JP-2022533436-A5 -

Dates

Publication Date

20230531

Application Date

20200524

Description

Group R 1 In some embodiments, R1 is a substituted C6 - C10 aryl. In some embodiments, R1 is an unsubstituted C6 - C10 aryl. The term “neurodegenerative disease” includes diseases and disorders associated with the progressive loss of structure or function of neurons, or the death of neurons. Neurodegenerative diseases and disorders include Alzheimer’s disease (including symptoms associated with mild, moderate, or severe cognitive impairment), amyotrophic lateral sclerosis (ALS), anoxic and ischemic injury, ataxia and convulsions (including the treatment and prevention of seizures caused by medications used to treat schizoaffective disorder or schizophrenia), benign amnesia, cerebral edema, cerebellar ataxia including McLeod’s neuroacanthopanaxic syndrome (MLS), and closed cerebrospinal fluid. Partial injury, coma, contusions (e.g., spinal cord injury and head injury), dementia including multi-infarct dementia and senile dementia, impaired consciousness, Down syndrome, drug-induced or drug-treatment-induced parkinsonism (such as neurogenic acute akathisia, acute dystonia, parkinsonism, or tardive dyskinesia, neuroleptic malignant syndrome, or drug-treatment-induced postural tremor), epilepsy, Fragility X syndrome, Gilles de la Tourette syndrome, head trauma, hearing impairment and loss, Han Chinton's disease, Lennox syndrome, levodopa-induced dyskinesia, intellectual disability, akinesia and akinesia (rigid) syndromes (including basal ganglia calcification, corticobasal degeneration, multiple system atrophy, parkinsonism-ALS dementia complex, Parkinson's disease, post-encephalitis parkinsonism, and progressive supranuclear palsy), chorea (benign hereditary chorea, drug-induced chorea, hemivalism, Huntington's disease, neuroacanthocytosis, Sydenham's chorea, and symptomatic chorea) (e.g., chorea), dyskinesia (including tics such as complex tics, simple tics, and symptomatic tics), myoclonus (including generalized myoclonus and focal syloclonus), tremor (e.g., resting tremor, postural tremor, and intentional tremor), and dystonia (axial dystonia, dystonic cramps, hemiplegic dystonia, paroxysmal dystonia, and, for example, blepharospasm, oromandibular dystonia, spasmodic dysphonia). Muscle spasms and disorders associated with muscle weakness, including dysphonia, and focal dystonia such as torticollis; ocular injuries of the eye; nerve injuries, including retinopathy or macular degeneration; stroke, thrombotic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm; hypoglycemia, amnesia, hypoxia, anoxia, neurotoxic injuries following perinatal asphyxiation and cardiac arrest; glaucoma (including blindness and associated symptoms of normal-tension visual field constriction); Parkinson's disease; epileptic seizures; status epilepticus; stroke, tinnitus, tubular sclerosis; and viral infection-induced neurodegeneration (e.g., caused by acquired immunodeficiency syndrome (AIDS) and encephalopathy). Neurodegenerative diseases include, but are not limited to, stroke, thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebral vasospasm, hypoglycemia, memory loss, hypoxia, anoxia, perinatal asphyxiation, and neurotoxic injury following cardiac arrest. Treatment or prevention of neurodegenerative diseases also includes treating or preventing the loss of neuronal function that is characteristic of neurodegenerative disorders. Synthesis of A198: To a solution of tert-butyl 4-cyano-3-methylpiperidine-1-carboxylate (600 mg, 2.67 mmol) in THF (10 mL), LDA (2.67 mL, 2 M in hexane, 5.34 mmol) was added at -70°C. After 30 minutes, 1-(bromomethyl)-4-fluorobenzene (655 mg, 3.47 mmol) in THF (10 mL) was added at -70°C, and the mixture was stirred for 2 hours. The mixture was saturated with NH₄Cl aqueous solution (50 mL), and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over Na₂SO₄ , filtered, and concentrated. The residue was purified by silica gel chromatography (PE/EtOAc = 5/1 to 3/1) to obtain tert-butyl 4-cyano-4-(4-fluorobenzyl)-3-methylpiperidine-1-carboxylate (300 mg, 33.8%). 1H NMR (400 MHz, CDCl3 ) δH 7.25–7.19 (m, 2H), 7.07–6.98 (m, 2H), 4.22–3.84 (m, 2H), 3.27 (d, 1H), 3.01–2.57 (m, 2H), 2.52 (d, 1H), 1.68–1.57 (m, 2H), 1.47–1.26 (m, 10H), 1.19 (d, 3H). Those skilled in the art will be able to recognize or confirm, by routine experimentation alone, many equivalents to the specific embodiments described herein. The scope of the embodiments described herein is not intended to be limited to the above description, but rather to the claims attached thereto. Those skilled in the art will understand that various changes and modifications to this description can be made without departing from the spirit or scope of the invention, as defined in the following claims. In one embodiment, for example, the following items are provided. (Item 1) Compound of formula I: or a pharmaceutically acceptable salt thereof During the ceremony, R1 is selected from the group consisting of C6 - C1