CN-121974874-A - Tetrahydrofuran compound, pharmaceutical composition and application thereof

Abstract

The invention discloses tetrahydrofuran compounds, or enantiomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, deuterides, solvates, hydrates, metabolites thereof, and pharmaceutical compositions and uses thereof. The tetrahydrofuran compound has good agonistic activity to Sigma-1 receptor and M-type acetylcholine receptor, and has good therapeutic effect on central nervous system diseases.

Inventors

• GUO CHANGYING
• JIANG CHENG
• ZHANG KUOJUN
• NI XIANG
• QI ZHIHAO
• GAO YICHAO
• LIANG YUYE
• LV YIWEI
• LIU YIRAN

Assignees

• 新疆大学
• 中国药科大学

Dates

Publication Date

20260505

Application Date

20260120

Claims (8)

1. 1. A tetrahydrofuran compound, or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, deuterate, solvate, hydrate, metabolite thereof, selected from any of the following structures: 。
2. 2. A pharmaceutical composition comprising a therapeutically effective amount of a tetrahydrofuran compound of claim 1, or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, deuterate, solvate, hydrate, metabolite, and a pharmaceutically acceptable carrier or adjuvant.
3. 3. Use of a tetrahydrofuran compound according to claim 1 or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, deuteride, solvate, hydrate, metabolite thereof, or a pharmaceutical composition according to claim 2 for the preparation of Sigma-1 receptor ligands and/or acetylcholine receptor type M ligands.
4. 4. Use of a tetrahydrofuran compound as defined in claim 1 or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, deuterate, solvate, hydrate, metabolite thereof, or a pharmaceutical composition as defined in claim 2, for the preparation of a medicament for modulating Sigma-1 receptor and/or type M acetylcholine receptor.
5. 5. Use of a tetrahydrofuran compound as defined in claim 1, or an enantiomer, racemate or mixture thereof, or a pharmaceutically acceptable salt, deuterate, solvate, hydrate, metabolite thereof, or a pharmaceutical composition as defined in claim 2, for the preparation of a medicament for the prophylaxis and/or treatment of a central nervous system disorder.
6. 6. The use according to claim 5, wherein the central nervous system disorder is a central nervous system disorder associated with an abnormality of Sigma-1 receptor and/or type M acetylcholine receptor.
7. 7. The use according to claim 6, wherein the central nervous system disorder is selected from any one or more of alzheimer's disease, parkinsonism, stroke, depression, rett's syndrome, tardive dyskinesia, huntington's chorea, amyotrophic lateral sclerosis, or pain.
8. 8. The use according to claim 7, wherein the central nervous system disorder is alzheimer's disease.

Description

Tetrahydrofuran compound, pharmaceutical composition and application thereof Technical Field The invention belongs to the field of innovative pharmaceutical chemistry, and relates to a tetrahydrofuran compound, a pharmaceutical composition and application thereof. Background The Sigma-1 receptor is a ligand complex which is positioned on the endoplasmic reticulum membrane related to mitochondria and forms Ca 2+ sensitivity with a molecular chaperone BiP/GRP78, and under the action of a specific activator, the Sigma-1 receptor is separated from the BiP and transferred to other positions of cells, and oxidative stress and mitochondrial functions are regulated by regulating inositol 1, 4, 5-triphosphate (inositol triphosphate, IP 3) receptor, N-methyl-D-aspartate (N-methyl-D-aspartate, NMDA) receptor, dopamine receptor or sodium, potassium and calcium ion channels, so that the production of tricarboxylic acid cycle (tricarboxylic ACID CYCLE, TCA) and ATP of the cells is influenced, and the secretion of various neurotransmitters is regulated. Sigma-1 receptors are involved in neuroprotection, neuroinflammation, neurotransmission and neuroplasticity, and are functionally intimately involved in advanced brain functions such as memory, cognition, emotion, pain and neurodegeneration. Various cell or animal model studies have shown that loss of Sigma-1 receptor expression or activity is associated with the occurrence of central neurodegenerative diseases, whereas Sigma-1 receptor activation can ameliorate the progression of Alzheimer's disease, parkinson's disease, stroke, dyskinesia, huntington's disease, depression, rate's syndrome, amyotrophic lateral sclerosis, etc. In Alzheimer's disease, sigma-1 receptor agonists can reduce Abeta toxicity, protect neuronal cells, inhibit Abeta-induced Tau protein hyperphosphorylation, maintain neuronal framework protein stability, inhibit neurofibrillary tangle formation, maintain neural function, increase hippocampal acetylcholine and glutamate transmitter levels, relieve Abeta-induced dysfunction of cholinergic and glutamatergic neuronal signaling systems, and improve cognitive dysfunction. Thus, sigma-1 receptor is an effective target for the prevention and treatment of CNS disorders. The muscarinic (M) acetylcholine receptors belong to the G protein-coupled receptor and are widely found on effector cell membranes innervated by parasympathetic postganglionic fibers, with 5 subtypes of M receptors (M 1、M2、M3、M4、M5) discovered so far. Among them, the M 1 receptor is highly expressed in hippocampal and cortical areas and exhibits a pro-cognitive effect in preclinical animal studies, and thus is widely considered as a key receptor mediating cognitive function, thereby becoming a therapeutic target for alzheimer's disease. Many orthosteric muscarinic agonists that utilize the natural ligand acetylcholine binding site have entered the clinic and have shown attractive therapeutic effects, such as the M1/M4 agonist xanomeline, the M1 agonist GSK1034702, which can improve the cognition, behavioral impairment and immediate and delayed memory, respectively, in patients, but are all terminated by adverse effects on the gastrointestinal and cardiovascular systems of the patient. Blarcamesine (ANAVEX 2-73) is a Sigma-1/M 1 acetylcholine receptor agonist, and has been used to complete phase IIa and phase IIb/III clinical trials of AD treatment. 。 Deuterated drugs refer to the replacement of some or all of the hydrogen atoms in the drug molecule with deuterium. Deuterated drugs generally retain the biological activity and selectivity of the original drug due to the shape and volume of deuterium in the drug molecule, which is similar to hydrogen. Since the C-D bond is more stable than the C-H bond, the introduction of deuterium into the drug molecule improves its metabolic stability, half-life is prolonged, and pharmacokinetic properties are improved. Since 2000, deuteration strategies have been widely used in drug research. Based on the prior art, the invention provides a series of deuterated compounds which can act on a Sigma-1 receptor and an M1 acetylcholine receptor simultaneously, and are expected to optimize the pharmacokinetic properties through deuteration modification on the basis of retaining the double-target agonistic activity, thereby providing a new drug choice for treating central nervous system diseases. Disclosure of Invention The invention provides tetrahydrofuran compounds or enantiomers, diastereomers, racemates or mixtures thereof, or pharmaceutically acceptable salts, deuterides, solvates, hydrates and metabolites thereof, which are selected from any one of the following structures; 。 The invention provides an application of tetrahydrofuran compound or enantiomer, racemate or mixture thereof or pharmaceutically acceptable salt, deuteride, solvate, hydrate and metabolite thereof in preparing Sigma-1 receptor ligand and/or M-type acetylcholine receptor ligand. The inven