CN-122010722-A - Novel lithium butyrate proline eutectic salt and preparation method and application thereof

Abstract

The application relates to a novel lithium proline butyrate eutectic salt and a preparation method and application thereof, and belongs to the technical field of medicines. The application provides a new molecular structure with better stability and stronger drug effect by co-crystallizing lithium salt of n-butyric acid and L-proline for the first time. The novel lithium-proline butyrate eutectic salt can obviously inhibit the activity of GSK3 beta in cell and animal models, effectively down regulate total tau protein and phosphorylation level thereof, shows potential value in treating neurodegenerative diseases such as Alzheimer disease and the like, and has wide application prospect in the aspects of reducing nerve inflammation and improving nerve protection effect. Meanwhile, the composition also has preventive and therapeutic values in GSK3 beta related diseases such as cancers, mental diseases, diabetes and the like.

Inventors

• TAN JUN
• CAI CHUANBIN
• ZHANG BINGJIE
• LI SONG
• ZI DAN
• LEI ZHIFENG
• CHEN JIANG

Assignees

• 安域生物科技(杭州)有限公司

Dates

Publication Date

20260512

Application Date

20251215

Claims (9)

1. 1. The lithium proline butyrate eutectic salt is characterized by being prepared by co-crystallizing lithium salt of n-butyric acid and proline or proline derivatives according to the same molar ratio.
2. 2. The lithium prolite co-crystal salt according to claim 1, characterized in that the prolite derivative is a proline chemically modified at the carboxyl and/or imino site of the functional group.
3. 3. The lithium prolite eutectic salt of claim 1 or 2, wherein the eutectic is one of solvent volatilizing crystallization, cooling crystallization, grinding crystallization, reaction crystallization, hot melt extrusion crystallization, melt crystallization, and sonic crystallization.
4. 4. The method for preparing the lithium proline butyrate eutectic salt according to any one of claims 1 to 3, which is characterized by comprising the following steps: and dissolving the lithium salt of n-butyric acid and the proline in a solvent according to an equal molar ratio, dissolving under heating and refluxing, cooling to separate out crystals, collecting the crystals and drying to obtain the lithium proline butyrate eutectic salt.
5. 5. The method of claim 4, wherein the solvent is selected from one or more of water, methanol, ethanol.
6. 6. Use of a lithium prolium butyrate eutectic salt according to any one of claims 1-3 in the manufacture of a medicament for at least one of: (1) Inhibition of gsk3β; (2) Lowering tau protein levels; (3) Lowering phosphorylated tau protein levels; (4) Reducing neuroinflammation; (5) Enhancing neuroprotection; (6) Maintaining neuronal function stable; (7) Preventing or treating neurodegenerative diseases; (8) Preventing or treating cancer; (9) Preventing or treating mental diseases; (10) Preventing or treating type II diabetes and/or its complications.
7. 7. A medicament, characterized by comprising the lithium prolium butyrate eutectic salt according to any one of claims 1-3 and at least one pharmaceutically acceptable excipient and/or diluent.
8. 8. The drug according to claim 7, wherein the dosage form of the drug is one selected from the group consisting of an oral preparation, an injection, an aerosol, a suppository, drops, and a transdermal patch.
9. 9. The medicament according to claim 7 or 8, wherein the medicament is administered via the respiratory system or the digestive system, or subcutaneously, or via the nasal mucosa or submucosa, or via the eye or ear, or rectally, or vaginally.

Description

Novel lithium butyrate proline eutectic salt and preparation method and application thereof Technical Field The application relates to the technical field of medicines, in particular to a novel lithium proline butyrate eutectic salt and a preparation method and application thereof. Background Glycogen synthase kinase-3 beta (GSK 3 beta) is a serine/threonine kinase which is conserved in evolution, widely exists in eukaryotic cells of mammals, can regulate differentiation, proliferation, survival and apoptosis of the cells, and is used as a key therapeutic target in various important diseases such as cancers, neurodegenerative diseases, mental diseases, type II diabetes and the like. In cancer, gsk3β affects tumor progression through a variety of pathways. In normal cells, GSK3 beta is taken as a key regulator of a Wnt/beta-catenin signal pathway, and can phosphorylate beta-catenin to degrade the beta-catenin and inhibit cell proliferation. However, in some cancers, GSK3 beta activity is inhibited, resulting in accumulation of beta-catenin and entry into the nucleus, activating the pro-cell proliferation gene. Meanwhile, GSK3 beta participates in cell cycle regulation, the abnormal activity of the GSK3 beta can cause cell cycle to be out of control, and can regulate the phosphorylation of apoptosis-related proteins to influence the death of cells, and in some cancers, the abnormal activity of the GSK3 beta can prevent the apoptosis of cells and promote the growth of tumors. In mental disease, gsk3β is expressed during neurodevelopmental, and is involved in multiple brain signaling pathways, whose abnormal activity may trigger neurodevelopmental disorders. It also modulates various signaling pathways, affecting neuronal function and neural network formation, and dysregulation of activity can lead to aberrant signaling. Furthermore, gsk3β can regulate gene expression through phosphorylation, which is critical to neurons and neural networks, and abnormal activity can cause deregulation of gene expression, thereby causing mental diseases. For type II diabetes, gsk3β is an important regulator of the insulin signal transduction pathway, and active abnormalities can block insulin signal transduction, triggering insulin resistance, which is one of the main features of type II diabetes. It also participates in several links of glucose metabolism, and can cause glucose metabolism disorder when abnormal, leading to hyperglycemia. In addition, gsk3β participates in the regulation of inflammatory response, and its active abnormality may trigger chronic inflammation, exacerbate insulin resistance and hyperglycemia, exacerbate the development of type II diabetes. Among neurodegenerative diseases, alzheimer's Disease (AD) is a prominent feature. AD has cognitive impairment and neuronal degeneration characteristics characterized by β -amyloid (aβ) deposition and tau hyperphosphorylation to form neurofibrillary tangles (NFTs), and gsk3β plays a key role in tau phosphorylation and pathological progression of AD, so gsk3β inhibitors are considered potential therapeutic approaches. Lithium salts, including lithium carbonate and lithium citrate, have been used as a common gsk3β inhibitor for the treatment of bipolar disorders and other neuropsychiatric disorders due to their neuroprotective effect and have shown some potential in the treatment of AD. However, the clinical use of existing lithium salts is limited by toxicity and narrow therapeutic window. To solve this problem, researchers have tried to modify the eutectic modification of short chain fatty acid with lithium, such as lithium proline isobutyrate, but the prior art still lacks the eutectic salt of short chain fatty acid lithium amino acid with high activity, low toxicity, high stability and good therapeutic effect. Lithium carbonate has also been investigated for the treatment of related diseases, but again has limitations. Therefore, the development of safer and more effective GSK3 beta inhibitors is of great significance for the treatment of various related diseases. Disclosure of Invention In order to solve at least one of the above technical problems, the technical scheme adopted by the application is as follows. The application provides a lithium-proline butyrate eutectic salt, which is prepared by co-crystallizing lithium salt of n-butyric acid and proline or proline derivatives according to the equimolar ratio. According to the pharmaceutical co-crystal regulatory classification guidelines (US Food and Drug administration, "Regulatory classification of pharmaceutical crystals" 2018), a co-crystal is a crystalline substance that contains 2 or more different molecules in the same crystal lattice. In the present application, it was unexpectedly found that gsk3β activity can be significantly inhibited by eutectic crystal formation of the lithium salt of n-butyric acid and the proline. N-butyric acid is used as one of short chain fatty acids, has bioactivity, can r