CN104230770B - The application of styryl sulfone compound, its preparation method as well as neuroprotective agent - Google Patents

The application of styryl sulfone compound, its preparation method as well as neuroprotective agent Download PDF

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CN104230770B
CN104230770B CN201310237874.4A CN201310237874A CN104230770B CN 104230770 B CN104230770 B CN 104230770B CN 201310237874 A CN201310237874 A CN 201310237874A CN 104230770 B CN104230770 B CN 104230770B
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styryl
compound
aryl
sulfone
alkyl
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CN104230770A (en
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吕新安
刘俊义
周受辛
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Huaxiashengsheng Pharmaceutical Beijing Co ltd
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Abstract

The application is related to the CAPE (CAPE) with neuroprotective activity extracted from natural propolis for primer; according to bioisosterism and hydrogen bond action scheduling theory; design the recruit that a kind of sulfone group replaces ester group; its structure is shown in formula I, and the definition of each group is as is described in the claims in formula.Also relate to the evaluation of Compound ira vitro oxidation resistance, the neuroprotective activity evaluation of cellular level and pass through blood-brain barrier merit rating.Activity evaluation shows that the noval chemical compound neuroprotective activity synthesized strengthens and is more easy to by blood-brain barrier, so as to turn into a kind of neuroprotective agent of novel therapeutic nerve degenerative diseases.

Description

Styryl sulfone compound, its preparation method as well as neuroprotective agent Using
Technical field
The present invention relates to medicinal chemistry art.More particularly it relates to have with what is extracted from natural propolis It is a kind of new available for treating nervus retrogression that the CAPE of neuroprotective activity is that raw material obtains through structure of modification The E-3 of disease, 4- disubstituted benzenes ethene sulfone compound, its preparation method and the purposes as medicine.
Background technology
Nerve degenerative diseases are a kind of chronic, progressive sacred diseases.Such disease mainly include senile dementia, Parkinson's, Huntington choreas, different type spinocerebellar ataxia, dentate nucleus rubrum globus pallidus corpus hypothalamicum wither Contracting and ALS etc..In recent years, nerve degenerative diseases number of the infected is increasing, for example, senile dementia Disease is in China's illness rate up to 2%~5%, and annual neopathy is up to 1%.Research finds, nerve degenerative diseases be by it is a variety of not Caused by reason, including neuron or Deiter's cells can not provide sufficient nutrition, glutamate receptor activity is too high, lives Property oxygen level is too high, metabolic pathway is impaired, reductions of mitochondria energy production, inflammation, virus infects and nucleus or mitochondria DNA mutation etc., influence each other between them, ultimately result in maladjusted nervous system and cell death.Because mechanism of action is complicated more Sample, the method and the medical treatment disease of effective maturation are there is no so far.Therefore finding a kind of efficient and Mutiple Targets medicine has Important social effect and economic value.
CAPE (CAPE), a kind of natural products extracted from natural propolis, there are multiple biological activities, such as (Chen Y., the Wang S., et such as antitumor, anti-oxidant, anti-inflammatory, antibacterial, antiatherosclerosis and anti-HIV-1 integrase Al.Anti-cancer drugs.2001,12 (2), 143-149).Recently, research finds that CAPE can pass through resistance Disconnected nervus retrogression damage, plays neuroprotection (Wei X, Ma Z., Fontanilla CV., et Al.Neuroscience.2008,155 (4), 1098-1105).Because CAPE is not easy to pass through blood-brain barrier, and Internal fast (Nicola C., Luana K., the et al.Joural of Agricultrual and Food of accretion rate Chemistry.2007,55,3398-3407), therefore neuroprotective activity is subject to certain restrictions.Inventor is with from caffeic acid Phenethyl ester is lead compound, and by further investigation, synthesis has obtained a large amount of new compounds, and have surprisingly been discovered that one Class novel nerve protective agent, antioxidation activity in vitro evaluation is carried out to these compounds, the neuroprotective activity of cellular level is commented Valency and transmission blood-brain barrier merit rating.Activity evaluation shows that noval chemical compound neuroprotective activity strengthens and is more easy to pass through Blood-brain barrier, stability is stronger, so as to which neuroprotective activity greatly improves.
The content of the invention
It is not easy to pass through blood-brain barrier for CAPE, and the shortcomings that accretion rate is fast in vivo, we enter it Row structural modification, noval chemical compound is set to be more easy to pass through blood-brain barrier, stability is stronger, so as to improve neuroprotective activity.
Present invention has discovered that compound of Formula I can be evaluated by removing free radical antioxidation activity in vitro, protection one The evaluation of nitrogen oxide inducing cell damage model, protection and H2O2The evaluation of inducing cell damage model, protection 6-OHDA inducing cell damages Wound model evaluation etc. embodies neuroprotection.Medicine of the present invention with neuroprotection, for treating A Zihai It is silent disease, Parkinson's disease, amyotrophic lateral sclerosis, primary lateral spinal sclerosis, Huntington's disease, prion disease, more Hair property sclerosis, cerebral atrophy, spinal muscular atrophy, multi-system atrophy, different type spinocerebellar ataxia, brain Ischemic, Alexander disease, A Erposhi diseases, amyotrophic lateral sclerosis, ataxia-telangiectasia, canavan's disease, section Triumphant grace syndrome, corticobasal degeneration, her time Fei Erte-cortico-striatal spinal degeneration, epilepsy, Kennedy disease, Krabbe disease, Louis of Crow Body is dull-witted, on the disease of Ma-about, pelizaeus-Merzbacher disease, Pick's disease, Refsum's disease, sandhoff disease, periaxial encephalitis, progressive core The neurodegenerative diseases such as property paralysis, peripheral neurophaty, diabetic neuropathy, apoplexy and tabetic crisis.
The present invention is realized by below general formula I, its hydrate, isomers or officinal salt：
Formula I
Wherein,
R1And R2Be each independently selected from for：H, halogen, cyano group, nitro, azido, OR3、N(R4)2, it is unsubstituted or by 1 To 6 halogens, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3 Independently selected from H, unsubstituted or by 1 to 6 halogen, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Saturation alkane Base, C2-4Alkenyl, C2-4Alkynyl group, C6-10Aryl, C5-9Heteroaryl, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl Or C6-8Sulfonyl, the Si (R of aryl substitution6)3, R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturation alkane Base, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9Heteroaryl, R6Independently selected from H, C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；
Preferably, R1And R2Be each independently selected from for：OR3, wherein R3Independently selected from H, unsubstituted or by 1 to 6 Halogen, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group, C6-10Virtue Base, C5-9Heteroaryl, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl or C6-8Sulfonyl, the Si (R of aryl substitution6)3, R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group or C6-10Virtue Base, C5-9Heteroaryl, R6Independently selected from H, C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；
It is particularly preferred that R1And R2Be each independently selected from for：OR3, wherein R3Independently selected from unsubstituted or by 1 to 6 Individual halogen, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Alkyl, C1-6Alkanoyl or C7-10Aroyl, or solely On the spot it is selected from by C1-3Alkyl or C6-8Sulfonyloxy, the OSi (R of aryl substitution6)3, wherein R4Independently selected from H or C1-6Saturation alkane Base, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9Heteroaryl, R6Independently select From H, C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；
Most preferably, R1And R2It is each independently selected from as methoxyl group, ethyoxyl, isopropoxy, tert-butoxy, cyclopropyl first Chloro- 1, the 1- difluoroethoxies of epoxide, cyclohexyloxy, chloromethane epoxide, bromine methoxyl group, cyanogen methoxyl group, nitrine methoxyl group, 2,2- bis-, Methylamino methoxyl group, dimethylamino methoxyl group, methoxymethoxy, tert-butoxymethoxy, benzyloxy ylmethoxy, methanoyl Base, acetoxyl group, new pentane acyloxy, benzoyloxy, chloroethene acyloxy, tribromo-acetyl epoxide, acetyl bromide epoxide, carbamyl Epoxide, mesyloxy, tolysulfonyl epoxide, trimethylsiloxy group, tert-butyl group dimethoxy siloxy, tert-butyl diphenyl Siloxy, tri isopropyl siloxany；
W is unsubstituted or by 1 to 3 halogen, cyano group, nitro, azido, C1-3Alkyl, N (R4)2Or OR5Substitution C1-6Alkylidene or C2-6Alkenylene, wherein R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9Heteroaryl；
Preferably, W is unsubstituted or by 1 to 3 halogen, C1-3Alkyl or N (R4)2Substituted C1-6Alkylidene or C2-6It is sub- Alkenyl, wherein R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkyne Base or C6-10Aryl, C5-9Heteroaryl；
It is particularly preferred that W is unsubstituted or by 1 to 3 halogen, C1-3Alkyl or N (R4)2Substituted C1-6Alkylidene or C2-6Alkenylene, wherein R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4 Alkynyl group or C6-10Aryl, C5-9Heteroaryl；
Most preferably, it is-CH that W, which is selected from,2-、-CH2CH2-、-CH2CH2CH2-、-CH(Cl)-、-CH(Br)-、-CH(Cl) CH2-、-CH(Cl)CH(Cl)-、-CH2(Cl)CHCH2-、-CH(CH3)-、-CH(CH3)CH2-、-CH[N(CH3)2]-、-CH2CH= CHCH2- ,-CH (Cl) CH=CHCH2-；
R is independently selected from for halogen, cyano group, nitro, azido, carboxyl, OR3, sulfydryl, N (R4)2, it is unsubstituted or by 1 To 6 halogens, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3 Independently selected from H, unsubstituted or by 1 to 6 halogen, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Saturation alkane Base, C2-4Alkenyl, C2-4Alkynyl group, C6-10Aryl, C5-9Heteroaryl, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl Or C6-8Sulfonyl, the Si (R of aryl substitution6)3, R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturation alkane Base, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9Heteroaryl, R6Independently selected from H, C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；
Preferably, R is independently selected from for halogen, cyano group, nitro, OR3、N(R4)2, it is unsubstituted or by 1 to 6 halogen, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3Independently selected from H, unsubstituted or by 1 to 6 Individual halogen, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group, C6-10 Aryl, C5-9Heteroaryl, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl or C6-8Sulfonyl, the Si of aryl substitution (R6)3, R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9Heteroaryl, R6Independently selected from H, C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；
It is particularly preferred that R is independently selected from for halogen, cyano group, nitro, OR3、N(R4)2, it is unsubstituted or by 1 to 6 halogen Element, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3Independently selected from H, it is unsubstituted or by 1 to 6 halogen, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group, C6-10Aryl, C5-9Heteroaryl, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl or C6-8Sulfonyl, the Si of aryl substitution (R6)3, R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9Heteroaryl, R6Independently selected from H, C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；
Most preferably, R is independently selected from for fluorine, chlorine, bromine, iodine, cyano group, nitro, methoxyl group, ethyoxyl, isopropoxy, chloromethane Epoxide, methylamino methoxyl group, dimethylamino methoxyl group, amino, methylamino, dimethylamino, methyl, ethyl, chloromethyl, ammonia first Base, phenyl, rubigan；
N is 0-5 integer.
Following is the example of particularly good compound：
E-2- (3,4- dihydroxy) styryl benzyls sulfone, E-2- (3,4- dihydroxy) styryl -4- chlorobenzyls sulfone, E- 2- (3,4- dihydroxy) styryl -4- t-butylbenzyls sulfone, E-2- (3,4- dihydroxy) styryl -4- trifluoromethyl benzyls Sulfone, E-2- (3,4- dihydroxy) styryl -4- methoxy-benzyls sulfone, E-2- (3,4- dihydroxy) styryl phenethyls sulfone, E-2- (3,4- dihydroxy) styryl phenylpropyls sulfone, E-2- (3,4- dihydroxy) styryl benzene butyl sulfone, E-2- (3,4- bis- Acetoxyl group) styryl benzyl sulfone, E-2- (3,4- diacetoxy) styryl -4- chlorobenzyls sulfone, E-2- (3,4- diethyls Acyloxy) styryl -4- t-butylbenzyls sulfone, E-2- (3,4- diacetoxy) styryl -4- trifluoromethyl benzyls sulfone, E-2- (3,4- diacetoxy) styryl -4- methoxy-benzyls sulfone, E-2- (3,4- diacetoxy) styryl benzene second Base sulfone, E-2- (3,4- diacetoxy) styryl phenylpropyls sulfone, E-2- (3,4- diacetoxy) styryl benzene butyl Sulfone, E-2- (3,4- dimethoxy) styryl phenethyl sulfone,
Its hydrate, isomers or officinal salt.
These compounds can be prepared according to known methods, such as be prepared as follows：
A) Compounds of formula II and TGA are reacted preparation compound of formula III by the basic conditions, wherein, W is It is unsubstituted or by 1 to 3 halogen, cyano group, nitro, azido, C1-3Alkyl, N (R4)2Or OR5Substituted C1-6Alkylidene or C2-6Alkenylene, wherein R4Independently selected from C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Chain Alkynyl or C6-10Aryl, C5-9Heteroaryl；R is independently selected from for halogen, cyano group, nitro, azido, OR3、N(R4)2, it is unsubstituted Or by 1 to 6 halogen, cyano group, nitro, azido, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl Base, wherein R3Independently selected from H, unsubstituted or by 1 to 6 halogen, cyano group, nitro, azido, N (R4)2Or OR5Substitution C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group, C6-10Aryl, C5-9Heteroaryl, C1-6Alkyl acyl or C7-10Aryl-acyl, By C1-3Alkyl or C6-8Sulfonyl, the Si (R of aryl substitution6)3, R4And R5It is defined as above；N is 0-5 integer；
Formula II
General formula III
B) by compound of formula III with oxidizing into sulfone compound formula IV, wherein, W, R and n definition are such as Described in step a)；
Formula IV
C) by compound of Formula IV and compounds of formula V in the presence of a catalyst, be condensed and decarboxylic reaction obtain formula I Compound, wherein, R1And R2Be each independently selected from for：H, halogen, cyano group, nitro, azido, OR3、N(R4)2, it is unsubstituted Or by 1 to 6 cyano group, nitro, azido or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3Independently Selected from H, unsubstituted or by 1 to 6 cyano group, nitro, azido or OR5Substituted C1-6Saturated alkyl, C2-4Alkenyl, C2-4 Alkynyl group, C6-10Aryl, C5-9Heteroaryl, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl or C6-8The sulphur of aryl substitution Acyl group, Si (R6)3, R4Independently selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4 Alkynyl group or C6-10Aryl, C5-9Heteroaryl, R6Independently selected from H, C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；W, R and n determines Justice is as described in step a)；
Formula V
D) compound of Formula I is optionally converted into its officinal salt by.
In above-mentioned preparation method, the alkalescence condition described in step a) can be used a variety of inorganic bases, organic base or its solution, Oil dispersion or water-containing crystal, and optional composition, include but is not limited to：Sodium acid carbonate, sodium carbonate, potassium carbonate, sodium acetate, Potassium acetate, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, methylamine, ethamine, propylamine, isopropylamine, butylamine, isobutyl amine, Tert-butylamine, cyclohexylamine, dimethylamine, ethylenediamine, 1,2- propane diamine, trimethylamine, triethylamine, tripropyl amine (TPA), monoethanolamine, triethanolamine, Hexa, N, N- diisopropyl ethyl amines, TMAH, TBAH, aniline, ortho-aminotoluene, Meta-aminotoluene, para-totuidine, diphenylamines, benzidine, benzylamine, urea, pyridine, piperidines, 2,2,6,6- tetramethyl piperidines, imidazoles, benzene And imidazoles, the carbon -7- alkene of 1,8- diazabicylos [5.4.0] 11,1,5- diazabicylos [4.3.0] nonyl- 5- alkene, Isosorbide-5-Nitrae-phenodiazine Miscellaneous two ring [2.2.2] octane, sodium hydride, hydrofining, sodium methoxide, caustic alcohol, sodium tert-butoxide, potassium tert-butoxide, n-BuLi, tertiary fourth Base lithium, lithium diisopropylamine, histidine, arginine, lysine.
In above-mentioned preparation method, a variety of oxidants can be used in the oxidant described in step b), include but is not limited to：It is different The aqueous hydrogen peroxide solution of concentration, hydrogen peroxide urea complex, organic peroxide acid, halogen compounds, transistion metal compound, Potassium hydrogen persulfate, N- methyl morpholine oxides, benzoyl peroxide dioctyl phthalate magnesium salts, dimethyldioxirane, oxygen.It is wherein described The mass percent of hydrogen peroxide is 10% to 95% in the aqueous hydrogen peroxide solution of various concentrations, and preferable mass percent is 25% to 35%；Described organic peroxide acid is selected from Peracetic acid, peroxy trifluoroacetic acid, peroxide lauric acid/dodecanoic acid, m-chloro peroxide benzene first Acid；Described halogen compounds is selected from sodium hypochlorite, two chloroiodobenzones, iodobenzene diacetate, sodium metaperiodate, periodic acid；Described mistake Cross metallic compound and be selected from chromium trioxide, potassium permanganate, zinc permanganate, copper permanganate.
In above-mentioned preparation method, the catalyst used in step c) may be selected from Beta-alanine, pyrrolidines and piperidines, preferably For Beta-alanine.
In addition, gained compound of Formula I can be prepared into solvate of hydrate and different solvents etc., its preparation side Method refers to common method, by controlling crystallization mode, temperature, quantity of solvent, solvent ratios etc. to join in water or in different solvents Count to prepare.
In addition, while institute I if any chiral centre, can be separated into known method its corresponding isomers and/or Diastereoisomer.For example, by chiral chromatogram post separation, by being recrystallized in optical activity solvent, or with optically active substance, Particularly the derivative of chiral organic acid and its activation or alcohol reaction generation can be based on the salt mixing that different solubilities are separated Thing or derivative.The example of wherein optically active substance includes but is not limited to：Dextrorotation-or left-handed-tartaric acid, dibenzoyl base liquor Stone acid, two-o-tolyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, (+)-or (-)-methanol.
In addition, gained compound of Formula I can also change into its salt, the medicine with the generation of inorganic or organic acid is particularly changed into The physiologically acceptable salt used on thing, suitable sour example include but is not limited to：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Acetic acid, formic acid, propionic acid, malonic acid, methanesulfonic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, fumaric acid, succinic acid, adipic acid, lactic acid, grass Acid, citric acid, salicylic acid, tartaric acid, butanedioic acid, mandelic acid, maleic acid, malic acid, D- gluconic acids, camphorsulfonic acid, glutamic acid, Aspartic acid, pyruvic acid, carboxyl butyric acid, phthalic acid.
In addition, so obtained compound of Formula I, if containing acidic-groups such as carboxyl, phenylols, can be with inorganic or have Machine alkali changes into its salt, particularly changes on its medicine the physiologically acceptable salt used, and the example of suitable alkali includes But it is not limited to：Sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, strontium hydroxide, monoethanolamine, diethanol amine, three ethanol Amine, tert-butylamine, cyclohexyl ammonia, lysine, arginine, histidine.
On the other hand, the invention further relates to pharmaceutical composition, it includes at least one formula compound I or its optics is different Structure body or its pharmaceutically acceptable salt and pharmaceutical carrier or excipient.
The pharmaceutical composition of the compounds of this invention can use following any-mode to apply：Orally, spraying suction, rectum are used Medicine, nasal cavity applied medicine, cheek medication, local application, non-bowel medication, such as subcutaneous, vein, intramuscular, intraperitoneal, intrathecal, intracardiac room, In breastbone or intravenous administration mode.The present invention pharmaceutical composition can be administered alone also with other neuroprotective drug Internet of Things Share medicine.Treated animal includes mammal, reptile, crustacean, amphibian animal, fish, poultry.Substantial scope is Mammal particularly people.
When oral medication, the compounds of this invention can be made into any oral acceptable dosage form, include but is not limited to Tablet, capsule, the aqueous solution or water slurry.Wherein, the carrier that tablet uses may include filler, lubricant, disintegrant, bonding Agent.Filler may include but be not limited to starch, pregelatinized starch, dextrin, Icing Sugar, lactose, mannitol, microcrystalline cellulose.Lubrication Agent includes but is not limited to stearic acid, calcium stearate, magnesium stearate, talcum powder, oxidation vegetable oil, polyethylene glycol, dodecyl sulphur Sour sodium, superfine silica gel powder, talcum powder.Disintegrant may include but be not limited to Ac-Di-Sol, PVPP, starch and Its derivative, low-substituted hydroxypropyl cellulose, gas-producing disintegrant.Adhesive may include but be not limited to hydroxypropyl cellulose, poly- dimension Ketone, starch slurry, dextrin, Icing Sugar, syrup, rubber cement, cellulose and its derivates.The diluent that capsule preparations use generally comprises breast Sugar and dried corn starch.Water suspended emulsion preparation is then to be used in mixed way active component and suitable suspending agent, and suspending agent can wrap Include but be not limited to wetting agent, flocculant, deflocculant.Optionally, can also be added in above oral dosage form some sweeteners, Aromatic or colouring agent.
When local application, particularly treat Local out dressing easy to reach and suffer from face or organ, such as glasses, skin or lower intestines During road neurogenic disease, the compound of the present invention can be made by different topical preparations shapes according to different suffer from face or organ Formula, it is described as follows：
When eye local application, the compounds of this invention can be configured to a kind of preparation shape of micronized suspension or solution Formula, used carrier are the isotonic Sterile Saline with certain PH, and preservative such as chlorination is also added without wherein can add Benzyl alkoxide.For ophthalmically acceptable, compound can be also made to cream form such as petroleum jelly cream.
When local skin in use, the compounds of this invention can be made into suitably ointment, lotion or white dosage form, wherein will Active component is suspended or dissolved in one or more carriers.Carrier includes but is not limited to workable for ointment formulation：Mineral oil, Albolene, albolene, propane diols, polyethylene glycol oxide, PPOX, emulsifying wax and water；Lotion or creme can be used Carrier include but is not limited to：Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene virtue Alcohol, 2- octyldodecanols, benzyl alcohol and water.
The compounds of this invention can the medication in the form of aseptic injection preparation, including aseptic injection water or oil suspend or sterile note Penetrate solution.Wherein, workable carrier or solvent include water, Ringer's solution and isotonic sodium chlorrde solution.In addition, sterilizing is non- Volatile oil also is used as solvent or suspension media, such as monoglyceride or two glyceride.
Above-mentioned compound of Formula I, its hydrate, isomers or officinal salt, and combinations thereof, there is valuable pharmacology Property is learned, particularly with anti-oxidant and neuroprotection characteristic, is withered available for treatment stages alzheimer's disease, Parkinson's disease, flesh Contracting lateral schlerosis, primary lateral spinal sclerosis, Huntington's disease, prion disease, multiple sclerosis, cerebellar atrophy Disease, spinal muscular atrophy, multi-system atrophy, different type spinocerebellar ataxia, cerebral ischemia, Alexander disease, Ah Ear Po Shi diseases, amyotrophic lateral sclerosis, ataxia-telangiectasia, canavan's disease, Ke Kaien syndromes, cortical basal Section denaturation, her time Fei Erte-cortico-striatal spinal degeneration of Crow, epilepsy, Kennedy disease, Krabbe disease, dementia with Lewy body, the disease of Ma-about, wear- Syphilis, Pick's disease, Refsum's disease, sandhoff disease, periaxial encephalitis, stein-leventhal syndrome, peripheral neurophaty, The neurodegenerative diseases such as diabetic neuropathy, apoplexy and tabetic crisis.
Furthermore, it should be pointed out that the dosage and application method of the compounds of this invention depend on factors, including patient Age, body weight, sex, natural health situation, the activity intensity of compound, Time of Administration, accretion rate, the serious journey of illness Degree, specific dosage and application method are judged by attending doctor according to the specific state of an illness of patient.
Brief description of the drawings
Accompanying drawing 1 shows that cell is targeted after compound protects 3h in advance, uses H202Processing, it is placed in 37 DEG C of incubators and is incubated 5h, use Mtt assay detects the result of cell survival rate.
Accompanying drawing 2 shows that cell is targeted after compound protects 3h in advance, with 6-0HDA processing, is placed in 37 DEG C of incubators and is incubated 48h, Using the result of mtt assay detection cell survival rate.
Embodiment
In order to which the present invention is expanded on further, a series of embodiments are given below.These embodiments be entirely it is illustrative, it Only be used for the present invention is specifically described, be not construed as limitation of the present invention.Unless otherwise specified, following implementations " decompression is spin-dried for solvent " refers generally to " Rotary Evaporators solvent evaporated is used under water pump reduced pressure " in example.Known of the present invention Beginning raw material can be used or synthesized according to methods known in the art, or can be in lark prestige Science and Technology Ltd., Aladdin Bought at the Reagent Companies such as reagent (Shanghai) Co., Ltd., Beijing coupling Science and Technology Ltd..
Embodiment 1：The preparation of E-2- (3,4- dihydroxy) styryl benzyl sulfones (3a)
Step 1: the preparation of 2- benzylthios acetic acid (1a)
TGA (0.69ml, 10mmol) is dissolved in the reaction bulb for filling 15ml methanol, dropwise addition NaOH (0.8g, Methanol solution (10ml) 20mmol), bromobenzyl (1.19ml, 10mmol) is then slowly added dropwise, 6h is stirred at room temperature, TLC detections are anti- Should be complete, decompression is spin-dried for solvent, adds a small amount of water, and it is 7 to be neutralized to pH value with 1N hydrochloric acid, ethyl acetate extraction, merges ester layer and uses Saturated common salt water washing, anhydrous sodium sulfate drying, it is solid to obtain white with silica gel column separating purification (petrol ether/ethyl acetate elution) Body 1a, 1.7g, yield 93.4%, m.p.62-63 DEG C.
1H NMR (400MHz, DMSO-d6) δ=12.61 (s, 1H, COOH), 7.24-7.35 (m, 5H, ArH), 3.81 (s, 2H, SCH2COOH), 3.12 (s, 2H, ArCH2S).
Step 2: the preparation of 2- benzyls sulfonyl acetic acid (2a)
2- benzylthios acetic acid (182mg, 1mmol) is dissolved in the reaction bulb for filling acetic acid (3ml), adds 30% mistake Hydrogen peroxide solution (1ml), reaction is stirred at room temperature overnight, TLC detection reactions are complete, and reaction solution is added drop-wise in frozen water and stirred, second Acetoacetic ester extracts, and merges ester layer saturated common salt water washing, anhydrous sodium sulfate drying, with silica gel column separating purification (petroleum ether/second Acetoacetic ester elutes) obtain white solid 2a, 180mg, yield 81.9%, m.p.138-140 DEG C.
1H NMR (400MHz, DMSO-d6) δ=13.51 (s, 1H, COOH), 7.39-7.40 (m, 5H, ArH), 4.62 (s, 2H, SCH2COOH), 4.15 (s, 2H, ArCH2S).
Step 3: the preparation of E-2- (3,4- dihydroxy) styryl benzyl sulfones (3a)
2- benzyls sulfonyl acetic acid (848mg, 4mmol) is dissolved in the reaction bulb for filling anhydrous THF (10m]), add β- Alanine (178mg, 2mmol), the THF (10ml) that 3,4 4-dihydroxy benzaldehydes (276mg, 2mmol) are then slowly added dropwise are molten Liquid, molecular sieve is added, agitating and heating backflow, overnight, TLC detection reaction product points no longer increase, and terminating reaction, subtract for lucifuge reaction Pressure is spin-dried for solvent, adds a small amount of water, ethyl acetate extraction, merges ester layer saturated common salt water washing, anhydrous sodium sulfate drying, use Silica gel column separating purification (petrol ether/ethyl acetate elution) obtains white solid 3a, 360mg, yield 62.1%, m.p.133- 134℃。
1H NMR (400MHz, DMSO-d6) δ=9.74 (s, 1H, p-ArOH), 9.24 (s, 1H, m-ArOH), 6.76-7.41 (m, 10H, ArH, CH=CH), 4.50 (s, 2H, ArCH2SO2).
13CNMR (100MHz, DMSO-d6) δ=149.34,146.11,144.27,131.56,129.57,128.76, 128.68,124.21,122.43,122.19,116.20,115.48,60.52
HR-MS(ESI+)m/z：291.06856[M+H]+.Found：291.06797[M+H]+, 308.09453 [M+NH4]+, 313.04980[M+Na]+
Embodiment 2：The preparation of E-2- (3,4- diacetoxy) styryl benzyl sulfones (4a)
Compound E-2- (3,4- dihydroxy) styryl benzyl sulfones (0.19g, 0.66mmol) are dissolved in aceticanhydride In (10ml), anhydrous pyridine (0.11ml, 1.34mmol) is added, stirring reaction 5min, TLC detection reaction is complete, by reaction solution Pour into frozen water and stir, ethyl acetate extraction, ester layer saturated common salt water washing, anhydrous sodium sulfate drying, with silica gel post separation Purifying (petrol ether/ethyl acetate elution) obtains white cotton shape solid 4a, 220mg, yield 89.8%, m.p.163-164 DEG C.
1H NMR (400MHz, CDCl3) δ=7.24-7.41 (m, 9H, ArH, ArCH=CHSO2), 6.66 (d, J= 15.2Hz, 1H, ArCH=CHSO2), 4.32 (s, 2H, ArCH2SO2), 2.33 (s, 3H, p-ArOCOCH3), 2.32 (s, 3H, m- ArOCOCH3).
13C NMR (100MHz, CDCl3) δ=167.98,167.88,144.36,143.66,142.52,130.93, 129.04,128.97,127.88,126.87,125.09,124.28,123.34,61.87,20.62,20.67
HR-MS(ESI+)m/z：375.08969[M+H]+.Found：375.08979[M+H]+, 392.11623 [M+NH4]+
Embodiment 3：The preparation of E-2- (3,4- dihydroxy) styryl -4- chlorobenzyls sulfones (3b)
Step 1: the preparation of 2- (4- chlorine) benzylthio acetic acid (1b)
Using as above compound 1a synthetic method, white solid 1d, yield are obtained by reactant of 4- bromine chlorides 85.5%, m.p.51-52 DEG C.
Step 2: the preparation of 2- (4- chlorine) benzyl sulfonyl acetic acids (2b)
Using as above compound 2a synthetic method, white solid is obtained as reactant using 2- (4- chlorine) benzylthio acetic acid 2d, yield 82.1%, m.p.144-145 DEG C.
Step 3：The preparation of E-2- (3,4- dihydroxy) styryl -4- chlorobenzyls sulfones (3b)
Using as above compound 3a synthetic method, white solid is obtained as reactant using 2- (4- chlorine) benzyl sulfonyl acetic acid 3b, yield 71.1%, m.p.166-167 DEG C.
1H NMR (400MHz, DMSO-d6) δ=9.75 (s, 1H, p-ArOH), 9.23 (s, 1H, m-ArOH), 6.76-7.45 (m, 9H, ArH, CH=CH), 4.53 (s, 2H, ArCH2SO2).
13C NMR (100MHz, DMSO-d6) δ=149.47,146.12,144.53,133.60,133.31,128.82, 128.74,124.14,122.52,121.94,116.20,115.53,59.63
HR-MS(ESI+)m/z：325.02958[M+H]+.Found：325.02885[M+H]+, 342.05537 [M+NH4]+
Embodiment 4：The preparation of E-2- (3,4- diacetoxy) styryl -4- chlorobenzyls sulfones (4b)
It is anti-with E-2- (3,4- dihydroxy) styryl -4- chlorobenzyl sulfones using as above compound 4a synthetic method Thing is answered to obtain white solid 4b, yield 75.5%, m.p.136-137 DEG C.
1H NMR (400MHz, CDCl3) δ=7.25-7.41 (m, 8H, ArH, ArCH=CHSO2), 6.67 (d, J= 15.6Hz, 1H, ArCH=CHSO2), 4.28 (s, 2H, ArCH2SO2), 2.33 (s, 3H, p-ArOCOCH3), 2.32 (s, 3H, m- ArOCOCH3),
13C NMR (100MHz, CDCl3) δ=167.99,167.87,144.50,144.06,142.63,135.30, 132.22,130.75,129.22,126.99,126.34,124.85,124.35,123.39,61.05,20.68,20.63
HR-MS(ESI+)m/z：409.05071[M+H]+.Found：409.05014[M+H]+, 426.07673 [M+NH4]+
Embodiment 5：The preparation of E-2- (3,4- dihydroxy) styryl -4- t-butylbenzyls sulfones (3c)
Step 1: the preparation of 2- (the 4- tert-butyl groups) benzylthio acetic acid (1c)
Using as above compound 1a synthetic method, white solid 1b, yield are obtained by reactant of 4- tert-butyl groups bromobenzyl 73.9%, m.p.75-76 DEG C.
Step 2: the preparation of 2- (the 4- tert-butyl groups) benzyl sulfonyl acetic acids (2c)
Using as above compound 2a synthetic method, it is solid to obtain white using 2- (the 4- tert-butyl groups) benzylthio acetic acid as reactant Body 2b, yield 82.3%, m.p.179-180 DEG C.
Step 3: the preparation of E-2- (3,4- dihydroxy) styryl -4- t-butylbenzyls sulfones (3c)
Using as above compound 3a synthetic method, white is obtained as reactant using 2- (the 4- tert-butyl groups) benzyl sulfonyl acetic acid Solid 3c, yield 65.0%, m.p.206-208 DEG C.
1H NMR (400MHz, DMSO-d6) δ=9.74 (s, 1H, p-ArOH), 9.24 (s, 1H, m-ArOH), 6.77-7.39 (m, 9H, ArH, CH=CH), 4.44 (s, 2H, ArCH2SO2), 1.27 (s, 9H, (CH3)3CAr).
13C NMR (100MHz, DMSO-d6) δ=151.12,149.36,146.12,144.13,131.28,126.32, 125.60,124.28,122.51,122.41,116.20,115.53,60.14,34.78,31.53
HR-MS(ESI+)m/z：347.13116[M+H]+.Found：347.13086[M+H]+, 364.15711 [M+NH4]+
Embodiment 6：The preparation of E-2- (3,4- diacetoxy) styryl -4- t-butylbenzyls sulfones (4c)
Using as above compound 4a synthetic method, with E-2- (3,4- dihydroxy) styryl -4- t-butylbenzyl sulfones White solid 4c is obtained for reactant, yield 80.3%, m.p.146-147 DEG C.
1H NMR (400MHz, CDCl3) δ=7.23-7.41 (m, 8H, ArH, ArCH=CHSO2), 6.66 (d, J= 15.2Hz, 1H, ArCH=CHSO2), 4.28 (s, 2H, ArCH2SO2), 2.31 (s, 6H, 2ArOCOCH3), 2.33 (s, 3H, COCH3), 1.31 (s, 9H, (CH3)3CAr),
13C NMR (100MHz, CDCl3) δ=167.96,167.89,152.15,144.31,143.52,142.58, 131.05,130.77,130.62,126.82,125.95,125.33,124.68,124.26,123.34,61.55,34.70, 31.25,20.68,20.62
HR-MS(ESI+)m/z：431.15229[M+H]+.Found：431.15244[M+H]+, 448.17909 [M+NH4]+
Embodiment 7：The preparation of E-2- (3,4- dihydroxy) styryl -4- trifluoromethyl benzyls sulfones (3d)
Step 1: the preparation of 2- (4- trifluoromethyls) benzylthio acetic acid (1d)
Using as above compound 1a synthetic method, white solid 1c is obtained by reactant of 4- trifluoromethyl benzyl bromines, is received Rate 88.0%, m.p.64-65 DEG C.
1H NMR (400MHz, DMSO-d6) δ=12.68 (s, 1H, COOH), 7.55-7.71 (m, 4H, ArH), 3.92 (s, 2H, SCH2COOH), 3.16 (s, 2H, ArCH2S).
Step 2: the preparation of 2- (4- trifluoromethyls) benzyl sulfonyl acetic acids (2d)
Using as above compound 2a synthetic method, white is obtained as reactant using 2- (4- trifluoromethyls) benzylthio acetic acid Solid 2c, yield 86.8%, m.p.158-159 DEG C.
Step 3: the preparation of E-2- (3,4- dihydroxy) styryl -4- trifluoromethyl benzyls sulfones (3d)
Using as above compound 3a synthetic method, obtained using 2- (4- trifluoromethyls) benzyl sulfonyl acetic acid as reactant white Color solid 3d, yield 95.0%, m.p.202-203 DEG C.
1H NMR (400MHz, DMSO-d6) δ=9.24 (s, 1H, p-ArOH), 9.78 (s, 1H, m-ArOH), 6.77-7.76 (m, 9H, ArH, CH=CH), 4.66 (s, 2H, ArCH2SO2).
13C NMR (100MHz, DMSO-d6) δ=149.53,146.13,144.73,134.45,125.65,125.61, 124.11,122.59,121.92,116.20,115.57,59.93
HR-MS(ESI+)m/z：359.05594[M+H]+.Found：359.05518[M+H]+
Embodiment 8：The preparation of E-2- (3,4- diacetoxy) styryl -4- trifluoromethyl benzyls sulfones (4d)
Using as above compound 4a synthetic method, with E-2- (3,4- dihydroxy) styryl -4- trifluoromethyl benzyls Sulfone is that reactant obtains white solid 4d, yield 88.3%, m.p.133-135 DEG C.
1H NMR (400MHz, CDCl3) δ=7.26-7.69 (m, 8H, ArH, ArCH=CHSO2), 6.60 (d, J= 15.6Hz, 1H, ArCH=CHSO2), 4.37 (s, 2H, ArCH2SO2), 2.33 (s, 6H, 2COCH3).
13C NMR (100MHz, CDCl3) δ=168.01,167.87,144.60,144.40,142.66,131.81, 131.36,130.63,127.01,125.93,125.89,124.74,124.38,123.42,61.30,20.66,20.61
HR-MS(ESI+)m/z：443.07707[M+H]+.Found：443.07684[M+H]+, 460.10333 [M+NH4]+
Embodiment 9：The preparation of E-2- (3,4- dihydroxy) styryl -4- methoxy-benzyls sulfones (3e)
Step 1: the preparation of 2- (4- methoxyl groups) benzylthio acetic acid (1e)
Using as above compound 1a synthetic method, white solid 1e, yield are obtained by reactant of 4- methoxybenzyls bromine 80.0%, m.p.47-48 DEG C.
1H NMR (400MHz, DMSO-d6) δ=12.57 (s, 1H, COOH), 6.88-7.23 (m, 4H, ArH), 3.75 (s, 2H, SCH2COOH), 3.74 (s, 3H, CH3O), 3.09 (s, 2H, ArCH2S).
Step 2: the preparation of 2- (4- methoxyl groups) benzyl sulfonyl acetic acids (2e)
Using as above compound 2a synthetic method, it is solid to obtain white using 2- (4- methoxyl groups) benzylthio acetic acid as reactant Body 2e, yield 80.9%, m.p.155-156 DEG C.
1H NMR (400MHz, DMSO-d6) δ=13.47 (s, 1H, COOH), 6.97-7.33 (m, 4H, ArH), 4.55 (s, 2H, SCH2COOH), 4.12 (s, 2H, ArCH2S), 3.77 (s, 3H, CH3OAr).
Step 3: the preparation of E-2- (3,4- dihydroxy) styryl -4- methoxy-benzyls sulfones (3e)
Using as above compound 3a synthetic method, white is obtained as reactant using 2- (4- methoxyl groups) benzyl sulfonyl acetic acid Solid 3e, yield 54.7%, m.p.205-206 DEG C.
1H NMR (400MHz, DMSO-d6) δ=9.73 (s, 1H, p-ArOH), 9.23 (s, 1H, m-ArOH), 6.76-7.28 (m, 9H, ArH, CH=CH), 4.41 (s, 2H, ArCH2SO2), 3.74 (s, 3H, CH3OAr).
13C NMR (100MHz, DMSO-d6) δ=159.70,149.34,146.11,144.09,132.73,124.27, 122.39,122.26,121.29,116.20,115.47,114.24,59.85,55.54
HR-MS(ESI+)m/z：338.10567[M+NH4]+.Found：338.10517[M+NH4]+
Embodiment 10：The preparation of E-2- (3,4- diacetoxy) styryl -4- methoxy-benzyls sulfones (4e)
Using as above compound 4a synthetic method, with E-2- (3,4- dihydroxy) styryl -4- methoxy-benzyl sulfones White solid 4e is obtained for reactant, yield 90.4%, m.p.101-102 DEG C.
1H NMR (400MHz, CDCl3) δ=7.38 (d, J=15.6Hz, 1H, ArCH=CHSO2), 6.91-7.33 (m, 7H, ArH), 6.65 (d, J=15.6Hz, 1H, ArCH=CHSO2), 4.27 (s, 2H, ArCH2SO2), 3.83 (s, 3H, CH3OAr), 2.33 (s, 3H, p-ArOCOCH3), 2.32 (s, 3H, m-ArOCOCH3),
13C NMR (100MHz, CDCl3) δ=167.98,167.88,160.18,144.32,143.50,142.58, 132.11,131.02,126.86,125.18,124.27,123.32,119.63,114.42,61.24,55.33,20.67, 20.63
HR-MS(ESI+)m/z：422.12680[M+NH4]+.Found：422.12660[M+NH4]+, 427.08177 [M+ Na]+
Embodiment 11：The preparation of E-2- (3,4- dihydroxy) styryl phenethyl sulfones (3f)
Step 1: the preparation of 2- phenethyls ethyl thioglycollic acid (1f)
Using as above compound 1a synthetic method, white solid 1f, yield are obtained by reactant of phenethyl bromide 75.1%, m.p.52-53 DEG C.
Step 2: the preparation of 2- phenethyls sulfonyl acetic acid (2f)
Using as above compound 2a synthetic method, white solid 2f is obtained by reactant of 2- phenethyls ethyl thioglycollic acid, Yield 65.8%, m.p.80-81 DEG C.
Step 3: the preparation of E-2- (3 ,-dihydroxy) styryl phenethyl sulfone (3f)
Using as above compound 3a synthetic method, white solid is obtained using 2- phenethyl sulfonyl acetic acids as reactant 3f, yield 62.5%, m.p.142-143 DEG C.
1H NMR (400MHz, DMSO-d6) δ=9.75 (s, 1H, p-ArOH), 9.23 (s, 1H, m-ArOH), 6.79-7.34 (m, 10H, ArH, CH=CH), 3.43-3.47 (m, 2H, ArCH2CH2SO2), 2.95-3.00 (m, 2H, ArCH2CH2SO2).
13C NMR (100MHz, DMSO-d6) δ=149.35,146.11,143.97,138.68,128.95,126.97, 124.32,122.50,122.45,116.17,115.71,55.37,28.71
HR-MS(ESI+)m/z：305.08421[M+H]+.Found：305.08341[M+H]+, 322.10988 [M+NH4]+
Embodiment 12：The preparation of E-2- (3,4- diacetoxy) styryl phenethyl sulfones (4f)
Using as above compound 4a synthetic method, with E-2- (3,4- dihydroxy) styryl phenethyl sulfones for reactant Obtain white solid 4f, yield 89.9%, m.p.99-100 DEG C.
1H NMR (400MHz, CDCl3) δ=7.54 (d, J=15.6Hz, 1H, ArCH=CHSO2), 7.22-7.36 (m, 8H, ArH), 6.65 (d, J=15.6Hz, 1H, ArCH=CHSO2), 3.35-3.39 (m, 2H, ArCH2CH2SO2), 3.13- 3.17 (m, 2H, ArCH2CH2SO2), 2.34 (s, 3H, p-ArOCOCH3), 2.33 (s, 3H, m-ArOCOCH3).
13C NMR (100MHz, CDCl3) δ=168.01,167.86,144.39,143.06,142.60,137.46, 130.91,128.97,128.50,127.07,127.01,125.95,124.25,123.36,56.54,28.89,20.68, 20.63
HR-MS(ESI+)m/z：389.10534[M+H]+.Found：389.10514[M+H]+, 406.13183 [M+NH4]+
Embodiment 13：The preparation of E-2- (3,4- dihydroxy) styryl phenylpropyl sulfones (3g)
Step 1: the preparation of 2- phenylpropyls ethyl thioglycollic acid (1g)
Using as above compound 1a synthetic method, colourless liquid 1g, yield are obtained by reactant of phenylpropyl alcohol bromide 90.5%.
1H NMR (400MHz, DMSO-d6) δ=12.51 (s, 1H, COOH), 7.16-7.28 (m, 5H, ArH), 3.22 (s, 2H, SCH2COOH), 2.63 (t, 2H, SCH2CH2CH2Ar), 2.57 (t, 2H, SCH2CH2CH2Ar), 1.81 (m, 2H, SCH2CH2CH2Ar)
Step 2: the preparation of 2- phenylpropyls sulfonyl acetic acid (2g)
Using as above compound 2a synthetic method, white solid 2g is obtained by reactant of 2- phenylpropyls ethyl thioglycollic acid, Yield 70.0%, m.p.96-97 DEG C.
1H NMR (400MHz, DMSO-d6) δ=13.40 (s, 1H, COOH), 7.19-7.31 (m, 5H, ArH), 4.26 (s, 2H, SO2CH2COOH), 3.25 (t, 2H, SO2CH2CH2CH2Ar), 2.70 (t, 2H, SO2CH2CH2CH2Ar), 2.01 (m, 2H, SO2CH2CH2CH2Ar)
Step 3: the preparation of E-2- (3,4- dihydroxy) styryl phenylpropyl sulfones (3g)
Using as above compound 3a synthetic method, white solid is obtained using 2- phenylpropyl sulfonyl acetic acids as reactant 3g, yield 70.8%, m.p.117-118 DEG C.
1H NMR (400MHz, DMSO-d6) δ=9.75 (s, 1H, p-ArOH), 9.21 (s, 1H, m-ArOH), 6.78-7.30 (m, 10H, ArH, ArCH=CHSO2), 3.10 (t, 2H, SO2CH2CH2CH2Ar), 2.70 (t, 2H, SO2CH2CH2CH2Ar), 1.94 (m, 2H, SO2CH2CH2CH2Ar)
13C NMR (100MHz, DMSO-d6) δ=149.33,146.11,143.87,141.22,128.91,128.82, 126.56,124.30,122.56,122.49,116.16,115.78,54.03,33.86,24.72
HR-MS(ESI+)m/z：319.09986[M+H]+.Found：319.09927[M+H]+, 341.08147 [M+Na]+
Embodiment 14：The preparation of E-2- (3,4- diacetoxy) styryl phenylpropyl sulfones (4g)
Using as above compound 4a synthetic method, with E-2- (3,4- dihydroxy) styryl phenylpropyl sulfones for reactant Obtain white solid 4g, yield 82.5%, m.p.76-77 DEG C.
1H NMR (400MHz, CDCl3) δ=7.54 (d, J=15.6Hz, 1H, ArCH=CHSO2), 7.18-7.42 (m, 8H, ArH), 6.75 (d, J=15.6Hz, 1H, ArCH=CHSO2), 3.05 (m, 2H, SO2CH2CH2CH2Ar), 2.79 (t, 2H, SO2CH2CH2CH2Ar), 2.34 (s, 3H, p-ArOCOCH3), 2.33 (s, 3H, m-ArOCOCH3), 2.16 (m, 2H, SO2CH2CH2CH2Ar).
13C NMR (100MHz, CDCl3) δ=168.02,167.85,144.39,143.05,142.63,139.80, 130.93,128.70,128.48,127.03,126.53,125.81,124.29,123.29,54.31,34.21,24.14, 20.67 20.63
HR-MS(ESI+)m/z：403.12099[M+H]+.Found：403.12080[M+H]+
Embodiment 15：The preparation of E-2- (3,4- dihydroxy) styryl benzene butyl sulfones (3h)
Step 1: the preparation of 2- benzene butyl ethyl thioglycollic acids (1h)
Using as above compound 1a synthetic method, colourless liquid 1h, yield are obtained by reactant of benzene butyl bromide 91.3%.
1H NMR (400MHz, DMSO-d6) δ=12.50 (s, 1H, COOH), 7.15-7.30 (m, 5H, ArH), 3.20 (s, 2H, SCH2COOH), 2.55-2.62 (m, 4H, SCH2CH2CH2CH2Ar), 1.64 (m, 2H, SCH2CH2CH2CH2Ar), 1.54 (m, 2H, SCH2CH2CH2CH2Ar)
Step 2: the preparation of 2- benzene butyl sulfonyl acetic acids (2h)
Using as above compound 2a synthetic method, white solid 2h is obtained using 2- benzene butyl ethyl thioglycollic acids as reactant, Yield 77.7%, m.p.76-77 DEG C.
1H NMR (400MHz, DMSO-d6) δ=13.43 (s, 1H, COOH), 7.17-7.31 (m, 5H, ArH), 4.24 (s, 2H, SO2CH2COOH), 3.32 (m, 2H, SOCH2CH2CH2CH2Ar), 2.61 (m, 2H, SOCH2CH2CH2CH2Ar), 1.68-1.73 (m, 4H, SOCH2CH2CH2CH2Ar)
13C NMR (100MHz, DMSO-d6) δ=165.20,142.04,128.77,126.27,57.80,52.95, 35.00,30.03,21.09
MS(ESI)m/z：257.0970[M+H]+, 279.1076 [M+Na]+.
Step 3: the preparation of E-2- (3 ,-dihydroxy) styryl benzene butyl sulfone (3h)
Using as above compound 3a synthetic method, white solid is obtained using 2- benzene butyl sulfonyl acetic acids as reactant 3h, yield 77.0%, m.p.99-100 DEG C.
1H NMR (400MHz, DMSO-d6) δ=9.75 (s, 1H, p-ArOH), 9.23 (s, 1H, m-ArOH), 6.79-7.28 (m, 10H, ArH, ArCH=CHSO2), 3.15 (m, 2H, SOCH2CH2CH2CH2Ar), 2.58 (m, 2H, SOCH2CH2CH2CH2Ar), 1.65-1.67 (m, 4H, SOCH2CH2CH2CH2Ar)
13C NMR (100MHz, DMSO-d6) δ=149.29,146.11,143.72,142.11,128.78,128.71, 126.21,124.32,122.66,122.42,116.17,115.70,60.23,54.20,34.93,29.94
HR-MS(ESI+)m/z：333.11551[M+H]+.Found：333.11499[M+H]+
Embodiment 16：The preparation of E-2- (3,4- diacetoxy) styryl benzene butyl sulfones (4h)
Using as above compound 4a synthetic method, with E-2- (3,4- dihydroxy) styryl benzene butyl sulfone for reactant Obtain white solid 4h, yield 88.5%, m.p.79-80 DEG C.
1H NMR (400MHz, CDCl3) δ=7.54 (d, J=15.6Hz, 1H, ArCH=CHSO2), 7.16-7.42 (m, 8H, ArH), 6.76 (d, J=15.6Hz, 1H, ArCH=CHSO2), 3.08 (m, 2H, SOCH2CH2CH2CH2Ar), 2.67 (m, 2H, SOCH2CH2CH2CH2Ar), 2.35 (s, 3H, p-ArOCOCH3), 2.34 (s, 3H, m-ArOCOCH3), 1.77-1.90 (m, 4H, SOCH2CH2CH2CH2Ar)
13C NMR (100MHz, CDCl3) δ=168.02,167.85,144.38,143.05,142.64,141.21, 130.97,128.49,128.36,127.00,126.10,124.29,123.29,54.97,35.31,30.10,22.21, 20.67
HR-MS(ESI+)m/z：417.13664[M+H]+.Found：417.13620[M+H]+, 434.16292 [M+NH4]+
Embodiment 17：The preparation of E-2- (3,4- dimethoxy) styryl phenethyl sulfones (4i)
2- benzyls sulfonyl acetic acid (260mg, 1.15mmol) is dissolved in the reaction bulb for filling anhydrous THF (10ml), added Enter pyrrolidines (0.09ml, 1mmol), the THF (10ml) of Veratraldehyde (170mg, 1mmol) is then slowly added dropwise Solution, molecular sieve being added, agitating and heating backflow, overnight, TLC detection reaction product points no longer increase, terminating reaction for lucifuge reaction, Decompression is spin-dried for solvent, adds a small amount of water, and ethyl acetate extracts, merging ester layer saturated common salt water washing, anhydrous sodium sulfate drying, White solid 4i, 190mg, yield 63.1%, m.p.132- are obtained with silica gel column separating purification (petrol ether/ethyl acetate elution) 133℃。
Embodiment 18：The preparation of the chloro- 4 '-ethoxybenzene methyl sulfones (4j) of E-2- styryls -1-
Step 1: the preparation of 2- (4- ethyoxyls) benzylthio acetic acid (1j)
Using as above compound 1a synthetic method, white solid 1j, yield are obtained by reactant of 4- ethoxy benzylidenes bromine 89.5%.
HR-MS(ESI+)m/z：227.07364[M+H]+.Found：227.07388[M+H]+。
Step 2: the preparation of 2- (4- ethyoxyls) phenethyl sulfonyl acetic acids (2j)
Using as above compound 2a synthetic method, obtained using 2- (4- ethyoxyls) phenethyl sulfonyl acetic acid as reactant White solid 2j, yield 86.8%.
HR-MS(ESI+)m/z：259.06347[M+H]+.Found：259.06310[M+H]+。
Step 3: the preparation of E-2- styryls -4 '-ethoxybenzene methyl sulfone (3j)
Using as above compound 3a synthetic method, obtained using 2- (4- ethyoxyls) phenethyl sulfonyl acetic acid as reactant White solid 3j, yield 85.1%.
HR-MS(ESI+)m/z：303.10494[M+H]+.Found：303.10523[M+H]+。
Step 4: the preparation of the chloro- 4 '-ethoxybenzene methyl sulfones (4j) of E-2- styryls -1-
E-2- styryls -4 '-ethoxybenzene methyl sulfone 605mg (2.00mmol) is placed in 100ml reaction bulbs, is added 40ml chloroforms, N-chlorosuccinimide (NCS) 255mg (1.91mmol), 2,2 '-azodiisobutyronitrile are added after stirring and dissolving (AIBN) 2mg (12 μm of ol), back flow reaction 8 hours, backflow start latter 1 hour, 3 hours AIBN for being separately added into a collection of 1mg. After the completion of the monitoring reaction of TLC point samples, decompression is spin-dried for solvent.Dissolved, with dichloromethane with the dichloromethane of minimum volume: n-hexane (2: 1) it is eluant, eluent, 505mg white solid 4j, yield 75.0% can be obtained by being rapidly purified through flash silica gel column.
HR-MS(ESI+)m/z：337.06597 339.06302 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 337.06558 339.06261 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 19：The preparation of the bromo- 4 '-ethoxybenzene methyl sulfones (5j) of E-2- styryls -1-
Using as above compound 4j synthetic method, with E-2- styryls -4 '-ethoxybenzene methyl sulfone (3j) and N- bromines Slightly yellow solid 5j, yield 78.2% are obtained for succinimide (NBS) reaction.
HR-MS(ESI+)m/z：381.01545 383.01341 [M+H]+(Br isotopic peaks, 1: 1) .Found： 381.01515 383.01311 [M+H]+(Br isotopic peaks, 1: 1).
Embodiment 20：The preparation of the chloro- 3 '-nitrophenethyl sulfones (3k) of E-2- (3,4- dihydroxy) styryl -1-
Step 1: the preparation of 2- [chloro- (3 '-nitro) phenethyls of 1-] ethyl thioglycollic acid (1k)
Using as above compound 1a synthetic method, obtained using 1- (the bromo- 2- chloroethyls of 2-) -3- nitrobenzene as reactant white Color solid 1k, yield 49.5%.
HR-MS(ESI+)m/z：276.00918 278.00623 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 276.00947 278.00651 [M+H]+(Cl isotopic peaks, 3: 1).
Step 2: the preparation of 2- [chloro- (3 '-nitro) phenethyls of 1-] sulfonyl acetic acid (2k)
Using as above compound 2a synthetic method, using 2- [chloro- (3 '-nitro) phenethyls of 1-] ethyl thioglycollic acid as reactant Obtain white solid 2k, yield 56.8%.
HR-MS(ESI+)m/z：305.98336 307.98041 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 305.98301 307.98006 [M+H]+(Cl isotopic peaks, 3: 1).
Step 3: the preparation of the chloro- 3 '-nitrophenethyl sulfones (3k) of E-2- (3,4- dihydroxy) styryl -1-
Using as above compound 3a synthetic method, using 2- [chloro- (3 '-nitro) phenethyls of 1-] sulfonyl acetic acids as reaction Thing obtains faint yellow solid 3k, yield 65.1%.
HR-MS(ESI+)m/z：382.01466 384.01171 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 382.01491 384.01195 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 21：The preparation of the chloro- 3 '-nitrophenethyl sulfones (4k) of E-2- (3,4- diethoxy) styryl -1-
The chloro- 3 '-nitrophenethyl sulfone 770mg (2mmol) of E-2- (3,4- dihydroxy) styryl -1- are dissolved in 20ml bis- In the mixed liquor of chloromethanes and 20ml water, TBAB 60mg (0.19mmol), sodium hydroxide 80mg (2mmol) are added, Iodoethane 0.16ml (2mmol), 35 degree of isothermal reactions 8 hours are instilled after stirring and dissolving.After the completion of reaction add 30ml water and 30ml dichloromethane liquid separations, and washed with dichloromethane (30ml*2) extraction, combined dichloromethane layer, decompression is spin-dried for solvent silica gel color Post purifying is composed, with the mixed solvent gradient elution of dichloromethane/n-hexane, obtains faint yellow solid 4k, yield 63.5%.
HR-MS(ESI+)m/z：438.07726 440.07431 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 438.07772 440.07476 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 22：The preparation of the chloro- 3 '-leptodactyline sulfone (31) of E-2- (4- hydroxyls) styryl -1,2- bis-
Step 1: the preparation of 2- [1,2- bis- chloro- (3 '-hydroxyl) phenethyl] ethyl thioglycollic acid (11)
Using as above compound 1a synthetic method, it is white to be that reactant obtains with 3- (bromo- 1, the 2- Dichloroethyls of 2-) phenol Color solid 11, yield 47.8%.
HR-MS(ESI+)m/z：280.98005 282.97710 [M+H]+(Cl isotopic peaks, 5: 3) .Found： 280.98045 282.97751 [M+H]+(Cl isotopic peaks, 5: 3).
Step 2: the preparation of 2- [1,2- bis- chloro- (3 '-hydroxyl) phenethyl] sulfonyl acetic acid (21)
It is anti-with 2- [1,2- bis- chloro- (3 '-hydroxyl) phenethyl] ethyl thioglycollic acid using as above compound 2a synthetic method Thing is answered to obtain white solid 2l, yield 52.7%.
HR-MS(ESI+)m/z：312.96987 314.96692 [M+H]+(Cl isotopic peaks, 5: 3) .Found： 312.97021 314.96725 [M+H]+(Cl isotopic peaks, 5: 3).
Step 3: the preparation of the chloro- 3 '-leptodactyline sulfone (31) of E-2- (4- hydroxyls) styryl -1,2- bis-
Using as above compound 3a synthetic method, it is with 2- [1,2- bis- chloro- (3 '-hydroxyl) phenethyl] sulfonyl acetic acid Reactant obtains faint yellow solid 3l, yield 43.1%.
HR-MS(ESI+)m/z：373.00626 375.00331 [M+H]+(Cl isotopic peaks, 5: 3) .Found： 373.00601 375.00306 [M+H]+(Cl isotopic peaks, 5: 3).
Embodiment 23：The chloro- 3 '-isopropoxy benzene ethyl sulfone (41) of E-2- (4- isopropoxies) styryl -1,2- bis- Prepare
Using as above compound 4k synthetic method, with bis- chloro- 3 '-hydroxy benzenes of E-2- (4- hydroxyls) styryl -1,2- Ethyl sulfone is that reactant obtains faint yellow solid 4l, yield 57.3%.
HR-MS(ESI+)m/z：457.10016 459.09721 [M+H]+(Cl isotopic peaks, 5: 3) .Found： 457.10044 459.09749 [M+H]+(Cl isotopic peaks, 5: 3).
Embodiment 24：The preparation of the chloro- 3 '-cyano group phenylpropyl sulfones (3m) of E-2- (4- hydroxyls) styryl -2-
Using three step synthetic methods of compound 3a in such as embodiment 1, using 3- (the bromo- 2- chloropropyls of 3-) benzonitriles as reaction Thing obtains faint yellow solid 3m, three-step reaction total recovery 24.7%.
HR-MS(ESI+)m/z：362.06122 364.05827 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 362.06144 364.05849 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 25：The preparation of the chloro- 3 '-cyano group phenylpropyl sulfones (4m) of E-2- (4- tert-butoxies) styryl -2-
Using as above compound 4k synthetic method, with the chloro- 3 '-cyano group phenylpropyls of E-2- (4- hydroxyls) styryl -2- Sulfone is that reactant obtains faint yellow solid 4m, yield 51.6%.
HR-MS(ESI+)m/z：418.12382 420.12087 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 418.12407 420.12113 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 26：E-2- (4- hydroxyls) styryl -1- methyl -3 ', the preparation of 5 '-dimethyl benzyl sulfone (3n)
It is anti-with 1- (1- bromoethyls) -3,5- dimethyl benzenes using three step synthetic methods of compound 3a in such as embodiment 1 Thing is answered to obtain white solid 3n, three-step reaction total recovery 48.6%.
HR-MS(ESI+)m/z：317.12059[M+H]+.Found：317.12023[M+H]+。
Embodiment 27：E-2- (4- rings propoxyl group) styryl -1- methyl -3 ', the system of 5 '-dimethyl benzyl sulfone (4n) It is standby
Using as above compound 4k synthetic method, with E-2- (4- hydroxyls) styryl -1- methyl -3 ', 5 '-dimethyl Benzyl sulfone is that reactant obtains white solid 4n, yield 67.6%.
HR-MS(ESI+)m/z：357.15189[M+H]+.Found：357.15151[M+H]+。
Embodiment 28：E-2- (4- hydroxyls) styryl -1- methyl -3 ', the preparation of 5 '-diethylbenzene methyl sulfone (3o)
It is anti-with 1- (1- bromoethyls) -3,5- diethylbenzenes using three step synthetic methods of compound 3a in such as embodiment 1 Thing is answered to obtain white solid 3o, three-step reaction total recovery 45.9%.
HR-MS(ESI+)m/z：345.15189[M+H]+.Found：345.15159[M+H]+。
Embodiment 29：E-2- (4- cyclohexyl) styryl -1- methyl -3 ', the preparation of 5 '-diethylbenzene methyl sulfone (4o)
Using as above compound 4k synthetic method, with E-2- (4- hydroxyls) styryl -1- methyl -3 ', 5 '-diethyl Benzyl sulfone is that reactant obtains white solid 4o, yield 62.8%.
HR-MS(ESI+)m/z：427.23014[M+H]+.Found：427.22987[M+H]+。
Embodiment 30：E-2- (4- hydroxyls) styryl -1- methyl -3 ', the preparation of 5 '-dihydroxy benzenes methyl sulfone (3p)
Using three step synthetic methods of compound 3a in such as embodiment 1, using 5- (1- bromoethyls)-Resorcinols as reaction Thing obtains white solid 3p, three-step reaction total recovery 42.6%.
HR-MS(ESI+)m/z：321.07912[M+H]+.Found：321.07935[M+H]+。
Embodiment 31：E-2- (4- chloromethanes epoxide) styryl -1- methyl -3 ', 5 '-dichloro mehtoxybenzyl sulfone (4p) Preparation
Using as above compound 4k synthetic method, with E-2- (4- hydroxyls) styryl -1- methyl -3 ', 5 '-dihydroxy Benzyl sulfone is that reactant obtains white solid 4p, yield 55.9%.
HR-MS(ESI+)m/z：465.00915 467.00620 [M+H]+(Cl isotopic peaks, 1: 1) .Found： 465.00926 467.00630 [M+H]+(Cl isotopic peaks, 1: 1).
Embodiment 32：The preparation of E-2- (4- hydroxyls) styryl -1- methyl -4 '-bromophenylethyl sulfone (3q)
Using three step synthetic methods of compound 3a in such as embodiment 1, obtained using the bromo- 4- of 1- (2- bromopropyls) benzene as reactant To white solid 3q, three-step reaction total recovery 39.5%.
HR-MS(ESI+)m/z：381.01545 383.01341 [M+H]+(Br isotopic peaks, 1: 1) .Found： 381.01574 383.01370 [M+H]+(Br isotopic peaks, 1: 1).
Embodiment 33：The preparation of E-2- (4- bromines methoxyl group) styryl -1- methyl -4 '-bromophenylethyl sulfone (4q)
Using as above compound 4k synthetic method, with E-2- (4- hydroxyls) styryl -1- methyl -4 '-bromophenylethyl Sulfone is that reactant obtains white solid 4q, yield 43.7%.
HR-MS(ESI+)m/z：472.94162 474.93957,476.93752 [M+H]+(Br isotopic peaks, 1: 2: 1) .Found：472.94201 474.93996,476.93791 [M+H]+(Br isotopic peaks, 1: 2: 1).
Embodiment 34：The preparation of E-2- (4- hydroxyls) styryl -2- phenylpropyls sulfones (3r)
Using three step synthetic methods of compound 3a in such as embodiment 1, white is obtained as reactant using (2- bromopropyls) benzene Solid 3r, three-step reaction total recovery 63.7%.
HR-MS(ESI+)m/z：303.10494[M+H]+.Found：303.10528[M+H]+。
Embodiment 35：The preparation of E-2- (4- cyanogen methoxyl group) styryl -2- phenylpropyls sulfone (4r)
Using as above compound 4k synthetic method, using E-2- (4- hydroxyls) styryl -2- phenylpropyls sulfone as reactant Obtain white solid 4r, yield 36.8%.
HR-MS(ESI+)m/z：342.11584[M+H]+.Found：342.11613[M+H]+。
Embodiment 36：The preparation of E-2- (4- hydroxyls) styryl -3 '-fluoro- 5 '-iodobenzyl sulfone (3s)
Using three step synthetic methods of compound 3a in such as embodiment 1, using the fluoro- 5- iodobenzenes of 1- (bromomethyl) -3- as reaction Thing obtains white solid 3s, three-step reaction total recovery 41.2%.
HR-MS(ESI+)m/z：418.96086[M+H]+.Found：418.96056[M+H]+。
Embodiment 37：E-2- (2,2- bis- chloro- 1,1- difluoroethoxies) styryl -3 '-fluoro- 5 '-iodobenzyl sulfone The preparation of (4s)
Using as above compound 4k synthetic method, with E-2- (4- hydroxyls) styryl -3 '-fluoro- 5 '-iodobenzyl sulfone White solid 4s, yield 40.8% are obtained for reactant.
HR-MS(ESI+)m/z：550.89537 552.89242 [M+H]+(Cl isotopic peaks, 5: 3) .Found： 550.89501 552.89206 [M+H]+(Cl isotopic peaks, 5: 3).
Embodiment 38：The preparation of E-2- (4- hydroxyls) styryl -3 '-hydroxyphenylmethyl sulfone (3t)
Using three step synthetic methods of compound 3a in such as embodiment 1, white is obtained as reactant using a bromomethyl phenol Solid 3t, three-step reaction total recovery 66.1%.
HR-MS(ESI+)m/z：291.06855[M+H]+.Found：291.06821[M+H]+。
Embodiment 39：E-2- [4- (N- tertbutyloxycarbonyl-N- methyl) ammonia methoxyl group] styryl -3 '-(N- tertiary butyloxycarbonyls Base-N- methyl) ammonia mehtoxybenzyl sulfone (4t) preparation
It is anti-using E-2- (4- hydroxyls) styryl -3 '-hydroxyphenylmethyl sulfone using as above compound 4k synthetic method Thing is answered to obtain white solid 4t, yield 45.9%.
HR-MS(ESI+)m/z：563.24216[M+H]+.Found：563.24177[M+H]+。
Embodiment 40：The system of E-2- (4- methylaminos methoxyl group) styryl -3 '-methylamino mehtoxybenzyl sulfone (5t) It is standby
By E-2- [4- (N- tertbutyloxycarbonyl-N- methyl) ammonia methoxyl group] styryl -3 '-(N- tertbutyloxycarbonyl-N- first Base) ammonia mehtoxybenzyl sulfone 750mg (1.99mmol) is dissolved in 25ml ethyl acetate, and logical hydrogen chloride gas continues after 30 minutes Stirring 30 minutes, filter and washed to obtain white solid 5t, yield 96.3% with ethyl acetate.
HR-MS(ESI+)m/z：377.15295[M+H]+.Found：377.15263[M+H]+。
Embodiment 41：The preparation of E-2- (4- hydroxyls) styryl -4 '-hydroxyphenylmethyl sulfone (3u)
Using three step synthetic methods of compound 3a in such as embodiment 1, to obtain white as reactant to bromomethyl phenol Solid 3u, three-step reaction total recovery 60.7%.
HR-MS(ESI+)m/z：291.06855[M+H]+.Found：291.06883[M+H]+。
Embodiment 42：E-2- (4- dimethylaminos methoxyl group) styryl -4 '-dimethylamino mehtoxybenzyl sulfone (4u) Preparation
It is anti-using E-2- (4- hydroxyls) styryl -4 '-hydroxyphenylmethyl sulfone using as above compound 4k synthetic method Thing is answered to obtain white solid 4u, yield 59.2%.
HR-MS(ESI+)m/z：405.18425[M+H]+.Found：405.18461[M+H]+。
Embodiment 43：The preparation of E-2- (4- hydroxyls) styryl -3 '-chloromethylbenzene methyl sulfone (3v)
Using three step synthetic methods of compound 3a in such as embodiment 1, using 1- (bromomethyl) -3- (chloromethyl) benzene as reaction Thing obtains faint yellow solid 3v, three-step reaction total recovery 36.9%.
HR-MS(ESI+)m/z：323.05032 325.04737 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 323.05008 325.04714 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 44：The preparation of E-2- (4- methoxymethoxies) styryl -3 '-chloromethylbenzene methyl sulfone (4v)
Using as above compound 4k synthetic method, using E-2- (4- hydroxyls) styryl -3 '-chloromethylbenzene methyl sulfone as Reactant obtains faint yellow solid 4v, yield 33.9%.
HR-MS(ESI+)m/z：367.07653 369.07358 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 367.07624 369.07328 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 45：E-2- (4- hydroxyls) styryl -2 ', the preparation of 3 ', 5 '-trichloro-benzenes methyl sulfone (3w)
Using three step synthetic methods of compound 3a in such as embodiment 1, with 1- (bromomethyl) -2,3,5- trichloro-benzenes are reaction Thing obtains white solid 3w, three-step reaction total recovery 62.7%.
HR-MS(ESI+)m/z：376.95672 378.95377 [M+H]+(Cl isotopic peaks, 1: 1) .Found： 376.95628 378.95333 [M+H]+(Cl isotopic peaks, 1: 1).
Embodiment 46：E-2- (4- tert-butoxymethoxies) styryl -2 ', the system of 3 ', 5 '-trichloro-benzenes methyl sulfone (4w) It is standby
Using as above compound 4k synthetic method, with E-2- (4- hydroxyls) styryl -2 ', 3 ', 5 '-trichlorine benzyl Sulfone is that reactant obtains white solid 4w, yield 67.7%.
HR-MS(ESI+)m/z：463.02989 465.02694 [M+H]+(Cl isotopic peaks, 1: 1) .Found： 463.02978 465.02682 [M+H]+(Cl isotopic peaks, 1: 1).
Embodiment 47：E-2- (4- hydroxyls) styryl -2 ', the preparation of 3 ', 5 ', 6 '-phenyl tetrafluoride methyl sulfone (3x)
Using three step synthetic methods of compound 3a in such as embodiment 1, with 1- (bromomethyl) -2,3,5,6- phenyl tetrafluorides are anti- Thing is answered to obtain white solid 3x, three-step reaction total recovery 58.3%.
HR-MS(ESI+)m/z：347.03595[M+H]+.Found：347.03612[M+H]+。
Embodiment 48：E-2- (4- benzyloxies ylmethoxy) styryl -2 ', 3 ', 5 ', 6 '-phenyl tetrafluoride methyl sulfone (4x) Prepare
Using as above compound 4k synthetic method, with E-2- (4- hydroxyls) styryl -2 ', 3 ', 5 ', 6 '-phenyl tetrafluoride Methyl sulfone is that reactant obtains white solid 4x, yield 70.1%.
HR-MS(ESI+)m/z：467.09347[M+H]+.Found：467.09369[M+H]+。
Embodiment 49：The preparation of E-2- (3,4- dihydroxy) styryl -3 '-methylbenzyl sulfone (3y)
Using three step synthetic methods of compound 3a in such as embodiment 1, white is obtained as reactant using an xylyl bromide Solid 3y, three-step reaction total recovery 69.5%.
HR-MS(ESI+)m/z：305.08420[M+H]+.Found：305.08401[M+H]+。
Embodiment 50：The preparation of E-2- (3,4- diformyloxy) styryl -3 '-methylbenzyl sulfone (4y)
E-2- (3,4- dihydroxy) styryl -3 '-methylbenzyl sulfone 610mg (2mmol) is dissolved in 5ml85% formic acid In the aqueous solution, 60 degree of heating responses 2 hours.Reaction adds 30ml water and 30ml dichloromethane liquid separations after terminating, and uses dichloromethane (20ml*2) extracting and washing water layer, after combined dichloromethane layer is dried, decompression is spin-dried for solvent.Purified with flash silica gel column available White solid 4y, yield 51.2%.
HR-MS(ESI+)m/z：361.07403[M+H]+.Found：361.07388[M+H]+。
Embodiment 51：The preparation of E-2- (3- hydroxyls) styryl -3 '-methylbenzyl sulfone (3z)
Using three step synthetic methods of compound 3a in such as embodiment 1, white is obtained as reactant using an xylyl bromide Solid 3z, three-step reaction total recovery 68.8%.
HR-MS(ESI+)m/z：289.08929[M+H]+.Found：289.08911[M+H]+。
Embodiment 52：The preparation of E-2- (3- new pentane acyloxies) styryl -3 '-methylbenzyl sulfone (4z)
E-2- (3- hydroxyls) styryl -3 '-methylbenzyl sulfone 580mg (2.01mmol) is dissolved in 5ml pyridines, added Enter 99% pivalyl chloride 0.3ml (2.41mmol), in 50 degree of isothermal reactions 6 hours.After TLC detection reactions completely, by reaction solution Pour into 100ml frozen water and stir, extracted with ethyl acetate (50ml*3), ethyl acetate layer saturated common salt water washing, nothing Aqueous sodium persulfate is dried, and with silica gel column separating purification (petrol ether/ethyl acetate elution), can obtain white solid 4z, yield 66.3%.
HR-MS(ESI+)m/z：373.14680[M+H]+.Found：373.14645[M+H]+。
Embodiment 53：The preparation of E-2- (3- hydroxyls) styryl -1- Dimethylaminobenzenes methyl sulfones (3A)
Using three step synthetic methods of compound 3a in such as embodiment 1, with the bromo- N of 1-, N- dimethyl -1- benzene methanamines are anti- Thing is answered to obtain white solid 3A, three-step reaction total recovery 61.2%.
HR-MS(ESI)m/z：318.11584[M+H]+.Found：318.11547[M+H]+。
Embodiment 54：E-2- (4- benzyloxies ylmethoxy) styryl -2 ', 3 ', 5 ', 6 '-phenyl tetrafluoride methyl sulfone (4A) Prepare
Using as above compound 4z synthetic method, with E-2- (3- hydroxyls) styryl -1- Dimethylaminobenzene methyl sulfones White solid 4A, yield 70.1% are obtained for reactant.
HR-MS(ESI+)m/z：422.14205[M+H]+.Found：422.14188[M+H]+。
Embodiment 55：The preparation of the chloro- 1- benzene-E-2- cyclobutenyls sulfones (3B) of E-2- (4- hydroxyls) styryl -4-
It is anti-using (the chloro- 2- cyclobutenyls of the bromo- 4- of E-4-) benzene using three step synthetic methods of compound 3a in such as embodiment 1 Thing is answered to obtain white solid 3B, three-step reaction total recovery 49.8%.
HR-MS(ESI+)m/z：349.06597 351.06302 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 349.06633 351.06339 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 56：The preparation of the chloro- 1- benzene-E-2- cyclobutenyls sulfones (4B) of E-2- (4- chloroethenes acyloxy) styryl -4-
Using as above compound 4z synthetic method, with the chloro- 1- benzene-E-2- butylene of E-2- (4- hydroxyls) styryl -4- Base sulfone is that reactant obtains white solid 4B, yield 66.3%.
HR-MS(ESI+)m/z：425.03756 427.03461 [M+H]+(Cl isotopic peaks, 5: 3) .Found： 425.03711 427.03415 [M+H]+(Cl isotopic peaks, 5: 3).
Embodiment 57：The system of the chloro- 1- benzene-E-2- cyclobutenyls sulfones (4C) of E-2- (4- tribromo-acetyls epoxide) styryl -4- It is standby
Using as above compound 4z synthetic method, with the chloro- 1- benzene-E-2- butylene of E-2- (4- hydroxyls) styryl -4- Base sulfone is that reactant obtains white solid 4C, yield 68.5%.
HR-MS(ESI+)m/z：492.95962 494.95667,496.95372 [M+H]+(Cl isotopic peaks, 3: 4: 2) .Found：492.95984 494.95689,496.95395 [M+H]+(Cl isotopic peaks, 3: 4: 2).
Embodiment 58：The preparation of E-2- (4- hydroxyls) styryl -1- benzene-E-2- cyclobutenyls sulfones (3D)
Using three step synthetic methods of compound 3a in such as embodiment 1, obtained using (the bromo- 2- cyclobutenyls of E-4-) benzene as reactant To white solid 3D, three-step reaction total recovery 62.4%.
HR-MS(ESI+)m/z：315.10494[M+H]+.Found：315.10445[M+H]+。
Embodiment 59：The preparation of E-2- (4- acetyl bromides epoxide) styryl -1- benzene-E-2- cyclobutenyls sulfones (4D)
Using as above compound 4z synthetic method, using E-2- (4- hydroxyls) styryl -1- benzene-E-2- cyclobutenyls sulfone as Reactant obtains faint yellow solid 4D, yield 56.0%.
HR-MS(ESI+)m/z：435.02602 437.02397 [M+H]+(Br isotopic peaks, 1: 1) .Found： 435.02635 437.02430 [M+H]+(Br isotopic peaks, 1: 1).
Embodiment 60：E-2- [4- (t-butoxycarbonyl amino) acetoxyl group] styryl -1- benzene-E-2- cyclobutenyl sulfones The preparation of (4E)
Using as above compound 4z synthetic method, using E-2- (4- hydroxyls) styryl -1- benzene-E-2- cyclobutenyls sulfone as Reactant obtains white solid 4E, yield 65.3%.
HR-MS(ESI+)m/z：472.17883[M+H]+.Found：472.17857[M+H]+。
Embodiment 61：The preparation of E-2- (4- ammonia acetoxyl group) styryl -1- benzene-E-2- cyclobutenyls sulfones (5E)
Using as above compound 5t synthetic method, with E-2- [4- (t-butoxycarbonyl amino) acetoxyl group] styrene Base -1- benzene-E-2- cyclobutenyls sulfone is that reactant obtains white solid 5E, yield 95.2%.
HR-MS(ESI+)m/z：372.12640[M+H]+.Found：372.12611[M+H]+。
Embodiment 62：The preparation of E-2- (4- hydroxyls) styryl -4 '-(t-butoxycarbonyl amino) benzyl sulfone (3F)
Using three step synthetic methods of compound 3a in such as embodiment 1, using to (t-butoxycarbonyl amino) bromobenzyl as reaction Thing obtains white solid 3F, three-step reaction total recovery 57.8%.
HR-MS(ESI+)m/z：390.13697[M+H]+.Found：390.13744[M+H]+。
Embodiment 63：E-2- (4- mesyloxies) styryl -4 '-(t-butoxycarbonyl amino) benzyl sulfone (4F) Prepare
Using as above compound 4z synthetic method, with E-2- (4- hydroxyls) styryl -4 '-(t-butoxycarbonyl amino) Benzyl sulfone is that reactant obtains white solid 4F, yield 59.0%.
HR-MS(ESI+)m/z：454.09887[M+H]+.Found：454.09912[M+H]+。
Embodiment 64：The preparation of E-2- (4- mesyloxies) styryl -4 '-aminobenzene methyl sulfone (5F)
Using as above compound 5t synthetic method, with E-2- (4- mesyloxies) styryl -4 '-(tertiary butyloxycarbonyl Base amino) benzyl sulfone be reactant obtain white solid 5F, yield 95.2%.
HR-MS(ESI+)m/z：354.04644[M+H]+.Found：354.04669[M+H]+。
Embodiment 65：The system of E-2- (4- hydroxyls) styryl -4 '-(N- tertbutyloxycarbonyls methylamino) benzyl sulfone (3G) It is standby
Using three step synthetic methods of compound 3a in such as embodiment 1, using to (N- tertbutyloxycarbonyls methylamino) bromobenzyl as Reactant obtains white solid 3G, three-step reaction total recovery 61.3%.
HR-MS(ESI+)m/z：404.15262[M+H]+.Found：404.15224[M+H]+。
Embodiment 66：E-2- (4- mesyloxies) styryl -4 '-(N- tertbutyloxycarbonyls methylamino) benzyl sulfone The preparation of (4G)
Using as above compound 4z synthetic method, with E-2- (4- hydroxyls) styryl -4 '-(N- tertbutyloxycarbonyl first Amino) benzyl sulfone be reactant obtain white solid 4G, yield 65.5%.
HR-MS(ESI+)m/z：558.16147[M+H]+.Found：558.16113[M+H]+。
Embodiment 67：The preparation of E-2- (4- mesyloxies) styryl -4 '-methylamino benzyl sulfone (5G)
Using as above compound 5t synthetic method, with E-2- (4- mesyloxies) styryl -4 '-(tertiary fourth oxygen of N- Carbonyl methylamino) benzyl sulfone be reactant obtain white solid 5G, yield 96.0%.
HR-MS(ESI+)m/z：458.10904[M+H]+.Found：458.10887[M+H]+。
Embodiment 68：The preparation of E-2- (4- hydroxyls) styryl -4 '-Dimethylaminobenzene methyl sulfone (3H)
It is white to be obtained to dimethylamino bromobenzyl as reactant using three step synthetic methods of compound 3a in such as embodiment 1 Color solid 3H, three-step reaction total recovery 60.7%.
HR-MS(ESI+)m/z：318.11584[M+H]+.Found：318.11628[M+H]+。
Embodiment 69：The preparation of E-2- (4- tolysulfonyl epoxide) styryl -4 '-Dimethylaminobenzene methyl sulfone (4H)
Using as above compound 4z synthetic method, with E-2- (4- hydroxyls) styryl -4 '-Dimethylaminobenzene methyl sulfone White solid 4H, yield 55.8% are obtained for reactant.
HR-MS(ESI+)m/z：472.12469[M+H]+.Found：472.12481[M+H]+。
Embodiment 70：The preparation of E-2- (4- trimethylsiloxy groups) styryl -4 '-Dimethylaminobenzene methyl sulfone (4I)
Using as above compound 4z synthetic method, with E-2- (4- hydroxyls) styryl -4 '-Dimethylaminobenzene methyl sulfone White solid 4I, yield 64.3% are obtained for reactant.
HR-MS(ESI+)m/z：390.15537[M+H]+.Found：390.15581[M+H]+。
Embodiment 71：The preparation of E-2- (4- hydroxyls) styrylbiphenyl -4- methyl sulfones (3J)
Using three step synthetic methods of compound 3a in such as embodiment 1, with 4- bromomethyl -1,1 '-biphenyl obtains for reactant To white solid 3J, three-step reaction total recovery 66.9%.
HR-MS(ESI+)m/z：351.10494[M+H]+.Found：351.10477[M+H]+。
Embodiment 72：The preparation of E-2- (4- tert-butyl group dimethoxys siloxy) styrylbiphenyl -4- methyl sulfones (4J)
Using as above compound 4z synthetic method, using E-2- (4- hydroxyls) styrylbiphenyl -4- methyl sulfones as reaction Thing obtains white solid 4J, yield 50.6%.
HR-MS(ESI+)m/z：497.18125[M+H]+.Found：497.18101[M+H]+。
Embodiment 73：The preparation of E-2- (4- tert-butyl diphenyls siloxy) styrylbiphenyl -4- methyl sulfones (4K)
Using as above compound 4z synthetic method, using E-2- (4- hydroxyls) styrylbiphenyl -4- methyl sulfones as reaction Thing obtains white solid 4K, yield 55.7%.
HR-MS(ESI+)m/z：589.22272[M+H]+.Found：589.22289[M+H]+。
Embodiment 74：The preparation of E-2- (4- hydroxyls) styryl -4 '-chlordiphenyl -4- methyl sulfones (3L)
Using three step synthetic methods of compound 3a in such as embodiment 1, with 4- bromomethyls -4 '-chloro- 1,1 '-biphenyl is anti- Thing is answered to obtain white solid 3L, three-step reaction total recovery 58.0%.
HR-MS(ESI+)m/z：385.06597 387.06302 [M+H]+(Cl isotopic peaks, 3: 1) .Found： 385.06642 387.06347 [M+H]+(Cl isotopic peaks, 3: 1).
Embodiment 75：The preparation of E-2- (4- tri isopropyl siloxanies) styryl -4 '-chlordiphenyl -4- methyl sulfones (4L)
Using as above compound 4z synthetic method, with E-2- (4- hydroxyls) styryl -4 '-chlordiphenyl -4- methyl sulfones White solid 4L, yield 60.4% are obtained for reactant.
HR-MS(ESI+)m/z：541.19940[M+H]+.Found：541.19967[M+H]+。
Embodiment 76：External Scavenging ability (DPPH) evaluation is carried out to synthesized compound
One experimental principle
1,1- diphenyl -2- trinitrophenyl-hydrazines (1,1-diphenyl-2-picryhydrazyl (DPPH)) are a kind of stable The free radical centered on nitrogen, when in DPPH solution add free radical scavenger when, when its lone pair electrons is paired, absorption disappears Lose or weaken, cause solution colour to shoal, its intensity of variation and radicals scavenging degree are linear.
Two experimental methods
DPPH is made into 0.1mM/L ethanol solution；Compound stock solution is diluted to different concentration ethanol solution.Take respectively The μ l of drug solution 100 of various concentrations add 100 μ l/ holes DPPH solution in 96 orifice plates, after lucifuge concussion 30min, in 517nm wavelength determines OD values.Each compound sets 5-6 concentration, the parallel 3-4 parallel hole of each concentration, is repeated 3 times.
Compound is as shown in table 1 to free radical scavenging activity result.
Three experimental results (are shown in Table 1)
The free radical scavenging activity (%) of the compound of table 1
The majority of compounds that experiment is participated in it can be seen from upper table result is respectively provided with the energy for substantially removing external free radical Power.4h, the 4i for not showing obvious Scavenging ability wherein are the protected compound of phenylol, and 3j, 4j are that do not have The compound of phenolic groups.And from the point of view of activity contrast of the biphenol base with monophenol based compound, there is the change of biphenol base Compound 3a-3g has obvious preferably activity.Prove that this series compound is removed in the ability and styryl of external free radical The number of phenolic hydroxyl group substitution has direct correlation.
Most of activity is better than CAPE.
Embodiment 77：H is carried out to synthesized compound2O2Inducing cell damage model activity rating
One experimental principle
Oxidative stress is the main molecules mechanism of neural cell injury.When intracellular free radicals content exceedes the removing of itself During ability, the effect for destroying lipid and cell membrane can be produced, and causes the oxygen radical toxic actions such as protein, nucleic acid damage. H2O2Cytolipin peroxidating, damage dna molecule can be caused by generating hydroxy radical, adjust gene participating in apoptosis to lure Guided cell apoptosis.Utilize H2O2Establish neural cell injury model and can be used for screening neuroprotection class medicine.
Two experimental methods
(1) PC12 cells are inoculated in (4*10 in 96 orifice plates4Individual/100 μ L), it is wet in 5%CO2,95% air saturation Spend in environment, in being incubated 1 day in 37 DEG C of incubator.
(2) every piece of 96 orifice plates set blank control group, H2O2Group, administration group and CAPE control groups, administration group are separately added into end Concentration is 2 μM/L, 4 μM/L, 8 μM/L compound solution, parallel 8 holes of each concentration, is placed in incubator and is incubated 3h.
(3) blank control group adds 20 μ L/ holes culture mediums, H2O2Group, administration group and CAPE control groups are separately added into H2O2It is molten The μ L/ holes of liquid 20, H2O2Final concentration of 500 μM/L, is placed in incubator and is incubated 5h.
(4) MTT20 μ L/ holes are added, is placed in incubator and is incubated 4h.
(5) Methyl thiazoly tetrazolium assay solution is drawn, dimethyl sulfoxide (DMSO) is added per hole, is gently shaked, in 570nm wavelength in enzyme Mark the every hole absorbance of measure on instrument.Repeat experiment 3 times.
Three experimental results (see accompanying drawing 1)
The experimental result as listed by accompanying drawing 1 can be seen that 3a-4h compounds have obvious protection H2O2The energy of inducing cell damage Power.When compound concentration is 2 μM/L and 4 μM/L, the protection of 3b, 4b, 3c, 4c, 3d, 4d, 3f, 4f, 3g, 4g, 3h, 4h compound H2O2The ability of inducing cell damage is significantly stronger than CAPE and the Ac-CAPE (chemical combination that CAPE two phenolic hydroxyl groups are protected by acetyl group Thing).Protective effect of the protection of phenolic hydroxyl group on compound simultaneously does not produce obvious influence.
Embodiment 78：6-OHDA inducing cell damage model activity ratings are carried out to synthesized compound
One experimental principle
The design of 1.1 pharmacological models
6-OHDA is selective d A neuron chemical damage agent.Neural cell injury model is established using 6-OHDA can be used for Screen neuroprotection class medicine.
Two experimental methods
(1) PC12 cells are inoculated in (4*10 in 96 orifice plates4Individual/100 μ L), it is wet in 5%CO2, the saturation of 95% air Spend in environment, in being incubated 1 day in 37 DEG C of incubator.
(2) every piece of 96 orifice plates set blank control group, 6-OHDA groups, administration group and CAPE control groups, administration group to add respectively Enter final concentration of 1 μM/L, 10 μM/L and 40 μM/L compound solution, be placed in incubator and be incubated 3h.
(3) blank control group adds 20 μ L/ holes culture mediums, and 6-OHDA groups, administration group and CAPE control groups are separately added into 6- The μ L/ holes of OHDA solution 20, the final concentration of 400 μM/L of 6-OHDA, are placed in incubator and are incubated 48h.
(4) 5mg/ml MTT20 μ L/ holes are added, is placed in incubator and is incubated 4h.
(5) Methyl thiazoly tetrazolium assay solution is drawn, dimethyl sulfoxide (DMSO) is added per hole, is gently shaked, in 570nm wavelength in enzyme Mark the every hole absorbance of measure on instrument.Repeat experiment 3 times.
Three experimental results (see accompanying drawing 2)
The experimental result as listed by accompanying drawing 2 can be seen that 3a-4e compounds, which substantially have, avoids cell from being induced damage by 6-OHDA The activity of wound.The energy of 3a, 4a, 3b, 4b, 3d, 4d, 3f, 4f, 3g, 4g, 3h, 4h compound protection 6-OHDA inducing cell damages Power is significantly stronger than CAPE and Ac-CAPE.Protective effect of the protection of phenolic hydroxyl group on compound simultaneously does not produce obvious influence.
Embodiment 79：Parallel artificial's membrane permeability experiment (PAMPA) evaluation is carried out to synthesized compound
One experimental principle
Blood-brain barrier (BBB) is one of obstacle of medicine for central nervous system treatment, by brain parenchym and external environment blood point Separate, maintain the stabilization of interior environment.Blood-brain barrier can be penetrated and play drug effect into focus as drugs for nervous Important prerequisite, therefore have great importance in drug research EARLY STAGE EVALUATION medicine through blood-brain barrier ability.We use flat Row artificial membrane permeability tests the evaluation that (PAMPA) carries out saturating blood-brain barrier ability to synthesized compound.
Two experimental methods
(1) stoste of compound is diluted to the solution that concentration is 25 μ g/ml with the PH buffer solutions for being 7.4.
(2) selection pig brain lipid-soluble extract (PBL) is dissolved in the solution that 20mg/ml is made into dodecane as immobilized artificial membrane Material.
(3) 4 μ LPBL solution are added dropwise on the polyvinylidene fluoride film of each 96 hole filter plate to form the phosphatide of simulation intracerebral environment Film.
(4) 300 μ l/ hole buffer solutions are added above the immobilized artificial membrane of 96 hole filter plates as receptor tube, in another piece of receiver board The 25 μ g/ml in 375 μ l/ holes drug solution is added as donor tube, parallel three holes of each medicine.
(5) 96 hole filter plates are placed on receiver board, enabling immobilized artificial membrane touch donor liquid, sandwich structure is formed, is placed in 18h is placed in 30 degree of isoperibols.
(6) after 18h, solution in 96 hole filter plates and receiver board is taken out respectively and moved in the orifice plate of a blank 96, at 340nm Survey OD values.Parallel 3 experiments.
According to document (Kiyohiko S., et al.Optimized conditions of bio-mimetic Artificial membrane permeation assay [J] .Int.J.Pharm., 2001,228,181-188) calculating has Imitate permeability Pe values.
Three experimental results (are shown in Table 2)
Compound number Pe values (* 10-6cm/s) Compound number Pe values (* 10-6cm/s)
CAPE 0.66 3u 2.24
Ac-CAPE 2.50 4u 10.59
3a 2.62 3v 3.12
3b 1.97 4v 7.45
4b 5.63 3w 3.24
3d 1.58 4w 8.14
4d 2.87 3x 2.97
3e 2.62 4x 7.78
3f 2.63 3y 1.94
4f 13.22 4y 3.26
3g 2.58 3z 2.51
4g 3.32 4z 5.19
3h 2.37 3A 2.77
4h 6.34 4A 12.47
4i 5.82 3B 2.86
3j 7.53 4B 6.28
4j 8.25 4C 6.65
5j 8.81 3D 2.62
3k 2.85 4D 6.15
4k 5.47 4E 9.24
3l 2.11 5E 7.01
4l 6.12 3F 3.04
3m 1.59 4F 7.95
4m 4.77 5F 5.21
4n 6.23 3G 3.35
3o 2.16 4G 13.12
4o 4.41 5G 9.57
3p 1.76 3H 2.46
4p 6.31 4H 8.59
4q 8.84 4I 6.50
3r 2.56 3J 2.94
4r 7.19 4J 7.53
4s 7.75 4K 10.28
3t 1.59 3L 2.88
4t 11.25 4L 9.15
5t 8.54
The Pe values of the compound of table 2
As can be seen from the above results：Synthesized sulfone compound is better than CAPE, and phenol hydroxyl through blood-brain barrier ability After base is protected by acetyl group, strengthen through blood-brain barrier ability.

Claims (9)

1. compound of Formula I and its officinal salt：
Wherein,
R1And R2It is each independently selected to be unsubstituted or by 1 to 6 halogen, cyano group, N (R4)2Or OR5Substituted C1-6Alcoxyl Base, it is unsubstituted or by 1 to 6 halogen, cyano group, N (R4)2Or OR5Substituted C1-6Alkyl acyloxy or C7-10Arylacyloxy, It is and unsubstituted or by C1-3Alkyl or C6-8The sulfonyloxy of aryl substitution, OSi (R6)3, wherein R4Independently selected from H or C1-6 Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9Heteroaryl, R6Solely On the spot it is selected from C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；
It is-CH that W, which is selected from,2-、-CH2CH2-、-CH2CH2CH2-、-CH(Cl)-、-CH(Br)-、-CH(Cl)CH2-、-CH(Cl)CH (Cl)-、-CH2(Cl)CHCH2-、-CH(CH3)-、-CH(CH3)CH2-、-CH[N(CH3)2]-、-CH2CH=CHCH2-、-CH(Cl) CH=CHCH2-；
R is independently selected from for halogen, cyano group, nitro, OR3、N(R4)2, it is unsubstituted or by 1 to 6 halogen, cyano group, nitro, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3Independently selected from H, unsubstituted or by 1 to 6 Individual halogen, cyano group, N (R4)2Or OR5Substituted C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group, C6-10Aryl, C5-9Heteroaryl Base, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl or C6-8Sulfonyl, the Si (R of aryl substitution6)3, R4、R5And R6's It is defined as above；
N is 0-5 integer.
2. compound as claimed in claim 1 and its officinal salt, wherein R1And R2Be each independently selected from for methoxyl group, ethyoxyl, Isopropoxy, tert-butoxy, cyclo propyl methoxy, cyclohexyloxy, chloromethane epoxide, bromine methoxyl group, cyanogen methoxyl group, 2,2- bis- are chloro- 1,1- difluoroethoxy, methylamino methoxyl group, dimethylamino methoxyl group, methoxymethoxy, tert-butoxymethoxy, benzyloxy Methoxyl group, formyloxy, acetoxyl group, new pentane acyloxy, benzoyloxy, chloroethene acyloxy, tribromo-acetyl epoxide, acetyl bromide Epoxide, carbamoyloxy, mesyloxy, tolysulfonyl epoxide, trimethylsiloxy group, tert-butyl group dimethoxy silica Base, tert-butyl diphenyl siloxy, tri isopropyl siloxany.
3. compound as claimed in claim 1 and its officinal salt, wherein R are independently selected from for halogen, cyano group, nitro, OR3、N (R4)2, it is unsubstituted or by 1 to 6 halogen, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3、R4And R5Definition as described in the appended claim 1.
4. compound as claimed in claim 3 and its officinal salt, wherein R independently selected from for fluorine, chlorine, bromine, iodine, cyano group, nitro, Methoxyl group, ethyoxyl, isopropoxy, chloromethane epoxide, methylamino methoxyl group, dimethylamino methoxyl group, amino, methylamino, diformazan Amino, methyl, ethyl, chloromethyl, aminomethyl, phenyl, rubigan.
5. compound of Formula I and its officinal salt described in claim 1, wherein compound are selected from E-2- (3,4- diethyl acyl-oxygens Base) styryl benzyl sulfone, E-2- (3,4- diacetoxy) styryl -4- chlorobenzyls sulfone, E-2- (3,4- diethyl acyl-oxygens Base) styryl -4- t-butylbenzyls sulfone, E-2- (3,4- diacetoxy) styryl -4- trifluoromethyl benzyls sulfone, E-2- (3,4- diacetoxy) styryl -4- methoxy-benzyls sulfone, E-2- (3,4- diacetoxy) styryl phenethyls sulfone, E-2- (3,4- diacetoxy) styryl phenylpropyls sulfone, E-2- (3,4- dimethoxy) styryl phenethyl sulfone.
6. compound of Formula I and its preparation method of officinal salt described in claim 1-5 any one, this method includes as follows Step：
A) Compounds of formula II and TGA are reacted preparation compound of formula III by the basic conditions, wherein, W is selected from For-CH2-、-CH2CH2-、-CH2CH2CH2-、-CH(Cl)-、-CH(Br)-、-CH(Cl)CH2-、-CH(Cl)CH(Cl)-、-CH2 (Cl)CHCH2-、-CH(CH3)-、-CH(CH3)CH2-、-CH[N(CH3)2]-、-CH2CH=CHCH2- ,-CH (Cl) CH= CHCH2-；R is independently selected from for halogen, cyano group, nitro, OR3、N(R4)2, it is unsubstituted or by 1 to 6 halogen, cyano group, nitre Base, N (R4)2Or OR5Substituted C1-6Alkyl or C6-10Aryl, C5-9Heteroaryl, wherein R3Independently selected from H, unsubstituted or by 1 To 6 halogens, cyano group, N (R4)2Or OR5Substituted C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group, C6-10Aryl, C5-9It is miscellaneous Aryl, C1-6Alkyl acyl or C7-10Aryl-acyl, by C1-3Alkyl or C6-8Sulfonyl, the Si (R of aryl substitution6)3, R4Independently Selected from H or C1-6Saturated alkyl, R5Independently selected from C1-6Saturated alkyl, C2-4Alkenyl, C2-4Alkynyl group or C6-10Aryl, C5-9It is miscellaneous Aryl, R6Independently selected from C1-6Alkyl, C1-6Alkoxy or C6-8Aryl；N is 0-5 integer；
B) by compound of formula III with oxidizing into sulfone compound formula IV, wherein, W, R and n definition such as step A) described in；
C) by compound of Formula IV and compounds of formula V in the presence of a catalyst, be condensed and decarboxylic reaction obtain formula I chemical combination Thing, wherein, R1And R2It is each independently selected to be unsubstituted or by 1 to 6 halogen, cyano group, N (R4)2Or OR5Substituted C1-6 Alkoxy, it is unsubstituted or by 1 to 6 halogen, cyano group, N (R4)2Or OR5Substituted C1-6Alkyl acyloxy or C7-10Aryl acyl Epoxide, and it is unsubstituted or by C1-3Alkyl or C6-8The sulfonyloxy of aryl substitution, OSi (R6)3；R4、R5、R6, W, R and n Definition is as described in step a)；
D) compound of Formula I is optionally converted into its officinal salt by.
7. pharmaceutical composition, it contains the compound and at least one pharmaceutical acceptable carrier any one of claim 1-5.
8. the pharmaceutical composition described in compound or claim 7 in claim 1-5 described in any one is preparing nerve Protect the purposes in medicine.
9. purposes according to claim 8, wherein the nerve protection medicine is the medicine for treating neurodegenerative disease Thing, the neurodegenerative disease are stages alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Primary lateral Hardening, Huntington's disease, prion disease, multiple sclerosis, cerebral atrophy, spinal muscular atrophy, multi-system atrophy, Different type spinocerebellar ataxia, cerebral ischemia, Alexander disease, A Erposhi diseases, canavan's disease, Ke Kaien syndromes, The not plain Mu Shi of corticobasal degeneration, epilepsy, Kennedy disease, Krabbe disease, dementia with Lewy body, pelizaeus-Merzbacher disease, Pick's disease, thunder Disease, sandhoff disease, periaxial encephalitis, stein-leventhal syndrome, peripheral neurophaty, diabetic neuropathy, apoplexy and ridge Marrow consumptive disease.
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