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(12) Patent Application Publication (10) Pub. No.: US 2014/0371260 A1 Moebius (43) Pub US 20140371260A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0371260 A1 Moebius (43) Pub. Date: Dec. 18, 2014 (54) COMBINATION THERAPY USING (60) Provisional application No. 60/420,918, filed on Oct. 1-AMINOCYCLOHEXANEDERVATIVES 24, 2002. AND ACETYLCHOLINESTERASE INHIBITORS Publication Classification (71) Applicant: MERZ PHARMA GmbH & CO. (51) Int. Cl KGaA, Frankfurt Am Main (GE) A613 L/473 (2006.01) A613 L/445 (2006.01) (72)72). InventorI tor: talHans-J is: Moebius.Oebus, FraFrankfurt Am A63/325 (2006.01) A613 L/13 (2006.01) (73) Assignee: MERZPHARMA GmbH & CO. (52) U.S. Cl. KGaA, Frankfurt Am Main (GE) CPC ............... A61 K3I/473 (2013.01); A61K3I/13 (2013.01); A61 K3I/445 (2013.01); A61 K (21) Appl. No.: 14/280,405 31/325 (2013.01) USPC ............................ 514/297: 514/319; 514/479 (22) Filed: May 16, 2014 Related U.S. Application Data (57) ABSTRACT (60) Continuation of application No. 12/661,639, filed on The invention relates to a novel drug combination therapy Mar. 22, 2010, which is a continuation of application useful in the treatment of dementia comprising administering No. 12/072,539, filed on Feb. 27, 2008, now aban an 1-aminocyclohexane derivative such as memantine or ner doned, which is a division of application No. 10/691, amexane and an acetylcholinesterase inhibitor (AChEI) such 895, filed on Oct. 23, 2003, now abandoned. as galantamine, tacrine, donepezil, or rivastigmine. Patent Application Publication Dec. 18, 2014 Sheet 2 of 3 US 2014/0371260 A1 Patent Application Publication Dec. 18, 2014 Sheet 3 of 3 US 2014/0371260 A1 US 2014/0371260 A1 Dec. 18, 2014 COMBINATION THERAPY USING released neurotransmitter acetylcholine (ACh). Recognition 1-AMINOCYCLOHEXANEDERVATIVES of the role of dysfunction of ACh signaling system in the AND ACETYLCHOLINESTERASE cognitive impairments associated with AD as well as a num INHIBITORS ber of other neurological and psychiatric disorders including Parkinson's disease, Schizophrenia, epilepsy, depression, FIELD OF THE INVENTION obsessive compulsive disorders, and bipolar disorders has led to the development of drugs that selectively enhance cholin 0001. The present invention relates to the combinations of ergic function by inhibition of the cholinergic catabolic 1-aminocyclohexane derivatives and acetylcholinesterase enzyme acetylcholinesterase (AChE), which destroys ACh inhibitors and their use in the treatment of dementia. after the latter has been secreted into the synaptic clefts (Goff and Coyle, Am. J. Psychiatry, 2001, 158: 1367-1377). At BACKGROUND OF THE INVENTION present, the most widely clinically used acetylcholinesterase 0002 Dementia is a serious disorder affecting as many as inhibitors (AChEI) are tacrine (THA; 1,2,3,4-tetrahydro-9- 10% of individuals older than 65 years and more than 24% of aminoacridine hydrochloride), DFP (diisopropylfluorophos those older than 85 years (Hofman et al., Int. J. Epidemiol. phate), physostigmine, donepezil, galantamine, and rivastig 1991, 20:736-748; Jorm and Jolley, Neurology, 1998, mine. Many of AChEI selectively inhibit AChE, but agents 51:728-733; Lobo et al., Neurology, 2000, 54(Suppl. 5):S4 that also target butyrylcholinesterase (BuChE) may provide S9). Alzheimer's disease (AD) is an increasingly prevalent added benefits as AD progresses and ACh regulation may form of neurodegeneration that accounts for approximately become increasingly dependent on BuChE. Dual inhibition 50-60% of the overall cases of dementia among people over may also help to slow the formation of amyloidogenic com 65 years of age. AD is characterized clinically by progressive pounds (Ballard, Eur. Neurol., 2002, 47:64–70). loss of memory, cognition, reasoning, judgement, and emo 0005 Donepezil tional stability that gradually leads to profound mental dete 0006 (I(R.S)-1-benzyl-4-(5,6-dimethoxy-1-indanon)-2- rioration and ultimately death. AD is a progressive disorder yl)-methylpiperidine hydrochloride; ARICEPT, previously with a mean duration of around 8.5 years between onset of clinical symptoms and death. AD is believed to represent the E-2020) is a reversible, noncompetitive, piperidine-type fourth most common medical cause of death and affects about AChEI, which is selective for AChE rather than BuChE (Sug 2-3 million people in the United States. Prevalence of AD imoto et al., Curr. Med. Chem., 2000, 7:303-39). Dooley et al. doubles every 5 years beyond age 65 (National Institute on (Drugs Aging, 2000, 16:199-226) have demonstrated that Aging: Prevalence and costs of Alzheimer's disease. Progress donepezil administered at doses of 5 and 10 mg/day signifi Report on Alzheimer's Disease. NIH Publication No. 99 cantly improved cognition and global clinical function com 3616, November 1998; Polyikoski et al., Neurology, 2001, pared with placebo in short term trials (14 to 30 weeks) in 161 56:1690-1696). AD currently affects about 15 million people to 818 patients with mild to moderate AD (see also Rogers et world-wide (including all races and ethnic groups) and owing al., Arch. Int. Med., 1998; 158:1021-1031). Long-term effi to the relative increase of elderly people in the population its cacy data obtained in these studies Suggest that improvements prevalence is likely to increase over the next two to three in cognition, global function or activities of daily living decades. AD is at present incurable. No treatment that effec (ADL) are maintained for about 21 to 81 weeks and that tively prevents AD or reverses its symptoms and course is donepezil is generally well tolerated with the majority of currently known. adverse events being mild and transient. 0003 AD is associated with death of pyramidal neurons 0007 Galantamine and loss of neuronal synapses in brains regions associated 0008 (REMINYL) is a reversible, competitive, tertiary with higher mental functions (Francis et al., 1999, J. Neurol. alkaloid AChEI, which is selective for AChE rather than Neurosurg. Psychiatry, 66:137-147). The brains of individu BuChE. As demonstrated by Scott et al. (Drugs, 2000; als with AD exhibit characteristic lesions termed senile (or 60:1095-122), 285 to 978 patients with mild to moderate AD amyloid) plaques, amyloid angiopathy (amyloid deposits in receiving galantamine at doses 16 or 24 mg/day achieved blood vessels) and neurofibrillary tangles. Smaller numbers significant improvements in cognitive and global symptoms of these lesions in a more restricted anatomical distribution relative to placebo recipients in trials of 3 to 6 months dura are also found in the brains of most aged humans who do not tion. Adverse events associated with galantamine in these have clinical AD. Amyloid plaques and amyloid angiopathy studies were usually mild to moderate in intensity and tran also characterize the brains of individuals with Trisomy 21 sient. Similar results were obtained by Coyle et al. (Biol. (Down's Syndrome) and Hereditary Cerebral Hemorrhage Psychiatry, 2001, 49:289-99). with Amyloidosis of the Dutch-Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observ 0009 Rivastigmine ing the aforementioned lesions in the brain tissue of patients (0010 (EXELON) is a dual inhibitor of AChE and BuChE who have died with the disease or, rarely, in small biopsied that has demonstrated benefits across the spectrum of AD samples of braintissue taken during an invasive neuroSurgical severity (BallardTM, Eur. Neurol., 2002, 47:64–70). Unlike procedure. tacrine and donepezil, which are classified as short-acting or 0004 AD is associated with a profound loss of cholinergic reversible agents, rivastigmine is an intermediate-acting or neurons within the nucleus basalis of Meynert (Perry et al., pseudo-irreversible agent, which inhibits AChE for up to 10 Br. Med. J., 1978, 2:1456-1459; Geula and Mesulam, Cho hours. Preclinical biochemical studies indicated that rivastig linergic systems and related neuropathological predilection mine has central nervous system (CNS) selectivity over patterns in Alzheimer disease. In: Alzheimer's Disease. Terry peripheral inhibition. Rivastigmine was shown to ameliorate et al. eds.; New York: Raven Press: 1994, pp. 263-291). The memory impairment in rats with forebrain lesions; and in the signaling in these neurons is mediated by the extracellularly two large multicenter clinical trials (total 1324 patients) at US 2014/0371260 A1 Dec. 18, 2014 doses 6-12 mg/day it was Superior to placebo on three cogni ing high affinity for the NMDA receptors are likely to impair tive and functioning scales (Jann, Pharmacotherapy, 2000, normal synaptic transmission and thereby cause numerous 20:1-12). side effects. Indeed, many NMDA receptor antagonists iden 0011. The excessive or pathological activation of tified to date produce highly undesirable side effects at doses glutamate receptors, particularly those that are selectively within their putative therapeutic range. Thus, clinical trials activated by N-methyl-D-aspartate (NMDA), has also been failed to Support good therapeutic utility due to numerous side implicated in the processes that underlie the degeneration of effects for such NMDA receptor antagonists as Dizocilpine cholinergic cells in the brains of AD patients (Greenamyre et ((+)MK-801; (+)-5-methyl-10,11-dihydro-5H-dibenzocy al., Neurobiol. Aging, 1989, 10:593-602; Francis et al., J. clohepten-5,10-imine maleate), Cerestat (CNS-1102), Neurochem., 1993, 60:263-291; Li et al., J. Neuropathol. Licostinel (ACEA 1021), Selfotel (CGS-19755), and D-CPP Exp. Neurol., 1997, 56:901-911; Wu and Rowan, Neurore ene (LeppikTM, Epilepsia, 1998, 39 (Suppl 5):2-6: Sveinb port, 1995, 6:2409-2413). The NMDA receptor is very well jornsdottir et al., Epilepsia, 1993, 34:493-521; SCRIP 2229/ established to be pivotal for several physiologic synaptic plas 30, 1997, p. 21). The challenge in the field has therefore been ticity processes, e.g., memory and learning (Collinridge and to develop NMDA receptor antagonists that prevent the Singer, Trends Pharmacol. Sci., 1990, 11: 290–296). The pathological activation of NMDA receptors but allow their functioning of the NMDA receptor requires the activation of physiological activity.
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