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(12) Patent Application Publication (10) Pub. No.: US 2016/0081987 A1 Lawton Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2016/0081987 A1 Lawton Et Al US 20160O81987A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0081987 A1 Lawton et al. (43) Pub. Date: Mar. 24, 2016 (54) CYSTEINE PRODRUGS Publication Classification (51) Int. Cl. (75) Inventors: Daniel Lawton, Bayside, WI (US); A613 L/426 (2006.01) Michael Neary, West Allis, WI (US); C07D 277/14 (2006.01) James A. Nieman, Sherwood Park (CA) A6II 45/06 (2006.01) C07D 24I/08 (2006.01) A63L/98 (2006.01) (73) Assignee: PROMENTIS C07D 267/10 (2006.01) PHARMACEUTICALS, INC., C07K5/062 (2006.01) Milwaukee, WI (US) (52) U.S. Cl. CPC ............ A6 IK3I/426 (2013.01); C07D 267/10 (21) Appl. No.: 14/391,785 (2013.01); C07D 277/14 (2013.01); C07K 5/0606 (2013.01); C07D 24I/08 (2013.01); (22) PCT Filed: Jul. 30, 2012 A6 IK3I/198 (2013.01); A61K 45/06 (2013.01) (86). PCT No.: PCT/US2O12/04882O (57) ABSTRACT Novel cysteine prodrugs and their use in the treatment of S371 (c)(1), diseases and/or conditions, including but not limited to dis (2), (4) Date: Jan. 13, 2015 eases and/or conditions of the Central Nervous System (CNS), including but not limited to schizophrenia, drug crav ing, drug addiction, bipolar disorder, anxiety, depression, Related U.S. Application Data Parkinson's disease, Alzheimer's disease, cognitive dysfunc (60) Provisional application No. 61/512,751, filed on Jul. tion, multiple Sclerosis, Amyotrophic lateral Sclerosis (ALS), 28, 2011. ischemic stroke, HIV dementia, and Huntington's disease. US 2016/008 1987 A1 Mar. 24, 2016 CYSTEINE PRODRUGS I-VII and/or NAC and 2) pre-existing first generation anti psychotic agents (including but not limited to chlorprom FIELD OF THE INVENTION azine, thioridazine, mesoridazine, loxapine, molindone, per phenazine, thiothixene, trifluoperazine, haloperidol. 0001. This invention relates to novel cysteine prodrugs fluphenazine, droperidol, Zuclopenthixol and prochlorpera and methods of using these compounds for the treatment of Zineperphenazine) and/or second generation anti-psychotic diseases and/or conditions, including but not limited to dis agents (including but not limited to amisulpride, aripiprazole, eases and/or conditions of the Central Nervous System asenapine, blonanserin, clotiapine, clozapine, illoperidone, (CNS), including but not limited to schizophrenia, drug crav lurasidone, mosapramine, olanzapine, paliperidone, per ing, drug addiction, bipolar disorder, anxiety, depression, oSpirone, quetiapine, remoxipride, risperidone, sertindole, Parkinson's disease, Alzheimer's disease, cognitive dysfunc Sulpiride, ziprasidone, Zotepine, bifeprunox (DU-127,090), tion, multiple Sclerosis, Amyotrophic lateral Sclerosis (ALS), pimavanserin (ACP-103), and vabicaserin (SCA-136)) for ischemic stroke, HIV dementia, and Huntington's disease. the treatment of a disease or condition of CNS, including but not limited to Schizophrenia, drug craving, drug addiction, BACKGROUND OF THE INVENTION bipolar disorder, anxiety, depression, Parkinson's disease, Alzheimer's disease, cognitive dysfunction, multiple Sclero 0002 Diseases and/or conditions of the Central Nervous sis, ALS, ischemic stroke, HIV dementia, and Huntington's System (CNS) affect a large number of people. One of the disease. CNS disorders, schizophrenia, is a debilitating disorder 0011 Thus, in one aspect, the present invention is directed afflicting 1% of the world's population. The development of to compounds of Formula I: effective medications to treat schizophrenia relies on advances in characterizing the underlying pathophysiology. 0003 Conventional approaches to treating schizophrenia Formula I and other CNS disorders have significant disadvantages, including Suboptimal efficacy and/or side effects associated with their use. For example, existing first and second genera tion antipsychotic agents have a number of shortcomings and significant side effects, such as extrapyramidal side effects, endocrine effects, obesity, elevated triglycerides, blood pres where Sure and glucose levels, type II diabetes, cardiovascular dis R is selected from the group consisting of alkyl and aryl, ease, renal toxicity and agranulocytosis. Thus, it is desirable preferably from methyl and phenyl. to develop novel agents that can improve treatment outcomes 0012. In another aspect, the present invention is directed to and safety. compounds of Formula II: 0004. Accordingly, there is a significant need for new therapeutical agents to treat disorders of the CNS. Formula II SUMMARY OF THE INVENTION 0005. In one aspect, the present invention is directed to cysteine prodrugs of Formulas I-VII as described below. 0006. In another aspect, the present invention provides methods of treating a disease or condition of the Central O Nervous System (CNS), including but not limited to schizo phrenia, drug craving, drug addiction, bipolar disorder, anxi where R is selected from the group consisting of ety, depression, Parkinson's disease, Alzheimer's disease, cognitive dysfunction, multiple Sclerosis, Amyotrophic lat On 29 UCN eral sclerosis (ALS), ischemic stroke, HIV dementia, and S and HO N. Huntington's disease comprising administering to a subject in need thereof a therapeutically effective amount of any of the inventive compounds. 0007. In some aspects, the methods and compositions of -s, the invention may be used in combination with N-acetyl 0013. In another aspect, the present invention is directed to cysteine (NAC). compounds of Formula III: 0008 Thus, in one embodiment, the invention is directed to a combinational use of: 1) a compound of any of Formulas Formula III I-VII and 2) NAC for the treatment of a disease or condition R of CNS including but not limited to schizophrenia, drug crav n S ing, drug addiction, bipolar disorder, anxiety, depression, H Parkinson's disease, Alzheimer's disease, cognitive dysfunc e N O tion, multiple sclerosis, ALS, ischemic stroke, HIV dementia, and Huntington's disease. 0009. In some aspects, the methods and compositions of OD N the invention may be used in combination with conventional it first and second generation anti-psychotic agents. S n 0010 Thus, in one embodiment, the invention is directed to a combinational use of: 1) a compound of any of Formulas US 2016/008 1987 A1 Mar. 24, 2016 where R is selected from the group consisting of -continued Formula VI O S X-( and 1. OH, and Formula VII where R is alkyl, preferably methyl, or aryl, preferably, phe nyl; or R comprises an amino acid with the carbonyl. 0014. In another aspect, the present invention is directed to compounds of Formula IV: NH O Formula IV R 0017. The invention also encompasses pharmaceutically S acceptable salts, esters, stereoisomers, enantiomers, and pro O drugs of the provided compounds. OH, 0018. A preferred route of administering to the subject is N via oral delivery. H 0019. In a preferred embodiment, the disease is schizo O phrenia. 0020. The invention further encompasses pharmaceutical compositions containing a compound of any of Formulas I-VII or a pharmaceutically acceptable salt thereof in combi nation with a pharmaceutically acceptable carrier. 0021 Methods of formulating/manufacturing such phar 0015 where R is selected from the group consisting of maceutical compositions for the treatment of a disease or condition in a subject are also within the invention’s scope. DETAILED DESCRIPTION OF THE INVENTION Definitions 0022. The following definitions are used, unless otherwise described. 0023 The term “prodrugs’ refers to compounds, includ KX H() is ing but not limited to monomers and dimers of the compounds of the invention, which become under physiological condi tions compounds of the invention or the active moieties of the compounds of the invention. 0024. The term “active moieties’ refers to compounds which are pharmaceutically active in vivo, whether or not Such compounds are compounds of the invention. 0025. The term “alkyl refers to a monovalent saturated aliphatic hydrocarbon including straight chain and branched chain groups. Preferably, the alkyl group has 1 to 20 carbon atoms. More preferably, it is a medium alkyl (having 1 to 10 carbonatoms). Most preferably, it is a lower alkyl (having 1 to 4 carbon atoms). The alkyl group may be substituted or 0016. In another aspect, the present invention is directed to unsubstituted. the compounds having the following structures: 0026. The term “alkoxy' group refers to both an —O-alkyl and an —O-cycloalkyl group; preferably an alkoxy group refers to a lower alkoxy, and most preferably methoxy or Formula V ethoxy. HS 0027. The term “aryl refers to a monocyclic or bicyclic O O aromatic group (e.g., phenyl or naphthyl) that can be unsub stituted or Substituted, for example, with one or more, and in > N Null OH, particular one to three, Substituents, such as halo, alkyl, H hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, haloalkyl, nitro, O amino, alkylamino, acylamino, alkylthio, alkylsulfonyl, and alkylsulfonyl. US 2016/008 1987 A1 Mar. 24, 2016 0028. The term "heteroaryl” refers to a monocyclic, bicy 0036. In general, unless indicated otherwise, a chemical clic, or tricyclic ring system containing one, two, or three group referred to anywhere in the specification can be option aromatic rings and containing at least one nitrogen, oxygen, ally substituted. or Sulfur atom in an aromatic ring, and which can be unsub 0037. The term “therapeutically effective amount’ means stituted or Substituted, for example, with one or more, and in the amount of a compound that, when administered to a particular one to three, Substituents, such as halo, alkyl, subject for treating
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