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  Halocombstatins and methods of synthesis thereofRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai, Oxygen Bonded Directly To A Carbon Or Hydrogen And Wherein The Oxygen Is Not Bonded Directly To PhosphorusHalocombstatins and methods of synthesis thereof description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070167412, Halocombstatins and methods of synthesis thereof. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATION DATA [0001] This application is based on and claims the benefit of U.S. Provisional Patent Application No. 60/505,935 filed on Sep. 24, 2003, the disclosure of which is incorporated herein in its entirety by this reference. TITLE OF INVENTION [0003] Halocombstatins and Methods of Synthesis Thereof. FIELD OF THE INVENTION [0004] This invention relates to novel compounds having utility in the treatment of cancer and/or as antimicrobials. BACKGROUND OF THE INVENTION [0005] Pharmaceutical agents to treat cancer and/or tumors are widely sought. Antiangiogenesis agents are being pursued as a promising antitwnor therapeutic agents. Combretastatin A-4 is one such antiangiogenesis agent. Studies have demonstrated that combretastatin A-4 disrupts the microtubules of human umbilical vein endothelial cells (HUVEC) in culture. It has also been shown that the tubulin-binding properties shown in cell-free systems are retained when the compound enters cells, and that tubulin binding is a significant component of biological acitivity. [0006] The African Bush Willow Combretum caffrum has proved to be a very important source of cancer cell growth inhibitory constituents named combretastatins. The most potent of these constituents is combretastatin A-4 (1a, "CA-4"), and its sodium phosphate derivative (1b, "CA-4P") was advanced to Phase I human cancer clinical trials in 1998. (Remick, S. C., et al., (1999) Phase I Pharmacokitictics Study of Single Dose Intravenous (IV) Combretastatin A-4 Prodrug (CA4P) in Patients (pts) with Advanced Cancer, Molecular Targets and Cancer Therapeutics Discovery Discovery, Development, and Clinical Validation, Proceedings of the AACR-NCI-EORTC International Congress, Washington, D.C., #16, p. 4.) Overall results continue to be promising, and human cancer Phase II and combination Ib trials are currently underway. [0007] Antivascular, antiangiogenesis and general antimetastatic activities of CA4P as well as its synergistic utility in combination with other anticancer drugs, radioimmunotherapy and hyperthermia are all areas of active research interest. (see Griggs, J., et al, Combretastatin A-4 Disrupts Neovascular Development in Non-Neoplastic Tissue, British J. of Cancer 2001, 84, 832-835; Folkman, J., Angiogenesis-Dependent Diseases, Seminars in Oncology 2001, 28, 536-542; Kruger, E. A. et al., Approaches to Preclinical Screening of Antiangiogenic Agents, Seminars in Oncology 2001, 28, 570-576; Jin, X., et al., Evaluation of Endostatin Antiangiogenesis Gene Therapy in vitro and in vivo, Cancer Gene Therapy 2001, 8, 982-989; Vacca, A., et al., Bone Marrow Angiogenesis in Patients with Active Multiple Myeloma, Seminars in Oncology 2001, 28, 543-550; Rajkumar, S. V., et al., Angiogenesis in Multiple Myeloma, Seminars in Oncology 2001, 28, 560-564, Griggs, J., et al., Potent Anti-metastatic Activity of Combretastatin AX, Int J Oncol. 2001, 821-825; Pedley, R. B. et al., Eradication of Colorectal Xenografts by Combined Radioirnunotherapy and Combretastatin A-4 3-O-Phosphate, Cancer Research 2001, 61, 4716-4722; Eikesdal, H. P., et al., Tumor Vasculature is Targeted by the Combination of Combretastatin A-4 and Hyperthermia, Radiotherapy and Oncology 2001, 61, 313-320.) [0008] Several of the compounds of the present invention are particularly concerned with treatment of thyroid gland cancer. By 2002, some 20,000 people in the United States were diagnosed with carcinoma of the thyroid gland; of these the distribution was about 80% papillary and 14% follicular differentiated carcinomas derived from follicular epithelial cells producing thyroid hormone. Of the remaining thyroid malignancies, about 4% were medullary carcinoma (neuroendocrine) and 2% of the exceptionally aggrwsive anaplastic carcinoma (median survival 4-5 months and a near 100% lethal outcome). Significantly, the incidence of both follicular and anaplastic carcinomas are elevated in geographic areas of iodine deficiency. Radiation exposure represents the most general risk factor for thyroid cancer. In addition, excess production of the pituitary homone thyroid-stimulating hormone (THS), which is very important m regulating thyroid gland growth and fimction, may be important in the etiology of thyroid cancer. Previously used clinical treatments for thyroid cancer include surgery, suppression of THS, .sup.131I-radiotherapy, and anticancer dmgs. But in 2002, another 1,300 victims of thyroid cancer in the U.S. died, emphasizing the great need for more routinely effective anticancer drugs. SUMMARY OF THE INVENTION [0009] The present invention relates to novel compounds constituting modifications of combretastatin A-3 (3a) and its phosphate prodrug (3b), wherein the 3-hydroxy group or the 3-hydroxy and 5-hydroxy groups are replaced with a halide. Representative halides are fluorine, chlorine, bromine and iodine. Salts of the novel compounds are also disclosed herein. Also described herein are phosphate ester derivatives of the 3-fluoro, 3-chloro, 3-bromo and 3-iodo-stilbenes. Compounds of the Invention Comprise: [0010] Wherein X is F, Cl Br or I [0011] Werein X is F, Cl, Br or I, and R is a metal cation such as Na, Li, K, Cs, Rb, Ca, Mg or is morpholine, piperidine, glycine-OCH.sub.3, tryptophan-OCH.sub.3 or NH(CH.sub.2OH).sub.3. [0012] Wherin X is F, Cl, Br or I, and Z is a metal cation such as Na, Li, K, Cs, Rb, Ca, Mg or is morpholine, piperidine, glycine-OCH.sub.3, trytophan-OCH.sub.3 or NH(CH.sub.2OH).sub.3. [0013] Several of the compounds of the invention exhibit greatly enhanced (>10-100x) cancer cell growth ibihbition, as compared to pnor art combretastin compounds such as CA-4 and CA-3, against a panel of human cancer cell lines and the muoine P388 leukemia. The iodo compounds appear to show particular promise in the treatment of thyroid cancers. The compounds of the present invention exhibit inhibiting of tubua polymerization and binding of colchicine to tablulin. In addition, several of the compounds exhibit antimicrobial properties. DESCRIPION OF THE DRAWINGS [0014] FIG. 1 shows the structural formulas of several prior art compounds. [0015] FIG. 2 shows the reaction scheme for synthesizing some of the compounds of the present invention, including strucbual formulas for the compounds of the invention. [0016] FIG. 3 shows a continuation of the reaction scheme of FIG. 2. [0017] FIG. 4 shows the reaction scheme for synthesizing some of the compounds of the present invention, including structural formulas for the compounds of the invention. [0018] FIG. 5 shows photographs of results of the cord formation assay. DETAILED DESCRIPTION OF THE INVENTION [0019] The concept of antiangiogenesis as a therapeutic approach for the treatment of cancer, particularly tumors, is being actively pursued as a promising strategy. The compound combretastatin A-4 has previously been demonstrated to disrupt the microtubules of hurnan umbilical vein endothelial cells (HUVEC) in culture. Those stes confirmed that the tubulin-binding properties shown in cell-free systems are retained when the compound enters cells, and that tubulin binding is a significant component of the biological activity. [0020] Thus, an object of the present invention is to provide new compounds that may be useful as tubulin binding agents. [0021] A further object of the invention is to provide compounds that possess antiangiogenesis properties. Continue reading about Halocombstatins and methods of synthesis thereof... Full patent description for Halocombstatins and methods of synthesis thereof Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Halocombstatins and methods of synthesis thereof patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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