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EA-053301-B1 - PHARMACEUTICAL COMPOUNDS

EA053301B1EA 053301 B1EA053301 B1EA 053301B1EA-053301-B1

Abstract

The present invention relates to compounds that are agonists of the muscarinic M1 and M4 receptors and that are useful for the treatment of diseases mediated by the muscarinic M1 and/or M4 receptors. Pharmaceutical compositions containing the compounds and the therapeutic use of these compounds are also provided. The disclosed compounds are compounds of formula (1) and their salts.

Inventors

  • Филдхаус Шарлотт
  • Конгрив Майлс Стюарт

Assignees

  • НКСЕРА ФАРМА ЮК ЛИМИТЕД

Dates

Publication Date
20260504
Application Date
20211220
Priority Date
20201218

Claims (15)

  1. an increase in the percentage of correct responses in the reversal phase of the task compared to the scPCP+vehicle group. Equivalents. The above examples are presented for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention in any way. It is obvious that numerous modifications and variations can be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. It is intended that all such modifications and variations be embraced by this application. CLAUSES OF THE INVENTION 1. Compound of formula (1): or its salt.
  2. 2. A salt of the compound according to claim 1.
  3. 3. A pharmaceutically acceptable salt of the compound according to claim 1.
  4. 4. An acid addition salt of the compound according to claim 1.
  5. 5. The hydrochloride salt of the compound according to claim 1.
  6. 6. A monohydrochloride salt of the compound according to claim 1.
  7. 7. The compound according to claim 1, which is a compound of formula (2): or its salt.
  8. 8. A salt of the compound according to claim 7.
  9. 9. A pharmaceutically acceptable salt of the compound according to claim 7.
  10. 10. An acid addition salt of the compound according to claim 7.
  11. 11. The hydrochloride salt of the compound according to claim 7.
  12. 12. The monohydrochloride salt of the compound according to claim 7.
  13. 13. Connection by p.1, which is a compound of formula (2b):
  14. 14. Connection by p.1, which is a compound of formula (2c):
  15. 15. Connection by p.1, which is a compound of formula (2): -

Description

The present invention relates to a class of novel heterocyclic compounds, their salts, pharmaceutical compositions containing them, and their therapeutic use in humans. In particular, the invention relates to a class of compounds that are agonists of the muscarinic M1 and/or M4 receptors and, therefore, are useful for the treatment of Alzheimer's disease, schizophrenia, cognitive disorders, and other diseases mediated by the muscarinic M1 / M4 receptors, including, inter alia, the treatment or relief of pain. Prior art of the present invention Muscarinic acetylcholine receptors (mAChRs) are members of the G protein-coupled receptor superfamily that mediate the actions of the neurotransmitter acetylcholine in both the central and peripheral nervous systems. Five mAChR subtypes, M1 through M5 , have been cloned. M1 mAChRs are predominantly expressed postsynaptically in the cortex, hippocampus, striatum, and thalamus; M2 mAChRs are predominantly located in the brainstem and thalamus, although they are also present in the cortex, hippocampus, and striatum, where they localize to cholinergic synaptic terminals (Langmead et al., 2008 Br J Pharmacol). However, M2 mAChRs are also expressed peripherally in cardiac tissue (where they mediate vagal innervation of the heart), in smooth muscle, and in exocrine glands. M 3 mAChRs are expressed at relatively low levels in the CNS, but are highly expressed in smooth muscle and glandular tissues such as sweat and salivary glands (Langmead et al., 2008 Br J Pharmacology). In the central nervous system, muscarinic receptors, particularly M1 mAChRs, play an important role in mediating higher cognitive functions. Diseases associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a loss of cholinergic neurons in the basal forebrain (Whitehouse et al., 1982 Science). In schizophrenia, which is also characterized by cognitive impairment, mAChR density is reduced in the prefrontal cortex, hippocampus, and dorsal striatum of patients (Dean et al., 2002 Mol Psychiatry). Furthermore, blockade or damage to central cholinergic pathways has been shown in animal models to result in profound cognitive deficits, and nonselective mAChR antagonists produce psychotomimetic effects in patients with psychiatric disorders. Cholinergic replacement therapy has largely relied on the use of acetylcholinesterase inhibitors to prevent the breakdown of endogenous acetylcholine. These compounds have demonstrated efficacy against symptomatic cognitive decline in the clinic, but have resulted in dose-limiting side effects resulting from stimulation of peripheral M2 and M3 mAChRs, including impaired gastrointestinal motility, bradycardia, nausea, and vomiting (http://www.Drugs.com/pro/donepezil.html; http://www. drugs. com/pro/rivastigmine. html). Further research aimed to identify direct M1 mAChR agonists for cognitive enhancement. This research led to the identification of several agonists, exemplified by compounds such as xanomeline, AF267B, sabcomeline, milameline, and cevimeline. Many of these compounds have been shown to be highly effective in preclinical cognitive models in rodents and/or non-human primates. Milameline demonstrated efficacy against scopolamine-induced deficits in working and spatial memory in rodents; subcomeline demonstrated efficacy in a visual object recognition task in marmosets; and xanomeline reversed the mAChR antagonist-induced deficit in passive avoidance testing. Alzheimer's disease (AD) is the most common neurodegenerative disease (26.6 million people worldwide in 2006), affecting older adults and resulting in profound memory loss and cognitive dysfunction. The etiology of the disease is complex but is characterized by two characteristic brain outcomes: accumulations of amyloid plaques, primarily composed of β-amyloid peptide (Λβ), and neurofibrillary tangles formed by hyperphosphorylated tau proteins. Αβ accumulation is considered a hallmark of AD progression, and therefore many putative AD treatments currently aim to inhibit Αβ production. Αβ is formed by proteolytic cleavage of membrane-bound amyloid precursor protein (APP). APP processing occurs via two pathways: non-amyloidogenic and amyloidogenic. Cleavage of APP by γ-secretase is common to both pathways, but in the former, APP is cleaved by α-secretase to form soluble APP. The cleavage site is located within the Αβ sequence, preventing its formation. However, in the amyloidogenic pathway, APP is cleaved by β-secretase to form soluble APΡΡβ as well as Αβ. In vitro studies have shown that mAChR agonists can promote APP processing through the non-amyloidogenic pathway, resulting in the soluble form. In vivo studies have shown that the mAChR agonist, AF267B, reverses AD-like pathology in 3xTgAD transgenic mice, a model of various components of Alzheimer's disease (Caccamo et al., 2006 Neuron). Finally, the mAChR agonist cevimeline has been shown to cause a small but significant reduction in c