阅读说明：本技术 一种白杨素衍生物及其制备方法 (Chrysin derivative and preparation method thereof ) 是由 谢永美 杨细飞 杨超 李书鹏 刘恭平 张芮铭 叶涛 于 2021-07-23 设计创作，主要内容包括：本发明提供了一种白杨素衍生物及其制备方法,白杨素衍生物具有式I所示结构,其生物活性和生物利用度显著高于白杨素。可以预防和/或治疗高血糖、高血脂、阿尔茨海默病(AD)、老年痴呆、帕金森(PD)、肌萎缩侧索硬化(ALS)、脑缺血、脑损伤、肥胖、糖尿病和/或糖尿病并发症、糖尿病眼病、糖尿病肾病、血脂异常、动脉粥样硬化、脂肪肝、非酒精性脂肪肝、肝硬化、肝炎、阻塞性黄疸、心梗等疾病。(The invention provides a chrysin derivative and a preparation method thereof, wherein the chrysin derivative has a structure shown in a formula I, and the bioactivity and bioavailability of the chrysin derivative are obviously higher than those of chrysin. Can be used for preventing and/or treating hyperglycemia, hyperlipemia, Alzheimer Disease (AD), senile dementia, Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complication, diabetic ophthalmopathy, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver, liver cirrhosis, hepatitis, obstructive jaundice, myocardial infarction, etc.)

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

wherein:

R₁、R₃、R₅and R₆Each independently selected from hydrogen, deuterium, halogen, hydroxy, amine, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆1 or more of amine groups;

R₂is-NR₇R₈Wherein R is₇And R₈Same or different, each independently is a hydrogen atom, substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy radical, C₃～C₈Cycloalkyl, N-methylpiperidin-4-yl, 2-pyridyl, phenyl, tolyl, xylyl, pyridin-2-yl and 2-methylpyridin-4-yl, and the like. -NR₇R₈Or a diallylamino, morpholinyl, pyrrolyl, piperidinyl, 4-benzylpiperidinyl, 4-substituted benzylpiperidinyl, 4-phenylpiperidinyl, 4-substituted phenylpiperidinyl, benzylpiperazinyl, substituted benzylpiperazinyl, the 4-position being substituted by C₁-C₁₂Piperazinyl substituted by alkyl, 4-position by C₁-C₁₂Alkyl-substituted piperidinyl, substituted phenyl 1, 2, 3, 4-tetrahydroisoquinolinyl; the substituted phenyl or substituted benzyl refers to that any substitutable position on a benzene ring is substituted by 1-4 groups selected from the following groups: F. cl, Br, I, C_1-4Alkyl radical, C_1-4Alkoxy, trifluoromethyl, trifluoromethoxy, nitro or cyano;

or said R is₇And R₈Together with the N atom, form a substituted or unsubstituted 3-10 membered heterocyclic ring; optionally the heterocyclic ring contains O, N, S or a P atom; optional heterocycles are monocyclic, bicyclic or polycyclic structures;

R₉is absent, hydrogen, deuterium, halogen, hydroxy, amino, substituted or notSubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Amino, substituted or unsubstituted C_1-10Cycloalkyl, substituted or unsubstituted C_1-10Heterocyclyl, substituted or unsubstituted C_6-15Aryl, substituted or unsubstituted C_1-10A heteroaryl group;

R₄selected from hydrogen, deuterium, substituted or unsubstituted C₁-C₁₂Alkyl, or-C (═ O) -R₂-R₉；

Wherein a is an integer of 0 to 5.

2. A compound, salt, or tautomer of a compound of claim 1 wherein R is₂Is piperidinyl, piperazinyl, tetrahydropyrrolyl, or morpholinyl.

3. A compound, salt, or tautomer of a compound of claim 1 wherein R is₂is-NR₇R₈Wherein R is₇And R₈Each independently is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

4. A compound, salt, or tautomer of a compound of claim 1 wherein R is₄Is H, -C (═ O) NR₇R₈-C (═ O) -piperidinyl, -C (═ O) -piperazinyl, -C (═ O) -tetrahydropyrrolyl, or-CO-morpholinyl.

5. A compound, salt, or tautomer of a compound according to claim 1 characterized by the structure shown below:

6. a pharmaceutical composition comprising a compound, salt of a compound, or tautomer of any one of claims 1-5, optionally further comprising a pharmaceutically acceptable carrier.

7. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is an oral formulation, an intravenous or intramuscular injection formulation, a topical formulation, an inhalation formulation.

8. The pharmaceutical composition of claim 6, wherein the pharmaceutical composition is a tablet, a capsule, a sustained release formulation, a controlled release formulation, an injectable powder, an injectable solution, a suspension, an emulsion, a pellet, a pill, a powder, a microemulsion, a targeted formulation, an inhalant.

9. A method of preparing a compound, comprising:

dissolving chrysin and anhydrous potassium carbonate in anhydrous acetonitrile, adding 1-chloroformyl-4-piperidyl piperidine hydrochloride, heating, refluxing and stirring; after the reaction is finished, the solvent is dried by decompression and spin-drying, water is added, dichloromethane is used for extraction, organic layers are combined, anhydrous sodium sulfate is used for drying, filtration, concentration and silica gel column chromatography purification are carried out, and the product is obtained.

Technical Field

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

Background

Chrysin (5, 7-dihydroxyflavone, Chrysin) is a flavonoid compound widely existing in nature, and has various pharmacological activities such as antioxidation, anti-inflammation, antianxiety, antitumor, antidiabetic, antibacterial and the like.

In the prior art, structural modification of chrysin results in a series of compounds, such as: the chrysin long-chain derivative is prepared in CN101774994A and is used for treating atherosclerosis. Iodine-containing chrysin derivatives for resisting radiation damage are prepared in CN 103896896A. CN105884735A, the chrysin derivative is prepared, and the derivative has an aminomethylation reaction on chrysin and can be used for treating hyperuricemia. KR101713026B 1A chrysin derivative for preventing and treating Coxsackie virus related diseases is prepared.

Through detailed research and investigation on the prior art, the common applicable rule of how to improve the structure of chrysin and further improve the drug effect of chrysin is found to be absent in the prior art.

Neurodegenerative Diseases (ND) are chronic diseases including alzheimer's disease, parkinson's disease, huntington's disease, etc. which cause gradual death of neurons, and often cause great pain and burden to patients and families. With the aging population, ND is expected to replace cancer as the second major disease causing human death by 2040 years, however, no drug is available worldwide for the treatment of neurodegenerative diseases.

Pathological and oxidative stress of ND, mitochondrial dysfunction, Ca²⁺The internal flow, the immune inflammation, the autophagy, the metal ions and the like are closely related, the traditional development strategy of the single-target high-selectivity medicine is difficult to be effective in the research and development of ND new medicines, the multi-target cooperative treatment can be realized, and the development of a novel anti-ND medicine with small toxic and side effects is already developedHas become a hot research point in recent years.

Lipids (lipids), also known as lipids, are a class of esters and their derivatives produced by the action of fatty acids and alcohols, and have a variety of biological functions, including storing and providing energy, participating in biofilm formation, protecting tissues and organs, and the like. Lipid metabolism is regulated by genetics, neurohumor, hormones, enzymes, and tissues and organs such as liver, and its homeostasis plays a crucial role in maintaining normal vital activities of cells, tissues and organs, and the whole body. A large number of researches show that with the development of economic level, the change of life style, the adjustment of dietary structure and the influence of genetic factors, the incidence of diseases which are mainly characterized by lipid metabolism disorder, such as obesity, dyslipidemia, fatty liver, atherosclerosis, etc., is increased year by year, and the pathology is complex and the treatment difficulty is high.

In the previous research, chrysin is found to have a certain treatment effect on diseases related to lipid metabolism disorder, but the clinical application of chrysin is limited by the defects of poor solubility, low intestinal absorption, easy glycosylation and metabolism of hydroxyl groups at positions 5 and 7, and the like.

The invention modifies the 5-position hydroxyl and the 7-position hydroxyl of chrysin respectively, and a series of compounds with remarkably improved drug effect and bioavailability are expected to be obtained for treating neurodegenerative diseases and/or diseases related to lipid metabolism abnormality.

Disclosure of Invention

The invention provides a chrysin derivative and a preparation method thereof.

The chrysin derivative can be used for preventing and/or treating Alzheimer Disease (AD), senile dementia, Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complications, diabetic eye disease, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver and non-alcoholic fatty liver.

The invention provides a compound, a salt of the compound or a tautomer of the compound, and application of the compound, the salt of the compound or the tautomer in preparing a medicament for preventing and/or treating neurodegenerative diseases, inflammatory diseases, endocrine diseases and diseases related to lipid metabolism disorder, preferably Alzheimer Disease (AD), senile dementia, Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complications, diabetic eye diseases, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver and non-alcoholic fatty liver.

The compound has the following structure:

wherein:

R₁、R₃、R₅and R₆Each independently selected from hydrogen, deuterium, halogen, hydroxy, amine, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆1 or more of amine groups;

R₂is-NR₇R₈Wherein R is₇And R₈Same or different, each independently is a hydrogen atom, substituted or unsubstituted C₁-C₁₂Alkyl, substituted or unsubstituted C₁-C₁₂Alkoxy radical, C₃～C₈Cycloalkyl, N-methylpiperidin-4-yl, 2-pyridyl, phenyl, tolyl, xylyl, pyridin-2-yl and 2-methylpyridin-4-yl, and the like. -NR₇R₈Or a diallylamino, morpholinyl, pyrrolyl, piperidinyl, 4-benzylpiperidinyl, 4-substituted benzylpiperidinyl, 4-phenylpiperidinyl, 4-substituted phenylpiperidinyl, benzylpiperazinyl, substituted benzylpiperazinyl, the 4-position being substituted by C₁-C₁₂Piperazinyl substituted by alkyl, 4-position by C₁-C₁₂Alkyl-substituted piperidinyl, substituted phenyl 1, 2, 3, 4-tetrahydroisoquinolinyl; the substituted phenyl or substituted benzyl refers to that any substitutable position on a benzene ring is substituted by 1-4 groups selected from the following groups: F. cl, Br, I, C_1-4Alkyl radical, C_1-4Alkoxy, trifluoromethyl, trifluoromethoxy, nitro or cyano;

or said R is₇And R₈Together with the N atom, form a substituted or unsubstituted 3-10 membered heterocyclic ring; optionally the heterocyclic ring contains O, N, S or a P atom; optional heterocycles are monocyclic, bicyclic or polycyclic structures; r₉Is absent, hydrogen, deuterium, halogen, hydroxy, amino, substituted or unsubstituted C₁-C₆Alkyl, substituted or unsubstituted C₁-C₆Alkoxy, substituted or unsubstituted C₁-C₆Amino, substituted or unsubstituted C_1-10Cycloalkyl, substituted or unsubstituted C_1-10Heterocyclyl, substituted or unsubstituted C_6-15Aryl, substituted or unsubstituted C_1-10A heteroaryl group;

R₄selected from hydrogen, deuterium, substituted or unsubstituted C₁-C₁₂Alkyl, or-C (═ O) -R₂-R₉；

Wherein a is an integer of 0 to 5.

A compound, salt of a compound, or tautomer of a compound as described above, characterized in that R is₂Is piperidinyl, piperazinyl, tetrahydropyrrolyl, or morpholinyl.

A compound, salt of a compound, or tautomer of a compound as described above, characterized in that R is₂is-NR₇R₈Wherein R is₇And R₈Each independently is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

A compound, salt of a compound, or tautomer of a compound as described above, characterized in that R is₄Is H, -C (═ O) NR₇R₈-C (═ O) -piperidinyl, -C (═ O) -piperazinyl, -C (═ O) -tetrahydropyrrolyl, or-CO-morpholinyl.

The medicament prepared by the invention also comprises a pharmaceutically acceptable carrier.

The medicine prepared by the invention is an oral preparation, an intravenous or intramuscular injection preparation, a local administration preparation and an inhalation preparation.

The medicine prepared by the invention is tablets, capsules, sustained release agents, controlled release agents, injection powder, injection, solutions, suspensions, emulsions, micro-pills, powder, micro-emulsions, targeted preparations and inhalants.

The invention also provides application of the compound, the salt of the compound or the tautomer in preparing medicines, which is characterized by being used for preventing and/or treating neurodegenerative diseases, inflammatory diseases, endocrine diseases and diseases related to lipid metabolism disorder.

The use as described above, including for the prevention and/or treatment of Alzheimer's Disease (AD), senile dementia, Parkinson's Disease (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.

The invention also provides the use of the compound as described above in the preparation of an agent that can reduce high fat diet-induced weight gain, reduce high fat diet-induced elevated blood glucose in mice, reduce high fat diet-induced elevated blood lipid (LDL) in mice, reduce high fat diet-induced elevated total cholesterol in mice, reduce high fat diet-induced elevated triglycerides in mice, reduce high fat diet-induced elevated urinary creatinine in mice, reduce high fat diet-induced elevated GPT in mice, reduce high fat diet-induced elevated GOT in mice, improve memory impairment in 5 × FAD mice, effectively increase grasping power of limbs in mice, improve bradykinesia symptoms, and significantly increase rod climbing time in MPTP mice.

The compound of the invention has higher bioactivity and bioavailability than chrysin. Compared with the chrysin compound, the compound can obviously reduce the weight gain induced by high-fat diet, the blood sugar rise of mice induced by high-fat diet, the blood fat (LDL) rise of mice induced by high-fat diet, the total cholesterol rise of mice induced by high-fat diet, the triglyceride rise of mice induced by high-fat diet, the urinary creatinine rise of mice induced by high-fat diet, the GPT rise of mice induced by high-fat diet, the GOT rise of mice induced by high-fat diet, the memory impairment of 5-FAD mice, the treatment effect on Amyotrophic Lateral Sclerosis (ALS) is better, the limb holding power of mice is more effectively increased, the exercise retardation symptom is improved, and the pole climbing time of MPTP mice is obviously increased. Has remarkable advantages in preventing and/or treating neurodegenerative diseases, inflammatory diseases, endocrine diseases and diseases related to lipid metabolism disorder. Can reduce low density lipoprotein, total cholesterol, and triglyceride; reducing urinary creatinine, glutamic-pyruvic transaminase, and glutamic-oxalacetic transaminase; can be used for preventing and/or treating hyperglycemia, hyperlipemia, Alzheimer Disease (AD), senile dementia, Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complication, diabetic ophthalmopathy, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver, liver cirrhosis, hepatitis, obstructive jaundice, myocardial infarction, etc.

The invention also provides a preparation method of the compound, which is characterized by comprising the following steps:

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

Where all of the above compounds exist in different tautomeric forms, the invention is not limited to any one particular tautomer, but includes all tautomeric forms.

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

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

The compounds disclosed herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, transdermally, by buccal administration, rectally, as an ophthalmic solution, or by other means in dosage unit formulations containing conventional pharmaceutical carriers. The pharmaceutical composition may be formulated in any pharmaceutical form, such as: aerosols, creams, gels, pills, capsules, tablets, syrups, transdermal patches, or ophthalmic solutions. Some dosage forms, such as tablets and capsules, can be subdivided into appropriate dosage unit 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 a pharmaceutical benefit.

Types of vectors include, but are not limited to: binders, buffering agents, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some vectors may be listed in more than one category, such as: vegetable oils may be used as lubricants in some formulations and as diluents in other formulations. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder (powdered tragacanth), malt, gelatin, talc and vegetable oils. Optional active agents may be included in the pharmaceutical composition which do not substantially affect the activity of the compounds of the invention.

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

The terminology convention:

"alkyl" includes both branched and straight chain saturated aliphatic hydrocarbon groups and has the indicated number of carbon atoms, typically1 to about 12 carbon atoms. The term C as used herein₁-C₆Alkyl represents an alkyl group having 1 to about 6 carbon atoms. When C is used in combination with another group herein₀-C_nWhen alkyl, with (phenyl) C₀-C₄Alkyl is an example, a group being specified, in which case phenyl is via a single covalent bond (C)₀) Either directly bonded or attached 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, tert-butyl, n-pentyl, and sec-pentyl.

"alkenyl" refers to straight and branched hydrocarbon chains comprising one or more unsaturated carbon-carbon bonds, which may occur at any stable point along the chain. Alkenyl groups described herein typically have from 2 to about 12 carbon atoms. Preferred alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to about 8 carbon atoms, such as: c₂-C₈、C₂-C₆And C₂-C₄An alkenyl group. Examples of alkenyl groups include ethenyl, propenyl, and butenyl.

"alkoxy" refers to an alkyl group as defined above having the specified number of carbon atoms connected by an oxygen bridge. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, 3-hexyloxy, and 3-methylpentyloxy.

The term "heterocycle" means a 5-to 8-membered saturated ring, a partially unsaturated ring, or an aromatic ring containing from 1 to about 4 heteroatoms selected from N, O and S with the remaining ring atoms being carbon, or a 7-to 11-membered saturated, partially unsaturated, or aromatic heterocyclic system and a 10-to 15-membered tricyclic ring system containing at least 1 heteroatom in a polycyclic ring system selected from N, O and S and containing up to about 4 heteroatoms independently selected from N, O and S in each ring of the polycyclic ring system. Unless otherwise indicated, the heterocycle may be attached to a group that is substituted at any heteroatom and carbon atom and results in a stable structure. When indicated, the heterocyclic rings described herein may be substituted on carbon or nitrogen atoms, as long as the resulting compounds are stable. The nitrogen atoms in the heterocycle may optionally be quaternized. Preferably the total number of heteroatoms in the heterocyclyl group is not more than 4 and preferably the total number of S and O atoms in the heterocyclyl group is not more than 2, more preferably not more than 1. Examples of heterocyclic groups include: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, 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, pyrrolidinyl, 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. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to each other. Preferably, the total number of S and O atoms in the heteroaryl group is no greater than 2. It is especially preferred that the total number of S and O atoms in the heteroaryl group is not more than 1. The nitrogen atoms in the heterocycle may optionally be 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, thereby forming, for example, a [1,3] dioxazolo [4,5-c ] pyridyl group. Examples of heteroaryl groups include, but are not limited to: pyridyl, indolyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, oxazolyl, furanyl, thiophenyl, thiazolyl, triazolyl, tetrazolyl, isoxazolyl, quinolinyl, pyrrolyl, pyrazolyl, benzo [ b ] thiophenyl, isoquinolinyl, quinazolinyl, quinoxalinyl, thienyl, isoindolyl, and 5,6,7, 8-tetrahydroisoquinoline.

"salts of 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 refers to pharmaceutically acceptable solvates, including hydrates, of such compounds and such 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; and the like, as well as combinations comprising one or more of the foregoing salts. Pharmaceutically acceptable salts include non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, non-toxic acidic salts include those derived from inorganic acids such as: hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; other acceptable inorganic salts include metal salts such as: sodium salt, potassium salt, cesium salt, etc.; alkaline earth metal salts such as: calcium salts, magnesium salts, and the like, as well as combinations comprising one or more of the foregoing salts.

Organic salts of the compounds include those formed from compounds such as acetic, trifluoroacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, methanesulfonic, ethanesulfonic, benzenesulfonic, sulfanilic, 2-acetoxybenzoic, fumaric, p-toluenesulfonic, methanesulfonic, ethanedisulfonic, oxalic, isethionic, HOOC- (CH)₂)_nSalts prepared with organic acids such as-COOH (wherein n is 0 to 4); organic amine salts, such as: triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, and the like; and amino acid salts, such as: arginine salts, aspartic acid salts, glutamic acid salts, and the like, as well as combinations comprising one or more of the foregoing salts.

Drawings

FIG. 1; c-1 significantly improved memory impairment in 5-FAD mice;

FIG. 2; c-1 obviously improves the movement function damage-pole climbing time of ALS mice;

FIG. 3; c-1 obviously improves the motor function damage-limb holding power of ALS mice;

FIG. 4; c-1 remarkably improves the motor function damage-pole climbing time of MPTP treated mice;

Detailed Description

Example 1:

dissolving chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (3.5mmol,483mg) in anhydrous acetonitrile (20ml), adding 1-chloroformyl-4-piperidinylpiperidine hydrochloride (1.0mmol,267mg), heating under reflux and stirring for 8 hours; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to obtain 400mg of a product with a yield of 89%.¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)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.

And mixing the obtained product with 15ml of a 1, 4-dioxane solution of 2mol/L HCl, stirring for 2 hours at normal temperature, filtering, and drying to obtain the hydrochloride of the product.

Example 2:

dissolving chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (3.5mmol,483mg) in anhydrous acetonitrile (20ml), adding N, N-dimethylcarbamoyl chloride (1.0mmol,107.5mg), heating under reflux and stirring for 8 hr; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 100:1) to obtain 300mg of a product in 92% yield.¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)δ182.91,164.57,161.74,157.05,156.77,153.49,132.07,131.11,129.16,126.39,108.46,106.06,106.04,105.30,100.92,100.90,36.84,36.61。

Example 3:

dissolving chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (8.0mmol,1.1g) in anhydrous acetonitrile (30ml), adding N, N-dimethylcarbamoyl chloride (5.0mmol,537.7mg), heating under reflux and stirring for 12 hr; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 50:1) to obtain 350mg of a product, the yield being 95%.¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)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:

chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (3.5mmol,483mg) were dissolved in anhydrous acetonitrile (20ml), followed by addition of 4-methylpiperazine-1-carbonyl chloride hydrochloride (1.0mmol,199mg), stirring at reflux for 8 hours at elevated temperature; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 40:1) to obtain 280mg of a product, yield 72%.¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)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。

And mixing the obtained product with 15ml of a 1, 4-dioxane solution of 2mol/L HCl, stirring for 2 hours at normal temperature, filtering, and drying to obtain the hydrochloride of the product.

Example 5:

chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (8.0mmol,1.1g) were dissolved in anhydrous acetonitrile (30ml), followed by addition of 4-methylpiperazine-1-carbonyl chloride hydrochloride (5.0mmol,1.0g), stirring at reflux for 12 hours at elevated temperature; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 40:1) to obtain 500mg of a product, with a yield of 98%. MS (ESI) M/z 507.2[ M + H ]]⁺。¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)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。

And mixing the obtained product with 15ml of a 1, 4-dioxane solution of 2mol/L HCl, stirring for 2 hours at normal temperature, filtering, and drying to obtain the hydrochloride of the product.

Example 6:

dissolving chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (3.5mmol,483mg) in anhydrous acetonitrile (20ml), adding 4-morpholine carbonyl chloride (1.0mmol,150mg), heating under reflux and stirring for 8 hr; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 100:1) to obtain 280mg of a product, yield 76%.¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)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。

Example 7:

dissolving chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (8.0mmol,1.1g) in anhydrous acetonitrile (30ml), adding 4-morpholine carbonyl chloride (5.0mmol,750mg), heating under reflux and stirring for 12 hr; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, the organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol 50:1) to obtain 450mg of a product, yield 93%.¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)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。

Example 8:

dissolving chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (3.5mmol,483mg) in anhydrous acetonitrile (20ml), adding 1-piperidinoyl chloride (1.0mmol,148mg), and stirring under reflux at elevated temperature for 8 hr; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 150:1) to obtain 280mg of a product, yield 76%. MS (ESI) M/z 366.1[ M + H]⁺。¹H NMR(400MHz,CDCl₃)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)。¹³C NMR(101MHz,CDCl₃)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。

Example 9:

dissolving chrysin (1.0mmol,254mg) and anhydrous potassium carbonate (8.0mmol,1.1g) in anhydrous acetonitrile (30ml), adding 1-piperidinoyl chloride (5.0mmol,738mg), heating under reflux and stirring for 12 hr; after completion of the reaction, the solvent was dried under reduced pressure, 50ml of water was added, extraction was carried out with 120ml of dichloromethane three times, organic layers were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol ═ 150:1) to obtain 420mg of a product, the yield being 88%.¹H NMR(400MHz,CDCl₃)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)；¹³C NMR(101MHz,CDCl₃)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. influence on high fat diet induced body weight in mice

The experimental method comprises the following steps: the change of the weight of the mouse reflects the obesity degree of the mouse, and the electronic balance is used for weighing the weight of the mouse in the experiment to determine the influence of the medicament on the weight of the mouse.

TABLE 1 influence of C-1 on the body weight of mice on a high-fat diet

As a result: after the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative (C-1) were subjected to the gastric lavage for 8 weeks, the weight gain induced by high-fat diet was significantly reduced, and no significant effect was observed on the weight gain induced by high-fat diet when the high dose group was subjected to equimolar dose of chrysin (50 mg/kg). Losartan (10mg/kg) also did not significantly change the body weight of mice treated with a high fat diet. P <0.05, p <0.01vs. N is 8-10/group; data are expressed as Mean ± SD.

2. Influence on high fat diet induced blood sugar of mice

The experimental method comprises the following steps: blood sugar of a high-fat diet mouse can be abnormally increased to present a diabetic symptom, the blood sugar of the mouse is measured by a glucometer and matched blood sugar test paper, and a blood sampling point is the tail of the mouse.

TABLE 2 influence of C-1 on blood glucose in mice on high-fat diet

Group of	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

As a result: after the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative (C-1) were subjected to the gavage treatment for 8 weeks, the high dose C-1 significantly reduced the blood glucose rise induced by the high-fat diet in the mice, and no significant effect was observed on the blood glucose rise induced by the high dose of the equimolar dose of chrysin (50 mg/kg). Losartan (10mg/kg) also did not significantly change blood glucose in mice treated with a high fat diet. P <0.05, p <0.01vs. N is 6-8/group; data are expressed as Mean ± SD. details in the table above.

And (4) conclusion: the chrysin derivative with high dose can obviously reduce the blood sugar of mice after being eaten by high-fat foods and has potential value for treating diabetes.

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

The experimental method comprises the following steps: low-density lipoprotein (LDL) can transport cholesterol to peripheral tissues, is one of main carriers of cholesterol in blood, and is one of four conventional indexes of blood fat. The LDL concentration of the LDL assay kit for experiments is measured by a biochemical analyzer.

TABLE 3 influence of C-1 on blood lipid (LDL) in mice on high-fat diet

Group of	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

As a result: after the low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1) are subjected to gastric lavage for 8 weeks, the low-dose and high-dose C-1 can remarkably reduce the high-fat diet-induced increase of blood lipid (LDL) of mice, and the high-dose equimolar dose chrysin (50mg/kg) has no remarkable effect on the high-fat diet-induced increase of LDL. Losartan (10mg/kg) failed to significantly alter high fat diet-induced increases in LDL. P <0.01vs. N is 6-8/group; data are expressed as Mean ± SD. The detailed results are shown in the table above.

The conclusion is that the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative can obviously improve the symptoms of high fat diet-induced increase of blood fat (LDL) of mice, and has potential value for reducing cardiovascular diseases.

Effect of C-1 on high fat diet induced Total Cholesterol in mice

The experimental method comprises the following steps: the total cholesterol measuring kit for the experiment measures the concentration of serum total cholesterol through a biochemical analyzer.

TABLE 4 influence of C-1 on blood lipid (TC) in mice on a high-fat diet

Group of	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

As a result: after the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative (C-1) are subjected to the gastric lavage for 8 weeks, the low dose and the high dose of C-1 can obviously reduce the high-fat diet-induced increase of the total cholesterol in mice, and the high dose of the chrysin (50mg/kg) with equimolar dose has no obvious effect on the high-fat diet-induced increase of LDL. Losartan (10mg/kg) failed to significantly alter high fat diet-induced total cholesterol elevation. P <0.01vs. N is 6-8/group; data are expressed as Mean ± SD. The detailed results are shown in the table above.

And (4) conclusion: the low dose (18.2mg/kg) and high dose (72.6mg/kg) of the chrysin derivative can obviously inhibit the increase of the total cholesterol of mice induced by high fat diet, and has potential value for improving dyslipidemia.

Effect of C-1 on high fat diet induced triglyceride in mice

The experimental method comprises the following steps: the triglyceride determination kit for the experiment can be used for measuring the concentration of the serum triglyceride through a biochemical analyzer.

TABLE 5 Effect of C-1 on blood lipid (TG) in mice on high-fat diet

Group of	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

As a result: after the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative (C-1) are subjected to the gastric lavage for 8 weeks, the low dose and the high dose of C-1 can both remarkably reduce the triglyceride rise of mice induced by high-fat diet, and the high dose of the chrysin (50mg/kg) with equimolar dose has no remarkable effect on the triglyceride rise induced by high-fat diet. Losartan (10mg/kg) failed to significantly alter high fat diet-induced triglyceride elevations. . P <0.01, hfd <0.001vs. N is 6-8/group; data are expressed as Mean ± SD. The detailed results are shown in the table above.

And (4) conclusion: the low dose (18.2mg/kg) and high dose (72.6mg/kg) of the chrysin derivatives can obviously reduce the content of triglyceride in mice with high fat diet, and are beneficial to improving the symptom of dyslipidemia.

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

The experimental method comprises the following steps: the urine creatinine concentration of the urine creatinine determination kit for the experiment is measured by a biochemical analyzer.

TABLE 6 influence of C-1 on urinary creatinine in mice on high fat diet

As a result: after the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative (C-1) are subjected to the gastric lavage for 8 weeks, the low dose and the high dose of C-1 can both remarkably reduce the increase of the high-fat diet-induced urinary creatinine in mice, and the high dose of the chrysin (50mg/kg) with equimolar dose has no remarkable effect on the increase of the high-fat diet-induced urinary creatinine. Losartan (10mg/kg) failed to significantly alter high fat diet-induced urinary creatinine elevation. P <0.01, hfd <0.001vs. N is 6-8/group; data are expressed as Mean ± SD. The detailed results are shown in the table above.

And (4) conclusion: the low dose (18.2mg/kg) and high dose (72.6mg/kg) of chrysin derivatives significantly reduced the high fat diet-induced increase in urinary creatinine in mice.

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

The experimental method comprises the following steps: the abnormal Glutamate Pyruvate Transaminase (GPT) is closely related to liver diseases such as liver cirrhosis, hepatitis, obstructive jaundice and the like, and the GPT serum concentration is determined by combining a GPT determination kit with a biochemical analyzer in the experiment.

TABLE 7 Effect of C-1 on GPT in mice on high fat diet

Group of	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

As a result: after the low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1) are subjected to gastric lavage for 8 weeks, the low-dose and high-dose C-1 can remarkably reduce the GPT rise of mice induced by high-fat diet, and the high-dose equimolar dose chrysin (50mg/kg) has no remarkable effect on the GPT rise induced by the high-fat diet. Losartan (10mg/kg) failed to significantly alter the high fat diet-induced elevation of GPT. P <0.01vs. N is 6-8/group; data are expressed as Mean ± SD. The detailed results are shown in the table above.

And (4) conclusion: the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative can obviously reduce the increase of GPT of mice induced by high fat diet, and effectively treat the abnormal liver functions of the mice.

Effect of C-1 on high fat diet-induced liver function GOT in mice

The experimental method comprises the following steps: glutamate-oxaloacetate transaminase (GOT) abnormity is closely related to various liver diseases, the early GOT of a myocardial infarction patient also can be abnormally increased, and the GOT serum concentration is determined by combining a GOT determination kit with a biochemical analyzer in the experiment.

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

As a result: after the low-dose (18.2mg/kg) and high-dose (72.6mg/kg) chrysin derivatives (C-1) are subjected to gastric lavage for 8 weeks, the low-dose and high-dose C-1 can both remarkably reduce the high-fat diet-induced GOT increase of mice, and the high-dose equimolar dose chrysin (50mg/kg) has no remarkable effect on the high-fat diet-induced GOT increase. Losartan (10mg/kg) failed to significantly alter high fat diet-induced elevations in GOT. P <0.05vs. hfd, p <0.01vs. hfd. N is 6-8/group; data are expressed as Mean ± SD. The detailed results are shown in the table above.

And (4) conclusion: the low dose (18.2mg/kg) and the high dose (72.6mg/kg) of the chrysin derivative can obviously reduce the high fat diet-induced increase of GOT in mice and effectively treat abnormal liver functions of the mice.

C-1 significantly improved memory impairment of 5-FAD mice

The experimental method comprises the following steps: the new object recognition is that the mouse is placed in a square frame (length, width, height, 40cm) with two objects (square or cylindrical, 3cm) of the same shape inside, after 5 minutes of training, one of the objects is changed to a new object with which the mouse is unfamiliar, and the instrument records the time the mouse stays in the familiar and unfamiliar objects within 5 minutes.

And (4) analyzing results: as shown in fig. 1, the time ratio of exploring the new object in the new object identification experiment was examined in 5 x FAD mice at 6 months of age after 8 weeks of C-1 treatment. 5 FAD mice were treated with low and high doses of C-1 (low dose: 18.2 mg/kg; high dose: 72.6mg/kg) and CHRY (50mg/kg), respectively. The new object exploration time ratio was significantly reduced in 5-FAD mice compared to wild control mice, and the high dose of C-1 significantly improved the 5-FAD exploration time ratio (figure 1). Data are presented as mean ± SEM; n-12 for each group, one-way anova and multiple comparisons showed differences between the two groups p <0.001vs. wt mic; # p <0.01vs.5 FAD mic.

And (4) conclusion: c-1 can significantly improve memory impairment of 5-FAD mice, and has potential value in treatment of Alzheimer's Disease (AD).

C-1 remarkably improves ALS mouse motor function damage

The experimental method comprises the following steps: the pole climbing experiment is often used for evaluating the coordination ability of the four limbs of the mouse and the phenomenon of motion delay, a wooden pole with the length of about 50cm and the diameter of about 1cm is manufactured, and medical gauze is wound on the wooden pole to increase the friction force of the wooden pole. The wooden pole is vertically placed on a horizontal desktop, the tail of the mouse is grabbed to enable the head of the mouse to face downwards, the four limbs of the mouse grab the pole top, timing is started after the tail of the mouse is released, the mouse is guaranteed to crawl downwards under the action of no external force, and the time that the mouse climbs to the bottom platform from the pole top is recorded (the time is unified until the limbs touch the ground). Mice were trained continuously for 3 days on the behavioristics before dosing, and mice that failed the test were rejected in triplicate for each mouse.

And (4) analyzing results: as shown in figure 2, after the administration is started, the behavioural test is carried out once every two weeks, the maximum value of the test result is not more than 15 seconds, and the value of the test result exceeding 15 seconds is recorded according to 15 seconds. Data are presented as mean ± SEM; n-10 for each group, one-way anova and multiple comparisons showed differences between the two groups p <0.01vs. wt (normal control) group; ALS (SOD-G93A) group, # p <0.01vs. ALS (SOD-G93A) group.

And (4) conclusion: c-1 has therapeutic effect on Amyotrophic Lateral Sclerosis (ALS), and can significantly shorten rod climbing time and improve bradykinesia.

C-1 remarkably improves ALS mouse motor function damage

The experimental method comprises the following steps: the mouse is lightly placed on a central platform of the grip plate, the tail of the mouse is lightly pulled to promote the mouse to grip the grip plate, the mouse is horizontally pulled backwards in time when the mouse forcibly grips the grip net, and data are recorded when the instrument has the maximum gripping force value. After the start of the administration, the grip value of the mice was measured every two weeks, and each mouse was repeatedly measured three times, and the maximum value among the results was taken as the maximum grip value of the mouse.

And (4) analyzing results: as shown in figure 3, after the ALS transgenic mice enter the disease period, the four limbs of the ALS transgenic mice have significantly smaller holding power than that of the WT mice, and after the ALS transgenic mice are treated by C-1, CHRY and riluzole with different doses, the C-1 with low dose and high dose can effectively increase the holding power of the four limbs of the mice and delay the deterioration of the decrease of the holding power of the four limbs of the ALS mice. Data are presented as mean ± SEM; 8-10 per group, one-way anova and multiple comparisons showed differences between the two groups p <0.001vs. wt (normal control) group; ALS (SOD-G93A) group, # # p <0.01vs.

And (4) conclusion: c-1 can improve the process of grip loss of Amyotrophic Lateral Sclerosis (ALS) mice and has potential therapeutic effect on ALS.

C-1 significantly ameliorates motor function impairment in MPTP-treated mice

The experimental method comprises the following steps: the pole climbing experiment is often used for evaluating the coordination ability of the four limbs of the mouse and the phenomenon of motion delay, a wooden pole with the length of about 50cm and the diameter of about 1cm is manufactured, and medical gauze is wound on the wooden pole to increase the friction force of the wooden pole. The wooden pole is vertically placed on a horizontal desktop, the tail of the mouse is grabbed to enable the head of the mouse to face downwards, the four limbs of the mouse grab the pole top, timing is started after the tail of the mouse is released, the mouse is guaranteed to crawl downwards under the action of no external force, and the time that the mouse climbs to the bottom platform from the pole top is recorded (the time is unified until the limbs touch the ground). Mice were trained continuously for 3 days on the behavioristics before dosing, and mice that failed the test were rejected in triplicate for each mouse.

And (4) analyzing results: fig. 4.C-1 significantly reduced the pole-climbing time of MPTP mice, modeled for MPTP, and the behavioural results after 14 days of dosing showed: the pole climbing time of the model group is prolonged compared with that of a normal control group, and the pole climbing time of an MPTP mouse is obviously prolonged after C-1 with low dose and high dose is treated; there was a trend of decreasing pole climbing time but no statistically significant difference in MPTP mice after positive control selegiline (10mg/kg) treatment. Data are presented as mean ± SD; each group n-12, one-way anova and multiple comparisons showed differences between the two groups p <0.001vs. # p <0.01vs. MPTP-treated mica.

And (4) conclusion: c-1 significantly improves motor function impairment in MPTP-treated mice and is potentially valuable for the treatment of Parkinson's Disease (PD).

The compound of the invention has higher bioactivity and bioavailability than chrysin. Compared with the chrysin compound, the compound can obviously reduce the weight gain induced by high-fat diet, the blood sugar rise of mice induced by high-fat diet, the blood fat (LDL) rise of mice induced by high-fat diet, the total cholesterol rise of mice induced by high-fat diet, the triglyceride rise of mice induced by high-fat diet, the urinary creatinine rise of mice induced by high-fat diet, the GPT rise of mice induced by high-fat diet, the GOT rise of mice induced by high-fat diet, the memory impairment of 5-FAD mice, the treatment effect on Amyotrophic Lateral Sclerosis (ALS) is better, the limb holding power of mice is more effectively increased, the exercise retardation symptom is improved, and the pole climbing time of MPTP mice is obviously increased. Has remarkable advantages in preventing and/or treating neurodegenerative diseases, inflammatory diseases, endocrine diseases and diseases related to lipid metabolism disorder. Can reduce low density lipoprotein, total cholesterol, and triglyceride; reducing urinary creatinine, glutamic-pyruvic transaminase, and glutamic-oxalacetic transaminase; can be used for preventing and/or treating hyperglycemia, hyperlipemia, Alzheimer Disease (AD), senile dementia, Parkinson Disease (PD), Amyotrophic Lateral Sclerosis (ALS), cerebral ischemia, brain injury, obesity, diabetes and/or diabetic complication, diabetic ophthalmopathy, diabetic nephropathy, dyslipidemia, atherosclerosis, fatty liver, non-alcoholic fatty liver, liver cirrhosis, hepatitis, obstructive jaundice, myocardial infarction, etc.

The foregoing description is a general description of the invention. Although specific terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation, as form changes and equivalents may be employed. Various changes or modifications may be effected therein by one skilled in the art and equivalents may be made thereto without departing from the scope of the invention as defined in the claims appended hereto.