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  Tetracyclic benzamide derivatives and methods of use thereofUSPTO Application #: 20070249653Title: Tetracyclic benzamide derivatives and methods of use thereof Abstract: The invention relates to Tetracyclic Benzamide Derivatives; compositions comprising a Tetracyclic Benzamide Derivative; and methods for treating or preventing an inflammatory disease, a reperfusion disease, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease, or cancer, comprising administering to a subject in need thereof an effective amount of a Tetracyclic Benzamide Derivative. (end of abstract)
Agent: Wilmer Cutler Pickering Hale And Dorr LLP - New York, NY, US Inventors: Prakash Jagtap, William Williams, Alexander Nivorozhkin, Csaba Szabo USPTO Applicaton #: 20070249653 - Class: 514285000 (USPTO) Related 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, Tetracyclo Ring System Having The Six-membered Hetero Ring As One Of The Cyclos, Plural Hetero Atoms In The Tetracyclo Ring System (e.g., Acronycines, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20070249653. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application is a continuation of U.S. application Ser. No. 10/788,228, filed Feb. 26, 2004, which claims the benefit of U.S. provisional application no. 60/450,925, filed Feb. 28, 2003, the entire disclosures of U.S. application no. 10/788,228 and of U.S. provisional application no. 60/450,925 being hereby incorporated by reference. 1. FIELD OF THE INVENTION [0003] The invention relates to Tetracyclic Benzamide Derivatives; compositions comprising an effective amount of a Tetracyclic Benzamide Derivative; and methods for treating or preventing an inflammatory disease, a reperfusion disease, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease, or cancer, comprising administering to a subject in need thereof an effective amount of a Tetracyclic Benzamide Derivative. 2. BACKGROUND OF THE INVENTION [0004] Inflammatory diseases, such as arthritis, colitis, and autoimmune diabetes, typically manifest themselves as disorders distinct from those associated with reperfusion diseases, e.g., stroke and heart attack, and can clinically manifest themselves as different entities. However, there can be common underlying mechanisms between these two types of disorders. In particular, inflammatory disease and reperfusion disease can induce proinflammatory cytokine and chemokine synthesis which can, in turn, result in production of cytotoxic free radicals such as nitric oxide and superoxide. NO and superoxide can react to form peroxynitrite (ONOO.sup.-) (Szabo et al., Shock 6:79-88, 1996). [0005] The ONOO.sup.--induced cell necrosis observed in inflammatory disease and in reperfusion disease involves the activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS), also known as poly (ADP-ribose) polymerase (PARP). Activation of PARP is thought to be an important step in the cell-mediated death observed in inflammation and reperfusion disease (Szabo et al., Trends Pharmacol. Sci. 19:287-98, 1998). [0006] A number of PARP inhibitors have been described in the art. See, e.g., Banasik et al., J. Biol. Chem., 267:1569-75, 1992, and Banasik et al., Mol. Cell. Biochem., 138:185-97, 1994; WO 00/39104; WO 00/39070; WO 99/59975; WO 99/59973; WO 99/11649; WO 99/11645; WO 99/11644; WO 99/11628; WO 99/11623; WO 99/11311; WO 00/42040; Zhang et al., Biochem. Biophys. Res. Commun., 278:590-98, 2000; White et al., J. Med. Chem., 43:4084-4097, 2000; Griffin et al., J. Med. Chem., 41:5247-5256, 1998; Shinkwin et al., Bioorg. Med. Chem., 7:297-308, 1999; and Soriano et al., Nature Medicine, 7:108-113, 2001. Adverse effects associated with administration of PARP inhibitors have been discussed in Milan et al., Science, 223:589-591, 1984. [0007] S. P. Hiremath et al., Oriental Journal of Chemistry 13(2):173-176 (1997) discloses isoquinoline compounds allegedly useful as antifungal, antibacterial or anthelmintic agents. [0008] S. P. Hiremath et al., Journal of the Indian Chemical Society 72(10):735-738 (1995) discloses isoquinolinone compounds [0009] S. P. Hiremath et al., Indian Journal of Heterocyclic Chemistry 3(1):37-42 (1993) discloses isoquinolinethione compounds allegedly useful as antifungal, antibacterial, oxytocic or anthelmintic agents. [0010] S. P. Hiremath et al., Indian Journal of Chemistry, Section B 24B(12):1235-1238 (1985) discloses indoloisoquinoline compounds. [0011] U.S. Pat. No. 4,623,304 to Ishizumi et al. discloses indoloisoquinoline compounds allegedly having anti-tumor activity. [0012] United Kingdom Patent No. GB 2025932 B2 by Sumitomo Chemical Co. discloses indoloisoquinoline compounds allegedly having bacteriacidal or fungicidal activity. [0013] G. Winters et al., Farmaco. Ed. Sci. 34(6):507-517 (1979) discloses indoloisoquinolinones allegedly having antibacterial or fungicidal activity. [0014] U.S. Pat. No. 4,113,731 to G. Winters et al. discloses indoloisoquinolines. [0015] U.S. Pat. Nos. 5,733,918, 5,710,162, and 6,028,079 to Okazaki et al. disclose indenoquinolines allegedly useful as antitumor agents. [0016] S. Srivastava et al., Journal of the Indian Chemical Society 66(4):276-81 (1989) discloses a synthesis of indenoisocoumarins and indenoisoquinolones. [0017] G. Jha et al., Indian Journal of Chemistry, Section B 24B(4):440-444 (1985) discloses a synthesis of indenoisocoumarins and indenoisoquinolones. [0018] J. N. Chatterjea et al., J. Indian Chem. Soc. 44(11):911-919 (1967) discloses a synthesis of dihydroisocoumarins. [0019] There remains, however, a need in the art for compounds useful for treating or preventing an inflammatory disease, a reperfusion disease, an ischemic condition, renal failure, diabetes, a diabetic complication, a vascular disease, or cancer. [0020] Citation of any reference in Section 2 of this application is not an admission that the reference is prior art. 3. SUMMARY OF THE INVENTION [0021] The present invention encompasses compounds having the Formula (I): and pharmaceutically acceptable salts and hydrates thereof, wherein: [0022] R.sub.5 is --C.sub.1-C.sub.10 alkyl, halo-substituted-(C.sub.1-C.sub.5 alkyl), HO-substituted-(C.sub.1-C.sub.5 alkyl), carboxy-substituted-(C.sub.1-C.sub.5 alkyl), --C(O)--C.sub.1-C.sub.10 alkyl, --C(O)-aryl, --C(O)-(3- to 7-membered monocyclic heterocycle), --C(O)-(7- to 10-membered bicyclic heterocycle) or -glycoside; Continue reading... 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