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  Cellular accumulation of phosphonate analogs of hiv protease inhibitor compoundsUSPTO Application #: 20070010489Title: Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds Abstract: Phosphonate substituted compounds with HIV protease inhibitory properties having use as therapeutics and for other industrial purposes are disclosed. The compositions inhibit 5 HIV protease activity and/or are useful therapeutically for the treatment of AIDS and other antiviral infections, as well as in assays for the detection of HIV protease. (end of abstract) Agent: Gilead Sciences Inc - Foster City, CA, US Inventors: Murty N. Arimilli, Mark W. Becker, Clifford Bryant, James M. Chen, Xiaowu Chen, Azar Dastgah, Maria Fardis, Gong-Xin He, Haolun Jin, Choung U. Kim, William A. Lee, Christopher P. Lee, Kuei-Ying Lin, Hongtao Liu, Richard L. Mackman, Michael L. Mitchell, Peter H. Nelson, Hyung-Jung Pyun, Tanisha D. Rowe, Mark Sparacino, Sundaramoorthi Swaminathan, James D. Tario, Jianying Wang, Matthew A. Wiliams, Lianhong Xu, Zheng-Yu Yang, Richard H. Yu, Jiancun Zhang, Lijun Zhang USPTO Applicaton #: 20070010489 - Class: 514079000 (USPTO) Related 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, Nitrogen Containing Hetero Ring The Patent Description & Claims data below is from USPTO Patent Application 20070010489. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Patent Application No. 60/670,844, filed Apr. 13, 2005, the specification of which is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] This invention relates to novel compounds which are useful for treating a variety of cell proliferative disorders such as cancer. BACKGROUND OF THE INVENTION [0003] A wide range of growth factors coordinate cell proliferation and differentiation. Malignant cells arise as a result of a stepwise progression of events that include the unregulated expression of growth factors or components of their signaling pathways. Tyrosine phosphorylation events initiated by receptor, cytoplasmic and nuclear kinases and regulated by phosphatases are central to these processes. Mutation, hyper-activation, translocation and overexpression of protein tyrosine kinases are all associated with tumorigenesis. In addition to increasing proliferative rates and immortalizing cells, overexpression of tyrosine kinases can lead to morphological transformation and cause anchorage independence, contributing to the promotion of migratory ability and possibly the induction of metastases. [0004] Certain compounds with structures based upon mimicry of ATP or phosphotyrosine have been shown to be effective kinase inhibitors. Those based upon phosphotyrosine have been demonstrated to be the more specific tyrosine kinase inhibitors. Because of their ability to inhibit tyrosine phosphorylation, these compounds may alter cell responses to growth factors or other process driven by tyrosine kinase activity, including unregulated growth as the result of tyrosine kinase overexpression, mutation, or translocation. Inhibition of tyrosine kinases occupying a central role in proliferative signaling pathways, or in pathways regulating cell cytoskeletal structure, even temporary or incomplete inhibition, may be sufficient to switch a cancerous cell from a proliferative cycle into programmed cell death, or apoptosis. Death by apoptosis is most often observed upon effective treatment with tyrosine kinase inhibitors. [0005] Selective inhibition of specific tyrosine kinases offers a method of targeting cancerous cell growth with a high degree of specificity and minimal toxicity to normally growing cells and tissues. Thus, specific inhibitors of tyrosine kinases have great potential as clinical anti-cancer treatments. A number of small molecules which act as tyrosine kinase inhibitors have been identified. For example, certain phenyl acrylonitrile compounds have been described as tyrosine kinase inhibitors, effective to inhibit cell proliferation (see for example, U.S. Pat. No. 5,891,917, U.S. Pat. No. 5,217,999, U.S. Pat. No. 5,773,476, U.S. Pat. No. 5,935,993, U.S. Pat. No. 5,656,655, U.S. Pat. No. 5,677,329 and U.S. Pat. No. 5,789,427). [0006] Inhibition of tyrosine kinases offers one mechanism by which cell proliferation can be inhibited. One of skill in the art will appreciate that other mechanisms of inhibition may also be involved. [0007] There is a need in the art to identify compounds that inhibit cell proliferation, for treating cancer with increased site specificity, improved stability and solubility, and increased potency. SUMMARY OF THE INVENTION [0008] A number of compounds have now been identified that inhibit abnormal cell proliferation, for example cancer cell growth, and/or inhibit angiogenesis. [0009] According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent, e.g., for treating a cancer selected from leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. [0010] In accordance with a further aspect of the present invention, there is provided a method for modulating cell proliferation, preferably inhibiting cell proliferation (e.g., a cancer selected from leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer), comprising administering an effective amount of a compound of the invention to a cell or animal in need thereof, e.g., diagnosed as having cancer and/or a tumor. The invention also includes use of a compound of the invention in the manufacture of a medicament to modulate cell proliferation, preferably inhibit cell proliferation (e.g., a cancer selected from leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer). [0011] In a preferred embodiment the present invention provides a method of inhibiting the proliferation of a cancer cell comprising administering an effective amount of a compound of the invention to a cell or animal in need thereof. The cancer cell treated may be any type of cancer including leukemia, lymphoma, myeloma, metastatic carcinoma, sarcoma or any other malignant transformation or any other malignancy, including a cancer selected from leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, prostate cancer, and breast cancer. [0012] In another aspect, the invention provides a method of modulating tyrosine kinase activity in a cell by administering an effective amount of a compound of the invention. In a further aspect, the invention provides a method of inhibiting tyrosine kinase activity in a cell by administering an effective amount of a compound of the invention. The present invention also provides a use of a compound of the invention to modulate, preferably inhibit, tyrosine kinase activity. The present invention further provides a use of a compound of the invention to prepare a medicament to modulate tyrosine kinase activity, preferably inhibit tyrosine kinase activity. It is appreciated that the inhibition of cell growth by the compounds of the invention may be effected by other mechanisms. [0013] In accordance with a further aspect of the present invention, there is provided a method for inhibiting angiogenesis, comprising administering an effective amount of a compound of the invention to a cell or animal in need thereof. The invention also includes a use of a compound of the invention in the manufacture of a medicament to inhibit angiogenesis. [0014] Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. DETAILED DESCRIPTION OF THE INVENTION [0015] A number of compounds have now been identified that are suitable for use to inhibit abnormal cell proliferation, for example cancer cell growth. I. Compounds of the Invention [0016] The present invention provides compounds of Formula I, and salts, solvates, or hydrates thereof: wherein [0017] Ar and Ar' are independently an optionally substituted phenyl ring; [0018] each n is, independently for each occurrence, either 0 or 1; [0019] X is selected from O, NR, and (CH.sub.2).sub.m; [0020] R is selected from H, OH, and alkyl, preferably C.sub.1-4alkyl; and [0021] m is an integer from 0 to 3, preferably 1 or 2. [0022] In certain embodiments, substituents on Ar or Ar' are selected from halo, cyano, sulfate, phosphate, SO.sub.3H, P(.dbd.O)(OH).sub.2, NO.sub.2, alkyl, haloalkyl (up to perhalo, e.g., perfluoro), OH, alkoxy, CH.sub.3O(CH.sub.2CH.sub.2O).sub.qCO.sub.2--, haloalkoxy (up to perhalo, e.g., perfluoro), --O--Si(alkyl)(alkyl)(alkyl), HO.sub.2C--, alkylO.sub.2C--, alkylC(O)--, alkylCO.sub.2--, alkylOCO.sub.2--, (R.sup.6)(R.sup.7)N--, R.sup.7C(O)N(R.sup.6)--, (R.sup.6)(R.sup.7)NCO--, (R.sup.6)(R.sup.7)NC(O)N(R.sup.6), (R.sup.6)(R.sup.7)NCO.sub.2--, SH, alkylthio, and --O(CH.sub.2).sub.yO--, wherein each y is, independently for each occurrence, an integer from 1 to 6, preferably 1 or 2, thereby forming a ring fused to the phenyl ring; R.sup.6 and R.sup.7 are each independently selected from hydrogen and C.sub.1-6alkyl, or R.sup.6 and R.sup.7 together are --(CH.sub.2).sub.pY(CH.sub.2).sub.p--, thereby forming a ring; each p is, independently for each occurrence, an integer from 1 to 3, preferably 1 or 2; and Y is selected from O, S, NH, NC.sub.1-4alkyl, and CH.sub.2. [0023] In certain embodiments, Ar and Ar' are independently substituted from one to three times at any of the 3-, 4-, or 5-positions (relative to the attachment to the rest of the molecule) with substituents selected from OH, alkyl, acyloxy, and alkoxy, preferably from OH, C.sub.1-6alkyl, C.sub.1-6alkylCO.sub.2, and C.sub.1-6alkoxy. Continue reading... Full patent description for Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Cellular accumulation of phosphonate analogs of hiv protease inhibitor compounds 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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