This invention is directed to compounds of the formula I described herein, to a pharmaceutical composition comprising such compounds and to methods of treating disorders or conditions that may be treated by administration of such compounds to a mammal in need, including humans. In particular, the compounds of the current invention are potentially useful for treating Alzheimer's disease and other dementias.
Alzheimer's disease is the most common form of dementia, producing memory loss and other intellectual disabilities serious enough to interfere with normal daily routine. It accounts for 60 to 80 percent of dementia cases. The majority of people with Alzheimer's are 65 and older; however, up to 5 percent of people with the disease have early onset Alzheimer's in their 40's or 50's. In 2010, there were between 21 and 35 million people worldwide with AD. In 2010, dementia was attributed to about 486,000 deaths in the U.S.
Alzheimer's is a progressive disease, where dementia symptoms gradually worsen over a number of years. In late-stage Alzheimer's, individuals lose the ability to carry on a conversation and respond to their environment. It is the sixth leading cause of death in the United States. Alzheimer's patients generally live an average of eight years after their symptoms become noticeable to others, but survival can range from four to 20 years, depending on age and other health conditions. Alzheimer's has no known cure and while current treatments don't stop Alzheimer's from progressing, they can temporarily slow the worsening of dementia symptoms and improve quality of life for those with Alzheimer's and their caregivers.
Alzheimer's disease (AD) is characterized by loss of neurons and synapses in the cerebral cortex and certain subcortical regions. This loss results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus. Degeneration is also present in brainstem nuclei like the locus coeruleus. Studies using MRI and PET have documented reductions in the size of specific brain regions in people with AD as they progressed from mild cognitive impairment to Alzheimer's disease, and in comparison with similar images from healthy older adults.
Both amyloid plaques and neurofibrillary tangles are clearly visible by microscopy in brains of those afflicted by AD. Plaques are dense, mostly insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons. Tangles (neurofibrillary tangles) are aggregates of the microtubule-associated protein tau which has become hyper-phosphorylated and accumulate inside the cells themselves. Although many older individuals develop some plaques and tangles as a consequence of ageing, the brains of people with AD have a greater number of them in specific brain regions such as the temporal lobe. Lewy bodies are not rare in the brains of people with AD.
The U.S. Food and Drug Administration (FDA) has approved a small number of cholinesterase inhibitors, including donepezil (Aricept™, the only cholinesterase inhibitor approved to treat all stages of Alzheimer's disease, including moderate to severe), rivastigmine (Exelon™, approved to treat mild to moderate Alzheimer's), galantamine (Razadyne™, mild to moderate patients) and memantine (Namenda™). Donepezil is the only cholinesterase inhibitor approved to treat all stages of Alzheimer's disease, including moderate to severe.

Memantine is prescribed to improve memory, attention, reason, language and the ability to perform simple tasks. It can be used alone or with other Alzheimer's disease treatments. There is some evidence that individuals with moderate to severe Alzheimer's who are taking a cholinesterase inhibitor might benefit by also taking memantine. It regulates the activity of glutamate, a different messenger chemical involved in learning and memory and it delays worsening of symptoms for some people temporarily. Many experts consider its benefits similar to those of cholinesterase inhibitors.
Recently, there has been increased awareness of the potential for compounds which function as sigma-1 receptor ligands. The structure and functions of the “receptor” have been described in a variety of publications (e.g., Duncan G and Wang L (2005) Experimental Eye Research, 81:121-122; Ortega-Roldan J L, Ossa F, Schnell J R (2013) Journal of Biological Chemistry, 288(29):21448-21457; Monnet F P (2005) Biol. Cell 97:873-883 (doi:10.1042/BC20040149); Ishikawa M, Hashimoto K (2010) Journal of Receptor, Ligand and Channel Research, 3:25-36)
In a paper by Nguyen, et al (Nguyen L, Lucke-Wold B P, Mookerjee S A Cavendish J Z, Robson M J, Scandinaro A L and Matsumoto R R, Journal of Pharmacological Sciences (2015) 127:17-29), the mechanisms of neurodegeneration, including Alzheimer's disease, and the potential for the use of highly selective sigma-1 receptor ligands is discussed in great detail. They describe the mechanisms by which drugs that interact with the sigma-1 receptor may provide neuroprotection, including calcium homeostasis, attenuation of reactive species (e.g., NO) production, modulation of endoplasmic reticulum (ER) and mitochondrial function and modulation of glial activity. Because of these capabilities, they postulate that sigma-1 ligands may have beneficial effects in the treatment of stroke, ALS and Huntington's diseases.
Anavex Life Sciences Corp. has recently begun Phase 2a clinical trials with ANAVEX 2-73, a compound which possesses mixed sigma-1 and muscarinic receptor affinities. The company claims that the drug has the potential to reduce protein misfolding in the brain, a hallmark of Alzheimer's disease, and has demonstrated improved cognitive function with mild to moderate AD patients. Furthermore, they claim a positive, synergistic response when patients were treated with ANAVEX 2-73 and the acetylcholinesterase inhibitor donepezil.
The present patent application discloses novel compounds which display affinity and selectivity for the human sigma-1 receptor and for muscarinic subtype receptors, particularly the M1 and M2 subtypes. They are therefore expected to have utility on their own, or in combination with the aforementioned cholinesterase inhibitors, in the treatment of Alzheimer's disease and other non-AD dementias, Parkinson's and Huntington's diseases and ALS (amyotrophic lateral sclerosis, also referred to as Lou Gehrig's disease).
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