CN109111400A - The preparation and application of phenylchinoline ketone and flavone derivative - Google Patents

The preparation and application of phenylchinoline ketone and flavone derivative Download PDF

Info

Publication number
CN109111400A
CN109111400A CN201710488414.7A CN201710488414A CN109111400A CN 109111400 A CN109111400 A CN 109111400A CN 201710488414 A CN201710488414 A CN 201710488414A CN 109111400 A CN109111400 A CN 109111400A
Authority
CN
China
Prior art keywords
compound
ketone
nmr
mhz
cdcl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201710488414.7A
Other languages
Chinese (zh)
Other versions
CN109111400B (en
Inventor
盛荣
楼金芳
严洪兵
胡永洲
唐黎
张冯敏
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HANGZHOU BIO-SINCERITY PHARMA-TECH Corp.,Ltd.
Original Assignee
Hangzhou Baicheng Pharmaceutical Technology Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Hangzhou Baicheng Pharmaceutical Technology Co Ltd filed Critical Hangzhou Baicheng Pharmaceutical Technology Co Ltd
Priority to CN201710488414.7A priority Critical patent/CN109111400B/en
Priority to PCT/CN2018/089970 priority patent/WO2018233483A1/en
Publication of CN109111400A publication Critical patent/CN109111400A/en
Application granted granted Critical
Publication of CN109111400B publication Critical patent/CN109111400B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • 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
    • 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

Landscapes

  • 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)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to phenylchinoline ketone and flavone derivatives and preparation method thereof; the derivative is histamine H 3 receptor antagonists; it can protect and restore the normal function of central nervous system; application especially in neurodegenerative disease and ischemic brain damage has huge clinical value.

Description

The preparation and application of phenylchinoline ketone and flavone derivative
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to the preparation of phenylchinoline ketone and flavone derivative is lived Property ingredient be histamine H 3 receptor antagonists, can protect and restore the normal function of central nervous system, and in nervus retrogression Disease, ischemic deficency encephalopathy, Parkinson's syndrome, hypnosia, epilepsy and the gradually application in the treatment of jelly disease.Described Phenylchinoline ketone and flavone derivative further include its pharmaceutically acceptable salt, compound, solvate etc..
Background technique
Histamine H3Receptor be present in cerebral cortex, corpus straitum, hippocampus, olfactory bulb, stria terminalis bottom core, thalamus, low brain stem ridge core, The positions such as cerebellum, histamine H3Receptor is the autoreceptor of neuronal synapse, and excited this receptor just inhibits histamine or other nerves to pass Matter release, antagonism this receptor then promote neurotransmitter regulator.
Cerebral ischemia mainly in the cerebrovascular occur thrombus, embolism or it is other due to cause caused by cerebral insufficiency One of cerebral infarction, and lead to mankind's deformity and dead number one killer.May be at present due to the complex mechanism of pathologic process Only, without effective medicinal application in clinic.
Existing research shows histamine H3Receptor antagonist can by promoting the synthesis and release of the neurotransmitters such as histamine, For treating Alzheimer's disease (AD), parkinsonism (PD) gradually freezes disease (ALS), hypnosia etc..
Wherein, Alzheimer's disease (AD) has been found that a century or more, number of the infected in rising year by year trend, research shows that Amyloid-beta peptide (β-amyloid, A β) aggregation, tau protein Hyperphosphorylationof, mitochondrial function imbalance, oxidative stress, nerve The many factors such as neurotransmitter systems afunction are likely between molecular mechanism related with its pathogenesis and different again mutually It is associated with, influences each other.Currently, clinically mainly having for the first-line treatment drug of AD --- acetylcholinesterase (AChE) inhibits Agent donepezil, benefit cut down department for bright, galanthamine and uncompetitive nmda receptor antagonist Memantine, they act on cognition Relevant neurotransmitter system cannot fundamentally improve morbid state or end though can alleviate the cognitive disorder of early stage patient Only disease process.
It the characteristics of being related to many factors for the process of AD Occurrence and development of disease, can be simultaneously for the effect of multiple target spots Drug (multitarget-directed ligands, MTDLs) has unique advantage, causes the extensive concern of people.Have Studies have shown that H3Receptor is the important receptor of intracerebral neurotransmitter regulation, H3Receptor antagonist blocks H3Receptor can effectively promote Into histamine, acetylcholine and other neurotransmitter regulators relevant to cognition, currently, having multiple histamine Hs3Receptor antagonist (ABT-288, AZD5213, CEP-26401, GSK239512 and MK0249) enter clinical research, for Alzheimer's disease, The treatment of the neurodegenerative diseases such as parkinsonism, hypnosia
Fig. 1 enters the part H3 receptor antagonist of clinical research.
Old patch (the senile of ambitus cerebri and cerebral cortex formation are deposited on after amyloid protein peptide A beta-aggregation Plaques, SP) it is one of most typical pathological characters of AD.Moreover, A β formed in accumulation process oligomer, fibrinogen and Fiber can generate toxicity to nerve cell, even result in nerve cell apoptosis.Therefore, Α beta-aggregation is generally considered the interior of AD In the cause of disease, the drug of A beta-aggregation is inhibited to have become the important directions of current AD drug development.
The present invention will improve the target spot of symptom on the basis of the biological characteristics to AD related target carry out network analysis (H3Receptor) and etiotropic target spot (A beta-aggregation) progress organic assembling, with rational drug design methods, designing can be same When antagonism H3Receptor and the multiple target point compound for inhibiting A beta-aggregation, such multiple target point compound can not only promote releasing for neurotransmitter It puts, improves the symptom of patient AD, delay the state of an illness；And the self assemble of A β can be inhibited simultaneously, fundamentally prevent the course of disease of AD Progress, reaches the effect of " multi-pronged, treating both manifestation and root cause of disease ", may have for the treatment of the neurodegenerative diseases such as AD unique Effect.
The invention also discloses protective effect of the invention compound to ischemic brain damage nervous function.
Histamine H3Receptor antagonist molecule structure is mostly chain molecule, is mainly made of three parts: western segment is Fat tertiary amine nitrogen-containing basic region and the part of connection chain composition, center are fat-soluble aromatic rings, and east segment is fat-soluble Aromatic ring or basic group (Fig. 2)
Fig. 2 target molecule design.
The present invention is from H3Receptor antagonist Pharmacophore Model is set out, with benzoquinoline ketone (benzopyrone) for fat-soluble virtue Ring (east segment), using benzene oxygen propyl group amine as other parts (center ring+western part segment), design has synthesized completely new phenylchinoline Ketone and flavone derivative；On the other hand, early-stage study shows N- amine propoxyphenyl-pyridine -4- with similar structure Ketone derivatives have good inhibitions A beta-aggregation it is active (N- substituted-phenyl pyridin-4-one derivatives and its preparation and application, ZL201310511154.2).Further active testing shows that designed phenylchinoline ketone and flavone derivative are tools There is antagonism H3Receptor and the double target spot compounds for inhibiting A beta-aggregation.
Summary of the invention
Term explanation: term used herein " alkyl ", different number of atom, refers to comprising 1-6 carbon unless indicated The linear chain or branched chain hydrocarbon chain of atom.The example of " alkyl " used in the present invention includes but is not limited to methyl, ethyl, n-propyl, isobutyl Base, isopropyl." alkyl " further includes replacing alkyl.The alkyl can be optionally by halogen or the one or many substitutions of hydroxyl.
Term used herein " alkoxy " refers to-O- alkyl group, and wherein alkyl is as defined above." alkane used herein The example of oxygroup " includes but is not limited to methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and tert-butoxy." alkane Oxygroup " further includes substituted alkoxy.Alkoxy can optionally be optionally substituted by halogen one or many.
" pharmaceutically acceptable salt " includes hydrochloride, sulfate, hydrobromate, (+) tartrate, (-) in the present invention Tartrate, fumarate, succinate, etc. common inorganic acid salt and acylate, amino-acid salt in pharmacy.
Benzoquinoline ketone provided by the invention, flavonoids and the like or its pharmaceutically acceptable salt, solvent close Object has following general formula structure (A):
General formula structure (A)
In formula:
X is selected from N or O；
R1Selected from H, C1-3Alkyl or C1-3Alkoxy；
R2Selected from H, hydroxyl or C1-3Alkoxy；
R3Selected from H, hydroxyl, C1-3Alkyl or C1-3Alkoxy.
NR ' R ' ' is selected from cyclic amine and the acyclic alkyl amine that the total number of carbon atoms is 3-6, including but not limited to following segment:
。
Further, currently preferred quinolinones and flavone derivative, it is describedSelected from following Two kinds of heterocycles:
。
Further, currently preferred quinolinones and flavone derivative and the like, R1Preferably hydrogen, methyl And ethyl；R2Preferably hydrogen, hydroxyl and methoxyl group；R3Preferably hydrogen, hydroxyl and methoxyl group.
It will be appreciated that the present invention includes all combinations and subgroup for the special groups that the present invention defines, including summary above Defined in, shown in each embodiment throughout the specification and substituent group described in appended claims.
More specifically, (or compound is pharmaceutically for the preferred compound of general formula quinolinones of the present invention and flavone derivative Acceptable salt, compound, solvate) selected from compound shown in table 1
The preferred compound of 1 quinoline ketone derivative of table
。
The preparation method of above compound provided by the invention, is prepared by following steps, but is not limited only to following methods.
General formula quinoline ketone derivative can be synthesized by following steps.
Compound I(quinoline ketone derivative) series in I-1, I-2 synthetic method (when the method is suitble to X=N):
。
Specific reaction process is: raw material 1,1,3- bromo-chloropropane and potassium carbonate being dissolved in acetonitrile and being heated to reflux, then In NaOH/CH3Intermediate 1 is reacted to obtain in OH system, then flow back in thionyl chloride solution to obtain intermediate 2, then by its with O-aminoacetophenone reacts to obtain intermediate 3 at room temperature, reacts to obtain intermediate 4 in microwave with potassium tert-butoxide, finally and second level Amine back flow reaction obtains target compound I-1, I-2.
Compound I(quinoline ketone derivative) series in I-3 ~ I-6 synthetic method (when the method is suitble to X=N):
。
Specific reaction process is: the intermediate 4 in embodiment 1 is dissolved in DMF, and sodium hydride and halogenated hydrocarbons, reaction is added Intermediate 5 is obtained, finally obtains target compound I-3~I-6 with secondary amine, triethylamine back flow reaction.
Compound I(quinoline ketone derivative) series in I-7, I-8 synthetic method (when the method is suitble to X=N):
。
Specific reaction process is: parahydroxyacet-ophenone (raw material 4) being dissolved in acetonitrile, 1,3- bromo-chloropropane and carbon is added Sour potassium back flow reaction obtains intermediate 6, then obtains bromo ketone intermediate 7 with bromine reaction under ice bath；The latter and ortho-aminobenzoic acid, Potassium carbonate heats in DMF reacts to obtain ester intermediate 8, obtains intermediate 9 through the reflux cyclization of ammonium acetate/acetic acid, finally with secondary amine, Triethylamine back flow reaction obtains target compound I-7, I-8.
Compound I(quinoline ketone derivative) series in I-9, I-10 synthetic method (when the method is suitble to X=N):
。
Specific reaction process is: intermediate 9, dimethyl suflfate and potassium carbonate in embodiment 3 are dissolved in acetone, reflux Intermediate 10 is reacted to obtain, then obtains target compound I-9, I-10 with secondary amine NHR ' R ' ' and triethylamine back flow reaction.
Compound II(flavone derivative) series in II-1, II-2 synthetic method (when the method is suitble to X=O):
。
Specific reaction process is: raw material 6 being dissolved in acetonitrile, after 1,3- bromo-chloropropane and potassium carbonate is added, reflux is anti- Deserved intermediate 11, in potassium hydroxide, the latter and parahydroxyacet-ophenone are condensed to yield intermediate 12, then through hydrogen peroxide/ KOH system cyclization obtains intermediate 13, finally obtains target compound II-1, II-2 with secondary amine, triethylamine back flow reaction.
Compound II(flavone derivative) series in II-3, II-4 synthetic method (when the method is suitble to X=O)
。
Specific reaction process is as follows: intermediate 13, iodomethane and potassium carbonate in embodiment 5 are dissolved in acetone, reflux Intermediate 14 is reacted to obtain, then obtains target compound II-3, II-4 with secondary amine, triethylamine back flow reaction.
Compound II(flavone derivative) series in II-5, II-6 synthetic method (when the method is suitble to X=O)
。
Specific reaction process is as follows: by intermediate 11 and 2,6- resacetophenone is dissolved in ethyl alcohol, and hydroxide is added Back flow reaction obtains intermediate 15 after potassium, and then under iodine and concentrated sulfuric acid effect, cyclization reaction obtains intermediate 16, finally and second level Amine, triethylamine back flow reaction obtain target compound II-5, II-6.
Compound II(flavone derivative) series in II-7, II-8 synthetic method (when the method is suitble to X=O)
。
Specific reaction process is as follows: 7 intermediate 16 of embodiment, potassium iodide and potassium carbonate are dissolved in acetone, back flow reaction Intermediate 17 is obtained, then obtains target compound II-7, II-8 with secondary amine, triethylamine back flow reaction.
It is a further object to provide the quinolinones, flavone derivative and its pharmaceutically acceptable The application of salt, solvate in medicine preparation, the drug are closed by the analog and pharmaceutically acceptable salt and solvent Object is made with pharmaceutically acceptable carrier or excipient.
" pharmaceutically acceptable carrier " refers to the pharmaceutical carrier of pharmaceutical field routine, the routine including pharmaceutical field Diluent, excipient such as water etc., filler such as starch etc., adhesive such as cellulose derivative, gelatin etc., wetting agent such as glycerol, Disintegrating agent such as agar, calcium carbonate etc., sorbefacient such as quaternary ammonium compound, surfactant such as hexadecanol, absorption carrier is such as Kaolin and soap clay, lubricant such as talcum powder etc., it may also be necessary to flavouring agent, sweetener etc. be added.
Pharmaceutical preparation is suitable for being administered by any appropriate approach, and such as oral (including buccal or sublingual administration), rectum are given Medicine, nose administration, local administration (including buccal, sublingual administration or percutaneous dosing) or parenteral (including subcutaneous injection, flesh Interior injection, intravenous injection or intracutaneous injection) approach.These preparations can be prepared by any method known in art of pharmacy.Example Method such as by the way that active constituent and carrier or excipient mix.
The present invention provides the compound and its preferred compound, the compound pharmaceutically acceptable salt, institute It states the solvate of compound, prodrug (ester or phosphate), stereoisomer, deuterated object and is used in combination with other drugs Treat the purposes in nervus retrogression related disease.Wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson Disease, hypnosia, epilepsy gradually freeze disease etc., particularly disclose compound and its preferred compound of the present invention to ischemic brain The protective effect of damage not only contributes to the recovery of nervous function, also effectively reduces cerebral infarction volume.
Specific embodiment
The specific embodiment that bread contains is in order to for example, being understood not to limitation of the scope of the invention.Furthermore It should be understood that after reading the content taught by the present invention, those skilled in the art can make various changes or be repaired to the present invention Change, these equivalent forms also fall within the scope of the appended claims of the present application.
I-1 in 1: I class compound (quinolinones) of embodiment, the synthesis of I-2.
Step 1: 4- (3- chloropropanol oxygen radical) benzoic acid (intermediate 1).
By ethyl-para-hydroxybenzoate II-1(12 g, 72 mmol), 1,3- bromo-chloropropane (14.2 mL, 144 mmol) And K2CO3(20 g, 144 mmol) are dissolved in 100mL acetonitrile, are heated to reflux 12 h.It filters and removes excessive K2CO3, decompression steaming Except solvent, colourless oil liquid is obtained.It is directly added into the NaOH solution and 30 mL CH of 15 mL, 6 N3OH, flow back 1 h.Wait react Liquid becomes clarification, cooling, is acidified to pH=2 with 2 N hydrochloric acid, a large amount of white solids are precipitated, and filters, is washed with water, whitely dry 14.5 g of solid powder.Yield 94%;1H NMR (500 MHz, CDCl3): δ 8.08 (d, J= 8.5 Hz, 2H), 6.96 (d, J = 8.5 Hz, 2H), 4.21 (t, J= 6.0 Hz, 2H), 3.77 (t, J= 6.5 Hz, 2H), 2.30-2.25 (m, 2H); ESI-MS: m/z =215 [M+H]+。
Step 2: N- (2- acetylphenyl) -4- (3- chloropropanol oxygen radical) benzamide (intermediate 3).
Intermediate 1(5.0 g, 23 mmol) in 10 mL SOCl21 ~ 2 drop DMF is added in reaction system by 1 h of middle reflux. After reaction, excessive SOCl is removed under reduced pressure2, obtain colourless liquid intermediate 2.By o-aminoacetophenone (2.83 g, 21 Mmol) it is dissolved in the anhydrous CH of 15 mL2Cl2In the anhydrous TEA of 6.5 mL, intermediate 2 is slowly added dropwise under 0 °C, drop finishes, and room temperature continues anti- 2h is answered, is filtered, filtrate is spin-dried for, and obtained residue obtains white solid through column chromatography for separation (petroleum ether: EtOAc=10:1) 5.0g.Yield 72%;1H NMR (500 MHz, CDCl3): δ 12.65 (s, 1H), 8.11 (d, J= 9.0 Hz, 1H), 8.05 (d, J= 9.0 Hz, 2H), 7.97 (dd, J= 8.0, 1.5 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.16 (t, J= 8.0 Hz, 1H), 7.02 (d, J= 9.0 Hz, 2H), 4.21 (t, J= 6.0 Hz, 2H), 3.78 (t, J= 6.5 Hz, 2H), 2.73 (m, 3H), 2.31-2.26 (m, 2H); ESI-MS: m/ z =332 [M+H]+。
Step 3: 2- (4- (3- chloropropanol oxygen radical) phenyl) quinoline -4 (1H) -one (intermediate 4).
Intermediate 3(995 mg, 3.0 mmol), potassium tert-butoxide (1.68 g, 15 mmol) are dissolved in 15 mL THF, 110 °C of 20 min of microwave reaction in closed container.After reaction, it is cooled to room temperature, pours into 100 mL ice water, 2N is added A large amount of yellow solids are precipitated in HCl tune pH to 5 ~ 6, washing, a small amount of ice acetone and CH2Cl2(1:1) washing, obtains intermediate 4,750 mg.Yield 80%;1H NMR (500 MHz, CDCl3): δ 11.63 (s, 1H), 8.10 (dd, J= 8.0, 1.0 Hz, 1H), 7.83 (d, J= 9.0 Hz, 2H), 7.78 (d, J= 8.0, 1H), 7.68 (t, J= 7.5 Hz, 1H), 7.35 (t, J= 7.5 Hz, 1H), 7.17 (d, J= 9.0 Hz, 2H), 6.33 (s, 1H), 4.21 (t,J= 6.0 Hz, 2H), 3.84 (t, J= 6.5 Hz, 2H), 2.24-2.18 (m, 2H); ESI-MS: m/z =314 [M+H]+。
Step 4: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) quinoline -4 (1H) -one (I-1).
Intermediate 4 (60 mg, 0.19mmol) is dissolved in 3mL acetonitrile, 41 mg (0.57 mmol) pyrroles is added dropwise to Alkane and 96 mg (0.96 mmol) TEA are warming up to back flow reaction and stay overnight.After reaction, cooling, evaporating solvent under reduced pressure, warp Column chromatography for separation (petroleum ether: EtOAc:TEA=1:5:0.1) obtains yellow solid 40mg.Yield 60%;1H NMR (500 MHz, CDCl3): δ 8.33 (d, J= 9.0 Hz, 1H), 7.86 (d, J= 8.0 Hz, 1H), 7.62 (t, J= 7.5 Hz, 1H), 7.55 (t, J= 8.5 Hz, 2H), 7.34 (t, J= 7.5 Hz, 1H), 6.76 (d, J= 8.5 Hz, 2H), 6.38 (s, 1H), 3.91 (t, J= 6.0 Hz, 2H), 2.95-2.88 (m, 6H), 2.12- 2.07 (m, 2H), 1.98-1.93 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 174.19, 155.44, 146.00, 136.03, 127.08, 124.08, 122.23, 120.66, 120.41, 118.90, 113.92, 109.83, 102.77, 60.93, 48.61, 47.68, 22.01, 18.61; ESI-MS: m/z =349 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) quinoline -4 (1H) -one (I-2).
Preparation method replaces pyrrolidines with compound I-1, with piperidines, obtains yellow solid.Yield 75%;1H NMR (500 MHz, CDCl3): δ 8.33 (d, J= 8.5 Hz, 1H), 7.79 (d, J= 8.5 Hz, 1H), 7.62 (t, J= 7.5 Hz, 1H), 7.59 (t, J= 8.5 Hz, 2H), 7.34 (t, J= 7.5 Hz, 1H), 6.84 (d, J= 8.5 Hz, 2H), 6.39 (s, 1H), 3.95 (t, J= 6.0 Hz, 2H), 2.59-2.54 (m, 6H), 2.04- 1.99 (m, 2H), 1.70-1.66 (m, 4H), 1.51-1.48 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 174.16, 155.86, 145.64, 135.72, 127.17, 123.84, 121.89, 120.82, 120.43, 118.94, 113.68, 110.07, 102.82, 61.52, 50.78, 49.56, 21.23, 20.50, 19.15; ESI-MS: m/z =363 [M+H]+。
The synthesis of I-3 ~ I-6 in 2: I class compound (quinolinones) of embodiment.
Step 1: 2- (4- (3- chloropropanol oxygen radical) phenyl) -1- methylquinoline -4 (1H) -one (intermediate 5a).
Intermediate 4(276mg, 0.88mmol) is dissolved in 5 mL DMF, is added 42 mg NaH(60%, 1.05 Mmol), after stirring 30 min at room temperature, iodomethane (138 mg, 0.97 mmol) is added, is warming up to 35 °C, reaction 30 min.Reaction solution is poured into 50 mL H2In O, extracted with EtOAc, washed, be saturated NaCl wash, anhydrous Na2SO4It is dry.Recycling After solvent, through column chromatography for separation (petroleum ether: EtOAc=10:1), 250 mg of white solid is obtained.Yield 87%;1H NMR (500 MHz, CDCl3): δ 8.17 (d, J= 8.0 Hz, 1H), 8.10-8.08 (m, 3H), 7.71 (d, J= 8.0, 1H), 7.48 (t, J= 7.5 Hz, 1H), 7.14 (s, 1H), 7.05 (d, J= 9.0 Hz, 2H), 4.21 (t,J= 6.0 Hz, 2H), 4.12 (s, 3H), 3.79 (t, J= 6.5 Hz, 2H), 2.31-2.26 (m, 2H); ESI-MS: m/z =328 [M+H]+。
Chloropropanol oxygen radical) phenyl) -1- ethyl quinolinium -4 (1H) -one (intermediate 5b).
Preparation method replaces iodomethane with compound intermediate 5a, with bromoethane, obtains yellow solid.Yield 67%;1H NMR (500 MHz, CDCl3): δ 8.21 (d, J= 8.0 Hz, 1H), 8.09-8.07 (m, 3H), 7.71 (d,J= 8.0, 1H), 7.48 (t, J= 7.5 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J= 9.0 Hz, 2H), 4.37 (q, J= 7.0 Hz, 2H), 4.21 (t, J= 6.0 Hz, 2H), 3.79 (t, J= 6.5 Hz, 2H), 2.31-2.26 (m, 2H), 1.62 (s, 3H); ESI-MS: m/z =342 [M+H]+。
Step 2: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) -1- methylquinoline -4 (1H) -one (I-3).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 5a, and secondary amine is pyrrolidines, and white solid is made I-3, yield 74%;1H NMR (500 MHz, CDCl3): δ 8.17 (d, J= 8.0 Hz, 1H), 8.09-8.06 (m, 3H), 7.70 (t, J= 8.0, 1H), 7.47 (t, J= 7.5 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J= 9.0 Hz, 2H), 4.13 (t, J= 6.0 Hz, 2H), 4.12 (s, 3H), 2.71 (t, J= 6.5 Hz, 2H), 2.61-2.57 (m, 4H), 2.10-2.05 (m, 2H), 1.85-1.80 (m, 4H); 13C NMR (100 MHz, CDCl3): δ 162.70, 160.18, 158.36, 149.15, 132.72, 129.87, 128.95, 128.79, 125.01, 121.57, 120.15, 114.66, 97.40, 66.51, 55.59, 54.28, 53.17, 28.82, 23.44; ESI-MS: m/z =363 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) -1- methylquinoline -4 (1H) -one (I-4).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 5a, and secondary amine replaces pyrrolidines with piperidines, is made White solid I-4, yield 71%;1H NMR (500 MHz, CDCl3): δ 8.17 (d, J= 8.0 Hz, 1H), 8.09- 8.06 (m, 3H), 7.70 (d, J= 8.0, 1H), 7.47 (t, J= 7.5 Hz, 1H), 7.14 (s, 1H), 7.04 (d, J= 9.0 Hz, 2H), 4.12 (s, 3H), 4.11 (t, J= 6.0 Hz, 2H), 2.58-2.52 (m, 2H), 2.50-2.44 (m, 4H), 2.08-2.03 (m, 2H), 1.66-1.62 (m, 4H), 1.47-1.45 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 162.70, 160.22, 158.41, 149.18, 132.75, 129.92, 128.99, 128.83, 125.06, 121.61, 120.18, 114.69, 97.46, 66.65, 56.04, 55.64, 54.69, 26.80, 25.97, 24.43; ESI-MS: m/z =377 [M+H]+。
Pyrrolidin-1-yl) propoxyl group) phenyl) -1- ethyl quinolinium -4 (1H) -one (I-5).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 5b, and secondary amine is pyrrolidines, and pale yellow colored solid is made Body I-5.Yield 74%;1H NMR (500 MHz, CDCl3): δ 8.21 (d, J= 8.0 Hz, 1H), 8.07-8.05 (m, 3H), 7.70 (t, J= 8.0, 1H), 7.47 (t, J= 7.5 Hz, 1H), 7.12 (s, 1H), 7.04 (d, J= 9.0 Hz, 2H), 4.37 (q, J= 7.0 Hz, 2H), 4.13 (t, J= 6.0 Hz, 2H), 2.77- 2.75 (m, 2H), 2.71-2.64 (m, 4H), 2.14-2.10 (m, 2H), 1.89-1.85 (m, 4H), 1.62 (t, J= 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ161.98, 160.17, 158.35, 149.25, 132.85, 129.77, 128.96, 128.78, 124.86, 121.69, 120.26, 114.67, 97.95, 66.53, 63.97, 54.27, 53.16, 28.82, 23.46, 14.54; ESI-MS: m/z =377 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) -1- ethyl quinolinium -4 (1H) -one (I-6).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 5b, and secondary amine is piperidines, and faint yellow solid is made I-6.Yield 85%;1H NMR (500 MHz, CDCl3): δ 8.21 (d, J= 8.0 Hz, 1H), 8.07-8.05 (m, 3H), 7.70 (t, J= 8.0, 1H), 7.47 (t, J= 7.5 Hz, 1H), 7.12 (s, 1H), 7.04 (d, J= 9.0 Hz, 2H), 4.37 (q, J= 7.0 Hz, 2H), 4.11 (t, J= 6.0 Hz, 2H), 2.60-2.52 (m, 2H), 2.51-2.44 (m, 4H), 2.10-2.05 (m, 2H), 1.68-1.63 (m, 4H), 1.62 (t, J= 7.0 Hz, 3H), 1.50-1.45 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 162.00, 160.18, 158.40, 149.25, 132.85, 129.83, 128.96, 128.81, 124.91, 121.73, 120.26, 114.68, 98.00, 66.63, 64.01, 56.00, 54.66, 26.77, 25.93, 24.41, 14.59; ESI- MS: m/z =391 [M+H]+。
The synthesis of I-7, I-8 in 3: I class compound (quinolinones) of embodiment.
Step 1: 4- (3- chloropropanol oxygen radical) acetophenone (intermediate 6).
By parahydroxyacet-ophenone (5.0 g, 36.7 mmol), 1,3- bromo-chloropropane (7.3 mL, 73.5 mmol) and K2CO3(10 g, 73.5 mmol) are dissolved in 30 mL acetonitriles, are heated to reflux 10 h.It filters and removes excessive K2CO3, decompression steaming Except solvent, 7.6 g of colourless liquid is obtained through column chromatography for separation (petroleum ether: EtOAc=10:1).Yield 98%;1H NMR (500 MHz, CDCl3): δ 7.95 (d, J= 9.0 Hz, 2H), 6.95 (d, J = 9.0 Hz, 2H), 4.20 (t, J= 6.0 Hz, 2H), 3.77 (t, J= 6.0 Hz, 2H), 2.56 (s, 3H), 2.29-2.24 (m, 2H); ESI- MS: m/z =213 [M+H]+。
Step 2: the bromo- 1- of 2- (4- (3- chloropropanol oxygen radical) phenyl) ethyl ketone (intermediate 7).
Intermediate 6(2.12 g, 10 mmol) is dissolved in 20 mL ether, Br is slowly added dropwise under 0 °C2(0.51 mL, 10 mmol), drop finishes, and 16 h are stirred at room temperature.Reaction solution is poured into saturation NaHCO3It in solution, is extracted with ether, organic layer is through nothing Water Na2SO4After drying, column chromatography for separation (petroleum ether: CH2Cl2=3:1), obtain 2.45 g of faint yellow solid.Intermediate 84%;1H NMR (500 MHz, CDCl3): δ 7.97 (d, J= 9.0 Hz, 2H), 6.97 (d, J = 9.0 Hz, 2H), 4.40 (s, 2H), 4.22 (t, J= 6.0 Hz, 2H), 3.77 (t, J= 6.0 Hz, 2H), 2.30-2.25 (m, 2H); ESI-MS: m/z =291 [M+H]+。
Step 3: 2- (4- (3- chloropropanol oxygen radical) phenyl) -2- oxoethyl -2- Aminobenzoate (intermediate 8).
By ortho-aminobenzoic acid (720 mg, 5.25 mmol) and K2CO3(760 mg, 5.5 mmol) are dissolved in 10 mL In DMF, 30 min are stirred at room temperature, rear that intermediate 7(1.46 g, 5.0 mmol is added), 50 °C are warming up to, after reacting 3 h, Reaction solution is poured into 100 mL water, is extracted with EtOAc, organic layer is done after 1 N NaOH solution, saturation NaCl solution washing It is dry, through column chromatographic purifying (petroleum ether: EtOAc=3:1) after evaporating solvent under reduced pressure, obtain 1.6 g of white solid.Yield 92%;1H NMR (500 MHz, CDCl3): δ 8.02 (dd, J= 8.0, 1.0 Hz, 1H), 7.96 (d, J= 8.5 Hz, 2H), 7.32 (t, J= 7.5 Hz, 1H), 6.98 (d, J = 8.5 Hz, 2H), 6.72-6.68 (m, 2H), 5.49 (s, 2H), 4.22 (t, J= 6.0 Hz, 2H), 3.77 (t, J= 6.0 Hz, 2H), 2.30-2.25 (m, 2H); ESI-MS: m/z =348 [M+H]+。
Step 4: 2- (4- (3- chloropropanol oxygen radical) phenyl) -3- oxyquinoline -4 (1H) -one (intermediate 9).
Intermediate 8(1.6 g, 4.6 mmol) and ammonium acetate (5.3 g, 69 mmol) are dissolved in 30 mL acetic acid, added Heat is to 3 h of back flow reaction.After reaction, reaction solution is poured into 250 mL water, a large amount of solids is precipitated, filtered, be washed to Property, dry 1.02 g of faint yellow solid.Yield 67%;1H NMR (500 MHz, CDCl3): δ 8.32 (d, J= 8.5 Hz, 1H), 7.80-7.76 (m, 2H), 7.61-7.57 (m, 2H), 7.32 (t, J= 7.5 Hz, 1H), 6.97- 6.95 (m, 2H), 6.72-6.68 (m, 2H), 4.12 (t, J= 6.0 Hz, 2H), 3.76 (t, J= 6.0 Hz, 2H), 2.26-2.23 (m, 2H); ESI-MS: m/z =330 [M+H]+。
Step 5: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) -3- oxyquinoline -4 (1H) -one (I-7).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 9, obtains buff white solid.Yield 59%;1H NMR (500 MHz, DMSO-d 6): δ 11.48 (s, 1H), 8.29 (s, 1H), 8.13 (dd, J = 8.0, 1.0 Hz, 1H), 7.78 (d, J= 9.0 Hz, 2H), 7.73 (d, J = 8.5 Hz, 1H), 7.60 (t, J = 7.5 Hz, 1H), 7.28 (t, J = 7.5 Hz, 1H), 7.13 (d, J= 9.0 Hz, 2H), 4.12 (t, J = 6.5 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H), 2.46-2.42 (m, 4H), 1.95-1.89 (m, 2H), 1.70- 1.67 (m, 4H); 13C NMR (125 MHz, DMSO-d 6): δ 170.22, 159.80, 138.42, 138.01, 131.81, 131.11, 130.85, 124.85, 124.80, 122.24, 122.15, 118.84, 114.66, 66.54, 54.13, 52.68, 28.63, 23.58; ESI-MS: m/z =365 [M+H]+。
Pyrrolidin-1-yl) propoxyl group) phenyl) -3- oxyquinoline -4 (1H) -one (I-8).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 9, and piperidines replaces pyrrolidines, obtains yellow solid.It receives Rate 67%;1H NMR (500 MHz, DMSO-d 6): δ 11.47 (s, 1H), 8.28 (s, 1H), 8.12 (dd, J = 8.0, 1.0 Hz, 1H), 7.77 (d, J= 9.0 Hz, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.59 (t,J = 7.5 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 7.12 (d, J= 9.0 Hz, 2H), 4.12 (t,J = 6.5 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H), 2.46-2.42 (m, 4H), 1.95-1.89 (m, 2H), 1.70-1.67 (m, 4H), 1.51-1.48 (m, 2H); 13C NMR (125 MHz, DMSO-d 6): δ 170.25, 159.49, 138.43, 138.03, 131.75, 131.17, 130.84, 125.04, 124.83, 122.26, 122.14, 118.88, 114.67, 65.99, 54.29, 53.08, 28.58, 24.19, 23.74; ESI-MS: m/z =379 [M+H]+。
The synthesis of I-9, I-10 in 4: I class compound (quinolinones) of embodiment.
Step 1: 2- (4- (3- chloropropanol oxygen radical) phenyl) -3- methoxyl group -1- methylquinoline -4 (1H) -one (intermediate 10).
By intermediate 9(660 mg, 2.0 mmol), dimethyl suflfate (0.75 mL, 8.0 mmol) and K2CO3(1.1 G, 8.0 mmol) it is dissolved in 10 mL acetone, it is heated to 4 h of back flow reaction.After reaction, cooling to filter, filtrate is through depressurizing After recycling design, column chromatographic purifying (petroleum ether: EtOAc=1:2) obtains 558 mg of yellow solid.Yield 78%;1H NMR (500 MHz, CDCl3): δ 8.59 (dd, J = 8.0, 1.0 Hz, 1H), 7.71 (t, J= 7.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 3.65 (s, 3H), 3.54 (s, 3H), 2.36-2.24 (m, 2H); ESI-MS: m/z =358 [M+H]+。
Step 2: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) -3- methoxyl group -1- methylquinoline -4 (1H)- Ketone (I-9).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 10, obtains beige solid.Yield: 65%;1H NMR (500 MHz, CDCl3): δ 8.59 (dd, J = 8.0, 1.5 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.65 (s, 3H), 3.53 (s, 3H), 2.70 (t, J = 7.5 Hz, 2H), 2.61-2.55 (m, 4H), 2.13-2.05 (m, 2H), 1.85-1.81 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 172.96, 159.69, 147.31, 141.26, 140.20, 131.85, 130.38, 127.14, 126.79, 124.35, 122.99, 115.78, 114.67, 66.46, 59.89, 54.30, 53.15, 37.12, 28.74, 23.47; ESI-MS: m/z =393 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) -3- methoxyl group -1- methylquinoline -4 (1H) -one (I-10).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 10, and piperidines replaces pyrrolidines, and it is solid to obtain rice white Body.Yield: 67%;1H NMR (500 MHz, CDCl3): δ 8.58 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.41 (t, J = 7.5 Hz, 1H), 7.29 (d, J = 8.5 Hz, 2H), 7.05 (d, J = 8.5 Hz, 2H), 4.10 (t, J = 6.0 Hz, 2H), 3.65 (s, 3H), 3.53 (s, 3H), 2.57-2.51 (m, 2H), 2.47-2.43 (m, 4H), 2.08-2.03 (m, 2H), 1.66-1.58 (m, 4H), 1.48-1.44 (s, 2H); 13C NMR (125 MHz, CDCl3): δ 172.95, 159.72, 147.28, 141.27, 140.21, 131.82, 130.38, 127.15, 126.79, 124.36, 122.97, 115.77, 114.68, 66.60, 59.88, 55.96, 54.66, 37.10, 26.77, 25.92, 24.39; ESI-MS: m/z =407 [M+H]+。
The synthesis of II-1, II-2 in embodiment 5:II class compound (flavonoid class).
Step 1: 4- (3- chloropropanol oxygen radical) benzaldehyde (intermediate 11).
Preparation method replaces parahydroxyacet-ophenone with intermediate 6, with parahydroxyben-zaldehyde, obtains faint yellow solid.Yield: 98%; 1H NMR (500 MHz, CDCl3): δ 9.89 (s, 1H), 7.85 (d, J= 9.0 Hz, 2H), 7.02 (d, J = 9.0 Hz, 2H), 4.22 (t, J= 6.0 Hz, 2H), 3.77 (t, J= 6.0 Hz, 2H), 2.30- 2.25 (m, 2H); ESI-MS: m/z =199 [M+H]+。
Step 2: 1- (2- hydroxy phenyl) -3- (4- (3- chloropropanol oxygen radical) phenyl) propyl- 2- alkene -1- ketone (intermediate 12).
Parahydroxyacet-ophenone (1.36 g, 10 mmol), intermediate 11(1.98 g, 10 mmol) is dissolved in 15 mL C2H5In OH, 1.68 g KOH(30 mmol are added), 2 h of back flow reaction.It is cooling, partial solvent is removed under reduced pressure, in remaining residue 200 mL ice water are added in object, with 2 N HCl tune pH to 4-5, a large amount of solids are precipitated, filters drying, obtains 2.82 g of yellow solid. Yield 89%;1H NMR (500 MHz, CDCl3): δ 12.92 (s, 1H), 7.94-7.89 (m, 2H), 7.63 (d,J = 8.5 Hz, 2H), 7.57 and 7.54 (s, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.97-6.93 (m, 3H), 4.20 (t, J = 6.0 Hz, 2H), 3.78 (t, J = 6.5 Hz, 2H), 2.30-2.25 (m, 2H); ESI-MS: m/z =317 [M+H]+。
Step 3: 2- (4- (3- chloropropanol oxygen radical) phenyl) -3- hydroxyl -4HBenzopyran-4-one (intermediate 13).
Intermediate 12(1.05 g, 3 mmol) is dissolved in 10 mL C2H5In OH, the KOH solution of 10 mL, 0.5 N is added, 0.6 mL H is added portionwise again2O2Aqueous solution (30%) pours into reaction solution in ice water after stirring 1 h at room temperature, is precipitated a large amount of solid Body filters, and filter cake is dry after being washed with water, and obtains 930 mg of yellow solid.Yield 94%;1H NMR (500 MHz, CDCl3): δ 8.61 (d, J = 7.5 Hz, 1H), 8.04 (d, J = 9.0 Hz, 2H), 7.61-7.58 (m, 2H), 7.28 (t, J = 7.0 Hz, 1H), 7.01 (d, J = 9.0 Hz, 2H), 4.15 (t, J = 6.0 Hz, 2H), 3.83 (t, J = 6.5 Hz, 2H), 2.23-2.17 (m, 2H); ESI-MS: m/z =331 [M+H]+。
Step 4: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) -3- hydroxyl -4HBenzopyran-4-one (II- 1).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 13, obtains yellow solid.Yield: 68%;1H NMR (500 MHz, CDCl3): δ 8.25-8.21 (m, 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.59 (d,J = 8.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 4.14 (t,J = 6.0 Hz, 2H), 2.74-2.67 (m, 2H), 2.64-2.58 (m, 4H), 2.11-2.06 (m, 2H), 1.86-1.80 (m, 4H); 13C NMR (125 MHz, DMSO-d 6): δ 173.10, 160.32, 154.88, 146.04, 138.65, 133.96, 129.87, 125.20, 124.95, 123.92, 121.81, 118.80, 114.94, 66.52, 54.10, 52.64, 28.56, 23.56; ESI-MS: m/z =366 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) -3- hydroxyl -4HBenzopyran-4-one (II-2).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 13, and piperidines replaces pyrrolidines, obtains yellow solid. Yield: 61%;1H NMR (500 MHz, CDCl3): δ 8.25-8.21 (m, 3H), 7.71 (t, J = 7.5 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 9.0 Hz, 2H), 4.12 (t, J = 6.5 Hz, 2H), 2.56 (t, J = 7.0 Hz, 2H), 2.46-2.42 (m, 4H), 1.95-1.89 (m, 2H), 1.70-1.67 (m, 4H), 1.52-1.48 (m, 2H); 13C NMR (125 MHz, DMSO-d 6): δ173.47, 160.24, 154.85, 145.98, 138.02, 133.85, 129.77, 125.19, 124.87, 124.09, 121.78, 118.78, 114.93, 66.61, 55.56, 54.59, 26.69, 26.07, 24.61; ESI-MS: m/z =380 [M+H]+。
The synthesis of II-3, II-4 in embodiment 6:II class compound (flavonoid class).
Step 1: 2- (4- (3- chloropropanol oxygen radical) phenyl) -3- methoxyl group -4HBenzopyran-4-one (intermediate 14).
By intermediate 13(660 mg, 2.0 mmol), iodomethane (8.0 mmol) and K2CO3(1.1 g, 8.0 mmol) are molten In 10 mL acetone, it is heated to 4 h of back flow reaction.After reaction, cooling to filter, filtrate is after being recovered under reduced pressure solvent, column Chromatographic purifying (petroleum ether: EtOAc=1:2), obtains 558 mg of yellow solid.Yield 78%;1H NMR (500 MHz, CDCl3): δ 8.59 (dd, J = 8.0, 1.0 Hz, 1H), 7.71 (t, J= 7.5 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.07 (d, J = 8.5 Hz, 2H), 4.22 (t, J = 6.0 Hz, 2H), 3.81 (t, J = 6.0 Hz, 2H), 3.65 (s, 3H), 3.54 (s, 3H), 2.36-2.24 (m, 2H); ESI-MS: m/z =358 [M+H]+。
Step 2: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) -3- methoxyl group -4HBenzopyran-4-one (II-3).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 14, obtains red solid.Yield: 54%;1H NMR (500 MHz, CDCl3): δ 8.26 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.5 Hz, 2H), 7.68-7.64 (m, 1H), 7.53-7.50 (m, 1H), 7.40-7.37 (m, 1H), 7.00 (d, J = 8.5 Hz, 2H), 4.12 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.74-2.67 (m, 2H), 2.64-2.58 (m, 4H), 2.11-2.06 (m, 2H), 1.86-1.80 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 175.01, 161.01, 155.72, 155.15, 140.80, 133.28, 130.24, 125.77, 124.58, 124.20, 123.07, 117.90, 114.50, 66.52, 59.92, 54.29, 53.07, 28.68, 23.46; ESI-MS: m/z =380 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) -3- methoxyl group -4HBenzopyran-4-one (II-4).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 14, and piperidines replaces pyrrolidines, obtains yellow solid. Yield: 57%;1H NMR (500 MHz, CDCl3): 8.26 (d, J = 8.0 Hz, 1H), 8.12 (d, J = 8.5 Hz, 2H), 7.68-7.64 (m, 1H), 7.53-7.50 (m, 1H), 7.40-7.37 (m, 1H), 7.00 (d, J = 8.5 Hz, 2H), 4.12 (t, J = 6.5 Hz, 2H), 3.89 (s, 3H), 2.56 (t, J = 7.0 Hz, 2H), 2.46-2.42 (m, 4H), 1.95-1.89 (m, 2H), 1.70-1.67 (m, 4H), 1.52-1.48 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 175.00, 161.03, 155.71, 155.16, 140.82, 133.27, 130.24, 125.80, 124.57, 124.22, 123.09, 117.90, 114.51, 66.65, 59.93, 55.89, 54.67, 26.68, 25.90, 24.38; ESI-MS: m/z =394 [M+H]+。
The synthesis of II-5, II-6 in embodiment 7:II class compound (flavonoid class).
Step 1: 1- (2,6- dihydroxy phenyl) -3- (4- (3- chloropropanol oxygen radical) phenyl) propyl- 2- alkene -1- ketone (intermediate 15).
Preparation method replaces o-hydroxyacetophenone with intermediate 12, with 2,6- resacetophenone, obtains yellow solid.It receives Rate: 85%; ESI-MS:m/z =333 [M+H]+。
Step 2: 2- (4- (3- chloropropanol oxygen radical) phenyl) -5- hydroxyl -4HBenzopyran-4-one (intermediate 16)
Intermediate 15(1.00 g, 3.2 mmol) is dissolved in 15 mL DMSO, I is added2(128 mg, 0.5 mmol) and 0.5 The mL concentrated sulfuric acid stirs 24 h under 85 °C.Reaction solution is poured into 200 mL H2In O, three times with EtOAc extraction, merge organic Layer is washed, is saturated NaCl and washes, anhydrous Na2SO4It is dry, then through column chromatography for separation (petroleum ether: EtOAc=4:1), obtain white 565 mg of solid.Yield: 45%;1H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 9.0 Hz, 2H), 7.55 (t, J = 8.5 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.23 (t, J = 6.0 Hz, 2H), 3.79 (t, J = 6.0 Hz, 2H), 2.32-2.27 (m, 2H); ESI-MS: m/z =331 [M+H]+。
Step 3: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) -5- hydroxyl -4HBenzopyran-4-one (II- 5).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 16, obtains yellow solid.Yield: 58%;1H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 9.0 Hz, 2H), 7.55 (t, J = 8.5 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.12 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H), 2.65-2.61 (m, 4H), 2.11-2.06 (m, 2H), 1.89-1.86 (m, 4H); ESI-MS: m/z =366 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) -5- hydroxyl -4HBenzopyran-4-one (II-6).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 16, and piperidines replaces pyrrolidines, obtains yellow solid. Yield: 64%;1H NMR (500 MHz, CDCl3): δ 7.87 (d, J = 9.0 Hz, 2H), 7.56 (t, J = 8.5 Hz, 1H), 7.04 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.65 (s, 1H), 4.13 (t, J = 6.0 Hz, 2H), 2.59-2.53 (m, 2H), 2.50- 2.44 (m, 4H), 2.10-2.04 (m, 2H), 1.70-1.62 (m, 4H), 1.48-1.45 (m, 2H); ESI- MS: m/z =380 [M+H]+。
The synthesis of II-7, II-8 in embodiment 8:II class compound (flavonoid class).
Step 1: 2- (4- (3- chloropropanol oxygen radical) phenyl) -5- methoxyl group -4HBenzopyran-4-one (intermediate 17).
Preparation method replaces intermediate 13 with intermediate 14, with intermediate 16, obtains beige solid.Yield: 75%;1H NMR (500 MHz, CDCl3): δ7.88 (d, J = 9.0 Hz, 2H), 7.55 (t, J = 8.5 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 4.21 (t, J = 6.0 Hz, 2H), 3.90 (s, 3H), 3.78 (t, J = 6.0 Hz, 2H), 2.32-2.27 (m, 2H); ESI-MS: m/z =345 [M+H]+。
Step 2: 2- (4- (3- (pyrrolidin-1-yl) propoxyl group) phenyl) -5- methoxyl group -4HBenzopyran-4-one (II-7).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 17, obtains yellow solid.Yield: 61%;1H NMR (500 MHz, CDCl3): δ7.87 (d, J = 9.0 Hz, 2H), 7.55 (t, J = 8.5 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 8.0 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 4.13 (t, J = 6.0 Hz, 2H), 3.91 (s, 3H), 2.76 (t, J = 6.0 Hz, 2H), 2.65-2.60 (m, 4H), 2.10-2.05 (m, 2H), 1.89-1.85 (m, 4H); ESI-MS: m/z = 380 [M+H]+。
Piperidin-1-yl) propoxyl group) phenyl) -5- methoxyl group -4HBenzopyran-4-one (II-8).
Preparation method replaces intermediate 4 with compound I-1, with intermediate 17, and piperidines replaces pyrrolidines, obtains yellow solid. Yield: 67%;1H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 9.0 Hz, 2H), 7.56 (t, J = 8.5 Hz, 1H), 7.05 (d, J = 9.0 Hz, 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H), 6.66 (s, 1H), 4.12 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 2.54-2.49 (m, 2H), 2.48-2.41 (m, 4H), 2.06-2.00 (m, 2H), 1.65-1.59 (m, 4H), 1.47-1.43 (m, 2H); ESI-MS: m/z =394 [M+H]+。
Embodiment 9: the histamine H of phenylchinoline ketone and flavone derivative3Receptor antagonist activity.
LANCE Ultra TR-FRET method and ThT fluorescence is respectively adopted using Clobenpropit as positive control in this part Measuring method has screened the histamine H of 18 synthesized target compounds3Receptor antagonist activity, other compounds of the invention with Cited compound is descended to have similar beneficial effect, but this should not be interpreted as to the compounds of this invention only to have below beneficial to effect Fruit.It the results are shown in Table 3
The histamine H 3 receptor antagonistic activity of table 3 phenylchinoline ketone and chromocor derivative
Compd hH3R (IC50, nM) Compd hH3R (IC50, nM)
I-1 2.41 II-1 8.41
I-2 2.94 II-2 10.46
I-3 0.97 II-3 0.18
I-4 1.23 II-4 0.34
I-5 0.69 II-5 7.15
I-6 0.40 II-6 6.05
I-7 12.82 II-7 3.87
I-8 15.43 II-8 4.30
I-9 0.30 Clobenpropit 1.15
I-10 0.19
By the receptor antagonist activity in table 3 it is found that selected phenylchinoline ketone compounds show stronger histamine H3By Body inhibitory activity, majority of compounds activity is suitable with Clobenpropit, and there are six molecular activity ratio Clobenpropit more It is good.
The 10 active measurement of anti-amyloid peptide aggregation of embodiment.
A ThT fluorometric investigation.
(1) solution and sample preparation: PBS buffer solution prepares (10mM, pH 7.4): weighing 57.996g Na2HPO4· 12H2O, 5.928g NaH2PO4·2H2O is dissolved in 1000mL water, is configured to the PBS stock solution that concentration is 0.2M；50mL is taken to store Liquid is diluted with water to 1000mL, 0.22 μm of filtering with microporous membrane.Gly-NaOH buffer (50mM, pH 8.5): claim It takes 3.7535g glycine to be dissolved in 800mL water, 0.1M NaOH solution tune pH to 8.5 is slowly added dropwise, water is added to be settled to 1000mL. A beta monomers preparation: by 1mg A β1-42It is dissolved in 1mL HFIP, sonic oscillation 10min, dispenses, and place 12h at room temperature, very Sky is dry, is stored in -20 °C of refrigerators.A beta monomers are redissolved with DMSO to 2mM, after of short duration vortex oscillation, are buffered with 10mM PBS Liquid is configured to 50 μM of stock solutions.Compound is prepared: compound is dissolved in the stock solution for being configured to that concentration is 10 mM in DMSO.With PBS is diluted to respective concentration.ThT solution prepares (5 μM): weighing 1.59g ThT and is dissolved in 100mL Gly-NaOH buffer, matches The stock solution that concentration is 50mM is made, is kept in dark place.It takes 10 μ L stock solutions to be diluted to 100mL with Gly-NaOH buffer, obtains 5 μM ThT solution.
(2) A β is added in EP pipe1-42And compound (positive control or PBS buffer solution) makes its final concentration be respectively 25 μM With 20 μM, be placed in 37 °C of lower constant temperature oscillations (150rpm), be incubated for for 24 hours.It takes 20 μ L Incubating Solutions that 96 orifice plates are added, adds 180 μ L 5 μM of ThT solution is protected from light and is incubated for 5min, and the fluorescence intensity of lower 485nm is excited using multi-function microplate reader test sample 450nm.
With A β1-42Fluorescent value after being individually incubated for is as control, and the fluorescence having in order to avoid compound itself is to result Interference, deduct fluorescent value that compound uses ThT to measure as background
The A beta-aggregation inhibitory activity of 4 phenylchinoline ketone of table and chromocor derivative
。
By above-mentioned experimental result it is found that the designed target molecule synthesized, the overwhelming majority all show good A β1-42Itself Aggregation activity, and positive control Clobenpropit is then without above-mentioned activity.
Further select compound I-6, II-1 transmission electron microscope observing they inhibit A β1-42Self assemble and promotion are Assemble A β1-42The activity of sample depolymerization.
It is tested with transmission electron microscope (TEM).
(1) solution and sample preparation: HEPES buffer solution is prepared: (6.6,150 μM of NaCl of 20 μM of HEPES, pH) It weighs 47.77mg HEPES and 87.66mg NaCl to be dissolved in 100mL water, is configured to mother liquor.5mL mother liquor is taken to be diluted to 400mL, The NaOH solution tune pH to 6.6 of 1mM is slowly added dropwise, is settled to 500mL.
Self assemble sample: A β is added in EP pipe1-42And compound (positive control Curcumin or PBS buffer solution) makes Its final concentration is respectively 25 μM and 20 μM, is placed in 37 °C of lower constant temperature oscillations (150rpm), is incubated for for 24 hours.
Depolymerized sample after self assemble: A β is added in EP pipe1-42(final concentration of 50 μM), are placed in 37 °C of lower constant-temperature incubations After for 24 hours, compound (positive control Curcumin or PBS buffer solution), which is added, makes itself and A β1-42Final concentration be respectively 20 μM and 25 μM, then common incubation is for 24 hours.
(2) it takes 10 μ L Incubating Solutions to be placed in carbon to support on film copper mesh, is blotted with filter paper from side after standing 2min, stand 30s The uranium acetate solution that 5 μ L 1% are added dropwise carries out negative staining to sample, is blotted with filter paper from side after standing 2min, dries postposition It is observed under transmission electron microscope, and shoots photo.Acceleration voltage is 80kV, 50,000 times of amplification factor
Influence of Fig. 3 compound to A β self assemble
([A β1-42 ]=25μM; [compd.]=20μM ; a. Aβ1-42 alone, 0h; b. a. Aβ1-42 alone, 24h; c. Aβ1-42 +I-6, 24h; d. Aβ1-42 + II-1,24h. PBS pH 7.4).
Compound I-6 and II-1 have carried out A β1-42Assemble Inhibition test, as shown above, compared with 0 hour, A beta monomers Apparent self assemble (Fig. 3 b) can occur after 24 hours, and two compounds can obviously inhibit A β self assemble (figure 3c, 3d).
Further depolymerization experiment is as shown below, and compound I-6 is added, and the sample depolymerization effect of II-1 is obvious, can will The fiber filament assembled is degraded into corynebacterium or granular (Fig. 4 b, 4c), and activity is better than curcumin (Fig. 4 d)
Influence of Fig. 4 compound to A β depolymerization
([A β1-42 ]=25μM, [compd.]=20μM; a. Aβ1-42 alone, 24h; b. Aβ1-42 fibrils+I-6, 24h; c. Aβ1-42 fibrils+II-1, 24h; d. Aβ1-42 fibrils+ Curcumin, 24h. PBS pH 7.4, 50,000x).
Effect of the embodiment 11 to ischemic brain damage.
With 10% chloraldurate (3.5ml/kg, intraperitoneal injection) anesthetized rat, fixation of lying on the back makees skin incision along left neck side, External carotid artery and side arteria carotis communis are ligatured, distal end internal carotid is closed with artery clamp folder, in external carotid artery and internal carotid bifurcated Locate notch, be inserted into bolt line (diameter 0.25mm, length 18mm), ligature notch, skin suture unclamps distal end internal carotid artery Folder.The stayed the end of a thread in position is gently mentioned after 2 hours to slightly resistance, realizes arteria cerebri media Reperfu- sion, modeling is completed.Sham-operation group is big Artery plug wire money in not making after mouse anesthesia, remaining operation are consistent.Kept for 37 ± 0.5 DEG C of body temperature with constant temperature blanket in experimentation, art Benzylpenicillin sodium salt withdrawal of currency from circulation raising is added dropwise in wound afterwards.The rat to survive 24 hours is randomly divided into sham-operation group, model group and each test Group, test group give compound of the present invention, with numbered packets corresponding to compound.
Each group intraperitoneal injection, model group and rats in sham-operated group give isometric physiological saline, the 1st administration 16 After hour, each group intraperitoneal injection 1 time again.
Neurotrosis symptom score method, 0 point: behavior is normal, and double forelimbs symmetrically stretch to ground when mentioning tail；1 point: mentioning tail When damage opposite side forelimb wrist flexion；2 points: damage opposite side forelimb elbow bending when mentioning tail；3 points: shoulder inward turning when mentioning tail；When walking, It is tilted to damage opposite side；4 points: without autonomic activities.
Respectively in the 1st administration, after administration 4 hours and after administration 20 hours, neurotrosis symptom is carried out to rat and is commented Point, after the 1st administration after 24 hours, disconnected neck quickly removes full brain after putting to death, and is placed on ice, and every group is taken out 3 separation seas at random Horse is for detecting histamine content, -20 DEG C of remainder freezings, is cut into 5 for brain is even with coronal-plane with blade, brain piece is set 1% Room temperature is protected from light dyeing 30 minutes in TTC, fixes 30 minutes with 4% paraformaldehyde.It will be sliced photographic analysis, calculate cerebral infarction volume Than (Infarction volume/full brain volume * 100%)
5 each group neurotrosis symptom of table, hippocampus histamine content, cerebral infarction volume compare measurement result
。
Respectively compared with model group, P < 0.05 each test group *；#P<0.01；ΔP<0.05；⊕P<0.01.
It scores rat behavior histological grading method, neurotrosis symptom after the 1st administration 4 hours, compound of the present invention There is significant difference with model group, after the 1st administration 20 hours, compound of the present invention and model group have significant difference, Illustrate that compound of the present invention is significantly improved effect to ischemic brain damage rat nerve function；Hippocampus histamine contains Amount, compound of the present invention is variant with model group, illustrates that compound of the present invention can effectively improve ischemic brain damage The content of histamine in rat brain；Infarction volume ratio, compound of the present invention and model group have significant difference, illustrate this hair The cerebral infarction volume of ischemic brain damage rat can be effectively reduced in the bright compound.
Embodiment 12 causes the effect of acute epilepsy mouse to pentylenetetrazole
Each group mouse gives investigational agent and positive drug dilantin sodium of the invention respectively, is filled by 0.1ml/10g stomach-filling volume Stomach administration, model group give the physiological saline of same volume, and positive controls give dilantin sodium dosage 50mg/kg, and reagent group is each Dosage is 50mg/kg, and reagent group gives compound of the present invention, with numbered packets corresponding to compound.
After each group gastric infusion 1h, pentylenetetrazole 70mg/kg, start recording myoclonia latent time is injected intraperitoneally (LTMJ), if not breaking out in 30 min, above-mentioned latent time is denoted as 30min.
Epileptic attack standard referring to Racine standard, occur the twitches of facial muscles or the corners of the mouth, the twitch of side limbs, Timing terminates tetanic or whole body limbs twitch epilepsy is broken out greatly comprehensively when
6 mouse epileptic attack latency result (n=6) of table
Rank Number of animals Incubation period (min)
Model group 8 3.56±0.88
Control group 8 10.11±6.69
I-3 group 8 13.64±5.76
I-6 group 8 14.49±7.17
I-9 group 8 15.11±8.19
II-4 group 8 17.86±9.53
II-7 group 8 14.39±8.69
The result shows that compared with model group, compound energy obvious postpone chmice acute epileptic attack of the present invention is hidden Phase extends 3 to 5 times；Compared with control group dilantin sodium, the incubation period of compound of the present invention is longer, illustrates institute of the present invention Compound is stated with significant antiepileptic action.

Claims (6)

1. salt, the solvate of benzoquinoline ketone provided by the invention, flavone derivative and its pharmaceutical acceptable, have Following general formula structure (A):
General formula structure (A)
In formula:
X is selected from N or O；
R1Selected from H, C1-3Alkyl or C1-3Alkoxy；
R2Selected from H, hydroxyl or C1-3Alkyl；
R3Selected from H, hydroxyl, C1-3Alkyl or C1-3Alkoxy；
NR ' R ' ' is selected from cyclic amine and the open chain alkoxy that the total number of carbon atoms is 3-6, including but not limited to following segment:
2. benzoquinoline ketone thiazine according to claim 1, flavone derivative, it is characterised in that:
DescribedSelected from following two heterocycle:
R1Selected from for hydrogen, methyl and ethyl；R2Selected from hydrogen, hydroxyl and methoxyl group；R3Selected from hydrogen, hydroxyl and methoxyl group.
3. benzoquinoline ketone thiazine according to claim 1, flavone derivative, it is characterised in that the compound choosing From:
And described in any item compounds, the solvate of acceptable salt and the compound, prodrug (ester or phosphate), Stereoisomer, deuterated object etc..
4. a kind of pharmaceutical composition, which is characterized in that described pharmaceutical composition includes at least one active component and at least one Kind of pharmaceutically acceptable carrier or excipient, the active component be selected from the described in any item compounds of claim 1-3, The compound pharmaceutically any one in the solvate of acceptable salt and the compound or any a variety of.
5. the described in any item compounds of claim 1-3, the solvate of acceptable salt and the compound, prodrug (ester Or phosphate), stereoisomer, deuterated object and be used in combination with other drugs, in treatment nervus retrogression related disease and The effect of ischemic brain damage.
6. wherein the neurodegenerative disease is selected from Alzheimer's disease, parkinsonism, hypnosia, epilepsy gradually freezes disease etc..
CN201710488414.7A 2017-06-23 2017-06-23 Preparation and application of phenylquinolinone and flavonoid derivatives Active CN109111400B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201710488414.7A CN109111400B (en) 2017-06-23 2017-06-23 Preparation and application of phenylquinolinone and flavonoid derivatives
PCT/CN2018/089970 WO2018233483A1 (en) 2017-06-23 2018-06-05 Preparation and use of phenylquinolinone and flavonoid derivatives

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710488414.7A CN109111400B (en) 2017-06-23 2017-06-23 Preparation and application of phenylquinolinone and flavonoid derivatives

Publications (2)

Publication Number Publication Date
CN109111400A true CN109111400A (en) 2019-01-01
CN109111400B CN109111400B (en) 2020-10-16

Family

ID=64733317

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710488414.7A Active CN109111400B (en) 2017-06-23 2017-06-23 Preparation and application of phenylquinolinone and flavonoid derivatives

Country Status (2)

Country Link
CN (1) CN109111400B (en)
WO (1) WO2018233483A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111533721A (en) * 2020-05-15 2020-08-14 浙江大学 Benzopyrone or quinolinone compounds and application thereof
CN114599362A (en) * 2019-10-15 2022-06-07 杭州百诚医药科技股份有限公司 Use of phenylquinolinone and flavonoid derivatives for treating neuropathic pain

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4251148A1 (en) 2020-11-27 2023-10-04 Richter Gedeon Nyrt. Histamine h3 receptor antagonists/inverse agonists for the treatment of autism spectrum disorder

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1326450A (en) * 1998-09-24 2001-12-12 三菱化学株式会社 Hydroxyflavone derivatives as tau protein kinase inhibitors
CN1960977A (en) * 2004-05-31 2007-05-09 万有制药株式会社 Quinazoline derivative
WO2009026657A1 (en) * 2007-08-29 2009-03-05 The University Of Sydney Flavonoid ppar agonists
WO2009097306A1 (en) * 2008-01-30 2009-08-06 Cephalon, Inc. Substituted pyridazine derivatives which have histamine h3 antagonist activity
CN101522638A (en) * 2006-07-25 2009-09-02 赛福伦公司 Pyridizinone derivatives
CN103087024A (en) * 2013-01-15 2013-05-08 四川大学 Flavone alkylamine compounds as well as preparation method and application thereof
CN103588702A (en) * 2013-10-26 2014-02-19 浙江大学 N-substituted phenyl-4-one derivatives, and preparation method and application thereof
CN103929959A (en) * 2011-08-12 2014-07-16 萨克生物研究学院 Neuroprotective polyphenol analogs

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1326450A (en) * 1998-09-24 2001-12-12 三菱化学株式会社 Hydroxyflavone derivatives as tau protein kinase inhibitors
CN1960977A (en) * 2004-05-31 2007-05-09 万有制药株式会社 Quinazoline derivative
CN101522638A (en) * 2006-07-25 2009-09-02 赛福伦公司 Pyridizinone derivatives
WO2009026657A1 (en) * 2007-08-29 2009-03-05 The University Of Sydney Flavonoid ppar agonists
WO2009097306A1 (en) * 2008-01-30 2009-08-06 Cephalon, Inc. Substituted pyridazine derivatives which have histamine h3 antagonist activity
CN103929959A (en) * 2011-08-12 2014-07-16 萨克生物研究学院 Neuroprotective polyphenol analogs
CN103087024A (en) * 2013-01-15 2013-05-08 四川大学 Flavone alkylamine compounds as well as preparation method and application thereof
CN103588702A (en) * 2013-10-26 2014-02-19 浙江大学 N-substituted phenyl-4-one derivatives, and preparation method and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114599362A (en) * 2019-10-15 2022-06-07 杭州百诚医药科技股份有限公司 Use of phenylquinolinone and flavonoid derivatives for treating neuropathic pain
CN111533721A (en) * 2020-05-15 2020-08-14 浙江大学 Benzopyrone or quinolinone compounds and application thereof

Also Published As

Publication number Publication date
WO2018233483A1 (en) 2018-12-27
CN109111400B (en) 2020-10-16

Similar Documents

Publication Publication Date Title
CN112654616B (en) 3-aryloxy-3-aryl-propylamines and application thereof
BR122017023795B1 (en) METHOD FOR PREPARING PHARMACEUTICAL COMPOSITION
CN112566909B (en) 3-aryloxy-3-five-membered heteroaryl-propylamine compound and application thereof
CN109111400A (en) The preparation and application of phenylchinoline ketone and flavone derivative
HUE027746T2 (en) Piperazine-substituted benzothiophene derivatives as antipsychotic agents
KR20040032113A (en) 5-halo-tryptamine derivatives used as ligands of the 5-ht6 and/or 5-ht7 serotonin receptors
JP6384923B2 (en) N- (3- (4- (3- (diisobutylamino) propyl) piperazin-1-yl) propyl) -1H-benzo [d] imidazol-2-amine sulfate, its preparation and its use
CN107922340B (en) 1,2,3, 4-tetrahydroisoquinoline derivatives, preparation method and application thereof
WO2013139929A1 (en) Novel means and methods for treating diseases of the central nervous system, metabolic and cardiac diseases and aging
EA031569B1 (en) Salt and crystal forms of plk-4 inhibitor
KR20220004174A (en) Solid form of GlyT1 inhibitor
JPWO2005079845A1 (en) Migraine prophylaxis
CN104812754A (en) Tetrahydroprotoberbine compounds and uses thereof in the treatment of neurological, psychiatric and neurodegenerative diseases
CN109265362A (en) A kind of 2,5- dihydroxy paraphenylene terephthalamide&#39;s amine compound, preparation method and use
US8492564B2 (en) Salvinorin derivatives and uses thereof
KR20170129906A (en) Organic compound
ES2648987T3 (en) (1R-trans) -N - [[2- (2,3-dihydro-4-benzofuranyl) cyclopropyl] methyl] propanamide metabolites
JP2018503602A (en) α-Asallylaldehyde ester, preparation method thereof and use
CN102267971A (en) Alicyclic-o[c] benzopyrone derivative and application thereof
CN111943943A (en) 3-aryloxy-3-pentabasic heteroaryl-propylamine compound and crystal form and application thereof
DE69211857T2 (en) 3- (N-ISOPROPYL-N-u-PROPYLAMINO) -5- (N-ISOPROPYL) CARBAMOYLCHROMAN
BR112015009243A2 (en) fluorosubstituted cyclic amine compound, method for preparing a fluorosubstituted cyclic amine compound, pharmaceutical composition, acetylcholinesterase inhibitor and use of the fluorosubstituted cyclic amine compound
CN108727352A (en) A kind of piperidines alkane carbamyl phthalide analog compound, preparation method and use
JP2021512958A (en) Medicines for the treatment of neurodegenerative diseases and their use
CA2350560C (en) Novel type condensed pyridazinone compounds

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
TA01 Transfer of patent application right

Effective date of registration: 20191126

Address after: Binjiang District River Street Hangzhou City, Zhejiang province Jiang Er Lu 310051 No. 400 Building No. 1 building 1201 room 12

Applicant after: HANGZHOU BAICHENG PHARMACEUTICAL TECHNOLOGY CO., LTD.

Applicant after: Zhejiang University

Address before: Binjiang District River Street Hangzhou City, Zhejiang province Jiang Er Lu 310051 No. 400 Building No. 1 building 1201 room 12

Applicant before: HANGZHOU BAICHENG PHARMACEUTICAL TECHNOLOGY CO., LTD.

TA01 Transfer of patent application right
CB02 Change of applicant information

Address after: 311103 building B203, No.9, Zhenxing East Road, Yuhang Economic and Technological Development Zone, Yuhang District, Hangzhou City, Zhejiang Province

Applicant after: HANGZHOU BAICHENG PHARMACEUTICAL TECHNOLOGY CO., LTD.

Applicant after: Zhejiang University

Address before: Binjiang District River Street Hangzhou City, Zhejiang province Jiang Er Lu 310051 No. 400 Building No. 1 building 1201 room 12

Applicant before: HANGZHOU BAICHENG PHARMACEUTICAL TECHNOLOGY CO., LTD.

Applicant before: Zhejiang University

CB02 Change of applicant information
GR01 Patent grant
GR01 Patent grant
TR01 Transfer of patent right

Effective date of registration: 20210112

Address after: 311100 Room 802, 8th floor, building 1, No. 502, Linping Avenue, Yuhang Economic and Technological Development Zone, Yuhang District, Hangzhou City, Zhejiang Province

Patentee after: HANGZHOU BIO-SINCERITY PHARMA-TECH Corp.,Ltd.

Address before: 311103 B203, building 1, 9 Zhenxing East Road, Yuhang Economic and Technological Development Zone, Yuhang District, Hangzhou City, Zhejiang Province

Patentee before: HANGZHOU BIO-SINCERITY PHARMA-TECH Corp.,Ltd.

Patentee before: ZHEJIANG University

TR01 Transfer of patent right