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Neuroprotective and anti-proliferative compoundsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Polycyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Bicyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Plural Hetero Atoms In The Bicyclo Ring SystemNeuroprotective and anti-proliferative compounds description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060199835, Neuroprotective and anti-proliferative compounds. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation-in-part of and claims priority to U.S. patent application Ser. No. 10/276,803 (filed May 18, 2001), the entirety of which is herein incorporated by reference. U.S. patent application Ser. No. 10/276,803 is the National Phase application of PCT/CA01/00718 (filed May 18, 2001), the entirety of which is herein incorporated by reference. This application claims priority to Canadian Patent Application Serial No. 2,308,994 (Filed May 19, 2000), the entirety of which is herein incorporated by reference. FIELD OF THE INVENTION [0002] This invention features compounds of formula I, which are useful in the treatment and prevention of cancer and inflammation by inducing apoptosis in proliferating cells. BACKGROUND OF THE INVENTION [0003] Cancer is one of the leading causes of death in North America. Cancer cells may be loosely characterized as rapidly multiplying and invasive cells which grow and migrate through out the body. Localized areas of cellular proliferation are referred to as tumors which may interrupt regular organ function, resulting in organ disfunction and death. These cells have overcome internal death signaling mechanisms which would normally regulate their population, proliferation, and mobility. Alternatively, these cells upregulate various survival mechanisms which prevent the cell from initiating apoptosis. In several cases, the cytotoxic properties of the indolocarbazoles such as staurosporine, UNC 01, Rebeccamycin and NB 506, have been exploited to affect a therapeutic use in cancer. [0004] Various cancers and cancer cell lines, including colon, lung, and breast, display elevated levels of the Inhibitor of Apoptosis Proteins (IAPs), including HIAP1,2 and XIAP, as either mRNA and/or protein (U.S. Pat. No. 5,919,912). The down-regulation of the IAPs in cancer cells can effectively shift the chemotherapeutic dose response required to kill such cancer cells, in the case of HAIP1, or to kill cancer cells outright, in the case of XIAP. Compounds that down-regulate the expression of these genes and/or proteins would therefore be useful in treating cancers. [0005] Diseases such as MS and ALS are characterized by progressive neuronal damage and cell loss in the central and peripheral nervous systems (CNS and PNS respectively). Pathology of MS is believed to involve autoimmune recognition of self-antigens by autoreactive T lymphocytes (Antel J. J. Neuroimmunol. (1999), 98, 45). Control over the development and relative populations of T-lymphocytes proceeds via apoptotic cell death. Aberant autoreactive T lymphocyte populations may lead to neuronal demyelinization and disease progression. Recently, it has been observed that these "potentially pathogenic autoreactive T-lymphocyctes" escape regular apoptotic control by the upregulation of the IAPs (Shareif M. K. et. al., J. Neuroimmunology (2002), 129, 159; 224). Therefore, therapies which induce apoptosis of autoreactive T-lymphocyctes represent novel therapies for inflammation and autoimmune diseases such as MS. [0006] Stimulation of the tumor necrosis factor (TNF) receptor family of proteins, such as CD95 (Fas/APO-1), TNFR1, and DR5, with their respective ligands Fas, TNF-.alpha., and TRAIL, result in the initiation of apoptosis via caspase-8 mediated death signal. Defects in this signaling mechanism may lead to cellular populations which overcome normal apoptotic signaling leading to uncontrolled cellular proliferation as seen in various inflammatory diseases, in aberrant autoreactive T-lymphocyte populations implicated in MS, and in tumor formation and cancer. The bis-indolemaleimides Bis VIII and Bis IX are known PKC inhibitors (Davis, P. D., et al., J. Med. Chem. (1992), 35, 994). These compounds have recently been shown to sensitize various Fas, TNF-.alpha., and/or TRAIL resistant cancer cell lines to TNF receptor mediated apoptosis (Zhou, T., et al., Nature Medicine, (1999), 5, 42). It is suggested that this sensitization is independent of PKC activity. Compounds which augment apoptosis mediated by TNF receptor family signaling will be useful in the treatment of uncontrolled cellular proliferation. [0007] The applicants have recently reported the synthesis of a series of 3-(indol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones and 3-(benzimidazol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones, represented by Formula I of PCT/CA01/00718. These compounds were prepared using a novel cyclization reaction, for the preparation of neuroprotective and anti-cancer compounds. [0008] The applicant herein discloses the preparation and use of a series of 3-(indol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones and 3-(benzimidazol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones which have been functionalized at R.sup.4 and/or R.sup.5 with alkylthioamidino related moieties (formula I). Additionally, 3-(indolin-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones, represented by formula II, are disclosed. [0009] Compounds of formula I and II have been shown by the applicant to induce apoptosis either alone or synergistically with anti-Fas to incude apoptosis in several cancer cells including jurkats. Jurkats are often used as a model of autoreactive T-lymphocytes and the ability to kill jurkats may often be correlated to efficacy in models of autoimmune disease. These compounds are useful in the treatment and prevention of cancer and inflammation. [0010] 3-(1-Indol-1-yl)-4-(1-methylindol-3-yl)-pyrrole-2,5-dione was first reported by Davis et al. (J. Med. Chem., 1992, 35, 177) as an inhibitor of PKC. This compound was prepared using a different chemistry than that of the applicant. No other reports or uses of these compounds have been disclosed. [0011] The disclosed compounds resemble but display distinctly different biological profiles to the indolocarbazole alkaloids Staurosporine and K252a. Various derivatives of these natural products have been described for the treatment of neurodegenerative disorders (U.S. Pat. No. 6,013,646 WO96/31515,WO 97/46565 and WO97/49406). Other indolocarbazole derivatives are disclosed by Glicksman, M. A. et al. (WO 95 07911), Lewis, M. E. (WO 94 02488), Lewis, M. E. et al. (U.S. Pat. No. 5,756,494, U.S. Pat. No. 5,741,808, and U.S. Pat. No. 5,621,101). Indolocarbazole derivatives have also been reported for use in treatment of cancer (EP 0 323 171, EP 0 643 966, U.S. Pat. No. 4,923,986, U.S. Pat. No. 4,877,776, WO 94/27982, WO99/47522), as antimicrobial agents (Prudhomme et al, J. Antibiotics, 1994, 47, 792) and in the treatment of hypertension (Hachisu et al. Life Sciences 1989, 44, 1351). [0012] A variety of synthetic procedures have been reported in the literature for the preparation of bis(indolyl)pyrrole-2,5-diones and indolocarbazoles. See, for example, Bit et al., J. Med. Chem., 1993, 63, 21; Bergman et al., Tetrahedron Lett., 1987, 28, 4441; Davis et al., Tetrahedron Lett., 1990, 31, 2353, 5201; Faul, M. M. et al., Tetrahedron Lett., 1999, 40, 1109; Faul M. M. et al. U.S. Pat. No. 5,859,261, U.S. Pat. No. 5,919,946, and U.S. Pat. No. 6,037,475. For synthetic studies see Wood, J. L. et al. J. Am. Chem. Soc. 1997, 119, 9641; and Danishefsky, S. et al. J. Am. Chem. Soc. 1996, 118, 2825. SUMMARY OF THE INVENTION [0013] The present invention provides novel compounds of formula I and II (defined as subcategories of a broader group of compounds of formula III). Compounds disclosed herein are useful in the prevention and treatment of disorders and physiological conditions characterized by loss of growth and cellular differentiation control, as exemplified in cancer and inflammation. [0014] The invention also relates to a general synthetic route, permitting preparation of compounds of formula I and If which are distinct from the indolocarbazole class of compounds and their synthetic precursors, which represent 3-(indol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones and 3-(benzimidazol-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones, represented by formula I, and 3-(indolin-1-yl)-4-(indol-3-yl)-pyrrole-2,5-diones, represented by formula II. [0015] Also included are inventive methods for the preparation of the compounds disclosed herein. [0016] The present invention are compounds of formula I and II: [0017] These are subcategories of a broader group of compounds of the formula III: [0018] Formulas I, II and III have functional groups designated as A.sup.1, A.sup.2, B.sup.1, B.sup.2, X.sup.1--X.sup.9 and R.sup.1--R.sup.8 as defined further herein. BRIEF DESCRIPTION OF THE DRAWINGS [0019] The invention is now described with reference to the accompanying drawings described below. [0020] FIG. 1 depicts the killing of DU145 prostate cancer cells with compound 136 (described in Example 136). A survival curve is shown for DU145 after seven days of treatment with the compound at varying concentrations. Continue reading about Neuroprotective and anti-proliferative compounds... 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