WO2018233483A1 - Préparation et utilisation de dérivés de phénylquinolinone et de flavonoïde - Google Patents

Préparation et utilisation de dérivés de phénylquinolinone et de flavonoïde Download PDF

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WO2018233483A1
WO2018233483A1 PCT/CN2018/089970 CN2018089970W WO2018233483A1 WO 2018233483 A1 WO2018233483 A1 WO 2018233483A1 CN 2018089970 W CN2018089970 W CN 2018089970W WO 2018233483 A1 WO2018233483 A1 WO 2018233483A1
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盛荣
楼金芳
严红兵
胡永洲
唐黎
张冯敏
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杭州百诚医药科技股份有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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 
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • 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
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/60—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2
    • C07D311/62—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with aryl radicals attached in position 2 with oxygen atoms directly attached in position 3, e.g. anthocyanidins

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to the preparation of phenylquinolinones and flavonoid derivatives, wherein the active ingredient is a histamine H3 receptor antagonist, which can protect and restore the normal function of the central nervous system, and in the neurodegenerative Application in the treatment of sexual diseases, ischemic gas-deficient encephalopathy, Parkinson's syndrome, narcolepsy, epilepsy and gradual freezing diseases.
  • the phenylquinolinones and flavonoid derivatives also include pharmaceutically acceptable salts, complexes, solvates thereof and the like.
  • Histamine H 3 receptor is present in the cerebral cortex, striatum, hippocampus, olfactory bulb, terminal nucleus, thalamus, low brainstem nucleus, cerebellum, etc. Histamine H 3 receptor is the neuronal synapse itself. Exciting the receptor inhibits the release of histamine or other neurotransmitters, and antagonizing the receptor promotes neurotransmitter release.
  • Cerebral ischemia is mainly caused by thrombosis, embolism or other causes of cerebral infarction caused by insufficient blood supply to the brain. It is also one of the number one killers of human disability and death. Due to the complex mechanism of the pathological process, no effective drug has been applied to the clinic so far.
  • histamine H 3 receptor antagonists can be used to treat Alzheimer's disease (AD), Parkinson's disease (PD), and gradual freezing by promoting the synthesis and release of neurotransmitters such as histamine. ALS), narcolepsy and more.
  • AD Alzheimer's disease
  • a ⁇ ⁇ -amyloid
  • the first-line therapeutic drugs for AD are mainly acetylcholinesterase (AChE) inhibitors donepezil, rivastigmine, galantamine and non-competitive NMDA receptor antagonist memantine, which all act on Cognitive-related neurotransmitter systems, while ameliorating cognitive impairment in early-stage patients, do not fundamentally improve disease status or halt disease progression.
  • AChE acetylcholinesterase
  • H 3 receptors are important receptors for the regulation of neurotransmitters in the brain, and H 3 receptor antagonists can effectively promote histamine, acetylcholine and other cognitive-related neurotransmitters by blocking H 3 receptors.
  • H 3 receptor antagonists ABT-288, AZD5213, CEP-26401, GSK239512 and MK0249
  • ABT-288, AZD5213, CEP-26401, GSK239512 and MK0249 have entered clinical studies for Alzheimer's disease, Parkinson's disease, narcolepsy, etc. Treatment of neurodegenerative diseases
  • Figure 1 Enteres part of the H3 receptor antagonist in clinical studies.
  • Senile plaques which are deposited on the edge of the brain and in the cerebral cortex after aggregation of amyloid peptide A ⁇ , are one of the most typical pathological features of AD. Moreover, the oligomers, fibrils and fibers formed by A ⁇ during aggregation can be toxic to nerve cells and even cause neuronal apoptosis. Therefore, ⁇ aggregation is generally considered to be the intrinsic cause of AD, and drugs that inhibit A ⁇ aggregation have become an important direction for the development of AD drugs.
  • the present invention systematically analyzes the biological characteristics of AD-related targets, organically combines a target for improving symptoms (H 3 receptor) and a target for disease (A ⁇ aggregation), and uses a rational drug design method. Designing multi-target compounds that simultaneously antagonize H 3 receptors and inhibit A ⁇ aggregation. These multi-target compounds not only promote the release of neurotransmitters, improve the symptoms of AD patients, delay the disease, but also inhibit A ⁇ . Self-aggregation can fundamentally prevent the progression of AD and achieve the effect of "multi-pronged approach, treating both the symptoms and the symptoms", and may have a unique effect on the treatment of neurodegenerative diseases such as AD.
  • the invention also discloses the protective effect of the compound of the invention on the neurological function of ischemic brain injury.
  • the molecular structure of histamine H 3 receptor antagonists is mostly chain-like molecules, which are mainly composed of three parts: the western part is a nitrogen-containing basic region of a fatty tertiary amine and a part of a connecting chain, and the center is a fat-soluble aromatic ring, and the east is Fragments are fat-soluble aromatic rings or basic groups (Figure 2)
  • the present invention is based on the H 3 receptor antagonist pharmacophore model, using benzoquinolinone (benzopyrone) as a fat-soluble aromatic ring (eastern fragment) and phenoxypropylamine as the other part (central ring) + western segment), designed and synthesized new phenylquinolinones and flavonoid derivatives; on the other hand, previous studies have shown that N-aminopropoxyphenyl-pyridin-4-one derivatives with similar structure It has good inhibition of A ⁇ aggregation activity (N-substituted phenylpyridin-4-one derivative and its preparation and application, ZL201310511154.2). Further tests showed that the activity of the designed phenyl quinolone derivatives and flavonoids H 3 receptor antagonist having two targets and inhibitory compound A ⁇ aggregation.
  • alkyl refers to a straight or branched hydrocarbon chain containing from 1 to 6 carbon atoms.
  • alkyl as used in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isobutyl, isopropyl.
  • Alkyl also includes substituted alkyl groups. The alkyl group may be optionally substituted one or more times with a halogen or a hydroxyl group.
  • alkoxy refers to an -O-alkyl group, wherein alkyl is as defined above.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and tert-butoxy.
  • Alkoxy also includes substituted alkoxy groups. The alkoxy group can be optionally substituted one or more times with a halogen.
  • the "pharmaceutically acceptable salts" in the present invention include hydrochlorides, sulfates, hydrobromides, (+) tartrates, (-) tartrates, fumarates, succinates, and the like which are commonly used in pharmacy. Inorganic acid salts and organic acid salts, amino acid salts.
  • X is selected from N or O
  • R 1 is selected from H, C 1-3 alkyl or C 1-3 alkoxy
  • R 2 is selected from H, hydroxy or C 1-3 alkoxy
  • R 3 is selected from H, hydroxy, C 1-3 alkyl or C 1-3 alkoxy.
  • NR'R is selected from cyclic amines and open-chain alkylamines having a total of 3 to 6 carbon atoms, including but not limited to the following fragments:
  • R 1 is preferably hydrogen, methyl and ethyl
  • R 2 is preferably hydrogen, hydroxy and methoxy
  • R 3 is preferably hydrogen , hydroxyl and methoxy.
  • preferred compounds of the formula quinolinones and flavonoid derivatives of the present invention are selected from the compounds shown in Table 1.
  • the preparation method of the above compound provided by the present invention is prepared by the following procedure, but is not limited to the following method.
  • the quinolinone derivatives of the formula can be synthesized by the following steps.
  • the specific reaction process is as follows: the raw material 1, 1,3-bromochloropropane and potassium carbonate are dissolved in acetonitrile and heated to reflux, and then reacted in a NaOH/CH 3 OH system to obtain an intermediate 1 and then in a thionyl chloride solution. Intermediate 2 is refluxed, and then it is reacted with o-aminoacetophenone at room temperature to obtain Intermediate 3, which is reacted with potassium t-butoxide in a microwave to obtain Intermediate 4, and finally reacted with a secondary amine to obtain the target compound I- 1, I-2.
  • the specific reaction process is as follows: the intermediate 4 in the first embodiment is dissolved in DMF, sodium hydride and a halogenated hydrocarbon are added to obtain the intermediate 5, and finally reacted with a secondary amine and triethylamine to obtain the target compound I-3. ⁇ I-6.
  • the specific reaction process is as follows: the intermediate 9, the dimethyl sulfate and the potassium carbonate in the third embodiment are dissolved in acetone, and the intermediate is obtained by refluxing, and then reacted with the secondary amine NHR'R" and triethylamine.
  • the specific reaction process is as follows: the raw material 6 is dissolved in acetonitrile, and after adding 1,3-bromochloropropane and potassium carbonate, the reaction is refluxed to obtain an intermediate 11 which is condensed with p-hydroxyacetophenone in potassium hydroxide.
  • the intermediate 12 is then cyclized to give the intermediate 13 through a hydrogen peroxide / KOH system, and finally reacted with a second amine and triethylamine to give the object compound II-1, II-2.
  • the specific reaction process is as follows: the intermediate 13 in Example 5, methyl iodide and potassium carbonate are dissolved in acetone, and the intermediate 14 is refluxed, and then reacted with a secondary amine and triethylamine to obtain the target compound II-3. II-4.
  • the specific reaction process is as follows: the intermediate 11 and 2,6-dihydroxyacetophenone are dissolved in ethanol, and after adding potassium hydroxide, the reaction is refluxed to obtain the intermediate 15, and then the cyclization reaction is carried out under the action of iodine and concentrated sulfuric acid.
  • Intermediate 16 is finally reacted with a secondary amine or triethylamine to give the target compound II-5, II-6.
  • Example 7 intermediate 16, potassium iodide and potassium carbonate are dissolved in acetone, and refluxed to obtain intermediate 17, which is then refluxed with a secondary amine or triethylamine to obtain the target compound II-7, II-8. .
  • Another object of the present invention is to provide the use of the quinolinones, flavonoid derivatives and pharmaceutically acceptable salts and solvates thereof for the preparation of a medicament derived from the analogs and pharmaceutically Acceptable salts and solvates are prepared with pharmaceutically acceptable carriers or excipients.
  • the "pharmaceutically acceptable carrier” means a conventional pharmaceutical carrier in the pharmaceutical field, including conventional diluents in the pharmaceutical field, excipients such as water, etc., fillers such as starch, etc., binders such as cellulose derivatives, gelatin, etc. , wetting agents such as glycerin, disintegrating agents such as agar, calcium carbonate, etc., absorption enhancers such as quaternary ammonium compounds, surfactants such as cetyl alcohol, adsorption carriers such as kaolin and soap clay, lubricants such as talc, etc., if necessary Flavoring agents, sweeteners and the like can also be added.
  • excipients such as water, etc.
  • fillers such as starch, etc.
  • binders such as cellulose derivatives, gelatin, etc.
  • wetting agents such as glycerin
  • disintegrating agents such as agar, calcium carbonate, etc.
  • absorption enhancers such as quaternary ammoni
  • the pharmaceutical preparations are suitable for administration by any appropriate route, such as oral (including buccal or sublingual administration), rectal administration, nasal administration, topical administration (including buccal, sublingual or transdermal administration). Or a parenteral administration (including subcutaneous, intramuscular, intravenous or intradermal) routes.
  • oral including buccal or sublingual administration
  • rectal administration nasal administration
  • topical administration including buccal, sublingual or transdermal administration
  • parenteral administration including subcutaneous, intramuscular, intravenous or intradermal routes.
  • These formulations can be prepared by any method known in the art of pharmacy. For example by a method of mixing the active ingredient with a carrier or excipient.
  • the present invention provides the compound and preferably a compound thereof, a pharmaceutically acceptable salt of the compound, a solvate of the compound, a prodrug (ester or phosphate), a stereoisomer, a deuterated substance, and the like
  • a combination of drugs in the treatment of neurodegenerative diseases.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, narcolepsy, epilepsy, gradual freezing, etc., in particular, the protection of the compound of the present invention and its preferred compounds against ischemic brain damage The effect is not only beneficial to the recovery of nerve function, but also effectively reduces the volume of cerebral infarction.
  • Example 1 Synthesis of I-1, I-2 in a class I compound (quinolinone).
  • Step 1 4-(3-Chloropropoxy)benzoic acid (Intermediate 1).
  • Step 2 N-(2-Acetylphenyl)-4-(3-chloropropoxy)benzamide (Intermediate 3).
  • Step three 2-(4-(3-Chloropropoxy)phenyl)quinolin-4(1H)-one (Intermediate 4).
  • Step 4 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)quinolin-4(1H)-one (I-1).
  • Example 2 Synthesis of I-3 to I-6 in a class I compound (quinolinone).
  • Step 1 2-(4-(3-Chloropropoxy)phenyl)-1-methylquinolin-4(1H)-one (Intermediate 5a).
  • Step 1 4-(3-Chloropropoxy)acetophenone (Intermediate 6).
  • Step 2 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)-3-methoxy-1-methylquinolin-4(1H)-one (I-9 ).
  • Example 5 Synthesis of II-1, II-2 in a class II compound (flavonoids).
  • Step 1 4-(3-Chloropropoxy)benzaldehyde (Intermediate 11).
  • Step 2 1-(2-Hydroxyphenyl)-3-(4-(3-chloropropoxy)phenyl)prop-2-en-1-one (Intermediate 12).
  • Step three 2-(4-(3-Chloropropoxy)phenyl)-3-hydroxy-4H-benzopyran-4-one (Intermediate 13).
  • Step 4 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)-3-hydroxy-4H-benzopyran-4-one (II-1).
  • Step 1 2-(4-(3-Chloropropoxy)phenyl)-3-methoxy-4H-benzopyran-4-one (Intermediate 14).
  • Example 7 Synthesis of II-5, II-6 in a class II compound (flavonoids).
  • Step 1 1-(2,6-Dihydroxyphenyl)-3-(4-(3-chloropropoxy)phenyl)prop-2-en-1-one (Intermediate 15).
  • Step 3 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)-5-hydroxy-4H-benzopyran-4-one (II-5).
  • Example 8 Synthesis of II-7, II-8 in a class II compound (flavonoids).
  • Step 1 2-(4-(3-Chloropropoxy)phenyl)-5-methoxy-4H-benzopyran-4-one (Intermediate 17).
  • Step 2 2-(4-(3-(Pyrrolidin-1-yl)propoxy)phenyl)-5-methoxy-4H-benzopyran-4-one (II-7).
  • Example 9 Histamine H 3 receptor antagonistic activity of phenylquinolinones and flavonoid derivatives.
  • This section uses Clobenpropit as a positive control, and screens the histamine H 3 receptor antagonistic activity of the 18 target compounds synthesized by LANCE Ultra TR-FRET method and ThT fluorescence assay, respectively.
  • Other compounds of the present invention are listed below. The compounds have similar beneficial effects, but it should not be understood that the compounds of the invention have only the following beneficial effects. The results are shown in Table 3.
  • Example 10 Determination of anti-amyloid peptide aggregation activity.
  • Solution and sample preparation Prepared in PBS buffer (10 mM, pH 7.4): Weigh 57.996 g of Na 2 HPO 4 ⁇ 12H 2 O, 5.928 g of NaH 2 PO 4 ⁇ 2H 2 O dissolved in 1000 mL of water to prepare a concentration. It is a 0.2M PBS stock solution; take 50mL of stock solution, dilute to 1000mL with water, and filter by 0.22 ⁇ m microporous membrane.
  • Gly-NaOH buffer preparation 50 mM, pH 8.5
  • a ⁇ monomer 1 mg of A ⁇ 1-42 was dissolved in 1 mL of HFIP, sonicated for 10 min, dispensed, and allowed to stand at room temperature for 12 h, vacuum dried, and stored in a -20 ° C refrigerator.
  • the A ⁇ monomer was reconstituted in DMSO to 2 mM, and after briefly vortexing, it was formulated into a 50 ⁇ M stock solution in 10 mM PBS buffer.
  • Compound Formulation The compound was dissolved in DMSO to prepare a stock solution at a concentration of 10 mM. Dilute to the corresponding concentration with PBS.
  • ThT solution (5 ⁇ M): 1.59 g of ThT was weighed and dissolved in 100 mL of Gly-NaOH buffer to prepare a stock solution having a concentration of 50 mM, and stored in the dark. 10 ⁇ L of the stock solution was diluted to 100 mL with Gly-NaOH buffer to obtain a 5 ⁇ M ThT solution.
  • a ⁇ 1-42 and a compound were added to the EP tube to a final concentration of 25 ⁇ M and 20 ⁇ M, respectively, and placed at 37 ° C under constant temperature (150 rpm) for 24 hours.
  • the fluorescence value after incubation with A ⁇ 1-42 alone was used as a control.
  • the fluorescence value of the compound measured by ThT was subtracted as the background.
  • Compounds I-6 and II-1 were further selected to observe their inhibition of A ⁇ 1-42 self-aggregation and the activity of depolymerization of the aggregated A ⁇ 1-42 sample by transmission electron microscopy.
  • HEPES buffer preparation (20 ⁇ M HEPES, pH 6.6, 150 ⁇ M NaCl) 47.77 mg HEPES and 87.66 mg NaCl were weighed and dissolved in 100 mL of water to prepare a mother liquor. Dilute 5 mL of mother liquor to 400 mL, slowly add 1 mM NaOH solution to adjust the pH to 6.6, and dilute to 500 mL.
  • Self-aggregated samples A ⁇ 1-42 and compounds (positive control Curcumin or PBS buffer) were added to the EP tube to a final concentration of 25 ⁇ M and 20 ⁇ M, respectively, and placed at 37 ° C with constant temperature shaking (150 rpm), and incubated for 24 hours.
  • a ⁇ 1-42 final concentration 50 ⁇ M was added to the EP tube, and after incubation at 37 ° C for 24 h, the compound (positive control Curcumin or PBS buffer) was added to make it with A ⁇ 1-
  • the final concentrations of 42 were 20 ⁇ M and 25 ⁇ M, respectively, and incubated for a further 24 h.
  • Example 11 Effect on ischemic brain injury.
  • the rats were anesthetized with 10% chloral hydrate (3.5 ml/kg, intraperitoneal injection), fixed on the back, skin incision along the left neck, ligation of the external carotid artery and lateral common carotid artery, and clamping of the telecentric neck with an artery clamp
  • the artery was incision at the bifurcation of the external carotid artery and the internal carotid artery.
  • a tying wire (diameter 0.25 mm, length 18 mm) was inserted, the incision was ligated, the skin was sutured, and the distal carotid artery artery clip was released.
  • Rats that survived for 24 hours were randomly divided into a sham operation group, a model group, and each test group, and the test group was administered the compounds described in the present invention, and grouped by the number corresponding to the compound.
  • each group was intraperitoneally administered, and the rats in the model group and the sham operation group were given an equal volume of physiological saline. After the first administration for 16 hours, each group was intraperitoneally administered once again.
  • Nerve injury symptom scoring method 0 points: normal behavior, the two forelimbs symmetrically extended to the ground when lifting; 1 point: the contralateral forearm wrist bending when lifting the tail; 2 points: the contralateral forelimb elbow bending when lifting the tail; 3 Points: The shoulders are rotated while lifting the tail; when walking, they are inclined to the opposite side of the injury; 4 points: no voluntary activity.
  • the rats were scored for neurological damage at the time of the first administration, 4 hours after the administration, and 20 hours after the administration, and 24 hours after the first administration, the whole brain was quickly taken out after the neck was sacrificed.
  • 3 isolated hippocampus were randomly selected from each group to detect histamine content, and the remaining part was frozen at -20 °C.
  • the brain was evenly cut into 5 pieces with a coronal plane, and the brain slices were placed at 1% TTC at room temperature in the dark. Dye for 30 minutes and fix with 4% paraformaldehyde for 30 minutes. Take a photo analysis and calculate the cerebral infarction volume ratio (infarct volume / whole brain volume * 100%)
  • each test group *P ⁇ 0.05; #P ⁇ 0.01; ⁇ P ⁇ 0.05; ⁇ P ⁇ 0.01.
  • the rat behavioral grading method was scored, and the symptoms of nerve injury 4 hours after the first administration, the compound of the present invention was significantly different from the model group, and the compound and model of the present invention were 20 hours after the first administration.
  • the group has significant difference, indicating that the compound of the present invention has a significant improvement on the neurological function of rats with ischemic brain injury; the histamine content in the hippocampus, the compound of the present invention is different from the model group, indicating the present invention
  • the compound can effectively increase the content of histamine in the brain of rats with ischemic brain injury; the infarct volume ratio, the compound of the present invention is significantly different from the model group, indicating that the compound of the present invention can effectively reduce ischemic brain damage The cerebral infarct volume of the mouse.
  • mice were given the test drug of the present invention and the positive drug phenytoin, and administered intragastrically according to a gavage volume of 0.1 ml/10 g.
  • the model group was given the same volume of physiological saline, and the positive control group was given a dose of phenytoin 50 mg/kg.
  • Each dose of the reagent group was 50 mg/kg, and the compound of the present invention was administered to the reagent group, and the compounds were grouped by the corresponding numbers.
  • the seizure standard is based on the Racine standard, and the aging of the facial muscles or the corners of the mouth, the convulsions of one side of the limbs, the rigidity or the limb twitching epilepsy
  • the compound of the present invention can significantly delay acute seizures in mice, and the incubation period is extended by 3 to 5 times; the incubation period of the compound of the present invention is longer than that of the control group of phenytoin.
  • the compounds of the invention have significant anti-epileptic effects.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Neurosurgery (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Neurology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
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  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
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Abstract

L'invention concerne des dérivés de phénylquinolinone et de flavonoïde et leurs procédés de préparation, les dérivés étant des antagonistes du récepteur de l'histamine H3, qui peuvent protéger et restaurer la fonction normale du système nerveux central; et en particulier l'invention concerne l'utilisation de ceux-ci dans une maladie neurodégénérative et une lésion cérébrale ischémique. Les dérivés de phénylquinolinone et de flavonoïde présentent une grande valeur d'application clinique.
PCT/CN2018/089970 2017-06-23 2018-06-05 Préparation et utilisation de dérivés de phénylquinolinone et de flavonoïde WO2018233483A1 (fr)

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CN201710488414.7A CN109111400B (zh) 2017-06-23 2017-06-23 苯基喹啉酮类和黄酮类衍生物的制备和应用

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021072642A1 (fr) * 2019-10-15 2021-04-22 杭州百诚医药科技股份有限公司 Utilisation de phénylquinolinones et de dérivés de flavonoïdes pour le traitement de la douleur neuropathique
WO2022113008A1 (fr) 2020-11-27 2022-06-02 Richter Gedeon Nyrt. Antagonistes/agonistes inverses du récepteur h3 de l'histamine pour le traitement d'un trouble du spectre autistique

Families Citing this family (1)

* Cited by examiner, † Cited by third party
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CN111533721B (zh) * 2020-05-15 2022-04-26 浙江大学 苯并吡喃酮或喹啉酮类化合物及其应用

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CN1326450A (zh) * 1998-09-24 2001-12-12 三菱化学株式会社 作为τ蛋白激酶1抑制剂的羟基黄酮衍生物
CN1960977A (zh) * 2004-05-31 2007-05-09 万有制药株式会社 喹唑啉衍生物
WO2009097306A1 (fr) * 2008-01-30 2009-08-06 Cephalon, Inc. Dérivés de pyridazine substitués à activité antagoniste des récepteurs h3 de l'histamine
CN101522638A (zh) * 2006-07-25 2009-09-02 赛福伦公司 哒嗪酮衍生物
CN103087024A (zh) * 2013-01-15 2013-05-08 四川大学 一类黄酮烷基胺类化合物、其制备方法和用途
CN103588702A (zh) * 2013-10-26 2014-02-19 浙江大学 N-取代苯基吡啶-4-酮衍生物及其制备和应用
CN103929959A (zh) * 2011-08-12 2014-07-16 萨克生物研究学院 神经保护性多酚类似物

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WO2009026657A1 (fr) * 2007-08-29 2009-03-05 The University Of Sydney Agonistes flavonoïdes de ppar

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Publication number Priority date Publication date Assignee Title
CN1326450A (zh) * 1998-09-24 2001-12-12 三菱化学株式会社 作为τ蛋白激酶1抑制剂的羟基黄酮衍生物
CN1960977A (zh) * 2004-05-31 2007-05-09 万有制药株式会社 喹唑啉衍生物
CN101522638A (zh) * 2006-07-25 2009-09-02 赛福伦公司 哒嗪酮衍生物
WO2009097306A1 (fr) * 2008-01-30 2009-08-06 Cephalon, Inc. Dérivés de pyridazine substitués à activité antagoniste des récepteurs h3 de l'histamine
CN103929959A (zh) * 2011-08-12 2014-07-16 萨克生物研究学院 神经保护性多酚类似物
CN103087024A (zh) * 2013-01-15 2013-05-08 四川大学 一类黄酮烷基胺类化合物、其制备方法和用途
CN103588702A (zh) * 2013-10-26 2014-02-19 浙江大学 N-取代苯基吡啶-4-酮衍生物及其制备和应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021072642A1 (fr) * 2019-10-15 2021-04-22 杭州百诚医药科技股份有限公司 Utilisation de phénylquinolinones et de dérivés de flavonoïdes pour le traitement de la douleur neuropathique
WO2022113008A1 (fr) 2020-11-27 2022-06-02 Richter Gedeon Nyrt. Antagonistes/agonistes inverses du récepteur h3 de l'histamine pour le traitement d'un trouble du spectre autistique

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