CN108727352A - A kind of piperidines alkane carbamyl phthalide analog compound, preparation method and use - Google Patents

A kind of piperidines alkane carbamyl phthalide analog compound, preparation method and use Download PDF

Info

Publication number
CN108727352A
CN108727352A CN201810285408.6A CN201810285408A CN108727352A CN 108727352 A CN108727352 A CN 108727352A CN 201810285408 A CN201810285408 A CN 201810285408A CN 108727352 A CN108727352 A CN 108727352A
Authority
CN
China
Prior art keywords
acid
piperidines
compound
pharmaceutically acceptable
carbamyl
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
CN201810285408.6A
Other languages
Chinese (zh)
Other versions
CN108727352B (en
Inventor
邓勇
宋青
徐锐
张小玉
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.)
Sichuan University
Original Assignee
Sichuan University
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 Sichuan University filed Critical Sichuan University
Publication of CN108727352A publication Critical patent/CN108727352A/en
Application granted granted Critical
Publication of CN108727352B publication Critical patent/CN108727352B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention discloses a kind of novel piperidines alkane carbamyl phthalide analog compounds（I）And its pharmaceutically acceptable salt, preparation method, pharmaceutical composition and the purposes in preparing treatment and/or preventing nervus retrogression relevant disease drug, including but not limited to neurodegenerative diseases such as vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma；

Description

A kind of piperidines alkane carbamyl phthalide analog compound, preparation method and use
Technical field
The invention belongs to medicinal chemistry arts, are related to a kind of novel piperidines alkane carbamyl phthalide analog compound（I）, its system Preparation Method, pharmaceutical composition and the purposes in preparing treatment and/or preventing nervus retrogression relevant disease drug, including but not Be limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, into The neurodegenerative diseases such as row lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Background technology
Alzheimer's disease（Alzheimer ' s disease, AD, senile dementia）Be one kind with progressive cognitive disorder With the central nervous system degenerative disease based on memory damage, incidence becomes in ascendant trend year by year and is only second to the heart The frequently-occurring disease of angiosis and cancer, it is the 4th of the cause of death to be had gone up in developed countries such as America and Europes.According to world health Organisation Report, global over-65s old man have 10% dysnoesia, wherein half to occur dull-witted, fall ill within 85 years old or more Rate nearly 50%.The AD patient numbers about 600-700 ten thousand in China, incidence are more than 5%.With adding for population in the world aging process Soon, incidence is in apparent ascendant trend, is announced in December, 2013 according to Alzheimer's Disease International 's《The global implication of Alzheimer's disease：2013-2050》It is pointed out in report, AD will face most as the coming few decades whole world Big Health challenges, to the year two thousand thirty, patient numbers will rise to 76,000,000 by 44,000,000 in 2013, to the year two thousand fifty, this numerical value It is up to surprising 1.35 hundred million.Due to AD clinical manifestations be memory capability, capacity of orientation, thinking and judgement decline, and Activity of daily living reduces, or even abnormal Behavioral and psychological symptom occur etc., keep patient care difficulty larger, to society and family's band Carry out heavy burden.The drug that approved is used to treat light/moderate AD at present has acetylcholinesterase（AChE）Inhibitor, Yi Jiyong In severe AD treatmentsNMethyl-DAspartic acid（NMDA）Receptor antagonist.But Clinical practice shows that these drugs can pass through It improves patient's body levels of acetylcholine or inhibits the exitotoxicity of excitatory amino acid to alleviate AD symptoms, but cannot be effective Prevent or reverse the course of disease, but also can cause hallucinations, misunderstanding, dizziness, headache, nausea, hepatotoxicity, loss of appetite and The serious toxic side effect such as stool frequency, thus long-term efficacy is not satisfactory.Therefore, clinically there is an urgent need to research and develop with novel work With the AD medicines of mechanism.
AD belongs to disease caused by many factors, and pathogenesis is complicated, and pathogenesis does not illustrate also completely so far, but studies Show patient's intracerebral levels of acetylcholine decline,βThe excessive of amyloid protein generates and the blood platelet in deposition, the cerebrovascular Aggregation, metal ion metabolic disorder, Ca2+Dysequilibrium,tauNeurofibrillary tangles caused by protein hyperphosphorylation, glutamic acid Receptor active is excessively high, oxidative stress generates a large amount of active oxygens（ROS）Exist with many factors such as free radical and Neuroinflammations It plays an important role in the pathogenic process of AD.For above-mentioned pathogenic factors, researcher is set using traditional " one target of a medicine " drug Stratagem is omited, it was found that largely has high activity and highly selective drug to a certain target spot, such as：Anticholinesterase andNFirst Base-DAspartate receptor agonist etc..But that there are action target spots is single for these drugs, Clinical practice toxic side effect is more, right Not the problems such as long-term efficacy of AD patient is not good enough.
In recent years, with constantly illustrating to AD pathogenesis, it is found that the occurrence and development of AD have multimachine system, multifactor It is the characteristics of effect, again interrelated between different mechanisms to influence each other, constitute complicated network during AD occurrence and development Regulator control system.Obviously, the medicine that research and development can act on multiple links in AD pathologic processes simultaneously is current inevitable choice. Based on the above results, researcher proposes " multiple target point targeted drug "（Multitarget-directed Ligands, MTDLs）Strategy researches and develops anti-neurodegenerative disease drug.So-called " multiple target point drug " refers to single chemical entities while acting on Multiple target spots in disease network can generate synergistic effect to the effect of each target spot, and gross effect is made the sum of to be answered more than each single-action, Such medicine is also referred to as " Multifunctional " or " Multipotential " drug.Multiple target point drug and multiple medicine use in conjunction And the main distinction of compound medicine is：Can reduce dosage, improve therapeutic effect, avoid interaction between drug and Thus the toxic side effect brought, uniform pharmacokinetic properties, be easy to use etc..Therefore, research and development have new chemical Structure, novel mechanism of action, and the anti-neurodegenerative disease therapeutic agent with multiple target effect, less toxic side effect not only accords with The active demand of social senilization's process is closed, and there are good market prospects.It designs and finds that there is inhibition acetyl simultaneously Cholinesterase, inhibitionβExcessive generation and deposition, anti-oxidation stress, anti-platelet aggregation and the anti-nerve of amyloid protein The multiple target point AD medicines of inflammatory reaction are still current important research direction.
Invention content
Present invention aims at open a kind of piperidines alkane carbamyl phthalide analog compounds（I）And its it is pharmaceutically acceptable Salt.
Another object of the present invention is to disclose such piperidines alkane carbamyl phthalide analog compound（I）And its it can pharmaceutically connect The preparation method for the salt received.
Another object of the present invention is to open comprising such piperidines alkane carbamyl phthalide analog compound（I）And its pharmacy The pharmaceutical composition of upper acceptable salt.
Still a further object of the present invention is to disclose such piperidines alkane carbamyl phthalide analog compound（I）And its it can pharmaceutically connect The salt received has multiple target effect, can be used for preparing the purposes in the drug for treating and/or preventing nervus retrogression relevant disease, Including but not limited to vascular dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple The neurodegenerative diseases such as sclerosis, progressive lateral sclerosis of spinal cord, neuropathic pain, glaucoma.
Piperidines alkane carbamyl phthalide analog compound provided by the present invention（I）Chemical structure of general formula be：
In formula：X indicates O, NR6Or S；R2And R3Each independently represent H, OH, SH, C1~C12Alkyl, C1~C12Alkoxy, CN, halogen Element, NR4R5Or C1~C12Alkylthio group；R4And R5Each independently represent H, C1~C12Alkyl；NR4R5Also illustrate that nafoxidine base, Quinoline base or piperidyl；R2And R3It can be in the arbitrarily possible position of phenyl ring；R1Indicate H, C1~C12Alkyl, benzyl or substituted benzyl；R6 Indicate H, C1~C12Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；M indicates 0-6；N indicates 0-12；The compound isRConfiguration,SConfiguration or raceme；Above-mentioned term " halogen " refers to F, Cl, Br or I；" substituted-phenyl " or " substituted benzyl " refers to The phenyl or benzyl replaced by 1-4 groups selected from the group below on phenyl ring：F,Cl,Br,I,C1-4Alkyl, C1-4Alkoxy, NR7R8, trifluoromethyl, trifluoromethoxy, nitro, amino, carboxyl, hydroxyl, cyano, R7And R8Each independently represent C1~C12Alkane Base, NR7R8Also illustrate that nafoxidine base, morpholinyl or piperidyl；These substituent groups can be in the arbitrary possible position of phenyl ring.
Piperidines alkylbenzene phthalein compounds proposed by the invention（I）It can be prepared by the following method to obtain：
With corresponding carboxyalkyl phthalide analog compound raceme or optical isomer（1）With piperidines -4- alkyl amine compounds（2） For starting material, reacts in appropriate solvent and under condensing agent existence condition, obtain corresponding piperidines alkane carbamyl phthalide-type Close object（I）Raceme or optical isomer；Conventional chiral HPLC chromatogram method can also be used by corresponding piperidines alkane carbamyl benzene Phthalein compounds（I）Raceme is detached, you can obtains corresponding optical isomer；Its reaction equation is as follows：
In formula：X,R1、R2、R3, m and n definition and piperidines alkane carbamyl phthalide analog compound（I）Chemical structure of general formula phase Together.
For said synthesis route, specific preparation method is described as follows：
Condensing agent is used in reaction：Chloro-carbonic acid C1-8Fatty alcohol ester type compound（Such as：Ethyl chloroformate, isobutylchloroformate, chlorine Benzyl formate etc.）,NCarbethoxyl group -2- ethyoxyl -1,2- dihydroquinoline（EEDQ）, carbodiimide compound（Such as：DCC, EDCI）, diethyl phosphorocyanidate（DEPC）, the chloro- 4,6- dimethoxys -1,3,5- triazines of 2-（Referred to as CDMT）, chlorination 4- (4, 6- dimethoxy -1,3,5- triazine -2- bases) -4- methyl morpholine salt（Referred to as DMTMM）, wherein the anion in DMTMM is Chlorine, bromine, perchlorate, fluoboric acid root, Loprazolam base, benzene sulfonic acid base, p-methyl benzenesulfonic acid base, camphorsulfonic acid base, sulfamic acid Base, preferably condensing agent are：Ethyl chloroformate, dicyclohexylcarbodiimide（DCC）, 1- ethyls -3- (3- dimethylamine propyls) carbon two Inferior amine salt hydrochlorate（EDCI）Or DMTMM；Reacting solvent for use is：Water, C1-6Alcohol, C3-8Aliphatic ketone, C5-10Fat alkane（Such as：Just Hexane, normal heptane etc.）,N,NDimethylformamide, ethers（Such as：Ether, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, second Glycol dimethyl ether etc.）,C1-6Aliphatic acid and C1-6The formed ester of fatty alcohol, halogenated hydrocarbons（Such as：Dichloromethane, chloroform, bis- chloroethenes of 1,2- Alkane, o-dichlorohenzene etc.）, aromatic hydrocarbon or substituted aroma hydrocarbon（Such as：Benzene, toluene）, acetonitrile, preferred solvent is：Tetrahydrofuran,N,N- two Methylformamide, water, dichloromethane, isopropanol, acetone, ethyl acetate, toluene；Carboxyalkyl phthalide analog compound raceme or light Learn isomers（1）：Piperidines -4- alkyl amine compounds（2）：The molar feed ratio of condensing agent is 1.0：1.0~9.0：1.0 ~ 9.0, It is preferred that molar feed ratio is 1.0：1.0~4.0：1.0~5.0；Setting-up point is 0 ~ 130 DEG C, and preferable reaction temperature is 0 ~ 50 ℃；Condensation reaction time is 30 minutes ~ 48 hours, and preferred reaction time is 1 ~ 20 hour.
The piperidines alkane carbamyl phthalide analog compound of gained according to the method described above（I）Contain amino in molecule, the amino In alkalinity, its pharmaceutically acceptable salt can be made by pharmaceutically conventional salifying method with any suitable acid, it is described Acid be：Hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, C1-6Aliphatic carboxylic acid（Such as：Formic acid, acetic acid, propionic acid etc.）, oxalic acid, benzene first Acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, malic acid, lipoic acid, C1-6Alkyl sulfonic acid（Such as：First Base sulfonic acid, ethylsulfonic acid etc.）, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
Starting material --- carboxyalkyl phthalide analog compound raceme or the optical isomer of the present invention（1）With piperidines -4- Alkyl amine compound（2）The technology that this field can be used common is made, including but not limited to the side disclosed in following documents Method：1,Matarlo J. S.et al.Biochemistry2015, 54(42), 6514-6524；2, the such as Lee fruitFinely With specialty chemicals2004, 12(12), 19-21；3,Guo L.et al.Syn. Commun.2004, 34(7), 1183- 1189；4,Antonia D. M.et al.Beilstein J. Org. Chem.2015, 11, 2591-2599；5, Keller M. et al.Bioorg. Med. Chem.2015, 23(14), 3970-3990；6,Asadipour A.et al.Eur. J. Med. Chem.2013, 70, 623-630；7,Zonghua L. et al.J. Med. Chem.2013, 56(22), 9089-9099。
Pharmaceutical composition disclosed in this invention includes one or more piperidines alkane carbamyl phthalides of therapeutically effective amount Class compound（I）Or its pharmaceutically acceptable salt, the pharmaceutical composition further can pharmaceutically connect containing one or more The carrier or excipient received." therapeutically effective amount " refers to causing researcher or targeted tissue, system or the animal of doctor Biology or medicine reaction drug or medicament amount；" composition " refers to by mixing more than one substances or component Made of product；" pharmaceutically acceptable carrier " refers to pharmaceutically acceptable substance, composition or carrier, such as：Liquid Body or solid-filling agent, diluent, excipient, solvent or packing substance, they carry or transport certain chemical substance.The present invention Its ideal ratio of the pharmaceutical composition provided is piperidines alkane carbamyl phthalide analog compound（I）Or it can pharmaceutically connect The salt received accounts for total weight than 2%~99.5% as active constituent.
Piperidines alkane carbamyl phthalide analog compound disclosed in this invention（I）And its pharmaceutically acceptable salt carries out Following bioactivity screening.
（1）Piperidines alkane carbamyl phthalide analog compound（I）It lives to the inhibition of acetylcholinesterase and butyrylcholine esterase Property
1.0 mmol/L acetylthiocholine iodides or iodine bisulfide are sequentially added into 96 orifice plates for BuCh（It is purchased from Sigma companies）30 μ L, 40 μ L of PBS buffer solution of pH7.4,20 μ L of testing compound solution（DMSO contents are less than 1%）With 10 μ L Acetylcholinesterase（Rat brain cortex 5% is homogenized supernatant, and the phosphate buffer of pH7.4 makees homogenate medium）Or BuCh ester Enzyme（25% supernatant of rat blood serum, pH7.4 phosphate buffers make homogenate medium）Solution, after finishing mixing, 37 DEG C of incubation 15min, 0.2% 5,5 '-two thio-bis- (2- nitrobenzoic acids) are added into each hole（DTNB is purchased from Sigma companies）30 μ L of solution Colour developing measures the optical density in each hole at 405nm with microplate reader（OD values）, compared with the blank well for being not added with sample to be tested, calculatingization Close inhibiting rate of the object to enzyme（Enzyme inhibition rate (%)=(1- sample sets OD values/blank group OD values) × 100%）；Select the five of compound To six concentration, its enzyme inhibition rate is measured, and with the inhibiting rate linear regression of the negative logarithm of the compound molar concentration and enzyme, ask Molar concentration when obtaining 50% inhibiting rate is the IC of the compound50.Measurement result shows disclosed in the embodiment of the present invention Piperidines alkane carbamyl phthalide analog compound（I）The effect of significantly inhibiting, IC are all had to acetylcholinesterase50It is 2.0 × 10-3NM ~ 10.0 μM, chiral configuration be not notable to the activity influence of acetylcholine esterase inhibition；Measurement result also shows, piperidines alkane ammonia Formoxyl phthalide analog compound（I）Inhibitory activity to butyrylcholine esterase is significantly higher than to the inhibitory activity of acetylcholinesterase （Selectivity is more than 100 times or more）, illustrate that compound disclosed in this invention makees acetylcholinesterase with selective depression With showing that such compound is smaller to the toxicity of peripheral-system.In addition, measurement result is also shown, the kappa clinically used The IC that La Ting inhibits AChE50It is 10.5 μM, the IC that butyrylcholine esterase is inhibited50It is 2.6 μM；And pair as follows According to compound（II）（Y in its chemical structural formula indicates O, NH or S respectively）And control compound（III）To acetylcholinesterase The IC of inhibition50It is all higher than 100 μM；
。
（2）Piperidines alkane carbamyl phthalide analog compound（I）Antioxidant activity（ORAC-FL methods）
Reference literature（Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331）The side reported Method is measured, i.e.,：6- hydroxyl -2,5,7,8- tetramethyl primary colours alkane -2- carboxylic acids（Trolox）It is made into the PBS buffer solution of pH7.4 The solution of 10-80 μm of ol/L, fluorescein（fluorescein）The solution of 250 nmol/L is made into the PBS buffer solution of pH7.4, 2,2 '-azo diisobutyl amidine dihydrochlorides（AAPH）Use the preceding solution that 40 mmol/L are made into the PBS buffer solution of pH7.4. The compound solution and luciferin solution of 50-10 μm of ol/L, mixing are added into 96 orifice plates, 37 °C of incubation 15min are added AAPH solution, it is 200 μ L to make every hole total volume, and mixing is immediately placed on Varioskan Flash Multimode Reader In (Thermo Scientific) instrument, 90 min of METHOD FOR CONTINUOUS DETERMINATION under 485 nm excitation wavelengths and 535 nm launch wavelengths.It calculates Go out area AUC under fluorescence decay curve, wherein with 1-8 μm of ol/L'sTroloxAs standard, to be not added with sample to be tested as blank, The antioxidant activity results expression of compound isTroloxEquivalent, calculation formula is：[(AUC Sample-AUC blank)/(AUC Trolox-AUC blank)] ×[(concentration of Trolox/concentration of Sample)], each compound measures 3 multiple holes every time, and every group of experiment is independent in triplicate.Measurement result shows present invention reality Apply the piperidines alkane carbamyl phthalide analog compound disclosed in example（I）Antioxidant activity beTrolox0.2~2.0 times, Illustrate that such compound has compared with strong anti-oxidative activity；And the antioxidant activity that Rivastigmine measures under the same conditions is less thanTrolox0.1 times.
（3）Piperidines alkane carbamyl phthalide analog compound（I）To Aβ 1-42The inhibitory activity of self assemble
Reference literature（Qiang, X.M.et al.Eur. J Med. Chem.2014, 76, 314-331）The side reported Method is measured, i.e.,：Pretreated Aβ 1-42It is made into storing solution with DMSO, is diluted to the PBS buffer solution of pH7.4 using preceding 50µM；Untested compound is made into 2.5 mM storing solutions with DMSO, and respective concentration is diluted to the PBS buffer solution of pH7.4 using preceding, Take the A of 20 μ Lβ 1-42The testing compound solution of+20 μ L of solution, the A of 20 μ Lβ 1-42The PBS buffer solution of+20 μ L of solution（Containing 2% DMSO）In 96 orifice plates, for 24 hours, the glycine-NaOH that the 50mM that 160 μ L contain 5 μM of thioflavine Ts is then added is slow for 37 °C of incubations Fliud flushing（pH=8.5）, measured under 446 nm excitation wavelengths and 490 nm launch wavelengths with multi-function microplate reader immediately after shaking 5s Fluorescent value；Aβ 1-42The fluorescent value of+untested compound is denoted as IFi, Aβ 1-42The fluorescent value of+PBS buffer solution is denoted as IFc, contain only The fluorescent value of PBS buffer solution is denoted as IF0, compound inhibition Aβ 1-42The inhibiting rate of self assemble is：100-(IFi-IF0)/(IFc- IF0)*100；Five to six concentration for selecting compound, measure its inhibiting rate；Each each concentration repetition measurement of compound three times, with Curcumin is positive control.Measurement result shows the piperidines alkane carbamyl phthalide-type chemical combination disclosed in the embodiment of the present invention Object（I）To Aβ 1-42Self assemble all has remarkable inhibiting activity, to A under 20.0 μM of concentrationβ 1-42The inhibiting rate of self assemble Between 30.0%~60.0%；And clinically widely used anti-AD drugs：Donepezil, Rivastigmine, memantine hydrochloride, And above-mentioned control compound（II）（Y in its chemical structural formula indicates O, NH or S respectively）And control compound（III）? To A under 25.0 μM of concentrationβ 1-42The inhibiting rate of self assemble is respectively less than 10%.
（4）Piperidines alkane carbamyl phthalide analog compound（I）Platelet aggregation inhibitory activity
Male rabbit 3 is taken, with lidocaine local anaesthesia, operation separation arteria carotis communis takes blood, takes 3.8% sodium citrate 1：9 Anti-freezing is centrifuged 10 minutes with 500r/min, prepares platelet rich plasma（PRP）, remainder centrifuges with 3000r/min again, makes Standby platelet poor plasma（PPP）, platelet aggregation test is carried out by turbidimetry.It measures in pipe and the PRP and 30 μ L of 240 μ L is added not With concentration of test drug, temperature is incubated 5 minutes, respectively with 30 μ L adenosine diphosphate (ADP)s（ADP）（Final concentration of 10 μm of ol/L）, 30 μ L blood coagulations Enzyme（Final concentration of 0.5U/mL）With 30 μ L arachidonic acids（AA）（Final concentration of 1.0 mmol/L）For derivant, 5 are observed and recorded Maximum aggregation rate in minute.Use physiological saline（NS）It compares, calculates the inhibiting rate of each test-compound（%）.Measurement result table It is bright, the piperidines alkane carbamyl phthalide analog compound disclosed in the embodiment of the present invention（I）To ADP induction, thrombin induction and The platelet aggregation of AA inductions significantly inhibits effect, and inhibiting rate is 15.0%~40.0%.And it is clinically widely used Anti- AD drugs：Donepezil, Rivastigmine, memantine hydrochloride and above-mentioned control compound（III）To platelet aggregation Inhibiting rate is respectively less than 5.0%；And control compound（II）（Y in its chemical structural formula indicates O, NH or S respectively）To platelet aggregation The inhibiting rate of collection is 8.2%~12.0%.
Specific implementation mode
The present invention can be further described by the following examples, however, the scope of the present invention is not limited to Following embodiments.One of skill in the art, can be right it is understood that under the premise of without departing substantially from the spirit and scope of the present invention The present invention carries out various change and modification.
1 piperidines alkane carbamyl phthalide analog compound of embodiment（I）Preparation lead to method
By carboxyalkyl phthalide analog compound raceme or optical isomer（1）1.0 mmol, piperidines -4- alkyl amine compounds （2）1.3 mmol and 25 ml of tetrahydrofuran are added in reaction bulb, and after stirring evenly, 1- ethyls -3- (3- dimethylamine propyls) is added Carbodiimide hydrochloride（EDCI）Reaction is stirred at room temperature 2.0~20.0 hours in 2.0 mmol（Reaction process is tracked with TLC）, instead After answering, solvent is removed under reduced pressure, 50 mL dichloromethane are added in residue, use deionized water, saturated sodium carbonate water-soluble successively Liquid and saturated sodium-chloride water solution washing, organic layer filter after being dried over anhydrous sodium sulfate, and remove solvent under reduced pressure, residue is through silicon It is gel column chromatography eluting（Eluent：Dichloromethane:Methanol=20~30:1 v/v）, obtain corresponding piperidines alkane carbamyl phthalide-type Compound（I）, yield 60.0%-95.0%, chemical constitution passes through1H-NMR、13C-NMR and ESI-MS confirmations；Gained object Purity through HPLC measurement be all higher than 97.0%.The object structure being prepared using above-mentioned logical method is as follows：
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
（It is continued on next page）
2 piperidines alkane carbamyl phthalide analog compound of embodiment（I）It is prepared at salt with acid and leads to method
The piperidines alkane carbamyl phthalide analog compound of gained in accordance with the above-mentioned embodiment 1 is added in reaction bulb（I）1.0 mmol With 25 ml of acetone, it is sour accordingly to be stirring evenly and then adding into 4.0 mmol, and temperature rising reflux is stirred to react 20 minutes, after reaction It is cooled to room temperature, removes solvent under reduced pressure, residue acetone recrystallization filters the solid of precipitation to get piperidines alkane carbamyl Phthalide analog compound（I）Salt, chemical constitution warp1H NMR and ESI-MS confirmations.

Claims (8)

1. a kind of piperidines alkane carbamyl phthalide analog compound or its pharmaceutically acceptable salt, it is characterised in that such compound Chemical structure of general formula such as（I）It is shown：
In formula：X indicates O, NR6Or S；R2And R3Each independently represent H, OH, SH, C1~C12Alkyl, C1~C12Alkoxy, CN, halogen Element, NR4R5Or C1~C12Alkylthio group；R4And R5Each independently represent H, C1~C12Alkyl；NR4R5Also illustrate that nafoxidine base, Quinoline base or piperidyl；R2And R3It can be in the arbitrarily possible position of phenyl ring；R1Indicate H, C1~C12Alkyl, benzyl or substituted benzyl；R6 Indicate H, C1~C12Alkyl, phenyl or substituted-phenyl, benzyl or substituted benzyl；M indicates 0-6；N indicates 0-12；The compound isRConfiguration,SConfiguration or raceme；Above-mentioned term " halogen " refers to F, Cl, Br or I；" substituted-phenyl " or " substituted benzyl " refers to The phenyl or benzyl replaced by 1-4 groups selected from the group below on phenyl ring：F,Cl,Br,I,C1-4Alkyl, C1-4Alkoxy, NR7R8, trifluoromethyl, trifluoromethoxy, nitro, amino, carboxyl, hydroxyl, cyano, R7And R8Each independently represent C1~C12Alkane Base, NR7R8Also illustrate that nafoxidine base, morpholinyl or piperidyl；These substituent groups can be in the arbitrary possible position of phenyl ring.
2. piperidines alkane carbamyl phthalide analog compound as described in claim 1 or its pharmaceutically acceptable salt, feature Be the pharmaceutically acceptable salt be such piperidines alkylbenzene phthalein compounds with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, Phosphoric acid, C1-6Aliphatic carboxylic acid, oxalic acid, benzoic acid, salicylic acid, maleic acid, fumaric acid, succinic acid, tartaric acid, citric acid, apple Acid, lipoic acid, C1-6The salt of alkyl sulfonic acid, camphorsulfonic acid, benzene sulfonic acid or p-methyl benzenesulfonic acid.
3. piperidines alkane carbamyl phthalide analog compound or its pharmaceutically acceptable salt as described in claim any one of 1-2 Preparation method, it is characterised in that the compound can be prepared by the following method to obtain：
In formula：X,R1、R2、R3, m and n definition and piperidines alkane carbamyl phthalide analog compound（I）Chemical structure of general formula phase Together；
With corresponding carboxyalkyl phthalide analog compound raceme or optical isomer（1）With piperidines -4- alkyl amine compounds（2） For starting material, reacts in appropriate solvent and under condensing agent existence condition, obtain corresponding piperidines alkane carbamyl phthalide-type Close object（I）Raceme or optical isomer；Conventional chiral HPLC chromatogram method can also be used by corresponding piperidines alkane carbamyl benzene Phthalein compounds（I）Raceme is detached, you can obtains corresponding optical isomer；
Utilize the piperidines alkane carbamyl phthalide analog compound of above method gained（I）Contain amino in molecule, which is in alkali Property, its pharmaceutically acceptable salt can be made by pharmaceutically conventional salifying method with any suitable acid.
4. the preparation side of piperidines alkane carbamyl phthalide analog compound as claimed in claim 3 or its pharmaceutically acceptable salt Method, it is characterised in that condensing agent is used in reaction：Chloro-carbonic acid C1-8Fatty alcohol ester type compound,NCarbethoxyl group -2- ethyoxyls - 1,2- dihydroquinoline, dicyclohexylcarbodiimide, 1- ethyls -3- (3- dimethylamine propyls) carbodiimide hydrochloride, cyano phosphoric acid The chloro- 4,6- dimethoxys -1,3,5- triazines of diethylester, 2-, chlorination 4- (4,6- dimethoxy -1,3,5- triazine -2- bases) -4- first Base alkylbenzyldimethylasaltsum saltsum.
5. the preparation side of piperidines alkane carbamyl phthalide analog compound as claimed in claim 3 or its pharmaceutically acceptable salt Method, it is characterised in that reacting solvent for use is：Water, C1-6Alcohol, C3-8Aliphatic ketone, C5-10Fat alkane,N,NDimethylformamide, Ether, isopropyl ether, methyl tertiary butyl ether(MTBE), tetrahydrofuran, glycol dimethyl ether, C1-6Aliphatic acid and C1-6The formed ester of fatty alcohol, Dichloromethane, chloroform, 1,2- dichloroethanes, o-dichlorohenzene, benzene, toluene, acetonitrile.
6. the preparation side of piperidines alkane carbamyl phthalide analog compound as claimed in claim 3 or its pharmaceutically acceptable salt Method, it is characterised in that carboxyalkyl phthalide analog compound raceme or optical isomer（1）：Piperidines -4- alkyl amine compounds （2）：The molar feed ratio of condensing agent is 1.0：1.0~9.0：1.0~9.0；Setting-up point is 0 ~ 130 DEG C；When condensation reaction Between be 30 minutes ~ 48 hours.
7. a kind of pharmaceutical composition, it is characterised in that comprising such as claim 1-2 any one of them piperidines alkane carbamyl benzene Phthalein compounds or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable carriers or excipient.
8. such as claim 1-2 any one of them piperidines alkane carbamyl phthalide analog compounds or its pharmaceutically acceptable salt Purposes in preparing treatment and/or preventing nervus retrogression relevant disease drug, this kind of nervus retrogression relevant disease are：Blood Pipe dementia, Alzheimer's disease, parkinsonism, Huntingdon disease, HIV related dementia disorders, multiple sclerosis, progressive ridge Marrow lateral schlerosis, neuropathic pain or glaucoma.
CN201810285408.6A 2017-04-14 2018-04-03 Piperidine alkane carbamoyl phthalide compounds, preparation method and application thereof Active CN108727352B (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN2017102418311 2017-04-14
CN201710241831 2017-04-14

Publications (2)

Publication Number Publication Date
CN108727352A true CN108727352A (en) 2018-11-02
CN108727352B CN108727352B (en) 2021-04-23

Family

ID=63941236

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201810285408.6A Active CN108727352B (en) 2017-04-14 2018-04-03 Piperidine alkane carbamoyl phthalide compounds, preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN108727352B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109265362B (en) * 2018-11-09 2021-04-27 四川大学 2, 5-dihydroxy terephthalamide compounds, preparation method and application thereof
CN114315689A (en) * 2020-10-09 2022-04-12 四川大学 Disulfanylphthalimide compound, preparation method and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05247022A (en) * 1990-07-10 1993-09-24 Tsumura & Co New phthalide and brain function improver containing the same as active ingredient
CN1330069A (en) * 2000-06-28 2002-01-09 中国医学科学院药物研究所 Substituted 2-benzo [c] furanone compound, its preparing process and medicinal composition containing it
CN101455661A (en) * 2008-11-19 2009-06-17 中国科学院上海有机化学研究所 Use of 3-substituted phthalide and the analogue
CN106432161A (en) * 2016-07-19 2017-02-22 四川大学 3-Alkyl-5,6-dioxo-substituted phthalide compounds, and preparation method and use thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH05247022A (en) * 1990-07-10 1993-09-24 Tsumura & Co New phthalide and brain function improver containing the same as active ingredient
CN1330069A (en) * 2000-06-28 2002-01-09 中国医学科学院药物研究所 Substituted 2-benzo [c] furanone compound, its preparing process and medicinal composition containing it
CN101455661A (en) * 2008-11-19 2009-06-17 中国科学院上海有机化学研究所 Use of 3-substituted phthalide and the analogue
CN106432161A (en) * 2016-07-19 2017-02-22 四川大学 3-Alkyl-5,6-dioxo-substituted phthalide compounds, and preparation method and use thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
XIAOMING QIANG ET AL.: "DL-3-n-butylphthalide-Edaravone hybrids as novel dual inhibitors of amyloid-β aggregation and monoamine oxidases with high antioxidant potency for Alzheimers therapy", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
YAN LI ET AL.: "Aurone Mannich base derivatives as promising multifunctional agents with acetylcholinesterase inhibition, anti-β-amyloid aggragation and neuroprotective properties for the treatment of Alzheimers disease", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109265362B (en) * 2018-11-09 2021-04-27 四川大学 2, 5-dihydroxy terephthalamide compounds, preparation method and application thereof
CN114315689A (en) * 2020-10-09 2022-04-12 四川大学 Disulfanylphthalimide compound, preparation method and application thereof
CN114315689B (en) * 2020-10-09 2023-04-07 四川大学 Disulfanylphthalimide compound, preparation method and application thereof

Also Published As

Publication number Publication date
CN108727352B (en) 2021-04-23

Similar Documents

Publication Publication Date Title
CN105481706B (en) The Hydroxylated Chalcones and Related compound of one class 2, preparation method and use
CN105481796B (en) One class carbamic acid chalcone ester type compound, preparation method and use
KR102012675B1 (en) 3,4-DIHYDRO-PYRROLO[1,2-a]PYRAZIN-1-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE(BACE)
KR101962216B1 (en) 4,7-DIHYDRO-PYRAZOLO[1,5-a]PYRAZIN-6-YLAMINE DERIVATIVES USEFUL AS INHIBITORS OF BETA-SECRETASE (BACE)
CN106632181B (en) Aurone Mannich alkaloid compound, preparation method and use
CN105439876B (en) 2 hydroxylated chalcone aminated compounds, preparation method and use
EP2382206B1 (en) Compounds and methods for the treatment of pain and other diseases
CN106831799B (en) Hydroxy styrenes pyridine Mannich alkaloid compound, preparation method and use
CN108727352A (en) A kind of piperidines alkane carbamyl phthalide analog compound, preparation method and use
CN111170884B (en) Salicylamide compound, preparation method and application thereof
CN109265362A (en) A kind of 2,5- dihydroxy paraphenylene terephthalamide's amine compound, preparation method and use
CN108101780A (en) A kind of Flurbiprofen chalcone compounds, preparation method and use
JP2022513030A (en) A pharmaceutical composition comprising a histone deacetylase 6 inhibitor
CN109734614A (en) 3- hydroxylated chalcone Mannich alkaloid compound, preparation method and use
CN108586411A (en) A kind of naringenin carbamate compound, preparation method and application
CN108912040B (en) salicylamide-O-carbamate compound and preparation method and application thereof
CN110698445B (en) 3-amine alkyl phthalide compound, preparation method and application thereof
CN108727350A (en) A kind of piperidines alkylbenzene phthalein compounds, preparation method and use
CN106632191B (en) Homoisoflavone Mannich alkaloid compound, preparation method and use
CN110698411B (en) 4- (aminoalkyl) phthalazine-1-ketone compound, preparation method and application thereof
CN106810532B (en) A kind of amine alkoxy thioxanthene ketone class compound, preparation method and use
CN109912443A (en) A kind of benzamido group Flurbiprofen class compound, preparation method and use
CN109665969A (en) The double Mannich alkaloid compounds of 3- methoxyl group -4-HC, preparation method and use
CN110003034A (en) A kind of hydroxyl Flurbiprofen Mannich alkaloid compound, preparation method and use
CN108203439A (en) Stibazole compounds, preparation method and use

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
GR01 Patent grant
GR01 Patent grant