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(12) Patent Application Publication (10) Pub. No.: US 2014/0194395 A1 TRENTO Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0194395 A1 TRENTO Et Al US 2014O194395A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0194395 A1 TRENTO et al. 43) Pub. Date: Jul. 10,9 2014 (54) COMPOSITIONS AND METHODS FOR (60) Provisional application No. 61/262.470, filed on Nov. TREATING CENTRALLY MEDIATED 18, 2009, provisional application No. 61/382,709, NAUSEA AND VOMITING filed on Sep. 14, 2010. (71) Applicant: Helsinn Healthcare S.A., Lugano/Pazzallo (CH) Publication Classification (72) Inventors: Fabio TRENTO, Pare (IT): Sergio CANTOREGGI, Cagiallo (CH): (51) Int. Cl. Giorgia ROSSI, Cernobbio (IT): A613 L/496 (2006.01) Roberta CANNELLA, Varese (IT): A 6LX3/573 (2006.01) Daniele BONADEO, Casalzuigno (IT) A613 L/473 (2006.01) (52) U.S. Cl. (73) Assignee: the laters CPC ............. A6 IK3I/496 (2013.01); A61 K3I/473 9. (2013.01); A61 K3I/573 (2013.01) (21) Appl. No.: 14/069,927 USPC ...................................... 514/171; 514/253.01 (22) Filed: Nov. 1, 2013 Related U.S. Application Data (57) ABSTRACT (63) Continuation of application No. 13/077.462, filed on Mar. 31, 2011, now Pat. No. 8,623,826, which is a Provided are compositions and methods for treating or pre continuation of application No. PCT/IB2010/003106, venting nausea and Vomiting in patients undergoing chemo filed on Nov. 18, 2010. therapy, radiotherapy, or Surgery. Patent Application Publication Jul. 10, 2014 Sheet 1 of 5 US 2014/O194395 A1 Figure 1 Patent Application Publication Jul. 10, 2014 Sheet 2 of 5 US 2014/O194395 A1 Analyte = Netupitant 700 6 O O -o-Treatment = Netupitant -o-Treatment = Palonosetron + Netupitant 3 O O 200 100 O O 12 24 36 48 60 72 84 96 108 120 132144 156 168 180 192204 216 228 240 Planned time (h) FIG.2 Patent Application Publication Jul. 10, 2014 Sheet 3 of 5 US 2014/O194395 A1 Analyte = Palonosetron -o-Treatment = Polonosetron -O-Treatment = Palonosetron + Netupitant s O 12 24 36 48 60 72 84 96 108 120 152 144 156 168 Planned time (h) FIG. 3 Patent Application Publication Jul. 10, 2014 Sheet 4 of 5 US 2014/O194395 A1 DexomethoSone Meon PloSmo Concentrations Versus Time, With and Without Co-administration of Netupitant. Analyte = Dexamethasone -o- Dexomethosone -- Dexamethasone + Netupitant 100mg -O-Dexamethasone + Netupitant 300mg -a - Dexamethasone + Netupitant 450mg 48 60 72 84 96 120 Planned Time (h) FIG.4 Patent Application Publication Jul. 10, 2014 Sheet 5 of 5 US 2014/O194395 A1 Stsia LE -S s S. Y2 1:18 iss Occipitat cortex 8 450 mg FIG. 5 US 2014/O 194395 A1 Jul. 10, 2014 COMPOSITIONS AND METHODS FOR Methods of synthesizing palonosetron are described in U.S. TREATING CENTRALLY MEDIATED Pat. Nos. 5.202,333 and 5,510,486. Pharmaceutically accept NAUSEA AND VOMITING ably dosage forms are described in PCT publications WO 2004/067005 and WO 2008/049552 from Helsinn Health CROSS-REFERENCE TO RELATED CaC. APPLICATIONS 0006 NK antagonists have also recently emerged as a 0001. This application is a continuation of U.S. applica tool for combating nausea and Vomiting from emetogenic tion Ser. No. 13/077, 462, filed Mar. 31, 2011, which is a medical procedures. Most recently, aprepitant was approved continuation of International Application No. PCT/IB2010/ by the Food and Drug Administration (“FDA) for use in 003106, filed Nov. 18, 2010, which claims priority to U.S. combination with other anti-emetic agents for the prevention Provisional Application No. 61/262.470, filed Nov. 18, 2009, of nausea and Vomiting from moderately and highly emeto and U.S. Provisional Application No. 61/382,709, filed Sep. genic chemotherapy. However, it quickly became apparent 14, 2010. All of the above applications are hereby incorpo that aprepitants effect was limited principally to vomiting— rated herein by reference in their entirety. not nausea—and that aprepitant did not provide as much benefit during the acute phase of CINV. When tested against FIELD OF THE INVENTION nausea in humans, aprepitant was unable to induce a signifi cant reduction in the incidence or severity of nausea following 0002 The present invention relates to the use of centrally moderately or highly emetogenic chemotherapy when com acting NK antagonists to treat nausea and Vomiting, particu pared to a 5-HT antagonist alone. See FDA Approved Label lar nausea and Vomiting induced by highly emetogenic che ing for EmendR). Thus, while aprepitant is approved by FDA motherapy, and to the treatment of Such nausea and Vomiting for the prevention of nausea and Vomiting in humans, this over multiple consecutive days. The present invention also indication is somewhat misleading because aprepitant did not relates to combined oral dosage forms of palonosetron and reduce nausea in the clinical trials preformed for aprepitant netupitant. more than nausea controlled by the other components of the anti-emetic regimen. In addition, the results reported in Grun BACKGROUND OF THE INVENTION berg et al., SUPPORT CANCER CARE (2009) 17:589-594, 0003. With the development of the 5-HTantagonist in the from a combined treatment of aprepitant and palonosetron, early 1990s, there emerged new strategies in the medical were far from promising. community to better control nausea and vomiting caused by 0007 Merck & Co. markets aprepitant, as EMENDR in various medical procedures, including chemotherapy the United States. The product is approved in a capsule dos (CINV), surgery (PONV), and radiation therapy (RINV). age form, and is marketed for the prevention of CINV (acute When added to steroids such as dexamethasone, several and delayed) in combination with other anti-emetic agents 5-HT antagonists have been demonstrated to significantly Such as ondansetron and metoclopramide. The product improve the standard of life for patients undergoing emeto reportedly has a terminal half-life of from 9 to 13 hours. genic medical procedures. Examples of 5-HT antagonists While aprepitant has demonstrated some effect against nau include ondansetron, marketed by GlaxoSmithKline, and pal sea, its effects have been inconsistent. Casopitant is another onosetron, developed by Helsinn Healthcare. NK antagonist that has been tested against nausea and Vom 0004 Palonosetron hydrochloride has recently emerged iting in humans. A clinical study of casopitant is discussed in as a highly efficacious anti-nauseant and anti-emetic agent. Therapeutics and Clinical Risk Management 2009:5 pp. 375 See PCT publications WO 2004/045615 and 2004/073714 384 to Ruhlmann et al. and Drug Metabolism and Disposi from Helsinn Healthcare. Palomosetron hydrochloride is sold tion, vol. 37, No. 8, 2009, pp. 1635-1645 to Pellegattietal. As in the United States as a sterile injectable liquid under the reported by Ruhlmann et al. in THERAPEUTICS AND ALOXIR) brand, insterile unit dose vials containing 0.075 or CLINICAL RISK MANAGEMENT, 2009:5375–384, caso 0.25 mg. of palonosetron hydrochloride. Palomosetron hydro pitant had no statistically significant effect against nausea chloride also is also sold as an orally administered soft-gel when administered in response to moderately emetogenic dosage form containing 0.5 mg. of palonosetron hydrochlo chemotherapy, and even induced nausea as a side effect. ride. Casopitant has the formula (2R,4S)-4-(4-acetytlpiperazin-1- 0005. The official chemical name for palonosetron hydro yl)-N-(1R)-1-3,5-bis(trifluoromethyl)phenylethyl-2-(4- chloride is (3aS)-2-(S)-1-AZabicyclo[2.2.2]oct-3-yl)-2,3, fluoro-2-methylphenyl)-N-methylpiperidine-1-carboxam 3a,4,5,6-hexahydro-1-oxo-1Hberizdeisoquinoline hydro ide, and the below chemical structure: chloride (CAS No. 119904-90-4); its empirical formula is CHNO.HCl, and its molecular weight is 332.87. The CF3 compound is represented by the following chemical struc O / \ H. ture: )-N N- t A. H.XYSct, H., CH3 F 0008 Netupitant is another selective NK receptor antago nist under development by Helsinn Healthcare, having the US 2014/O 194395 A1 Jul. 10, 2014 formula 2-3,5-bis(trifluoromethyl)phenyl-N,2-dimethyl dence of nausea and Vomiting induced by these emetic events, N-4-(2-methylphenyl)-6-(4-methylpiperazin-1-yl)pyridin there is a need for treating such nausea and vomiting for a 3-ylpropanamide, or Benzeneacetamide, N.C.C.-trimethyl prolonged period of time. Further, there is a need for the N-4-(2-methylphenyl)-6-(4-methyl-1-piperazinyl)-3- development of dosage forms to reduce drug-drug interac pyridinyl-3,5-bis(trifluoromethyl)-, and the below chemical tion, improve stability, and potentiate effects of each compo Structure: nent of the combined dosage forms. OBJECTS OF THE INVENTION HC 0012. Accordingly, it is an object of the invention to pro vide new methods for treating or preventing nausea and Vom ON CF3 iting using an NK antagonist, particularly netupitant. 0013. It is another object of the invention to provide meth ods for treating or preventing nausea and Vomiting in patients N CF undergoing chemotherapy, radiotherapy, or Surgery. 0014 Still another object of the invention is to augment HC CH, CH existing treatments for CINV. RINV or PONV by steroids and 5-HT antagonists, and thereby provide additional protection against both nausea and Vomiting, especially during the acute and delayed phases. 0015. Another object of the invention is to provide a single Methods of synthesizing and formulating netupitant and its combined dose of netupitant and a 5-HT antagonist and to prodrugs are described in U.S. Pat. Nos. 6.297,375, 6,719,996 the use of that single dose without further dosing, for the and 6,593,472 to Hoffmann La Roche. treatment of nausea and Vomiting during the acute and 0009. Other representative NK antagonists include delayed phases of CINV. RINV or PONV. ZD4974 (developed by AstraZeneca), CGP49823 (developed 0016. It is another object to provide novel methods to treat by Ciba-Geigy), Lanepitant and LY686017 (developed by Eli nausea, vomiting, and other undesirable effects from moder Lilly), FK888 (developed by Fujisawa), Vofopiitant, Vestipi ately emetogenic and highly emetogenic chemotherapy tant and Orvepitant (developed by GlaxoSmithKline), (“MEC and HEC), especially HEC, during the acute and Befetupitant (developed by Hoffmann-La Roche), R116031 delayed phases following such treatments.
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