(19) TZZ Z_T (11) EP 2 547 660 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 231/16 (2006.01) C07D 261/12 (2006.01) 07.01.2015 Bulletin 2015/02 C07D 327/04 (2006.01) C07D 417/12 (2006.01) C07D 513/04 (2006.01) C07D 515/04 (2006.01) (2006.01) (2006.01) (21) Application number: 11711417.3 A61K 31/15 A61P 35/00 (22) Date of filing: 18.03.2011 (86) International application number: PCT/US2011/029072 (87) International publication number: WO 2011/116336 (22.09.2011 Gazette 2011/38) (54) NITROXYL (HNO) RELEASING COMPOUNDS AND USES THEREOF IN TREATING DISEASES NITROXYL (HNO)-FREISETZENDE VERBINDUNGEN UND IHRE VERWENDUNG ZUR BEHANDLUNG VON ERKRANKUNGEN COMPOSÉS LIBÉRANT DU NITROXYLE (HNO) ET LEURS UTILISATIONS DANS LE TRAITEMENT DE MALADIES (84) Designated Contracting States: • BASUDHAR, Debashree AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Tucson GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO Arizona 85719 (US) PL PT RO RS SE SI SK SM TR • KEEFER, Larry K. Bethesda (30) Priority: 28.05.2010 US 349716 P Maryland 20817 (US) 19.03.2010 US 315604 P • SAAVEDRA, Joseph E. Thurmont (43) Date of publication of application: Maryland 21788 (US) 23.01.2013 Bulletin 2013/04 • ANDREI, Daniela Elmwood Park (73) Proprietors: Illinois 60707 (US) • TheUnited States Of America, As Represented By The Secretary, Department of Health and Human (74) Representative: Pfenning, Meinig & Partner GbR Services Patent- und Rechtsanwälte Bethesda, Maryland 20892-7660 (US) Theresienhöhe 11a • The Arizona Board Of Regents On Behalf 80339 München (DE) Of The University of Arizona Tucson, Arizona 85721 (US) (56) References cited: • K. M. MIRANDA ET AL.: "Comparison of the NO (72) Inventors: and HNO donating properties of • MIRANDA, Katrina M. diazeniumdiolates: primary amine adducts Tucson release HNO in vivo.", JOURNAL OF MEDICINAL Arizona 85719 (US) CHEMISTRY, vol. 48, 12 June 2005 (2005-06-12), • WINK, David A. pages 8220-8228, XP002634945, cited in the Hagerstown application Maryland 21742 (US) • K. M. MIRANDA: "Donors of HNO.", CURRENT • SALMON, Debra J. TOPICS IN MEDICINAL CHEMISTRY, vol. 5, 2005, Tucson pages 649-664, XP002634946, Arizona 85719 (US) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 547 660 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 547 660 B1 Description CROSS-REFERENCE TO RELATED APPLICATIONS 5 BACKGROUND OF THE INVENTION [0001] Nitroxyl (HNO) is an elusive chemical species that has been shown to possess intriguing biological properties. For example, nitroxyl has been implicated in the mechanism of cyanamide’s inhibitory effect on aldehyde dehydrogenase in treating alcohol abuse as well as reversing experimental heart failure. 10 [0002] Despite HNO having been described in the chemical literature for decades, there are surprising gaps in the literature that complicate the rational exploitation of its pharmacological properties. Historically, Angeli’s salt (AS) has been known to generate HNO in solution. Recently, IPA/NO (1, the sodium salt of diazeniumdiolated isopropylamine) has been shown to mimic AS in its chemical and biological properties (Journal of Medicinal Chemistry 2005, 48, 8220-8228). Unfortunately, neither of these salts are suitable from the drug development perspective since both are 15 difficult to purify. 20 25 [0003] Thus, there remains an unmet need for compounds that can generate reliable, controlled fluxes of HNO in physiological media or conditions. In addition, there exists an unmet need for compounds that release both HNO and drugs such as non-steroidal anti-inflammatory drugs (NSAID). 30 BRIEF SUMMARY OF THE INVENTION [0004] An embodiment of the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof: 35 40 45 wherein: 1 R is selected from C1-12 alkyl, C3-12 alkenyl, C3-12 alkynyl, C3-8 cycloalkyl, and heterocyclyl, each of which is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-2 50 alkyl, halo-C1-12 alkyl, amino-C1-12 alkyl, C1-12 alkoxy, aryloxy, C1-12 thioalkoxy, nitro, sulfonato, C1-12 acyl, C2-12 acyloxy, carboxyl, mercapto, C 1-12 alkoxy-carbonyl, C1-12 alkoxy-carbonyloxy, amido, amino, C 1-12 alkylamino, and di-C1-12 alkyl-amino; 2 3 R and R are the same or different and each is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, 55 C3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more moieties selected from the group consisting of halo, OH, CN, hydroxy-C1-12 alkyl, halo-C1-12 alkyl, amino-C1-12 alkyl, C1-12 alkoxy, aryloxy, C1-12 thioalkoxy, nitro, sulfonato, C1-12 acyl, C2-12 acyloxy, carboxyl, mer- capto, C1-12 alkoxy-carbonyl, C1-12 alkoxy-carbonyloxy, amido, amino, C1-12 alkylamino, and di-C1-12 alkyl-amino; 2 EP 2 547 660 B1 and 4 5 5 R is -C(=O)R , wherein R is selected from hydrogen, C1-12 alkyl, C2-12 alkenyl, C1-12 alkynyl, C3-8 cycloalkyl, heterocyclyl, aryl, and heteroaryl, each of which, other than hydrogen, is optionally substituted with one or more 5 moieties selected from the group consisting of halo, OH, CN, hydroxy-C 1-12 alkyl, halo-C 1-12 alkyl, amino-C 1-12 alkyl, C1-12 alkoxy, aryloxy, C1-12 thioalkoxy, nitro, sulfonato, C1-12 acyl, C2-12 acyloxy, carboxyl, mercapto, C1-12 alkoxy- carbonyl, C1-12 alkoxy-carbonyloxy, amido, amino, C1-12 alkylamino, and di-C1-12 alkyl-amino; or R4 is a non-steroidal anti-inflammatory drug (NSAID) moiety retaining its NSAID activity. 10 [0005] A compound of formula (I) or a salt thereof undergoes a slower hydrolysis than 1 at physiological pH, such that the compound of formula (I) generates a correspondingly lower steady-state concentration of HNO, minimizing its dimer- ization/dehydration to N2O. As a result, a compound of formula (I) or a salt thereof releases HNO that is more efficiently available to biological targets for therapeutic uses. 15 [0006] The compounds of formula (I), wherein R4 is a non-steroidal anti-inflammatory drug (NSAID) moiety retaining its NSAID activity, combine the advantages of HNO release and the advantageous properties of NSAIDS. They provide increased efficacy against cancer and cardiovascular disease. [0007] The invention further provides a pharmaceutical composition and the latter for use in a method of treating various disorders, for example, a cardiovascular disorder, cancer, chronic pain, alcohol dependence, or inflammation, 20 in a patient comprising administering an effective amount of a compound or salt of formula (I). [0008] In a specif advantage, the compounds of the invention are useful in chemopreventing as well as treating cancers. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS 25 [0009] Figures 1A and 1B are graphs illustrating the reductive nitrosylation of metMb (50 mM) by (Fig. 1 A) IPA/NO, 1 (100 mM), or (Fig. 1B) AcOM-IPA/NO, 2 (O2-(acetoxymethyl) 1-(isopropylamino)diazen-1-ium-1,2-diolate; 100 mM) in an embodiment of the invention. The assay was performed in phosphate buffered saline (PBS), pH 7.4, containing 50 30 mM DTPA at 37 °C under deaerated conditions and was followed until there were no further spectral changes at 543 and 575 nm (1, 2, 4, 6, 9, 14, 23 and 46 min for 1; 3-107 min in 4- to 10-min intervals shown for 2). Figures 2A-D are graphs illustrating the effect of glutathione (GSH) on the reductive nitrosylation of metMb (50 mM) by (Fig. 2A) 1 (100 mM), (Fig. 2B) 2 (100 mM), (Fig. 2C) DEA/NO (50 mM), or (Fig. 2D) Angeli’s salt (100 mM). The assay was performed in PBS (pH 7.4) containing 50 mM DTPA and 250 mM GSH at 37 °C under deaerated conditions 35 over 1 h at 30-s cycles for 1 and 1.8 h at 30-s intervals for 2. Scans were plotted in Fig. 2A at 2, 4, 6, 9, 14, 23 and 56 min for 1. Scans were plotted in Fig. 2B at 0.5 and 60 min for 2. Scans were plotted in Fig. 2C at 1-min intervals to 8 min and then at 11, 14, 18, 23, 28 and 40 min. Scans were plotted in Fig. 2D at 500 s, when the decomposition of Angeli’s salt was complete, and at 60 min, respectively. Figures 3A and 3B are graphs illustrating the pH-dependence of the rate constant of decomposition of (Fig. 3A) 1 40 (100 or 200 mM) and (Fig. 3B) 2 (100 mM) at 37 °C in PBS containing 50 mM DTPA measured at 250 nm (mean 6 SEM, n ≥ 3). Figures 4A-C are graphs illustrating spontaneous hydrolysis (Figs. 4A and 4B) and esterase-catalyzed hydrolysis (Fig. 4C) of 2 in an embodiment of the invention. In Fig. 4A, spectra were collected every 60 s (10-min intervals shown) after dissolving 2 in PBS (pH 7.4) at 37 °C, and only loss of the parent compound was observed. In Fig. 4B, 45 the pH was elevated to 12, and scans were collected every 0.5 s (through 2.5 s and 3.5, 5.5, 9.5, and 54.5 s shown).