CN108084216A - A kind of microglia IL-1 β antiperspirants, preparation method and its usage - Google Patents
A kind of microglia IL-1 β antiperspirants, preparation method and its usage Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to neuroinflammatory conditions fields.Specifically, the present invention relates to the 1 β antiperspirants of microglia IL of one kind phenylboric acid containing symmetric double structure, its preparation method and the applications in treatment neuroinflammatory conditions drug is prepared.Wherein, R is selected from C1‑C10Alkyl, C3‑C8Cycloalkyl.
Description
Technical field
The present invention relates to the drug fields of neuroinflammatory conditions.It is controlled in particular it relates to have to above-mentioned disease
Microglia IL-1 β antiperspirants, its preparation method of a kind of structure of phenylboric acid containing symmetric double for the treatment of effect, Yi Ji
Purposes in pharmacy.
Background technology
Neuroinflammatory disorder is mainly caused by the abnormal height of neuroglia (especially microglia) or chronic activation
Process.The neuroglia of this overacfivity state generates the molecule of higher levels of inflammation and response to oxidative stress, so as to lead
Cause neure damage or death.Neure damage or death can also inducing neural microglia activation, neuroinflamation is promoted locally to have
The harmful cycle propagates.The prior art has confirmed can have by the activation for inhibiting Deiter's cells especially microglia
Effect inhibits Neuroinflammation.Neuroinflammatory disorder includes senile dementia (Alzheimer's disease), Parkinson's disease, muscle
It is atrophic lateral schlerosis, autoimmune disease, prions disease, apoplexy, traumatic brain injury, spinal muscular atrophy, multiple
Property hardening, epilepsy, neuropathic pain etc..
Senile dementia is also referred to as Alzheimer's disease (Alzheimer ' s disease, AD), and incidence is a variety of
It ranks first in neurodegenerative disease, is that a kind of central nervous system based on progressive cognitive disorder and memory capability damage becomes
Property disease.The clinical manifestation of the disease is recent memory dysfunction, is then continuation hypophrenia, judging and deducing ability is lost
Mistake, aphasia, dyskinesia etc..Its pathological characters is substantial amounts of senile plaque expelling (senile plaques, SPs) and neurofibrillary tangles
(neurofibrilary tangles,NFTs)。
Having now been found that mainly includes for the mechanism of action of anti senile dementia drug：Pass through the work of acetylcholine esterase inhibition
Property, it reduces the degradation of acetylcholine, the acetylcholinesteraseinhibitors inhibitors that improve intracerebral cholinergic tone and establish and passes through suppression
Each action site inside nmda receptor surface processed or ion channel reduces the hormesis of nmda receptor, inhibits its activity
And the nmda receptor antagonist set up.Occurs a kind of popular and generally acknowledged mechanism of action " amyloid beta in recent years
Theory ", the mechanism think that amyloid precusor protein (APP) forms insoluble amyloid beta accumulation structure after being hydrolyzed fracture
Into senile plaque expelling, thus trigger a series of pathological change, including neuroinflamation, neural cell loss and death etc., finally
Cause senile dementia.According to the flow of the mechanism, by block cycle in each step to change the process of disease, it is possible to
Achieve the purpose that mitigation or treatment.Various new drugs such as β-hydrolase inhibitor, the γ developed at present according to such mechanism of action-
Hydrolase inhibitor, vaccine, tau protein phosphorylation inhibitor, neuroinflamation inhibitor etc., the overwhelming majority are based on beta-amyloyd egg
White theory.
The invention discloses the microglia IL-1 β antiperspirants of one kind phenylboric acid containing symmetric double structure, these
Compound can be used for the drug for preparing neuroinflammatory conditions.
The content of the invention
It is an object of the present invention to provide a kind of microglia IL-1 β antiperspirants with general formula I.
It is a further object to provide prepare the method with compounds of formula I.
It is also another object of the present invention to provide contain compounds of formula I as active ingredient and its in treatment nerve
Application in terms of inflammation disease.
Present invention is specifically described in conjunction with the purpose of the present invention.
Compound of the present invention with logical formula (I) is with following structural formula：
Wherein, R is selected from C1-C10Alkyl, C3-C8Cycloalkyl.
It is preferred that below general formula (I) compound,
Wherein, R is selected from C1-C5Alkyl, C3-C6Cycloalkyl.
The more preferred compound with logical formula (I) is as follows,
Logical formula (I) compound of the present invention can be synthesized by following route：
Cyclopentadiene II first with alkali process, then reacts again with 2eq compounds III, obtains compound IV；Compound IV is first
With n-BuLi processing, corresponding aryl lithium is obtained, the latter reacts with trimethylborate, then obtains compound with acid treatment again
V；Compound V and 2eq bromine reactions, obtain VI；Compound VI alkali process, obtains compound I；R is defined as described above.
Compound of Formula I of the present invention has microglia IL-1 β secretion inhibitions, active ingredient can be used as to use
In the medicine for preparing neuroinflammatory conditions.The activity of compound of Formula I of the present invention is by inhibiting small colloid in vitro
Cell secretion IL-1 β are verified.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.Such as the dosage taken daily is about
In the range of 1mg-700mg/ people, it is divided into and once or is for several times administered.The dosage for actually taking compound of Formula I of the present invention can be by curing
It takes root according to related situation to determine.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.The various change that those skilled in the art's training centre according to the present invention is made should all
Within the protection domain required by the application claim.
The synthesis of 1 compound I-1 of embodiment
The synthesis of step A. compounds IV-1
Compound II (0.66g, 10mmol) is dissolved in the DMSO of 20mL dryings, stirring, addition solid KOH (1.40g,
25mmol), continue stirring 1 it is small when.Compound III-1 (5.50g, 22mmol) is added in, then stirring was continued at room temperature overnight,
TLC checks that reaction is completed.Reaction mixture is carefully poured into 300mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges
Extraction phase is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated, is changed on a rotary evaporator
Close object IV-1.ESI-MS, m/z=405 ([M+H]+)。
The synthesis of step B. compounds V-1
Compound IV-1 (2.83g, 7mmol) is dissolved in the THF of 30mL dryings, is stirred under nitrogen protection, is cooled to -78
℃.The hexane solution (4.4mL, 7mmol) of the n-BuLi of 1.6M is slowly added dropwise with syringe, after being added dropwise, reaction is mixed
Close object stir at such a temperature 1 it is small when, then slowly be added dropwise trimethylborate (0.83g, 8mmol) and 3mL drying THF preparation
Solution, be added dropwise rear reaction mixture continue at such a temperature stirring 1 it is small when, be then stirred at room temperature overnight.Reaction
Mixture is carefully poured into 200mL ice water, is adjusted pH=2-3 with concentrated hydrochloric acid, when stirring 1 is small, is then adjusted pH=3-4 again,
With 50mL × 3CH2Cl2Extraction merges extraction phase, is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate exists
It is evaporated on Rotary Evaporators, residue is purified using silica gel column chromatography, obtains compound V-1.ESI-MS, m/z=333 ([M-
H]-)。
The synthesis of step C. compounds I-1
Compound V-1 (1.34g, 4mmol) is dissolved in 20mL CH2Cl2In, stirring adds in liquid bromine (1.60g, 10mmol),
Continue to stir at room temperature, then when reflux 1 is small.TLC display reactions are completed.Reaction mixture is evaporated on a rotary evaporator,
Obtained residue is dissolved in the DMSO of 20mL dryings, adds in KOH (1.12g, 20mmol), when stirring 1 is small at room temperature, is then existed
It is stirred overnight at 80 DEG C.TLC display reactions are completed.Reaction mixture is carefully poured into 200mL ice water, and pH is adjusted with concentrated hydrochloric acid
=2-3, with 50mL × 3CH2Cl2Extraction merges extraction phase, is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier,
Filtrate is evaporated on a rotary evaporator, and residue is purified using silica gel column chromatography, obtains compound I-1, white solid.ESI-
MS, m/z=490 ([M-H]-)。
The synthesis of 2 compound I-2 of embodiment
The synthesis of step A. compounds IV-1
Compound II (0.66g, 10mmol) is dissolved in the DMSO of 20mL dryings, stirring, addition solid KOH (1.40g,
25mmol), continue stirring 1 it is small when.Compound III-2 (5.81g, 22mmol) is added in, then stirring was continued at room temperature overnight,
TLC checks that reaction is completed.Reaction mixture is carefully poured into 300mL ice water, stirring, with 50mL × 3CH2Cl2Extraction merges
Extraction phase is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated, is changed on a rotary evaporator
Close object IV-2.ESI-MS, m/z=433 ([M+H]+)。
The synthesis of step B. compounds V-2
Compound IV-2 (3.02g, 7mmol) is dissolved in the THF of 30mL dryings, is stirred under nitrogen protection, is cooled to -78
℃.The hexane solution (4.4mL, 7mmol) of the n-BuLi of 1.6M is slowly added dropwise with syringe, after being added dropwise, reaction is mixed
Close object stir at such a temperature 1 it is small when, then slowly be added dropwise trimethylborate (0.83g, 8mmol) and 3mL drying THF preparation
Solution, be added dropwise rear reaction mixture continue at such a temperature stirring 1 it is small when, be then stirred at room temperature overnight.Reaction
Mixture is carefully poured into 200mL ice water, is adjusted pH=2-3 with concentrated hydrochloric acid, when stirring 1 is small, is then adjusted pH=3-4 again,
With 50mL × 3CH2Cl2Extraction merges extraction phase, is washed with brine, anhydrous sodium sulfate drying.It filters and removes drier, filtrate exists
It is evaporated on Rotary Evaporators, residue is purified using silica gel column chromatography, obtains compound V-2.ESI-MS, m/z=361 ([M-
H]-)。
The synthesis of step C. compounds I-2
Compound V-2 (1.45g, 4mmol) is dissolved in 20mL CH2Cl2In, stirring adds in liquid bromine (1.60g, 10mmol),
Continue to stir at room temperature, then when reflux 1 is small.TLC display reactions are completed.
Reaction mixture is evaporated on a rotary evaporator, and obtained residue is dissolved in the DMSO of 20mL dryings, adds in KOH
(1.12g, 20mmol) when stirring 1 is small at room temperature, is then stirred overnight at 80 DEG C.TLC display reactions are completed.Reaction mixing
Object is carefully poured into 200mL ice water, pH=2-3 is adjusted with concentrated hydrochloric acid, with 50mL × 3CH2Cl2Extraction merges extraction phase, uses
Salt water washing, anhydrous sodium sulfate drying.It filters and removes drier, filtrate is evaporated on a rotary evaporator, and residue uses silica gel
Column chromatography purifies, and obtains compound I-2, white solid powder.ESI-MS, m/z=519 ([M-H]-)。
Embodiment 3-5
With reference to the method for embodiment 1,2, compound listed in Table has been synthesized.
6 Compound ira vitro of embodiment inhibits microglia secretion IL-1 β effects
The active testing of the application compound is measured using method as known in the art, is inhibited according to candidate compound
Microglia secretes the efficiency of IL-1 β to assess its potential application value.
Mouse source microglia system BV2It is cultivated respectively in the DMEM culture mediums containing 10%FBS with glioma cell line C6
In, the cell in culture the 6th generation to the 15th generation is used for candidate compound screening active ingredients.Cell is cultivated to be inoculated with by 50000 cells/wells
In 24 porocyte culture plates, be changed to after cultivating 1 day low blood serum medium (addition 2%FBS) continue culture 16 it is small when.It is training
It supports and 300ng/ml is added in base (for inducing BV2Cell) or 1mg/ml (for inducing C6 cells) LPS (Salmonella
Typhimutium) Fiber differentiation cell secretion IL-1 β.And simultaneously by final concentration 100nM, 3 μM and 100 μM addition samples to be tested
(DMSO≤0.1%)；0.1%DMSO is added in as solvent control group to blank.
After when LPS inductions/drug-treated 24 is small, collects culture solution and quantitatively detect wherein IL-1 β levels.Culture solution sample in
4 DEG C centrifuge (8000G) 10 minutes, remove the suspended particulate impurity in culture solution.Supernatant is diluted 1 times, 150 μ L samples is taken to use
It is detected in ELISA (Bioso μ rce).It cultivates cell processing and ELISA detections is carried out using double-blind study.Candidate compound inhibits effect
Rate is calculated according to formula [1], and calculates the IC of each candidate compound50。
Formula [1]：Inhibiting rate (%)=([IL-1 β]LPS is induced-[IL-1β]Drug-treated)/[IL-1β]LPS is induced× 100%.
The IC of each compound50Test result see the table below.
Can be seen that the compound of the present invention from upper table result has very strong inhibition to microglia secretion IL-1 β
Effect, can be as the drug for preparing treatment neuroinflammatory conditions.
Claims (5)
1. the compound with logical formula (I) structure,
Wherein, R is selected from C1-C10Alkyl, C3-C8Cycloalkyl.
2. there is the compound of logical formula (I) defined in claim 1,
Wherein, R is selected from C1-C5Alkyl, C3-C6Cycloalkyl.
3. lead to formula (I) compound defined in claim 2, selected from following compounds,
4. synthesize the method for the claim 1-3 compounds as defined in any one for belonging to logical formula (I)：
Cyclopentadiene II first with alkali process, then reacts again with 2eq compounds III, obtains compound IV；Compound IV first uses n-
BuLi processing obtains corresponding aryl lithium, and the latter reacts with trimethylborate, then obtains compound V with acid treatment again；Change
Object V and 2eq bromine reactions are closed, obtains VI；Compound VI alkali process, obtains compound I；The definition of R such as claim 1-3 is any
Described in.
5. lead to formula (I) compound answering in terms for the treatment of neuroinflammatory conditions drug is prepared defined in one of claim 1-3
With.
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| CN201711415642.8A CN108084216A (en) | 2017-12-25 | 2017-12-25 | A kind of microglia IL-1 β antiperspirants, preparation method and its usage |
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| CN201711415642.8A CN108084216A (en) | 2017-12-25 | 2017-12-25 | A kind of microglia IL-1 β antiperspirants, preparation method and its usage |
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| CN101851211A (en) * | 2009-03-31 | 2010-10-06 | 中国科学院广州生物医药与健康研究院 | Novel piperazinoamide compound |
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| CN101851211A (en) * | 2009-03-31 | 2010-10-06 | 中国科学院广州生物医药与健康研究院 | Novel piperazinoamide compound |
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