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(12) United States Patent (10) Patent No.: US 9.402,830 B2 Cialella Et Al

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(12) United States Patent (10) Patent No.: US 9.402,830 B2 Cialella Et Al USOO940283OB2 (12) United States Patent (10) Patent No.: US 9.402,830 B2 Cialella et al. (45) Date of Patent: * Aug. 2, 2016 (54) METHODS OF TREATING DYSKINESIA AND FOREIGN PATENT DOCUMENTS RELATED DSORDERS WO 93.18767 A1 9, 1993 (71) Applicant: Melior Discovery, Inc., Exton, PA (US) OTHER PUBLICATIONS (72) Inventors: John Ciallella, Exton, PA (US); John Afanasev et al., Effects of amphetamine and Sydnocarbon dopamine Gruner, Exton, PA (US); Andrew G. release and free radical generation in rat striatum, Pharmacol Reaume, Exton, PA (US); Michael S. Biochem Behav, 2001, 69(3-4):653-8. Saporito, Exton, PA (US) Anderzhanova et al., Effect of d-amphetamine and Sydnocarb on the extracellular level of dopamine, 3,4-dihydroxyphenylacetic acid, and (73) Assignee: Melior Discovery, Inc., Exton, PA (US) hydroxyl radicals generation in rat striatum, Ann NY AcadSci, 2000, 914:137-45. Anderzhanova et al., Effects of Sydnocarb and D-amphetamine on the (*) Notice: Subject to any disclaimer, the term of this extracellular levels of amino acids in the rat caudate-putamen, Eur J patent is extended or adjusted under 35 Pharmacol, 2001, 428(1):87-95. U.S.C. 154(b) by 0 days. Bashkatova et al., Neuroshemical changes and neurotoxic effects of This patent is Subject to a terminal dis an acute treatment with Sydnocarb, a novel psychostimulant: com claimer. parison with D-amphetamine, Ann NY AcadSci, 2002,965: 180-192. Cody, Precursor medications as a source of methamphetamine and/or amphetamine positive drug testing results, J Occup Environ Med, (21) Appl. No.: 14/702,242 2002, 44(5):435-50. Erdo et al., Inhibition of dopamine uptake by a new psychoStimulant (22) Filed: May 1, 2015 mesocarb (Sydnocarb), Pol J Pharmacol Pharm, 1981, 33(2):141-7. Flood et al. The effects of d-amphetamine, methylphenidate, (65) Prior Publication Data Sydnocarb, and caffeine on prepulse inhibition of the startle reflex in DBA/2 mice, Psychopharmacology (Berl), 2010, 211(3):325-36. US 2015/O2311 16 A1 Aug. 20, 2015 Gainetdinov et al., Effects of a psychostimulant drug Sydnocarbon rat brain dopaminergic transmission in vivo, Eur J Pharmacol, 1997. 340(1):63-8. Related U.S. Application Data Gruner et al., Characterization of pharmacological and wake-pro (63) Continuation of application No. 14/472,794, filed on moting properties of the dopaminergic stimulant Sydnocarb in rats, J Pharmacol Exp. Ther, 2011, 337(2):380-90. Aug. 29, 2014, now Pat. No. 9,051,312, which is a Hauser et al., Randomized trial of the triple monoamine reuptake continuation of application No. PCT/US2014/029827, inhibitor NS 2330 (tesofensine) in early Parkinson's disease, Mov filed on Mar. 14, 2014. Disord, 2007, 22(3):359-65. (60) Provisional application No. 61/786,714, filed on Mar. Lee (BCMJ, vol.43, No. 4, May 2001, pp. 206-209). Lokk, Daytime sleepiness in elderly Parkinson's disease patients and 15, 2013. treatment with the psychoStimulant modafinil: a preliminary study, Neuropsychiatr Dis Treat, 2010, 6:93-7. (51) Int. Cl. Olson et al. (Brain (2000), 123,331-339). CO7D 413/2 (2006.01) Rascoletal. Tesofinsine (NS2330), a monoaminereuptake inhibitor, C07D 27L/04 (2006.01) in patients with advanced Parkinson disease and motor fluctuations: A6 IK3I/98 (2006.01) the ADVANS Study, Arch Neurol, 2008, 65(5):577-83. A6 IK3I/506 (2006.01) Vinaret al., A Survey of psychotropic medications not available in the A6 IK3I/50 (2006.01) United States, Neuropsychopharmacology, 1991, 5(4):201-17. A6 IK3I/4245 (2006.01) Witkin et al., Behavioral, topix, and neurochemical effects of (52) U.S. Cl. Sydnocarb, a novel psychomotor stimulant: comparisons with CPC ........... A61 K3I/4245 (2013.01); A61 K31/198 methamphetamine, J Pharmacol Exp Ther, 1999, 288(3): 1298-310. (2013.01) * cited by examiner (58) Field of Classification Search None Primary Examiner — Paulos MNatnael See application file for complete search history. (74) Attorney, Agent, or Firm — Pepper Hamilton LLP (56) References Cited (57) ABSTRACT U.S. PATENT DOCUMENTS The present disclosure describes compounds and pharmaceu tically acceptable salts thereof and compositions and formu 3,312,690 A 4, 1967 Masuda et al. 4,446,322 A 5, 1984 Stein lations comprising the same that are useful in methods of 5,179,206 A 1/1993 Kujath et al. treating dyskinesia or related disorders, and methods for 2004/0039004 A1 2/2004 Baraldi ................ CO7D 487/14 treating dyskinesia or related disorders. 514,267 2011/0288137 A1 11/2011 Chen et al. 12 Claims, 7 Drawing Sheets U.S. Patent Aug. 2, 2016 Sheet 1 of 7 US 9.402,830 B2 & S.S w8m &šiaise wer .888 is six ise & w8 sis: w- $ysikaris iris: s & Systext 3 is s : s y Figire is: U.S. Patent Aug. 2, 2016 Sheet 2 of 7 US 9.402,830 B2 ss s is a 3 is stir &rs, it Syxx: i8 gics Sigire 2 8. ww. 3. 8 &x S is: & s. s s st: ko. s E. s 8 3:3:3&i. & its vs. scie i vesic: 3 is visite is .--&iya () is Syd88c38 it 'gic: : -ija figure 3 U.S. Patent Aug. 2, 2016 Sheet 3 of 7 US 9.402,830 B2 3. y s S & is: 888&s 2 : & S s: Sysicscs: i) {3 Skg 3 : Sysis sexist: {} igits: & askg & 8 figure 100. 80 w a& 20 t.d old axasto 2. 3.d4.d. so e.e. to 8.8 s. $8 88isks & six$8 figure is U.S. Patent Aug. 2, 2016 Sheet 5 Of 7 US 9.402,830 B2 arisexieties it risis “S&S -- isstyrisis: 8 sits st's 8 $8 ". s is is is is ise ini's 'it's sy S. $88s 88 88sists S 8 s SS 88 S S&eiss Say 8 &&s: 88s 8::sists: 8 8 " "," "," "is is veii:ie: 3 is Sysia&c3rty i{i Yisk: Fissire: 8 U.S. Patent Aug. 2, 2016 Sheet 6 of 7 US 9.402,830 B2 says F&S 8: S: s: 88: say 3 AS f s ES Si: t irrest its viiie i-disa: R is .-six 8 Sykissoci:') is Ytskg. š is - 3. it Sysis33; it sks Figure U.S. Patent Aug. 2, 2016 Sheet 7 Of 7 US 9.402,830 B2 say a S. c. 38sing & a S& six is Sysic&t 8 g.g. 8 S8 SR & SR *:: Sisses 38y 2 Ai Nis (A.{ } Sysis 38 is sigis, s: ,-i, 33. S3 S3 SR & S. Sisses Figa's US 9,402,830 B2 1. 2 METHODS OF TREATING DYSKNESIA AND Supra; Witkin et al., Supra; Anderzhanova et al., Supra). Rela RELATED DSORDERS tive to D-AMPH, equimolar doses of sydnocarb produce less hyperlocomotion and stereotype as well as Smaller changes in FIELD the marker of neurotoxicity Such as DA depletion, generation of reactive oxygen species, or increases in specific indices of The present disclosure describes compounds, composi lipid peroxidation (Gainetdinov et al., supra; Witkin et al., tions, and formulations comprising therapeutically or pro Supra; Anderzhanova et al., Supra; Afanasev et al., Supra; phylactically active compounds or pharmaceutically accept Bashkatova et al., Ann. NY Acad. Sci., 2002,965, 180-192). able salts thereof, for treating and/or preventing dyskinesias Furthermore, sydnocarb does not exhibit the rebound hyper or other disorders, and methods for treating dyskinesia or 10 somnolence seen with D-AMPH as a result of the dopamine other disorders. release characteristics associated with D-AMPH (Gruner et BACKGROUND al., Supra). Several studies aimed at investigating the utility of DAT inhibitors in Parkinson's Disease have indicated very Sydnocarb (i.e., 3-(B-phenylisopropyl)-N-phenylcarbam 15 little or no utility towards this disease, especially as regards oylsydnonimine), also known as mesocarb, is a psychomotor the potential utility of DAT inhibitors towards L-dopa-in stimulant. In Russia, sydnocarb has been used for over 30 duced dyskinesias associated with Parkinson's Disease years to treat a variety of neuropsychiatric comorbidities Such (Lökk, J., Neuropsych. Dis. Treat., 2010, 6, 93-97: Hauser et as asthenia, apathy, and adynamia (Anokhina et al., Zh al., Mov. Disord., 2007, 22,359-365; and Rascolet al., Arch Nevropatol Psikhiatr Im S S Korsakova, 1974, 74,594-602; Neurol., 2008, 65,577-583). Vinar et al., Neuropsychopharmacology, 1991, 5, 201-217: and Cody, J. Occup. Environ. Med., 2002, 44, 435-450). Although mostly anecdotal, evidence may suggest that Syd SUMMARY nocarb increases endurance during heavy physical activity and resistance to environmental stressors such as hypother 25 The present disclosure encompasses compounds, compo mia, low gravity, and oxygen deprivation. Sydnocarb may sitions, and formulations that may be useful in treating dys also have beneficial effects in treating alcohol abuse, attention kinesia or other disorders in a mammal. In some embodi deficit hyperactivity disorder (ADHD), and cognitive impair ments, the mammal has or is suspected of having a dyskinesia ment (Rudenko et al., Agressologie, 1979, 20, 265-270; Vinar or another disorder. In particular, the compounds, composi et al., Supra; Cody, Supra). 30 tions, and formulations useful in treating a dyskinesia or other Although Sydnocarb-induced facilitation of dopamine disorders include, but are not limited to, compounds, compo (DA)-mediated transmission has been well established in sitions, and formulations comprising a compound of Formula microdialysis studies, the exact nature of this action (i.e., DA I set forth herein. release versus DA transporter (DAT) inhibition) is not clear (Gainetdinov et al., Eur. J. Pharmacol., 1997, 340, 53-58: 35 The present disclosure provides compounds of Formula Afanasev et al., Pharmacol. Biochem. Behav., 2001, 69, Ia-1, Formula Ia-2, Formula Ib-1, Formula Ib-2, Formula 653-658; Anderzhanova et al., Eur.
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