(19) TZZ¥Z_ _ T (11) EP 3 081 214 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 19.10.2016 Bulletin 2016/42 A61K 31/4178 (2006.01) A61K 31/422 (2006.01) A61P 25/28 (2006.01) (21) Application number: 16000020.4 (22) Date of filing: 30.08.2004 (84) Designated Contracting States: • Yuan, Junying, AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Newton, HU IE IT LI LU MC NL PL PT RO SE SI SK TR MA 02468 (US) • Jagtap, Prakash, (30) Priority: 29.08.2003 US 498882 P North Andover, MA 01845 (US) (62) Document number(s) of the earlier application(s) in • Degterev, Alexei, accordance with Art. 76 EPC: Brookline, 10011481.8 / 2 384 753 MA 02445 (US) 04821344.1 / 1 663 184 (74) Representative: Bösl, Raphael Konrad (71) Applicants: Isenbruck Bösl Hörschler LLP • THE BRIGHAM AND WOMEN’S HOSPITAL, INC. Patentanwälte Boston, MA 02115 (US) Prinzregentenstraße 68 • President and Fellows of Harvard College 81675 München (DE) Cambridge, MA 02138 (US) Remarks: (72) Inventors: •This application was filed on 05-01-2016 as a • Cuny, Gregory D., divisional application to the application mentioned Houston, under INID code 62. TX 77004 (US) •Claims filed after the date of filing of the application (Rule 68(4) EPC). (54) INHIBITORS OF CELLULAR NECROSIS (57) The present invention relates to compounds and pharmaceutical preparations and their use in therapy for preventing or treating trauma, ischemia, stroke and degenerative diseases associated with cell death. Methods and compositions of the invention are particularly useful for treating neurological disorders associated with cellular necrosis. EP 3 081 214 A2 Printed by Jouve, 75001 PARIS (FR) EP 3 081 214 A2 Description FEDERALLY SPONSORED RESEARCH 5 [0001] This invention was made with Government support under National Institute of Health Grant No. GM-64703. The Government may have certain rights to this invention. PRIORITY INFORMATION 10 [0002] This application claims the benefit under 35 U.S.C. § 119(e) of the filing date of US Provisional Application No. 60/498,882 filed August 29, 2003, herein incorporated by reference. FIELD OF INVENTION 15 [0003] The invention relates to compositions and methods for preventing and treating diseases involving cell death. In particular, the invention relates to therapeutic compounds and methods for treating neurological diseases involving cell death. BACKGROUND OF INVENTION 20 [0004] Acute and chronic neurological diseases can be caused by a number of different factors. However, many of these diseases are characterized by cell death in specific regions of the central nervous system. [0005] Neurological diseases are a group of maladies that afflict a significant portion of the human population. The medical and socio-economic impacts of these diseases are significant. Although the etiology of each acute and chronic 25 neurological disease is likely different, one common feature that many share is rapid or progressive irreversible cell death in specific regions of the central nervous system (Standaert, D. G.; Young, A. B. In Goodman & Gilman’s The Pharmacological Basis of Therapeutics, Tenth Edition; Hardman, J. G.; Limbird, L. E., Eds.; McGraw-Hill: New York, 2001; Chapter 22, pp 549 - 568; Mattson, M. P. Nature Rev. Mol. Cell. Biol. 2000, 1, 120 -129). Compelling evidence is emerging that neuron cell death occurs in acute neurological diseases, such as stroke and trauma (Raghupathi, R.; 30 Graham, D.I.; McIntosh, T.K. J. Neurotrauma 2000, 17(10), 927 - 38) and in neurodegenerative diseases, such as Parkinson’s disease - PD (Vila, M.; Wu, D. C.; Przedborski, S. Trends in Neuroscience 2001, 24(11), S49 - S55), Huntington’s disease - HD (McMurry, C. T. Trends in Neuroscience 2001, 24(11), S32 - S38), amyotrophic lateral sclerosis - ALS (Beckman, J. S.; Estéves, A. G.; Crow, J. P. Trends in Neuroscience 2001, 24(11), S15 - S20), and human immunodeficiency virus associated dementia - HAD (Kaul, M.; Garden, G. W.; Lipton, S. A. Nature 2001, 410, 35 988 - 994). Studies have also suggested that cell death occurs in Alzheimer’s disease-AD (Eldadah, B. A.; Faden, A. I. J. Neurotrauma 2000, 17(10), 811- 829). Albeit, neurons present in AD may be chronically dysfunctional without nec- essarily undergoing active cell death (Selkoe, D. J. Nature 1999, 399 (Suppl), A23 - A30). [0006] Most current approaches to developing treatments for neurological diseases, such as stroke, Parkinson’s dis- ease (PD),Alzheimer’s disease (AD),amyotrophic lateralsclerosis (ALS), Huntington’s disease (HD), and HIV-associated 40 dementia (HAD) target mechanisms that are hypothesized to be involved in the initiation-phase of the disease. For example, current approaches involve using compounds that attempt to inhibit the initiation of toxicity caused by aggre- gation of α-synuclein in PD, or aggregation of β-amyloid, tau, and/or ApoE in AD, or aggregation of huntingtin protein in HD, or oxidative stress from reactive oxygen species in ALS, or excessive extracellular excitotoxins, such as glutamate, in stroke or trauma. An alternative approach is to target basic cell death machinery that may be activated as a result of 45 a cellular insult. Current approaches are directed towards a specific death process called apoptosis involving cysteine proteases called caspases. However, a number of recent studies establish that many cell death paradigms, especially those associated with neurodegeneration, involve non-apoptotic/caspase-independent mechanisms. [0007] Therefore, there is a need in the art for compositions and methods to prevent or treat cellular necrosis including cellular necrosis associated with neurodegeneration. 50 SUMMARY OF INVENTION [0008] The present invention provides compounds and pharmaceutical preparations that are useful for treating disor- ders associated with cellular necrosis. 55 [0009] According to one aspect the invention, the compound has the formula: 2 EP 3 081 214 A2 5 10 15 a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein X represents O; Y represents S; G represents O or NR7; R1, R2, and R3 represent independently H, OH, OR8, F, Cl, Br, I, N(R8)2, COOH, CO2R8, NO2, NHC(O)R8, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R4 represents independently H, OH, OR8, F, Cl, Br, I, N(R8)2, COOH, CO2R8, NO2, NHC(O)R8, methyl, 20 methoxyl, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, amine, piperizin e; R5, R 6, and R 7 represent independently H or lower alkyl; R 8 represents lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, or substituted heteroaryl; R 9, R10, R9’, R10’, represent independently H, F, Cl, Br, I, lower alkyl, substituted lower alkyl, or a three to six membered cycloalkyl or substituted cycloalkyl that includes C n and/or Cn’; n and n’ equals an integer from zero to five. 25 [0010] In another aspect the compound has the formula: 30 35 40 a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein X represents O; Y represents NR8; G represents O or NR7; R1, R2, and R3 represent independently H, OH, OR 8, F, Cl, Br, I, N(R 8)2, COOH, CO2R8, NO2, NHC(O)R8, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted 45 heteroaryl; R4 represents independently H, OH, OR8, F, Cl, Br, I, N(R8)2, COOH, CO2R8,NO2, NHC(O)R8, methyl, methoxyl, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, amine, piperizin e; R5, R 6, and R 7 represent independently H or lower alkyl; R 8 represents lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, or substituted heteroaryl; R 9, R10, R9’, R10’, represent independently H, F, Cl, Br, I, lower alkyl, substituted lower alkyl, or a three to six membered cycloalkyl or substituted cycloalkyl that includes C n 50 and/or Cn’; n and n’ equals an integer from zero to five. [0011] In another aspect of the invention the compound has the formula: 55 3 EP 3 081 214 A2 5 10 15 a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein X represents O; Y represents NH; R 1, R2, and R 3 represent independently H, OR 8, F, Cl, Br, I, N(R 8)2, CO2R8, NO2, NHC(O)R8, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; R 4 represents independently H, OR8. F, Cl, Br, I, N(R 8)2, CO2R8, NO2, NHC(O)R8, methyl, methoxyl, lower alkyl, substituted lower alkyl, aryl, substituted 20 aryl, heteroaryl, or substituted heteroaryl, amine, piperizine; R5, R6and R7 represent independently H or lower alkyl, except R6 can not be methyl, ethyl, propyl, isopropyl or t-butyl when R 1, R2, R3, R4, R5 and R7 are H; R8 represents H, lower alkyl, substituted lower alkyl, aryl, substituted aryl, arylalkyl, alkenyl, alkynyl, heteroaryl, or substituted heteroary l; R9, R10, R9’, R10’, represent independently H, F, Cl, Br, I, lower alkyl, substituted lower alkyl, or a three to six membered cycloalkyl or substituted cycloalkyl that includes C n and/or Cn’; n and n’ equals an integer from zero to five. 25 [0012] In another aspect the compound has the formula: 30 35 40 a stereoisomeric form thereof, a pharmaceutically acceptable acid or base addition salt thereof, wherein X represents O; Y represents NH; R1, R2, and R3 represent independently H, OH, OR8, F, Cl, Br, I, N(R8)2, COOH, CO2R8, NO2,