WO2023001268A1 - Dérivé de chrysine, procédé de préparation associé et utilisation associée - Google Patents

Dérivé de chrysine, procédé de préparation associé et utilisation associée Download PDF

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WO2023001268A1
WO2023001268A1 PCT/CN2022/107271 CN2022107271W WO2023001268A1 WO 2023001268 A1 WO2023001268 A1 WO 2023001268A1 CN 2022107271 W CN2022107271 W CN 2022107271W WO 2023001268 A1 WO2023001268 A1 WO 2023001268A1
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substituted
compound
unsubstituted
mice
chrysin
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PCT/CN2022/107271
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English (en)
Chinese (zh)
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杨细飞
谢永美
李书鹏
杨超
刘恭平
张芮铭
叶涛
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深圳枫语生物医药科技有限公司
陕西鸿德农林科技有限公司
商洛市为安实业有限公司
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Priority claimed from CN202110842880.7A external-priority patent/CN113773293B/zh
Priority claimed from CN202110841265.4A external-priority patent/CN113768915B/zh
Application filed by 深圳枫语生物医药科技有限公司, 陕西鸿德农林科技有限公司, 商洛市为安实业有限公司 filed Critical 深圳枫语生物医药科技有限公司
Publication of WO2023001268A1 publication Critical patent/WO2023001268A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention relates to the technical field of medicines, in particular to a chrysin derivative and its preparation method and application.
  • 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.
  • chrysin for example, CN101774994A prepared long-chain chrysin derivatives for treating atherosclerosis.
  • CN103896896A prepares iodine-containing chrysin derivatives for resisting radiation damage.
  • 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.
  • Neurodegenerative diseases 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.
  • ND Newcastle disease neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm ne, ne, ne, neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm neoplasm n
  • 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.
  • 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.
  • 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.
  • AD Alzheimer's disease
  • PD senile dementia
  • ALS amyotrophic lateral sclerosis
  • cerebral ischemia brain injury
  • obesity diabetes and /or diabetic complications
  • diabetic eye disease diabetic nephropathy
  • dyslipidemia atherosclerosis
  • atherosclerosis fatty liver, non-alcoholic fatty liver.
  • 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 ⁇
  • 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;
  • a is an integer of 0-5.
  • the R 2 is piperidinyl, piperazinyl, tetrahydropyrrolyl, or morpholinyl.
  • 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.
  • 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.
  • the pharmaceutical composition is oral formulation, intravenous or intramuscular injection formulation, local administration formulation or inhalation formulation.
  • 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.
  • 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.
  • the carrier includes excipients and diluents.
  • 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:
  • 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.
  • 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.
  • LDL blood lipid of mice induced by 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
  • the biological activity and bioavailability of the compounds of the present invention are significantly higher than those of chrysin.
  • 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 ,
  • LDL blood lipid
  • 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
  • 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.
  • isotopes include atoms with the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • a heterocycle can be attached to a group where it substitutes at any heteroatom and carbon atom and results in a stable structure.
  • 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.
  • 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.
  • 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, pipe
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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 trie
  • FIG 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
  • FIG. 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.
  • Embodiment 6 is a diagrammatic representation of Embodiment 6
  • Embodiment 7 is a diagrammatic representation of Embodiment 7:
  • Embodiment 8 is a diagrammatic representation of Embodiment 8
  • Embodiment 9 is a diagrammatic representation of Embodiment 9:
  • mice The change of the weight of the mice reflects the degree of obesity of the mice.
  • the weight of the mice was weighed with an electronic balance to determine the effect of the drug on the weight of the mice.
  • mice on a high-fat diet will increase abnormally, showing symptoms of diabetes.
  • 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.
  • LDL Low-density lipoprotein
  • 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
  • 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
  • GPT Abnormal alanine aminotransferase
  • GOT Abnormal aspartate aminotransferase
  • 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
  • mice 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.
  • C-1 can significantly improve memory impairment in 5*FAD mice, and has potential value in the treatment of Alzheimer's disease (AD).
  • mice 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 our.
  • 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.
  • C-1 has a therapeutic effect on amyotrophic lateral sclerosis (ALS), significantly shortening the pole climbing time and improving bradykinesia.
  • ALS amyotrophic lateral sclerosis
  • mice 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.
  • C-1 can improve the process of grip loss in amyotrophic lateral sclerosis (ALS) mice, and has potential therapeutic effect on ALS.
  • ALS amyotrophic lateral sclerosis
  • 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.
  • 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.
  • 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.
  • 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.
  • the biological activity and bioavailability of the compound of the present invention are significantly higher than those of chrysin.
  • 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 ,
  • LDL blood lipid
  • 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

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Abstract

La présente invention concerne le domaine technique des médicaments et concerne plus précisément un dérivé de chrysine, un procédé de préparation associé et une utilisation associée. Le dérivé de chrysine a une structure telle que représentée par la formule I, et son activité biologique et sa biodisponibilité sont considérablement plus élevées que celles de la chrysine. Le dérivé de chrysine peut prévenir et/ou traiter des maladies telles que l'hyperglycémie, l'hyperlipidémie, la maladie d'Alzheimer, la démence sénile, la maladie de Parkinson, la sclérose latérale amyotrophique, l'ischémie cérébrale, une lésion cérébrale, l'obésité, le diabète et/ou les complications diabétiques, les maladies diabétiques de l'œil, la néphropathie diabétique, la dyslipidémie, l'athérosclérose, la stéatose hépatique, la stéatohépatite non alcoolique, la cirrhose, l'hépatite, l'ictère rétentionnel et l'infarctus du myocarde.
PCT/CN2022/107271 2021-07-23 2022-07-22 Dérivé de chrysine, procédé de préparation associé et utilisation associée WO2023001268A1 (fr)

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CN202110842880.7A CN113773293B (zh) 2021-07-23 2021-07-23 一种白杨素衍生物及其制备方法
CN202110841265.4A CN113768915B (zh) 2021-07-23 2021-07-23 一种白杨素衍生物在制备药物中的应用
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