WO2023001268A1 - Chrysin derivative, and preparation method therefor and use thereof - Google Patents

Abstract

The present invention relates to the technical field of drugs, and specifically relates to a chrysin derivative, and a preparation method therefor and the use thereof. The chrysin derivative has a structure as represented by formula I, and the biological activity and bioavailability thereof are significantly higher than those of chrysin. The chrysin derivative can prevent and/or treat diseases, such as hyperglycemia, hyperlipidemia, Alzheimer's disease, senile dementia, Parkinson's disease, amyotrophic lateral sclerosis, cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complications, diabetic eye diseases, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver, cirrhosis, hepatitis, obstructive jaundice and myocardial infarction.

Description

A kind of chrysin derivative and its preparation method and application

This application is also required to be submitted to the Chinese Patent Office on July 23, 2021. The application number is CN202110841265.4. Patent Office, the priority of two Chinese patent applications with the application number CN202110842880.7 and the title of the invention "a chrysin derivative and its preparation method", the entire contents of which are incorporated in this application by reference.

technical field

The invention relates to the technical field of medicines, in particular to a chrysin derivative and its preparation method and application.

Background technique

Chrysin (5,7-dihydroxyflavone, Chrysin) is a flavonoid compound that widely exists in nature and has various pharmacological activities such as anti-oxidation, anti-inflammation, anti-anxiety, anti-tumor, anti-diabetes, and antibacterial.

In the prior art, a series of compounds have been obtained by modifying the structure of chrysin, for example, CN101774994A prepared long-chain chrysin derivatives for treating atherosclerosis. CN103896896A prepares iodine-containing chrysin derivatives for resisting radiation damage. In CN105884735A, chrysin is subjected to aminomethylation reaction to prepare chrysin derivatives, which are used for treating hyperuricemia. KR101713026B1 prepared chrysin derivatives for the prevention and treatment of Coxsackie virus-related diseases.

Through exhaustive research and investigation of the prior art, it is found that there is no generally applicable rule in the prior art on how to improve the structure of chrysin, thereby improving the efficacy of chrysin.

Neurodegenerative diseases (Neurodegenerative diseases, ND) are chronic diseases that lead to the gradual death of neurons, including Alzheimer's disease, Parkinson's disease and Huntington's disease, which often bring great pain and suffering to patients and families. burden. With the aging of the population, it is expected that by 2040, ND will replace cancer and become the second largest type of disease that causes human death. However, there is currently no drug that can effectively treat ND in the world.

The pathology of ND is closely related to oxidative stress, mitochondrial dysfunction, Ca ²⁺ influx, immune inflammation, autophagy, and metal ions. It is difficult to be effective in the development of new drugs, and the development of new anti-ND drugs that can achieve multi-target synergistic therapy and have less toxic side effects has become a research hotspot in recent years.

Lipids, also known as lipids, are a class of esters and their derivatives produced by the action of fatty acids and alcohols. They have various biological functions such as storing and providing energy, participating in the formation of biofilms, and protecting tissues and organs. The metabolism of lipids is regulated by genetics, neurohumoral, hormones, enzymes, liver and other tissues and organs, and its homeostasis plays a decisive role in maintaining the normal life activities of cells, tissues and organs and the whole body. A large number of studies have shown that with the development of the economic level, the change of lifestyle, the adjustment of dietary structure, and the influence of genetic factors, diseases characterized by abnormal lipid metabolism, such as obesity, dyslipidemia, fatty liver, atherosclerosis, etc. The incidence rate of sclerosis etc. increases year by year, and its pathology is often more complicated, and treatment is difficult.

In previous studies, we found that chrysin has a certain therapeutic effect on diseases related to abnormal lipid metabolism, but its clinical application is limited by its poor solubility, low intestinal absorption, and the 5 and 7 hydroxyl groups are easily metabolized by glycosylation.

Contents of the invention

The invention provides a chrysin derivative and its preparation method and application. The chrysin derivatives can be used to prevent and/or treat hyperglycemia, hyperlipidemia, Alzheimer's disease (AD), senile dementia, Parkinson's (PD), amyotrophic lateral sclerosis (ALS), cerebral insufficiency Blood, brain injury, obesity, diabetes and/or diabetic complications, diabetic eye disease, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver, cirrhosis, hepatitis, obstructive jaundice, myocardial infarction, etc. disease.

The invention provides the application of a compound, a salt of the compound, or a tautomer in the preparation of a medicine, and the medicine is used for preventing and/or treating neurodegenerative diseases, inflammatory diseases, endocrine diseases, and abnormal lipid metabolism Related diseases, preferably, prevent and/or treat Alzheimer's disease (AD), senile dementia, Parkinson (PD), amyotrophic lateral sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and /or diabetic complications, diabetic eye disease, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver.

Described compound has the structure shown in formula I:

in:

R ₁ , R ₃ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ One or more of alkoxy, substituted or unsubstituted C ₁ -C ₆ amino groups;

R ₂ is -NR ₇ R ₈ , wherein R ₇ and R ₈ are the same or different, and R ₇ and R ₈ are each independently hydrogen atom, substituted or unsubstituted C ₁ -C ₁₂ alkyl, substituted or unsubstituted C ₁ ~C ₁₂ alkoxy, C ₃ ~C ₈ cycloalkyl, N-methylpiperidin-4-yl, 2-pyridyl, phenyl, tolyl, xylyl, pyridine-2- Base and 2-methylpyridin-4-yl; or the R ₂ is diallylamino, morpholinyl, pyrrolyl, piperidinyl, 4-benzylpiperidinyl, 4-substituted benzylpiperidinyl , 4-phenylpiperidinyl, 4-substituted phenylpiperidinyl, benzylpiperazinyl, substituted benzylpiperazinyl, piperazinyl substituted by C ₁ ~C ₁₂ alkyl at the 4-position, 4- Piperidinyl and substituted phenyl 1,2,3,4-tetrahydroisoquinolinyl substituted by C1～C12 alkyl; the substituted phenyl or substituted benzyl is that any substitution position on the benzene ring is replaced by 1 Substituted by ~4 groups, the group is selected from F, Cl, Br, I, C _1~4 alkyl, C _1~4 alkoxy, trifluoromethyl, trifluoromethoxy, nitro or cyano;

Or the R ₇ and R ₈ together with the N atom form a substituted or unsubstituted 3-10 membered heterocyclic ring; the heterocyclic ring contains O, N, S or P atoms; the heterocyclic ring is a monocyclic ring, Bicyclic or polycyclic structures;

R ₉ is absent, hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ amino group, substituted or unsubstituted C _1-10 cycloalkyl group, substituted or unsubstituted C _1-10 heterocyclic group, substituted or unsubstituted C _6-15 aryl group, substituted or Unsubstituted C _1～10 heteroaryl;

R ₄ is selected from hydrogen, deuterium, substituted or unsubstituted C ₁ -C ₁₂ alkyl, or -C(=O)-R ₂ -R ₉ ;

a is an integer of 0-5.

Preferably, the R ₂ is piperidinyl, piperazinyl, tetrahydropyrrolyl, or morpholinyl.

Preferably, the R ₂ is -NR ₇ R ₈ , wherein R ₇ and R ₈ are each independently methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

Preferably, the R ₄ is H, -C(=O)NR ₇ R ₈ , -C(=O)-piperidinyl, -C(=O)-piperazinyl, -C(=O)- Tetrahydropyrrolyl, or -CO-morpholinyl.

Preferably, it is specifically the structure shown in formula C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8 or C-9:

The present invention provides a pharmaceutical composition, comprising the compound, the salt of the compound, or a tautomer described in the above technical scheme; and a pharmaceutically acceptable carrier.

Preferably, the pharmaceutical composition is oral formulation, intravenous or intramuscular injection formulation, local administration formulation or inhalation formulation.

Preferably, the pharmaceutical composition is tablet, capsule, sustained-release agent, controlled-release agent, injection powder, injection, solution, suspension, emulsion, micropill, pill, powder, microemulsion, target To preparations, inhalants.

Preferably, the pharmaceutical composition comprises about 0.1 mg to about 1000 mg, about 1 mg to about 500 mg, or about 10 mg to about 200 mg of the compound of formula I and about 0.1 mg to about 2000 mg, about 10 mg to about Oral dosage forms of 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the other active agent.

Preferably, the carrier includes excipients and diluents.

Preferably, the types of the carrier include but are not limited to: binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, Surfactants, tableting agents, and wetting agents.

The present invention provides the preparation method of the C-1 compound described in the above technical scheme:

Dissolve chrysin and anhydrous potassium carbonate in anhydrous acetonitrile, then add 1-chloroformyl-4-piperidinylpiperidine hydrochloride, heat up and reflux and stir; after the reaction, spin the solvent to dry under reduced pressure, add water, Extract with dichloromethane, combine organic layers, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain compound C-1.

The present invention provides the application of the compound described in the above technical scheme, the salt of the compound, or the tautomer in the preparation of medicine, and the medicine is used for preventing and/or treating neurodegenerative diseases, inflammatory diseases, endocrine diseases, Diseases related to abnormal lipid metabolism.

Preferably, the drug is used to prevent and/or treat hyperglycemia, hyperlipidemia, Alzheimer's disease, senile dementia, Parkinson, amyotrophic lateral sclerosis, cerebral ischemia, brain injury, obesity, diabetes and/or Diabetic complications, diabetic eye disease, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver, cirrhosis, hepatitis, obstructive jaundice, myocardial infarction and other diseases.

The present invention also provides the application of the above-mentioned compound in the preparation of reagents, which can reduce the weight gain induced by high-fat diet, reduce the increase of blood sugar in mice induced by high-fat diet, and reduce the blood lipid of mice induced by high-fat diet (LDL) increase, reduce the increase of total cholesterol in mice induced by high-fat diet, reduce the increase of triglyceride in mice induced by high-fat diet, reduce the increase of urinary creatinine in mice induced by high-fat diet, and reduce the increase of high-fat diet Diet-induced increase of GPT in mice, reduction of high-fat diet-induced increase of GOT in mice, improvement of memory impairment in 5*FAD mice, effective increase of mouse limb grasping, improvement of bradykinesia symptoms, significantly increased MPTP mice climbing time.

The biological activity and bioavailability of the compounds of the present invention are significantly higher than those of chrysin. Compared with the chrysin compound, the compound of the present invention can significantly reduce the weight gain induced by high-fat diet, significantly reduce the increase of blood sugar in mice induced by high-fat diet, and significantly reduce the increase of blood lipid (LDL) in mice induced by high-fat diet , Significantly reduce the increase of total cholesterol in mice induced by high-fat diet, significantly reduce the increase of triglyceride in mice induced by high-fat diet, significantly reduce the increase of urinary creatinine in mice induced by high-fat diet, and significantly reduce the increase of urine creatinine in mice induced by high-fat diet Induced the increase of GPT in mice, significantly reduced the increase of GOT in mice induced by high-fat diet, significantly improved the memory impairment of 5*FAD mice, and had a better therapeutic effect on amyotrophic lateral sclerosis (ALS), It is more effective in increasing the grip strength of the limbs of mice, improving the symptoms of slow movement, and significantly increasing the climbing time of MPTP mice. It has significant advantages in the prevention and/or treatment of neurodegenerative diseases, inflammatory diseases, endocrine diseases, and diseases related to abnormal lipid metabolism. Can reduce low-density lipoprotein, total cholesterol, triglyceride; reduce urinary creatinine, alanine aminotransferase, aspartate aminotransferase; for the prevention and/or treatment of hyperglycemia, hyperlipidemia, Alzheimer's disease (AD), senile dementia, Parkinson's (PD), amyotrophic lateral sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complications, diabetic eye disease, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non- Alcoholic fatty liver, liver cirrhosis, hepatitis, obstructive jaundice, myocardial infarction and other diseases.

The present invention also provides a preparation method of the compound:

The compound is prepared by reacting chrysin with carbamoyl chloride derivative in the presence of base.

All of the compounds described above, where the compounds exist in different tautomeric forms, the present invention is not limited to any one specific tautomeric form, but includes all tautomeric forms.

All compounds mentioned above include compounds having all possible isotopes of atoms occurring in the compounds. Isotopes include atoms with the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon ^include11C , ^13C , ^and14C .

The present invention also provides a pharmaceutical composition. The compounds disclosed in the present invention may be administered as a pure chemical, but preferably as a pharmaceutical composition. Accordingly, the present disclosure provides pharmaceutical compositions comprising a compound or pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier. Pharmaceutical compositions may contain a compound or salt as the sole active agent, but preferably contain at least one other active agent. In certain embodiments, the pharmaceutical composition is a compound of formula I comprising from about 0.1 mg to about 1000 mg, from about 1 mg to about 500 mg, or from about 10 mg to about 200 mg and optionally from about 0.1 mg to about 2000 mg in a unit dosage form , about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the other active agent.

The compounds disclosed in this invention may be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, orally, rectally, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutical carriers. way to give. The pharmaceutical composition can be formulated into any pharmaceutical form, such as: aerosol, cream, gel, pill, capsule, tablet, syrup, transdermal patch, or ophthalmic solution. Some dosage forms, such as tablets and capsules, can be subdivided into appropriate dosage unit dosage forms containing appropriate quantities of the active component, such as an effective amount to achieve the desired purpose.

Carriers include excipients and diluents, and must be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the patient to be treated. The carrier may be inert or it may itself have pharmaceutical benefits.

Types of carriers include but are not limited to: binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in more than one category, eg vegetable oil may be used as a lubricant in some formulations and as a diluent in others. Exemplary pharmaceutical carriers include sugar, starch, cellulose, powdered tragacanth, malt, gelatin, talc and vegetable oils. Optional active agents may be included in the pharmaceutical compositions which do not substantially interfere with the activity of the compounds of the invention.

The compounds or salts of the invention may be the only active agent administered or may be administered in conjunction with other active agents.

Terminology Conventions:

"Alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the indicated number of carbon atoms, generally 1 to about 12 carbon atoms. The term C1-C6 alkyl as used herein denotes an alkyl group having 1 to about 6 carbon atoms. When a C0-Cn alkyl group is used herein in conjunction with another group, for example, (phenyl)C0-C4 alkyl, the designated group, in this case, the phenyl group is formed by a single covalent bond (C0 ) directly bonded or connected through an alkyl chain having the indicated number of carbon atoms (in this case, 1 to about 4 carbon atoms). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, 3-methylbutyl, t-butyl, n-pentyl, and sec-pentyl.

"Alkenyl" refers to straight and branched hydrocarbon chains that include one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. The alkenyl groups described herein typically have 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those having 2 to about 8 carbon atoms, such as: C2-C8, C2-C6, and C2-C4 alkenyl. Examples of alkenyl groups include ethenyl, propenyl, and butenyl.

"Alkoxy" means an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.

The term "heterocyclic ring" means a 5- to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring comprising 1 to about 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, or is a 7- to 11-membered saturated ring, a partially unsaturated ring, or an aromatic heterocyclic ring system and a 10- to 15-membered tricyclic ring system containing at least 1 heteroatom selected from N, O and S polycyclic ring systems And comprising up to about 4 heteroatoms independently selected from N, O and S in each ring in the polycyclic ring system. Unless otherwise indicated, a heterocycle can be attached to a group where it substitutes at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocyclic rings described herein may be substituted on a carbon or nitrogen atom so long as the resulting compound is stable. The nitrogen atoms in the heterocycle can be optionally quaternized. Preferably the total number of heteroatoms in the heterocyclyl group is not greater than 4 and preferably the total number of S and O atoms in the heterocyclyl group is not greater than 2, more preferably not greater than 1. Examples of heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridizinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]thiophenyl (benz[b]thiophenyl), isoquinolyl, quinazolinyl, quinoxalinyl, Thienyl, isoindolyl, dihydroisoindolyl, 5,6,7,8-tetrahydroisoquinoline, pyridyl, pyrimidinyl, furyl, thienyl, pyrrolyl, pyrazolyl, pyrrolidine morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl.

"Aryl or heteroaryl" means a stable 5- or 6-membered monocyclic or polycyclic ring containing 1 to 4, or preferably 1 to 3 heteroatoms selected from N, O and S, and the remaining ring atoms being carbon. ring. When the total number of S and O atoms in the heteroaryl exceeds 1, these heteroatoms are not adjacent to each other. It is preferred that the total number of S and O atoms in the heteroaryl group is not greater than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not greater than one. The nitrogen atoms in the heterocycle can be optionally quaternized. When indicated, these heteroaryl groups may also be substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion with a 5 to 7-membered saturated cyclic group optionally containing 1 or 2 heteroatoms independently selected from N, O and S, to form, for example, [1,3]dioxin Azolo[4,5-c]pyridyl. Examples of heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, Azolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo[b]phenylthio, isoquinolyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl , and 5,6,7,8-tetrahydroisoquinoline.

"Salts of the compounds" are derivatives of the disclosed compounds wherein the parent compound is modified by the preparation of non-toxic acid or base addition salts thereof, and also refer to pharmaceutically acceptable solvates, including hydrates, of these compounds and these salts . Examples of pharmaceutically acceptable salts include, but are not limited to: inorganic or organic acid addition salts of basic residues such as amines; base or organic addition salts of acidic residues such as carboxylic acids; Combinations of the above salts. Pharmaceutically acceptable salts include, for example, non-toxic and quaternary ammonium salts of the parent compound formed from non-toxic inorganic or organic acids. For example, non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; other acceptable inorganic salts include metal salts such as sodium, potassium, Cesium salts, etc.; alkaline earth metal salts such as: calcium salts, magnesium salts, etc., and combinations comprising one or more of the above salts.

Organic salts of compounds include those derived from compounds such as acetic acid, trifluoroacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid , phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, fumaric acid, p-toluenesulfonic acid, methyl Salts prepared from organic acids such as sulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, HOOC-(CH ₂ ) _n -COOH (where n is 0 to 4); organic amine salts, such as triethylamine salt, pyridinium salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, etc.; and amino acid salts, such as: arginine salt, aspartame Acid salts, glutamic acid salts, etc., and combinations comprising one or more of the above salts.

Instructions attached

Figure 1 shows that C-1 significantly improved memory impairment in 5*FAD mice;

Figure 2 shows that C-1 significantly improves the motor function impairment of ALS mice - climbing pole time;

Figure 3 is; C-1 significantly improves the motor function impairment of ALS mice-limb grip;

Figure 4 shows that C-1 significantly improved the motor function impairment of MPTP-treated mice - climbing pole time.

detailed description

Example 1:

Chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (3.5mmol, 483mg) were dissolved in anhydrous acetonitrile (20mL), then 1-chloroformyl-4-piperidinylpiperidine hydrochloride (1.0mmol , 267 mg), heated and refluxed and stirred for 8 hours; after the reaction, the solvent was spin-dried under reduced pressure, 50 mL of water was added, extracted three times with 120 mL of dichloromethane, after the organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated, the obtained The residue was purified by silica gel column chromatography (dichloromethane:methanol=20:1) to obtain 400mg of the product with a yield of 89%.

¹ HNMR (400MHz, CDCl ₃ ) δ12.67(s, 1H), 7.88(dd, J＝8.0, 1.4Hz, 2H), 7.59–7.47(m, 3H), 6.90(d, J＝2.1Hz, 1H ),6.71(s,1H),6.58(d,J=2.0Hz,1H),4.35(d,J=12.9Hz,2H),2.95(dt,J=24.8,12.6Hz,2H),2.67(s ,5H), 1.78–1.68(m,4H), 1.64(d,J=11.9Hz,2H), 1.51(d,J=4.9Hz,2H), 1.39–1.27(m,2H). ¹³ C NMR(101MHz,CDCl ₃ )δ182.88,164.59,161.73,156.90,156.74,152.10,132.10,131.02,129.15,126.37,108.49,106.04,106.00,105.32,105.29,100.92,62.51,50.14,44.28,43.90,34.44 ,27.80,27.16,27.12,25.55,24.22.

Mix the obtained product with 15 mL of 2mol/L HCl in 1,4-dioxane, stir at room temperature for 2 hours, filter, and dry to obtain the hydrochloride of the product.

Example 2:

Dissolve chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (3.5mmol, 483mg) in anhydrous acetonitrile (20mL), then add N,N-dimethylcarbamoyl chloride (1.0mmol, 107.5mg), and heat up to reflux Stir for 8 hours; after the reaction, the solvent was spin-dried under reduced pressure, 50 mL of water was added, extracted three times with 120 mL of dichloromethane, and the organic layers were combined, dried with anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column Analysis and purification (dichloromethane: methanol = 100:1) yielded 300 mg of the product with a yield of 92%. ¹ H NMR (400MHz, CDCl ₃ )δ12.68(s,1H),7.88(dd,J＝8.0,1.4Hz,2H),7.59–7.49(m,3H),6.93(d,J＝2.0Hz, 1H), 6.72 (s, 1H), 6.60 (d, J=2.0Hz, 1H), 3.08 (d, J=29.5Hz, 6H). ¹³ C NMR (101MHz, CDCl ₃ ) δ182.91, 164.57, 161.74, 157.05, 156.77, 153.49, 132.07, 131.11, 129.16, 126.39, 108.46, 106.06, 106.04, 105.30, 100.940, 36.10

Example 3:

Chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (8.0mmol, 1.1g) were dissolved in anhydrous acetonitrile (30ml), then N,N-dimethylcarbamoyl chloride (5.0mmol, 537.7mg) was added, and the temperature was raised Reflux and stir for 12 hours; after the reaction was completed, the solvent was spin-dried under reduced pressure, 50 mL of water was added, extracted three times with 120 mL of dichloromethane, and the organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated, and the obtained residue was purified by silica gel column Purified by chromatography (dichloromethane:methanol=50:1) to obtain 350mg of the product with a yield of 95%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.84 (dd, J=7.6, 1.8Hz, 2H), 7.50 (d, J=7.0Hz, 3H), 7.36 (d, J=2.2Hz, 1H), 6.92 (d, J=2.2Hz, 1H), 6.64(s, 1H), 3.20(s, 3H), 3.10(s, 3H), 3.05(d, J=7.1Hz, 6H). ¹³ C NMR(101MHz,CDCl ₃ )δ176.91,162.21,157.66,154.86,154.59,153.23,151.08,131.58,131.30,129.04,126.16,114.08,114.03,108.63,108.58,108.16,108.13,36.85,36.81,36.58,36.56 .

Example 4:

Dissolve chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (3.5mmol, 483mg) in anhydrous acetonitrile (20ml), then add 4-methylpiperazine-1-formyl chloride hydrochloride (1.0mmol, 199mg ), heated and refluxed and stirred for 8 hours; after the reaction was completed, the solvent was spin-dried under reduced pressure, 50 mL of water was added, extracted three times with 120 mL of dichloromethane, after the organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated, the obtained residue Purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain 280mg of the product with a yield of 72%. ¹ H NMR (400MHz, CDCl ₃ ) δ12.62(s, 1H), 7.81(dd, J=8.1, 1.4Hz, 2H), 7.53–7.42(m, 3H), 6.85(d, J=2.1Hz, 1H), 6.65(s, 1H), 6.52(d, J=2.1Hz, 1H), 3.59(d, J=31.6Hz, 4H), 2.46–2.37(m, 4H), 2.29(s, 3H). ¹³ C NMR(101MHz,CDCl ₃ )δ182.90,164.60,161.79,156.86,156.77,152.24,132.10,131.08,129.17,126.39,108.54,106.09,106.07,105.31,100.94,100.92,54.73,54.53,46.10,44.60,44.00 .

Mix the obtained product with 15 mL of 2mol/L HCl in 1,4-dioxane, stir at room temperature for 2 hours, filter, and dry to obtain the hydrochloride of the product.

Example 5:

Dissolve chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (8.0mmol, 1.1g) in anhydrous acetonitrile (30ml), then add 4-methylpiperazine-1-formyl chloride hydrochloride (5.0mmol, 1.0 g), heated and refluxed and stirred for 12 hours; after the reaction was completed, the solvent was spin-dried under reduced pressure, 50 mL of water was added, extracted three times with 120 mL of dichloromethane, after the organic layers were combined, dried with anhydrous sodium sulfate, filtered, and concentrated, the obtained The residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain 500 mg of the product with a yield of 98%. MS (ESI) m/z: 507.2 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ7.84(dd, J=7.8, 1.7Hz, 2H), 7.56–7.46(m, 3H), 7.36(d, J=2.3Hz, 1H), 6.94(d, J=2.3Hz, 1H), 6.67(s, 1H), 3.88–3.55(m, 8H), 2.62–2.43(m, 8H), 2.36(d, J=11.4Hz, 6H). ¹³ C NMR(101MHz,CDCl ₃ )δ176.74,162.18,157.64,154.64,153.04,151.94,150.85,131.60,131.28,129.06,126.14,115.23,114.08,108.65,108.60,108.33,108.30,54.70,54.63,54.53,46.24 , 46.17, 46.11, 44.70, 44.63, 44.10, 44.05.

Mix the obtained product with 15 mL of 2mol/L HCl in 1,4-dioxane, stir at room temperature for 2 hours, filter, and dry to obtain the hydrochloride of the product.

Embodiment 6:

Chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (3.5mmol, 483mg) were dissolved in anhydrous acetonitrile (20ml), then 4-morpholine carbonyl chloride (1.0mmol, 150mg) was added, and the temperature was raised to reflux and stirred for 8 hours; After the reaction was finished, the solvent was spin-dried under reduced pressure, 50 mL of water was added, extracted three times with 120 mL of dichloromethane, after the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated, the obtained residue was purified by silica gel column chromatography (2 Chloromethane:methanol=100:1) to obtain 280 mg of the product, with a yield of 76%. ¹ H NMR (400MHz, CDCl ₃ ) δ12.63(s, 1H), 7.80(dd, J=8.1, 1.4Hz, 2H), 7.52–7.41(m, 3H), 6.85(d, J=2.1Hz, 1H), 6.65 (s, 1H), 6.52 (d, J=2.1Hz, 1H), 3.69 (d, J=4.7Hz, 4H), 3.57 (d, J=33.2Hz, 4H). ¹³ C NMR(101MHz,CDCl ₃ )δ182.88,164.62,161.82,156.76,156.67,152.32,132.13,131.04,129.17,126.39,108.62,106.10,106.08,105.28,105.27,100.91,66.59,66.46,45.02,44.23。

Embodiment 7:

Dissolve chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (8.0mmol, 1.1g) in anhydrous acetonitrile (30ml), then add 4-morpholine carbonyl chloride (5.0mmol, 750mg), heat and reflux and stir for 12 hours After the reaction finishes, the solvent is spin-dried under reduced pressure, 50mL water is added, extracted three times with 120mL dichloromethane, after the organic layer is combined, it is dried with anhydrous sodium sulfate, filtered, concentrated, and the obtained residue is purified by silica gel column chromatography ( Dichloromethane:methanol=50:1) to obtain 450mg of the product with a yield of 93%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.85(dd, J=7.8, 1.6Hz, 2H), 7.57–7.47(m, 3H), 7.38(d, J=2.3Hz, 1H), 6.95(d, J=2.3Hz, 1H), 6.67(s, 1H), 3.85–3.72(m, 8H), 3.72–3.65(m, 4H), 3.61(d, J=3.2Hz, 4H). ¹³ C NMR(101MHz,CDCl ₃ )δ176.75,162.38,157.67,154.51,153.27,152.01,150.80,131.71,131.19,129.10,126.18,115.22,114.01,113.96,108.62,108.57,108.43,66.62,66.57,66.49,66.42 , 47.24, 44.39, 44.30, 44.23.

Embodiment 8:

Chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (3.5mmol, 483mg) were dissolved in anhydrous acetonitrile (20ml), then 1-piperidinyl chloride (1.0mmol, 148mg) was added, and the temperature was raised and stirred under reflux for 8 hours; After the end, the solvent was spin-dried under reduced pressure, 50mL of water was added, extracted three times with 120mL of dichloromethane, after the organic layers were combined, they were dried with anhydrous sodium sulfate, filtered, concentrated, and the resulting residue was purified by silica gel column chromatography (dichloromethane Methane:methanol=150:1) to obtain 280 mg of product, yield 76%. MS (ESI) m/z: 366.1 [M+H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ )δ12.67(s,1H),7.87(dd,J＝8.0,1.4Hz,2H),7.60–7.46(m,3H),6.91(d,J＝2.0Hz, 1H), 6.71(s, 1H), 6.59(d, J=2.0Hz, 1H), 3.57(d, J=28.6Hz, 4H), 1.66(s, 6H). ¹³ C NMR(101MHz,CDCl ₃ )δ182.90,164.52,161.72,157.19,156.76,152.29,132.05,131.09,129.14,126.36,108.39,106.02,106.00,105.32,100.94,100.92,45.76,45.27,25.95,25.49,24.22 .

Embodiment 9:

Chrysin (1.0mmol, 254mg) and anhydrous potassium carbonate (8.0mmol, 1.1g) were dissolved in anhydrous acetonitrile (30ml), then 1-piperidinyl chloride (5.0mmol, 738mg) was added, and the temperature was raised to reflux and stirred for 12 hours; After the reaction was finished, the solvent was spin-dried under reduced pressure, 50 mL of water was added, extracted three times with 120 mL of dichloromethane, after the combined organic layers were dried with anhydrous sodium sulfate, filtered, and concentrated, the obtained residue was purified by silica gel column chromatography (2 Chloromethane: Methanol = 150:1) to obtain 420 mg of the product with a yield of 88%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.88–7.81(m,2H),7.56–7.46(m,3H),7.35(d,J=2.2Hz,1H),6.92(d,J=2.2Hz, 1H), 6.66(s, 1H), 3.71(s, 2H), 3.57(d, J=24.9Hz, 6H), 1.74–1.63(m, 12H); ¹³ C NMR(101MHz, CDCl ₃ ) δ176.85, 164.84 ,162.08,157.66,154.95,153.30,152.02,151.11,131.53,131.35,129.03,126.13,115.16,114.13,114.10,108.61,108.08,47.92,45.92,45.74,45.28,25.78,25.58,25.49,24.78,24.42,24.19 .

Experimental Example 1: Activity Test Method:

1. Effect on body weight of mice induced by high-fat diet

Experimental method: The change of the weight of the mice reflects the degree of obesity of the mice. In this experiment, the weight of the mice was weighed with an electronic balance to determine the effect of the drug on the weight of the mice.

Table 1 Effect of C-1 on the body weight of high-fat diet mice

group	ND	HFD	HFD/C-1(Low)	HFD/C-1(High)	HFD/CHRY	HFD/Losartan
mean	31.37	41.27	34.58*	31.64**	40.42	38.42
SD	1.59	3.23	2.47	2.27	3.76	3.34

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), they could significantly reduce the weight gain induced by high-fat diet, and the high-dose group No significant effect of equimolar doses of chrysin (50 mg/kg) on high-fat diet-induced body weight gain was observed. Losartan (10 mg/kg) also did not significantly alter the body weight of mice treated with a high-fat diet. *p<0.05, **p<0.01 vs. HFD. N=8-10/group; data expressed as Mean±SD.

2. Effect on high-fat diet-induced blood glucose in mice

Experimental method: The blood sugar of mice on a high-fat diet will increase abnormally, showing symptoms of diabetes. In this experiment, a blood glucose meter and its matching blood sugar test strips are used to measure the blood sugar of the mice, and the blood collection point is the tail of the mice.

Table 2 Effect of C-1 on blood glucose in high-fat diet mice

group	ND	HFD	HFD/C-1(Low)	HFD/C-1(High)	HFD/CHRY	HFD/Losartan
mean	7.16	8.39	7.91*	7.22**	8.63	8.52
SD	0.69	0.72	0.71	0.83	0.95	0.78

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), high-dose C-1 significantly reduced the levels of mice induced by a high-fat diet. Elevation of blood glucose, high-dose equimolar dose of chrysin (50mg/kg) had no significant effect on the increase of blood glucose induced by high-fat diet. Losartan (10 mg/kg) also did not significantly alter blood glucose in mice treated with a high-fat diet. *p<0.05, **p<0.01 vs. HFD. N=6-8/group; the data are expressed as Mean±SD. The detailed results are shown in the table above.

Conclusion: High doses of chrysin derivatives can significantly reduce blood sugar in mice fed a high-fat diet, and have potential value for the treatment of diabetes.

3. Effect of C-1 on blood lipid (LDL) in mice induced by high-fat diet

Experimental method: Low-density lipoprotein (LDL) can transport cholesterol to peripheral tissues. It is one of the main carriers of cholesterol in the blood and one of the four routine indicators of blood lipids. In this experiment, the LDL determination kit was used to measure the LDL concentration through a biochemical analysis instrument.

The impact of table 3 C-1 on high fat diet mice blood lipid (LDL)

group	ND	HFD	HFD/C-1(Low)	HFD/C-1(High)	HFD/CHRY	HFD/Losartan
mean	0.49	0.82	0.55**	0.51**	0.74	0.676
SD	0.06	0.14	0.09	0.07	0.13	0.08

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), both low-dose and high-dose C-1 could significantly reduce hyperlipidemia Diet-induced elevation of blood lipid (LDL) in mice, high-dose equimolar dose of chrysin (50mg/kg) had no significant effect on the elevation of LDL induced by high-fat diet. Losartan (10 mg/kg) failed to significantly alter the high-fat diet-induced LDL elevation. **p<0.01 vs. HFD. N=6-8/group; data are expressed as Mean±SD. See the table above for detailed results.

Conclusion: Low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives can significantly improve the symptoms of elevated blood lipid (LDL) in mice induced by high-fat diet, and have potential for reducing cardiovascular disease. the value of.

4. Effect of C-1 on total cholesterol in mice induced by high-fat diet

Experimental method: Excessive total cholesterol can easily induce coronary heart disease and stroke. It is one of the indicators of lipid metabolism disorder and dyslipidemia. This experiment uses a total cholesterol determination kit and biochemical analysis equipment to measure the serum total cholesterol concentration.

The impact of table 4 C-1 on the blood fat (TC) of high-fat diet mice

group	ND	HFD	HFD/C-1(Low)	HFD/C-1(High)	HFD/CHRY	HFD/Losartan
mean	1.24	2.92	1.74**	1.42**	2.95	2.17
SD	0.25	0.46	0.53	0.18	0.23	0.24

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), both low-dose and high-dose C-1 could significantly reduce hyperlipidemia Diet-induced increase of total cholesterol in mice, high-dose equimolar dose of chrysin (50mg/kg) had no significant effect on the increase of LDL induced by high-fat diet. Losartan (10 mg/kg) failed to significantly alter the high-fat diet-induced increase in total cholesterol. **p<0.01 vs. HFD. N=6-8/group; data are expressed as Mean±SD. See the table above for detailed results.

Conclusion: Low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives can significantly inhibit the increase of total cholesterol in mice induced by high-fat diet, which has potential value for improving dyslipidemia.

5. Effect of C-1 on triglycerides in mice induced by high-fat diet

Experimental method: Excessive triglycerides can cause atherosclerosis and fatty liver, which is one of the indicators of lipid metabolism disorder and dyslipidemia. In this experiment, a triglyceride determination kit was used to measure serum triglycerides through biochemical analysis instruments. ester concentration.

The impact of table 5 C-1 on high-fat diet mice blood lipid (TG)

group	ND	HFD	HFD/C-1(Low)	HFD/C-1(High)	HFD/CHRY	HFD/Losartan
mean	12.10	24.73	16.81**	13.95***	23.92	17.65
SD	1.23	2.12	1.18	1.31	2.24	1.92

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), both low-dose and high-dose C-1 could significantly reduce hyperlipidemia Diet-induced increase in triglycerides in mice, high-dose equimolar doses of chrysin (50mg/kg) had no significant effect on the increase in triglycerides induced by high-fat diet. Losartan (10 mg/kg) failed to significantly alter high-fat diet-induced triglyceride elevation. . **p<0.01, ***p<0.001 vs. HFD. N=6-8/group; data are expressed as Mean±SD. See the table above for detailed results.

Conclusion: Low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives can significantly reduce the content of triglycerides in mice fed a high-fat diet, which is beneficial to improve the symptoms of dyslipidemia.

6. Effect of C-1 on urinary creatinine in mice induced by high-fat diet

Experimental method: Excessive urinary creatinine is commonly seen in acromegaly, diabetes, infection, excessive meat consumption, etc. In this experiment, a urine creatinine determination kit was used to measure the concentration of urine creatinine through a biochemical analyzer.

Table 6 Effect of C-1 on urinary creatinine in high-fat diet mice

group	ND	HFD	HFD/C-1(Low)	HFD/C-1(High)	HFD/CHRY	HFD/Losartan
mean	2729.56	4817.33	3785.00**	3105.78***	4529.35	4406.67
SD	114.65	203.79	164.81	134.54	225.56	194.73

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), both low-dose and high-dose C-1 could significantly reduce hyperlipidemia Diet-induced increase in urinary creatinine in mice, high doses of equimolar doses of chrysin (50mg/kg) had no significant effect on the increase in urine creatinine induced by high-fat diet. Losartan (10 mg/kg) failed to significantly alter the high-fat diet-induced increase in urinary creatinine. **p<0.01, ***p<0.001 vs. HFD. N=6-8/group; data are expressed as Mean±SD. See the table above for detailed results.

Conclusion: Low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives can significantly reduce the increase of urinary creatinine in mice induced by high-fat diet.

7. Effect of C-1 on high-fat diet-induced liver function GPT in mice

Experimental method: Abnormal alanine aminotransferase (GPT) is closely related to liver diseases such as cirrhosis, hepatitis, and obstructive jaundice. In this experiment, the serum concentration of GPT was measured by using a GPT assay kit combined with a biochemical analyzer.

The effect of table 7 C-1 on the GPT of high-fat diet mice

group

ND

HFD

HFD/C-1(Low)

HFD/C-1(High)

HFD/CHRY

HFD/Losartan

mean	36.88	146.45	57.43**	46.35**	137.43	97.38
SD	3.12	12.77	9.26	5.36	13.78	10.28

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), both low-dose and high-dose C-1 could significantly reduce hyperlipidemia Diet-induced increase of GPT in mice, high-dose equimolar dose of chrysin (50mg/kg) had no significant effect on the increase of GPT induced by high-fat diet. Losartan (10 mg/kg) failed to significantly alter the high-fat diet-induced increase in GPT. **p<0.01 vs. HFD. N=6-8/group; data are expressed as Mean±SD. See the table above for detailed results.

Conclusion: Low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives can significantly reduce the increase of GPT in mice induced by high-fat diet, and effectively treat abnormal liver function in mice.

8. Effect of C-1 on liver function GOT induced by high-fat diet

Experimental method: Abnormal aspartate aminotransferase (GOT) is closely related to various liver diseases, and GOT will also be abnormally elevated in the early stage of patients with myocardial infarction. In this experiment, the GOT serum concentration was measured by using a GOT assay kit combined with a biochemical analyzer.

Table 8 Effect of C-1 on GOT of high-fat diet mice

group	ND	HFD	HFD/C-1(Low)	HFD/C-1(High)	HFD/CHRY	HFD/Losartan
mean	116.35	203.82	147.62*	128.31**	193.71	160.676
SD	6.28	9.41	6.29	6.17	8.36	8.76

Results: After 8 weeks of intragastric administration of low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1), both low-dose and high-dose C-1 could significantly reduce hyperlipidemia Diet-induced increase of GOT in mice, high-dose equimolar dose of chrysin (50mg/kg) had no significant effect on the increase of GOT induced by high-fat diet. Losartan (10 mg/kg) failed to significantly alter the high-fat diet-induced GOT elevation. *p<0.05 vs. HFD, **p<0.01 vs. HFD. N=6-8/group; data are expressed as Mean±SD. See the table above for detailed results.

Conclusion: Low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives can significantly reduce the increase of GOT in mice induced by high-fat diet, and effectively treat abnormal liver function in mice.

9. C-1 significantly improved memory impairment in 5*FAD mice

Experimental method: New object recognition is to put mice in a square frame (length, width and height 40cm*40cm*40cm), which has two objects of the same shape (square or cylindrical 3cm), and the mice are trained for 5 minutes , Change one of the objects to a new object that the mouse is not familiar with, and the instrument records the time that the mouse stays in the familiar and unfamiliar objects within 5 minutes.

Analysis of the results: As shown in Figure 1, after 6-month-old 5*FAD mice were treated with C-1 for 8 weeks, the new object recognition test was used to detect the time ratio of mice exploring new objects. 5*FAD mice were treated with low dose and high dose of C-1 (low dose: 18.2mg/kg; high dose: 72.6mg/kg) and CHRY (50mg/kg). Compared with wild control mice, the rate of novel object exploration time was significantly decreased in 5*FAD mice, and the high dose of C-1 significantly improved the rate of 5*FAD exploration time (Figure 1). Data are expressed as mean ± SEM; n = 10-12 for each group. One-way ANOVA and multiple comparisons showed differences between the two groups. **p<0.001 vs. WTmice; ##p<0.01 vs. 5*FAD mice.

Conclusion: C-1 can significantly improve memory impairment in 5*FAD mice, and has potential value in the treatment of Alzheimer's disease (AD).

10. C-1 significantly improved the motor function impairment of ALS mice

Experimental method: The rod climbing test is often used to evaluate the motor coordination ability and motor delay of mice. A wooden pole with a length of about 50cm and a diameter of about 1cm is made by ourselves. The pole is wrapped with medical gauze to increase the friction of the wooden pole. Place the wooden pole vertically on a horizontal table, hold the tail of the mouse so that the mouse's head is facing downwards, grasp the top of the pole with its limbs, release the tail of the mouse, and start timing to ensure that the mouse is not affected by external force Crawl down, and record the time for the mouse to climb from the top of the rod to the platform at the bottom (unified hindlimb landing shall prevail). The mice were continuously trained on the behavior for 3 days before administration, and each mouse was subjected to three repeated tests, and the mice that did not reach the standard were eliminated.

Result analysis: as shown in Figure 2, after the administration begins, the behavior is tested once every two weeks, the maximum value of the test result is no more than 15 seconds, and the value exceeding 15 seconds is recorded as 15 seconds. Calculate the time for the mice to climb the pole three times The average value was used as the final pole-climbing time. ALS (SOD-G93A) transgenic mice showed obvious slowness of movement after the onset of the disease. Severe, and given different doses of C-1, CHRY and riluzole treatment, it was found that high doses of C-1 can significantly improve the symptoms of bradykinesia. Data are expressed as mean ± SEM; n = 10 for each group. One-way ANOVA and multiple comparisons showed differences between the two groups. **p<0.01 vs. WT (normal control) group; #p<0.05 vs. ALS (SOD-G93A) group, ##p<0.01 vs. ALS (SOD-G93A) group.

Conclusion: C-1 has a therapeutic effect on amyotrophic lateral sclerosis (ALS), significantly shortening the pole climbing time and improving bradykinesia.

11. C-1 significantly improved the motor function impairment of ALS mice

Experimental method: The limb grasping test is directly used to evaluate the muscle strength of mice. Put the mouse lightly on the central platform of the grip board, and gently pull the tail of the mouse to prompt the mouse to grasp the grip board, and wait for the mouse to grasp firmly When holding the grip net, pull it back horizontally in time, and record the data when the instrument shows the maximum grip value. After the administration started, the grip value of the mice was tested every two weeks, each mouse was measured three times, and the maximum value among the three results was taken as the maximum grip value of the mouse.

Result analysis: As shown in Figure 3, after the ALS transgenic mice entered the onset period, the grasping power of their limbs was significantly smaller than that of WT mice. C-1 can effectively increase the grip strength of the limbs of mice, and delay the deterioration of the decline in the grip strength of the limbs of ALS mice. Data are expressed as mean ± SEM; n = 8-10 for each group. One-way ANOVA and multiple comparisons showed differences between the two groups. **p<0.001 vs. WT (normal control) group; ##p<0.01 vs. ALS (SOD-G93A) group.

Conclusion: C-1 can improve the process of grip loss in amyotrophic lateral sclerosis (ALS) mice, and has potential therapeutic effect on ALS.

12. C-1 significantly improved the motor function impairment of MPTP-treated mice

Experimental method: The pole climbing test is often used to evaluate the motor coordination ability and motor delay of mice. A wooden pole with a length of about 50cm and a diameter of about 1cm is homemade. The pole is wrapped with medical gauze to increase the friction of the pole. Place the wooden pole vertically on a horizontal table, hold the tail of the mouse so that the mouse's head is facing downwards, grasp the top of the pole with its limbs, release the tail of the mouse, and start timing to ensure that the mouse is not affected by external force Crawl down, and record the time for the mouse to climb from the top of the rod to the platform at the bottom (unified hindlimb landing shall prevail). The mice were continuously trained on the behavior for 3 days before administration, and each mouse was subjected to three repeated tests, and the mice that did not reach the standard were eliminated.

Result analysis: Figure 4.C-1 significantly reduces the pole-climbing time of MPTP mice. Modeling of MPTP, the behavioral results after 14 days of administration show that the pole-climbing time of the model group is longer than that of the normal control group, and the low-dose and high-dose After C-1 treatment, the pole climbing time of MPTP mice was significantly increased; after the treatment of positive control selegiline (10mg/kg), the pole climbing time of MPTP mice tended to decrease, but there was no statistically significant difference. Data are expressed as mean ± SD; n = 10-12 for each group. One-way ANOVA and multiple comparisons showed differences between the two groups. **p<0.001 vs. WT group. ##p<0.01 vs. MPTP-treated mice.

Conclusion: C-1 significantly improves the motor function impairment of MPTP-treated mice, and has potential value for the treatment of Parkinson's (PD).

The biological activity and bioavailability of the compound of the present invention are significantly higher than those of chrysin. Compared with the chrysin compound, the compound of the present invention can significantly reduce the weight gain induced by high-fat diet, significantly reduce the increase of blood sugar in mice induced by high-fat diet, and significantly reduce the increase of blood lipid (LDL) in mice induced by high-fat diet , Significantly reduce the increase of total cholesterol in mice induced by high-fat diet, significantly reduce the increase of triglyceride in mice induced by high-fat diet, significantly reduce the increase of urinary creatinine in mice induced by high-fat diet, and significantly reduce the increase of urine creatinine in mice induced by high-fat diet Induced the increase of GPT in mice, significantly reduced the increase of GOT in mice induced by high-fat diet, significantly improved the memory impairment of 5*FAD mice, and had a better therapeutic effect on amyotrophic lateral sclerosis (ALS), It is more effective in increasing the grip strength of the limbs of mice, improving the symptoms of slow movement, and significantly increasing the climbing time of MPTP mice. It has significant advantages in the prevention and/or treatment of neurodegenerative diseases, inflammatory diseases, endocrine diseases, and diseases related to abnormal lipid metabolism. Can reduce low-density lipoprotein, total cholesterol, triglyceride; reduce urinary creatinine, alanine aminotransferase, aspartate aminotransferase; for the prevention and/or treatment of hyperglycemia, hyperlipidemia, Alzheimer's disease (AD), senile dementia, Parkinson's (PD), amyotrophic lateral sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complications, diabetic eye disease, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non- Alcoholic fatty liver, liver cirrhosis, hepatitis, obstructive jaundice, myocardial infarction and other diseases.

The above description is a general description of the invention. Changes in form and substitution of equivalents may be made according to circumstances or actual needs, and although specific terms are used herein, these terms are intended to be descriptive rather than limiting. Those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (14)

1. A compound, a salt of the compound, or a tautomer, the compound has a structure shown in formula I:

   

   in:

   R ₁ , R ₃ , R ₅ and R ₆ are each independently selected from hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ One or more of alkoxy, substituted or unsubstituted C ₁ -C ₆ amino groups;

   R ₂ is -NR ₇ R ₈ , wherein R ₇ and R ₈ are the same or different, and R ₇ and R ₈ are each independently hydrogen atom, substituted or unsubstituted C ₁ -C ₁₂ alkyl, substituted or unsubstituted C ₁ ~C ₁₂ alkoxy, C ₃ ~C ₈ cycloalkyl, N-methylpiperidin-4-yl, 2-pyridyl, phenyl, tolyl, xylyl, pyridine-2- Base and 2-methylpyridin-4-yl; or the R ₂ is diallylamino, morpholinyl, pyrrolyl, piperidinyl, 4-benzylpiperidinyl, 4-substituted benzylpiperidinyl , 4-phenylpiperidinyl, 4-substituted phenylpiperidinyl, benzylpiperazinyl, substituted benzylpiperazinyl, piperazinyl substituted by C ₁ ~C ₁₂ alkyl at the 4-position, 4- Piperidinyl substituted by C ₁ ~C ₁₂ alkyl, substituted phenyl 1,2,3,4-tetrahydroisoquinolinyl; the substituted phenyl or substituted benzyl is any substitution position on the benzene ring Substituted by 1 to 4 groups selected from F, Cl, Br, I, C _{1 to 4} alkyl, C _{1 to 4} alkoxy, trifluoromethyl, trifluoromethoxy, Nitro or cyano;

   Or the R ₇ and R ₈ together with the N atom form a substituted or unsubstituted 3-10 membered heterocyclic ring; the heterocyclic ring contains O, N, S or P atoms; the heterocyclic ring is a monocyclic ring, Bicyclic or polycyclic structures;

   R ₉ is absent, hydrogen, deuterium, halogen, hydroxyl, amino, substituted or unsubstituted C ₁ -C ₆ alkyl, substituted or unsubstituted C ₁ -C ₆ alkoxy, substituted or unsubstituted C ₁ -C ₆ amino group, substituted or unsubstituted C _1-10 cycloalkyl group, substituted or unsubstituted C _1-10 heterocyclic group, substituted or unsubstituted C _6-15 aryl group, substituted or Unsubstituted C _1～10 heteroaryl;

   R ₄ is selected from hydrogen, deuterium, substituted or unsubstituted C ₁ -C ₁₂ alkyl, or -C(=O)-R ₂ -R ₉ ;

   a is an integer of 0-5.
2. The compound, the salt of the compound, or the tautomer as claimed in claim 1, wherein the R ₂ is piperidinyl, piperazinyl, tetrahydropyrrolyl or morpholinyl.
3. The compound, the salt of the compound, or the tautomer according to claim 1, wherein said R ₂ is -NR ₇ R ₈ , wherein R ₇ and R ₈ are each independently methyl, ethyl , propyl, isopropyl, n-butyl, isobutyl or tert-butyl.
4. The compound, the salt of the compound, or the tautomer according to claim 1, wherein said R ₄ is H, -C(=O)NR ₇ R ₈ , -C(=O)-piper Pyridyl, -C(=O)-piperazinyl, -C(=O)-tetrahydropyrrolyl, or -CO-morpholinyl.
5. The compound, the salt of the compound, or the tautomer as claimed in claim 1, is characterized in that, it is specifically formula C-1, C-2, C-3, C-4, C-5, C-6 , C-7, C-8 or the structure shown in C-9:

   

   
6. A pharmaceutical composition, characterized by comprising the compound, the salt of the compound, or a tautomer according to any one of claims 1-5; and also comprising a pharmaceutically acceptable carrier.
7. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is an oral preparation, an intravenous or intramuscular injection preparation, a topical administration preparation or an inhalation preparation.
8. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition is a tablet, a capsule, a sustained release agent, a controlled release agent, an injection powder, an injection, a solution, a suspension, an emulsion , pellets, pills, powders, microemulsions, targeted formulations, inhalants.
9. The pharmaceutical composition according to claim 6, wherein the pharmaceutical composition comprises about 0.1 mg to about 1000 mg, about 1 mg to about 500 mg, or about 10 mg to about 200 mg of the compound of formula I in a unit dosage form And oral dosage forms of about 0.1 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 800 mg, or about 200 mg to about 600 mg of the other active agent.
10. The pharmaceutical composition according to claim 6, wherein the carrier includes excipients and diluents.
11. The pharmaceutical composition according to claim 6, wherein the types of the carrier include but are not limited to: binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, flow aids agents, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents.
12. The preparation method of the C-1 compound described in claim 5, is characterized in that:

    

    Dissolve chrysin and anhydrous potassium carbonate in anhydrous acetonitrile, then add 1-chloroformyl-4-piperidinylpiperidine hydrochloride, heat up and reflux and stir; after the reaction, spin the solvent to dry under reduced pressure, add water, Extract with dichloromethane, combine organic layers, dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain compound C-1.
13. The application of the compound, the salt of the compound, or the tautomer according to any one of claims 1 to 5 in the preparation of medicine, characterized in that the medicine is used to prevent and/or treat neurodegenerative diseases, inflammation Diseases, endocrine diseases, abnormal lipid metabolism related diseases.
14. According to the application of claim 13, the drug is used for preventing and/or treating hyperglycemia, hyperlipidemia, Alzheimer's disease, senile dementia, Parkinson's, amyotrophic lateral sclerosis, cerebral ischemia, brain injury, Obesity, diabetes and/or diabetic complications, diabetic eye disease, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver, cirrhosis, hepatitis, obstructive jaundice, myocardial infarction and other diseases.

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