Sulofenur; Tacrolimus; Tamoxifen; Tegafur; Teloxantrone Hydrochloride; Temozolomide; Teniposide; Testolactone; Tetrasodium Meso-tetraphenylporphinesulphonate; Thioguanine; Thioinosine; Thiotepa; Topotecan; Toremifene; Treosulfan; Trimetrexate; Trofosfamide; Tumor Necrosis Factor; Ubenimex; Uramustine; Vinblastine Sulphate; Vincristine Sulphate; Vindesine Sulphate; Vinorelbine Tartrate; Vorozole; Zinostatin; Zolimomab Aritox; and Zorubicin Hydrochloride.
For about four decades, the antimetabolite 5-fluorouracil (5-FU), and nucleosides which include this base (e.g., 5-fluoro-2′-deoxyuridine or FdUrd), have remained among the few “standard” drugs effective against solid tumors in man. 5-Fluorouracil is used mainly for the treatment of colorectal, ovarian, renal, breast and head and neck cancers. 5-Fluoro-2′-deoxyuridine is used for the treatment of solid tumors, including hepatic metastases of advanced gastrointestinal adenocarcinomas, renal cell carcinomas, advanced ovarian cancer, and squamous cell carcinomas of the head and neck. The clinical utility of the fluoropyrimidines is limited by the host-toxicity induced by the administration of these compounds. Manifestations of the host-toxicity of the fluoropyrimidines include mainly gastrointestinal epithelial ulceration, myelosuppression and, to a lesser extent, cardiotoxicities, hepatotoxicities and neurotoxicities. A population of cancer patients is intolerant to treatment with 5-fluorouracil and 5-fluoro-2′-deoxyuridine. Moreover, it has also been shown that cancers, treated with fluoropyrimidines, become resistant, i.e., develop tolerance towards these drugs.
Colorectal cancer (CRC) is a multi-step process resulting from the accumulation of mutations in clonal populations of colonocytes. Mutations of the p53 tumor suppressor gene are a relatively late, yet common event in the pathogenesis of colorectal cancer, occurring in over 80% of late adenomas and carcinomas (Fearon, et al., FASEB J. 6, 2789 (1992); Srivastarva, et al., Contemp. Oncol. April 63 (192); Kline, et al., Cancer (Phila. 73, 28 (1994). Conventional therapy for advanced dise
Hoong Lee K.
Medford Russell M.
Saxena Uday
Somers Patricia K.
AtheroGenics, Inc.
King & Spalding LLP
Knowles, Esq. Sherry M.
Robinson Binta
Rotman Alan L.
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