US 2008.0312247A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2008/0312247 A1 Gant et al. (43) Pub. Date: Dec. 18, 2008 (54) SUBSTITUTED PIPERAZINES Publication Classification (51) Int. Cl. (75) Inventors: Thomas G. Gant, Carlsbad, CA A63/495 (2006.01) (US); Sepehr Sarshar, Cardiff by A6IP 9/00 (2006.01) the Sea, CA (US) A6IP 9/10 (2006.01) C07D 24I/04 (2006.01) Correspondence Address: (52) U.S. Cl. .................................... 514/252.12:544/400 GLOBAL PATENT GROUP - APX (57) ABSTRACT Ms. LaVern Hall Disclosed herein are substituted piperazine late Na" channel 10411 Clayton Road, Suite 304 modulators of Formula I, process of preparation thereof, ST. LOUIS, MO 63131 (US) pharmaceutical compositions thereof, and methods of use thereof. (73) Assignee: AUSPEX PHARMACEUTICALS, INC., Formula I Vista, CA (US) Rs R14 Ris R10 R R31 (21) Appl. No.: 12/138,169 R6 R4 R11 R 23. R24V > R9 N N R O R56 N (22) Filed: Jun. 12, 2008 R O 2K O R30 R 8 R2 R ". 20R,\ R. R. Related U.S. Application Data R. R3 19 R22 R4 R29 (60) Provisional application No. 60/943,731, filed on Jun. R28 13, 2007. US 2008/0312247 A1 Dec. 18, 2008 SUBSTITUTED PPERAZINES nal of Clinical Pharmacology 2005, 45,802-09; Chaitman et al, Journal of the Americal College of Cardiology 2004, 43(8), 1375-82; Opie, European Heart Journal 2003, 24, 0001. This application claims the benefit of priority of 1854-56: Anderson et al, Heart Disease 2001, 3, 263-69; U.S. provisional application No. 60/943,731, filed Jun. 13, Zacharowski etal, European Journal of Pharmacology 2001, 2007, the disclosure of which is hereby incorporated by ref 418, 105-10; McCormacket al. General Pharmacology 1998, erence as if written herein in its entirety. 30(5), 639-45). FIELD SUMMARY OF THE INVENTION 0002 The present invention is directed to substituted pip 0005 Disclosed herein is a compound having structural erazines, pharmaceutically acceptable salts and prodrugs Formula I: thereof, the chemical synthesis thereof, and medical use of Such compounds for the treatment and/or management of angina, intermittent claudication, ischemia, and/or any disor (I) der ameliorated by modulating late Na channels. Rs R14 Ris R10 R13 R R31 BACKGROUND R6 R4 | RIR 2 R16 R24V DN R9 N N N R O R6 Q 0003 R O 2K O R30 R 8 R2 R is R 20R,\ R. R. OH No R. R3 17 K-9 R22 R1 R29 N-- NH p-1 or a pharmaceutically acceptable salt, Solvate, or prodrug thereof, wherein: O -> 0006 R. R. R. R. R. R. R. R. R. R. R. R. R. R14. R1s. R 63 R17, R 83 R19. R20. R21. R22. R2s. R24. R2s. R26. Ranolazine R7, Rs. Ro Ro, R. R. and Rs are selected from the group consisting of hydrogen or deuterium; and 0004 Ranolazine (RanexaR), N-(2,6-dimethyl-phenyl)- 0007 at least one of R. R. R. R. Rs. Re, R7Rs, Ro Ro, 2-4-2-hydroxy-3-(2-methoxy-phenoxy)-propyl-piper R11, R12, R13, R14, R1s. R16, R17, Ris, R19, R20 R2, R22, R23. azin-1-yl)-acetamide, is indicated for treating chronic stable R24, R2s, R26, R27, R2s, R-29, Rao, Rs 1, R32, and Rss is deute angina. Ranolazine improves left ventricular diastolic func rium. tion in patients with ischemic heart disease (Hayashida W. et 0008 Further, disclosed herein are methods of modulating al., Cardiovasc Drugs. Ther 1994, 8,741-7). Ranolazine is a late Na" channels. selective inhibitor of late Na" channels (Pharmacotherapy 0009 Disclosed herein is a method for treating, prevent 2007, 27(12), 1659-1676). At therapeutic concentrations (up ing, or ameliorating one or more symptoms of a late Na" to 10 Limol/L), ranolazine selectively inhibits late sodium channel-mediated disorder in a subject, comprising adminis current (I) with an ICso of 5-21 umol/L. (Antzelevitch C, et tering a therapeutically effective amount of a compound as al., J. Cardiovasc Pharmacol Therapeut 2004, 9(suppl 1), disclosed herein. S65-83). At therapeutic plasma concentrations, ranolazine 0010 Further disclosed herein is a method wherein the does not significantly inhibit late I in healthy myocytes late Na" channel-mediated disorder is selected from the (nonischemic and/or nonfailing myocytes), but does signifi group consisting of, but not limited to, angina, intermittent cantly inhibit late I in ischemic or failing myocytes in claudication, ischemia, and/or any disorder ameliorated by which the current is amplified and problematic. By inhibiting modulating late Na" channels. late I, there is an overall reduction in intracellular Na". The 0011. Also disclosed herein are articles of manufacture reduction in intracellular Na" contributes to a reduction in the and kits containing compounds as disclosed herein. By way magnitude of ischemia-induced Ca" overload, and improves of example only a kit or article of manufacture can include a myocardial function as well as myocardial perfusion (Belar container (Such as a bottle) with a desired amount of at least dinelli L, et al., Eur Heart J2004, Suppl. 6, 13-7; Antzelevitch one compound (or pharmaceutical composition of a com C, et al. Circulation 2004, 110, 904-10; Wu L, et al., J Phar pound) as disclosed herein. Further, such a kit or article of macol Exp Ther 2004, 310, 599-605). Ranolazine produces manufacture can further include instructions for using said this anti-ischemic effect without significantly altering either compound (or pharmaceutical composition of a compound) heart rate, blood pressure, or increase the rate-pressure prod disclosed herein. The instructions can be attached to the con uct. Ranolazine at high doses is reported to shift ATP produc tainer, or can be included in a package (such as a box or a tion away from fatty acid oxidation and towards glucose plastic or foil bag) holding the container. oxidation, thereby reducing lactic acid production and tissue 0012. In another aspect is the use of a compound as dis acidosis (Tianetal, Journal of Chromatography B, 2007, 846, closed herein in the manufacture of a medicament for treating 346–50; McCormack, Biochemical Society Transactions a disorder in an animal in which late Na" channels contribute 2006, 34(2), 238-42; Jerling, Clinical Pharmacokinetics to the pathology and/or symptomology of the disorder. In a 2006, 45(5), 469-91; Jerling et al. Clinical Pharmacology & further embodiment, said disorder is, but not limited to, Therapeutics 2005, 78(3), 288-97: Abdallah et al. The Jour angina, intermittent claudication, and/or ischemia. US 2008/0312247 A1 Dec. 18, 2008 0013 In another aspectare processes for preparing a com 0025. In yet other embodiments said therapeutic agent is a pound as described herein as a late Na" channel modulator, or Beta-blocker. other pharmaceutically acceptable derivatives Such as pro 0026 Infurther embodiments said beta-blocker is selected drug derivatives, or individual isomers and mixture of iso from the group consisting of alprenolol, oXprenolol, pindolol. mers or enantiomers thereof. propranolol, timolol, Sotalol, nadolol, mepindolol, carteolol. 0014. In another aspectare processes for preparing a com tertatolol, bopindolol, bupranolol, penbutolol, cloranolol, pound as disclosed herein as a late Na" channel modulator. practolol, metoprolol, atenolol, acebutolol, betaxolol, bevan 0015. Also disclosed herein are processes for formulating tolol, bisoprolol, celiprolol, esmolol, epanolol, S-atenolol. pharmaceutical compositions with a compound disclosed nebivolol, tallinolol, labetalol, and carvedilol. herein. 0027. In yet other embodiments said therapeutic agent is a 0016. In certain embodiments said pharmaceutical com nitrate or nitrite. position comprises one or more release-controlling excipi 0028. In further embodiments said nitrate or nitrite is entS. selected from the group consisting of glyceryl trinitrate, isos 0017. In other embodiments said pharmaceutical compo orbide dinitrate, isosorbide mononitrate, pentaerythritol tet sition further comprises one or more non-release controlling ranitrate, methylpropylpropanediol dinitrate, propatylnitrate, excipients. troInitrate, eritrity1 tetranitrate, amyl nitrite, butyl nitrite, 0018. In certain embodiments said pharmaceutical com ethyl nitrite, methyl nitrite, isopropyl nitrite, isobutyl nitrite, position is Suitable for oral, parenteral, or intravenous infu and cyclohexyl nitrite. sion administration. 0029. In yet other embodiments said therapeutic agent is an ACE inhibitor. 0019. In yet other embodiments said pharmaceutical com 0030. In further embodiments said ACE inhibitor is position comprises a tablet, or capsule. selected from the group consisting of captopril, enalapril, 0020. In certain embodiments the compounds as disclosed lisinopril, perindopril, ramipril, quinapril, benazepril, cilaza herein are administered in a dose of 0.5 milligram to 1000 pril, fosinopril, trandolapril, spirapril, delapril, moexipril, milligram. temocapril. Zofenopril, and imidapril. 0021. In yet further embodiments said pharmaceutical 0031. In yet other embodiments said therapeutic agent is a compositions further comprise another therapeutic agent. statin. 0022. In yet other embodiments said therapeutic agent is 0032. In further embodiments said statin is selected from selected from the group consisting of calcium channel block the group consisting of atorvastatin, cerivastatin, fluvastatin, ers, beta-blockers, nitrates or nitrites, ACE inhibitors, statins, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, platelet aggregation inhibitors, adenosine, digitoxin, anti-ar and simvastatin. rhythmic agents, sympathomimetic drugs, steroidal drugs, 0033. In yet other embodiments said therapeutic agent is a non-steroidal anti-inflammatory