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(12) Patent Application Publication (10) Pub. No.: US 2014/0349976 A1 HACKSELL Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0349976 A1 HACKSELL Et Al US 20140349976A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0349976 A1 HACKSELL et al. (43) Pub. Date: Nov. 27, 2014 (54) CO-ADMINISTRATION OF PIMAVANSERIN Publication Classification WITH OTHERAGENTS (51) Int. Cl. (71) Applicant: Acadia Pharmaceuticals Inc., San A613 L/4465 (2006.01) Diego, CA (US) A6II 45/06 (2006.01) A613 L/473 (2006.01) (72) Inventors: Uli HACKSELL, San Diego, CA (US); (52) U.S. Cl. Krista MCFARLAND, San Marcos, CA CPC ........... A6 IK3I/4465 (2013.01); A61 K3I/473 (US) (2013.01); A61K 45/06 (2013.01) USPC ........... 514/129; 514/329; 514/297: 514/292: (73) Assignee: Acadia Pharmaceuticals Inc., San 514f139 Diego, CA (US) (21) Appl. No.: 14/289,450 (57) ABSTRACT (22) Filed: May 28, 2014 As disclosed herein, co-administration of pimavanserin with 9 an agent that ameliorates one or more cholinergic abnormali Related U.S. Application Data ties can have a synergistic effect on the efficacy of the agent. Disclosed herein are compositions which include pimavan (63) Continuation of application No. 12/234,573, filed on serin in combination with an agent that ameliorates one or Sep. 19, 2008, now abandoned. more cholinergic abnormalities. Also disclosed herein are (60) Provisional application No. 60/974,426, filed on Sep. methods forameliorating or treating a disease condition char 21, 2007, provisional application No. 60/986,250, acterized by one or more cholinergic abnormalities that can filed on Nov. 7, 2007, provisional application No. include administering pimavanserin in combination with an 61/050,976, filed on May 6, 2008. agent that ameliorates one or more cholinergic abnormalities. Patent Application Publication Nov. 27, 2014 Sheet 1 of 6 US 2014/0349976 A1 Patent Application Publication Nov. 27, 2014 Sheet 2 of 6 US 2014/0349976 A1 | Patent Application Publication Nov. 27, 2014 Sheet 3 of 6 US 2014/0349976 A1 ««;*** **** Patent Application Publication Nov. 27, 2014 Sheet 4 of 6 US 2014/0349976 A1 CO sp th 3 : 3 3 (top) polar, curvato g II. S3 9. N -- 4 - II,S (up) poAuqouvasG Patent Application Publication Nov. 27, 2014 Sheet 5 of 6 US 2014/0349976 A1 3 up) parene. Bouesig Patent Application Publication Nov. 27, 2014 Sheet 6 of 6 US 2014/0349976 A1 g S. 5 St O t EY g a pa D s 3: O ve 3 uo. 3Club / US 2014/0349976 A1 Nov. 27, 2014 CO-ADMINISTRATION OF PIMAVANSERN which also suffers from treatment induced side effects that WITH OTHERAGENTS severely limit its clinical utility. RELATED APPLICATION INFORMATION SUMMARY 0001. This application claims priority to U.S. Provisional 0008. One embodiment described herein relates to a com Application Ser. No. 60/974,426, entitled “N-SUBSTI position that can include: pimavanserin, or a salt, a Solvate, a TUTED PIPERIDINE DERIVATIVES AS SEROTONIN polymorph or an isolated, Substantially pure metabolite RECEPTORAGENTS. filed on Sep. 21, 2007; 60/986,250, thereof, and an agent that ameliorates one or more cholinergic entitled “CO-ADMINISTRATION OF PIMAVANSERIN abnormalities. In some embodiments, the agent that amelio WITH OTHER AGENTS filed Nov. 7, 2007 and 61/050, rates one or more cholinergic abnormalities can be a cho 976; entitled “CO-ADMINISTRATION OF PIMAVAN linesterase inhibitor. In an embodiment, the cholinesterase SERIN WITH OTHER AGENTS’ filed May 6, 2008, all of inhibitor can be selected from an acetyicholinesterase inhibi which are incorporated herein by reference in their entireties, tor and a butyrylcholinesterase inhibitor. Exemplary cho including all drawings, for all purposes. linesterase inhibitors include, but are not limited to, metri fonate, physostigmine, neostigmine, pyridostigmine, BACKGROUND ambenonium, demarcarium, rivastigmine, aldicarb, bendio carb, bufencarb, carbaryl, carbendazim, carbetamide, carbo 0002 1. Field furan, chlorbufam, chloropropham, ethiofencarb, formetan 0003. The present application relates to the fields of chem ate, methiocarb, methomyl, oxamyl, phenmedipham, istry and medicine. More particularly, disclosed herein are pinmicarb, pirimicarb, propamocarb, propham, propoXur, methods and compositions that can be used to treat disease galantamine, donepezil (E-2020), tacrine, edrophonium, phe conditions such as those characterized by cholinergic abnor nothiazines, echothiophate, diisopropyl fluorophosphate, malities. dimebon, Huperzine A, T-82 ((2-2-(1-benzylpiperidin-4-yl) 0004 2. Description of the Related Art ethyl-2,3-dihydro-9-methoxy-1H-pyrrolo3,4-bduinolin 0005 Conditions associated with cognitive impairment, 1-one hemifumarate)), TAK-147 (Zanapezil), phenserine, Such as Alzheimer's disease, are accompanied by loss of quilostigmine, gainstigmine, butyrophenones, imipramines, acetylcholine in the brain. This is believed to be the result of tropates, phencyclidines, curariforms, ethephon, ethopro degeneration of cholinergic neurons in the basal forebrain, pazine, iso-OMPA, tetrahydrofurobenzofuran cymserine, which widely innervate multiple areas of the brain, including N'phenethyl-norcymserine, N-benzylnorcymserine, N.N- the association cortices and hippocampus that are critically bisnorcymserine, N'- N'-bisbenzylnorphysostigmine, involved in higher processes. N',N'-bisbenzylmorphenserine and N',N'-bisbenzylnor 0006 Efforts to increase acetylcholine levels have focused cymserine. In an embodiment, the cholinesterase inhibitor on increasing levels of choline, the precursor for acetylcho can be tacrine. line synthesis, and on blocking acetylcholinesterase (AChE). 0009. In other embodiments, the agent that ameliorates the enzyme that metabolizes acetylcholine. To date, attempts one or more cholinergic abnormalities can be a muscarinic to augment central cholinergic function through the admin receptor agonist. Examples of Suitable muscarinic receptor istration of choline or phosphatidylcholine have not been agonists include, but are not limited to, Xanomeline, carbam successful. AChE inhibitors have shown therapeutic efficacy, ylcholine, oxotremorine, methacholine, bethanechol, but have been found to have frequent cholinergic side effects cevimeline (AF102B), AF150(S), AF267B, aceclidine, due to excessive increases in acetylcholine in the periphery arecoline, milameline, talsaclidine, pilocarpine and (S)-2- mediated and central-mediated, including abdominal cramps, ethyl-8-methyl-1-thia-4,8-diaza-spiro4.5 decan-3-one (Tor nausea, vomiting, and diarrhea. These gastrointestinal side rey Pines NGX267). In an embodiment, the muscarinic effects have been observed in about a third of the patients receptor agonist can be Xanomeline. treated. In addition, some AChE inhibitors, such as tacrine, 0010. In still other embodiments, the agent that amelio have also been found to cause significant hepatotoxicity with rates one or more cholinergic abnormalities can be a elevated liver transaminases observed in about 30% of glutamatergic antagonist. Suitable glutamatergic antagonists patients. Consequently, the adverse effects of AChE inhibi include, but are not limited to, amantadine, dextromethor tors have severely limited their clinical utility. phan, dextrorphan, ibogaine, ketamine, tramadol, metha 0007 Attempts to ameliorate the effects of decreased ace done, and memantine. In an embodiment, the glutamatergic tylcholinergic transmission by directagonism of the musca antagonist can be memantine. rinic M subtype of acetylcholine receptor has not proven 0011. In some embodiments, the agent that ameliorates Successful because known muscarinic agonists lack specific one or more cholinergic abnormalities can be a cholinergic ity in their actions at the various muscarinic receptor Sub agonist. Exemplary cholinergic agonists include, but are not types, leading to dose-limiting side effects that limit their limited to, pramiracetam, piracetam, oxiracetam, choline-L- clinical utility. For example, the M muscarinic agonist alfoscerate, nebracetam, besipirdine, and taltirelin. arecoline has been found to be an agonist of M as well as M. 0012. In other embodiments, the agent that ameliorates muscarinic receptor Subtypes, and is not very effective in one or more cholinergic abnormalities can be a carnitine treating cognitive impairment, most likely because of dose acetyltransferase stimulant. Exemplary carnitine acetyltrans limiting M and M receptor mediated side effects. Similarly, ferase stimulants include, but are not limited to, levocarnitine, Xanomeline (Shannon et al., J. Pharmacol. Exp. Ther: 1994, ST-200 (acetyl-1-carnitine), and nefiracetam. 269,271; Shannon et al., Schizophrenia Res. 2000, 42,249) is 0013. In still other embodiments, the agent that amelio an M/M preferring muscarinic receptor agonist shown to rates one or more cholinergic abnormalities can be an acetyl reduce psychotic behavioral symptoms in Alzheimer's dis choline release stimulant. Exemplary acetylcholine release ease patients (Bodick et al., Arch. Neurol. 1997, 54, 465), stimulants include, but are not limited to, SIB-1553A ((+/-)- US 2014/0349976 A1 Nov. 27, 2014 4-2-(1-methyl-2-pyrrolidinyl)ethylthiophenolhydrochlo disease condition can be Alzheimer's disease. In some ride) and T-588 ((1R)-1-benzobthiophen-5-yl-2-[2-(diethy embodiments, the disease condition can be a cognitive disor lamino)ethoxyethan-1-ol hydrochloride). der. 0014. In even other embodiments, the agent that amelio rates one or more cholinergic abnormalities can be a choline BRIEF DESCRIPTION OF THE DRAWINGS uptake stimulant. In an embodiment, the choline uptake 0019 FIG. 1 is a graph that illustrates the results of an stimulant can be MKC-231 (2-(2-oxopyrrolidin-1-yl)-N-(2,
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