CN107325058A - Two fragrant methylene disulfide compounds and preparation method and application - Google Patents
Two fragrant methylene disulfide compounds and preparation method and application Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
- C07C321/12—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms
- C07C321/20—Sulfides, hydropolysulfides, or polysulfides having thio groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/01—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton
- C07C323/02—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/07—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and halogen atoms, or nitro or nitroso groups bound to the same carbon skeleton having sulfur atoms of thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
- C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
- C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
- C07C323/56—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
Abstract
The present invention relates to technical field of pharmaceuticals, more particularly to two fragrant methylene disulfide compounds and preparation method and application.Experimental result, the two fragrant methylene disulfide compounds that the present invention is provided, the effect of neurotoxicity caused by the effect and suppression hydrogen peroxide with neurotoxicity caused by suppression excessive glutamate on cell model；Also there is the effect of platelet aggregation-against, the effect of brain infarction area can be reduced in mouse MCAO model.These results show that this kind of two fragrant methylene disulfide compounds that the present invention is provided can have the effect of prevention and/or treatment for cerebral apoplexy.
Description
Technical field
The present invention relates to technical field of pharmaceuticals, more particularly to two fragrant methylene disulfide compounds and its preparation side
Method and application.
Background technology
" cerebral apoplexy " (cerebral stroke) is also known as " apoplexy ", " cerebrovas-cularaccident " (cerebralvascular
Accident, CVA).It is a kind of acute cerebrovascular diseases, is due to that cerebral vessels rupture or because angiemphraxis causes blood suddenly
It cannot flow into brain and cause one group of disease of brain tissue impairment.
Worldwide, headstroke is the cause of the death that the whole world is number three, and is also to cause the primary cause of disease of adult disability.
According to statistics, there is 50~750,000 people morbidity in the U.S. every year.In China, headstroke number of the infected is up to 2,500,000/year, and death toll is up to 160
Ten thousand/year.Cerebral apoplexy exceedes miocardial infarction, as the primary cause of disease that compatriots are dead.Not only fatal rate is high for headstroke, and survival
Patient can also leave the sequelae such as neurobehavioral function damage and cognitive disorder, cause heavy society and household economy to bear
Load, with the incidence of disease is high, the high death rate and the characteristics of high disability rate.
Headstroke is broadly divided into two types.More than 70% is ischemia apoplexy, and it refers to various thrombus in different brains
Area causes the cerebrovascular to block, so as to cause ischemic brain damage, most common of which blocks for arteria cerebri media.Internal carotid and
Vertebral artery occlusion and it is narrow cause cerebral arterial thrombosis, the age is more more than 40 years old, and male is more compared with women, and severe patient can cause
It is dead.It is in addition the cerebral hemorrhage caused by rupture of blood vessel in brain less than 30%, finally also results in cerebral blood supply insufficiency and ischemic brain is damaged
Wound.Cerebral ischemia is also one of consequence caused by heart arrest.
Compared with the seriousness and the extent of injury of headstroke, the medicine of current headstroke is also very limited.Face now
Drug therapy on bed mainly has Thrombolytic Drugs, expands blood vessel medicine, platelet aggregation inhibitor and neuroprotective agent.For example, for lacking
Courageous and upright headstroke, internationally recognized sole drug treatment means are with tissue plasminogen activator's acute stage thrombolysis.But due to
The therapeutic window of tissue plasminogen activator is short and side effect significantly (such as causes cerebral hemorrhage and aggravation excititoxic),
The patients with cerebral ischemic that can be treated at present with tissue plasminogen activator is less than the 5% of patient populations.Existing research is it is also shown that brain
Palsy can cause a series of cells of intracerebral and Molecular responses mechanism, and these mechanism weave ins ultimately result in brain damage.For example,
Caused by cerebral arterial thrombosis neuronal death or the mechanism of damage mainly have overactivity oxygen radical produce neurotoxicity,
Neure damage mechanism, many Poly ADP-ribose polymerase excessive activations are led caused by excessive excitatory amino acid such as glutamic neuron
Neurological inflammatory injury mechanism caused by intracerebral excessive inflammation response caused by the neuronal death and cerebral ischemia of cause.These diseases
Damage mechanisms are managed to the development of headstroke medicine and develop significant, and are found for there are a variety of pathology simultaneously
The corresponding medicine of damage mechanisms turns into the Critical policies for researching and developing new Treatment of Cerebral Stroke medicine.
To sum up, in view of cerebral apoplexy harm is big, and Current therapeutic means are extremely limited, thus the new cerebral apoplexy of research and development is pre-
Anti- and/or medicine is always the focus of this area forward position scholar's extensive concern, significant.
The content of the invention
In view of this, the technical problem to be solved in the present invention be to provide two fragrant methylene disulfide compounds and
Its preparation method and application.The compound that the present invention is provided, which is not only able to have in neural cell model, more preferably suppresses excessive paddy ammonia
Neurotoxic effect and removing excessive free radicals effect caused by acid, with suppression platelet aggregation, and with to brain
The mouse brain of ischemical reperfusion injury has good protective effect, thus for cerebral apoplexy there is prevention or treatment to make
With.
The invention provides structural compounds shown in Formulas I：
Wherein, Ar is 3,5,6-trimethylpyrazinyl or 4-COOCH3-Ph。
The compound that the present invention is provided is [(3,5,6- trimethylpyrazine -2- bases) methyl] disulfides of 1,2- bis- or 4,4'-
Double (methylene) the dibenzoic acid methyl esters of disulphanes diyl.The structure of both compounds is not disclosed before this, prepared by the present invention
Both compounds are obtained, and verify that they can realize the prevention or therapeutic action to cerebral apoplexy by number of ways.
Application of the structural compounds shown in Formulas I of the present invention in the preparation for preparing protection neuronal cell；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-
BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
The protective effect to neuronal cell is included to the protective effect of neurotoxicity caused by glutamic acid or to mistake
The protective effect of neurotoxicity caused by hydrogen oxide.The neuronal cell is hippocampus neurons in mice HT-22 cells.It is described to protect
Shield is referred specifically to：Protect glutamate induction damage HT22 cells, or protection H2O2Induced damage HT22 cells, illustrate that compound of formula I has
It is reduced toxicity of excitatory amino acid and removes H2O2The Free Radical of generation.Wherein, [(3,5, the 6- trimethyl pyrroles of 1,2- bis-
Piperazine -2- bases) methyl] disulfide effect anti-glutamate toxic action it is optimal, compared with glutamic acid group, its cell survival rate is notable
Property increase.
Application of the structural compounds shown in Formulas I in the preparation for suppressing platelet aggregation is prepared；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-
BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
Experiments indicate that, the compound that the present invention is provided can significantly reduce hematoblastic maximum aggregation rate, specifically
, addition 0.1,0.5,1mM 1,2- bis- [(3,5,6- trimethylpyrazine -2- bases) methyl] disulfide, blood platelet maximum aggregation
Rate is remarkably decreased (P<0.05, P<0.01), prompting 1,2- bis- [(3,5,6- trimethylpyrazine -2- bases) methyl] disulfide has very
Good platelet aggregation inhibitory activity.
Application of the structural compounds shown in Formulas I in the preparation for preparing preventing and treating cerebral ischemia re-pouring Brain Injury After；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-
BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
The preventing and treating cerebral ischemia re-pouring Brain Injury After specifically includes reduction cortex, corpus straitum and cerebrum hemispheric infarction body
Product.Experiment shows that artery occlusion is after 24 hours in the brain, compared with solvent group mouse, 1, the 2- bis- of Reperfu- sion injection in 3 hours
[(3,5,6- trimethylpyrazine -2- bases) methyl] disulfide can significantly reduce cortex, corpus straitum and cerebrum hemispheric infarction volume,
Show that [(3,5,6- trimethylpyrazine -2- bases) methyl] disulfides of 1,2- bis- block the Ischemia Brain Damage caused to arteria cerebri media
There is significant protective effect.
Except [(3,5,6- trimethylpyrazine -2- bases) methyl] disulfides of 1,2- bis- or the double (methylenes of 4,4'- disulphanes diyl
Base) outside dibenzoic acid methyl esters, it has also been found that, other two fragrant methylene disulfide compounds also have preventing and treating brain soldier
In effect.Its mechanism of action is neurotoxicity caused by suppression excessive glutamate.
Application of the structural compounds shown in Formulas I in the preparation for preparing preventing and treating cerebral apoplexy；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-
BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
In the present invention, cerebral apoplexy is cerebral apoplexy caused by the cerebral apoplexy caused by cerebral vessels embolism and/or cerebral hemorrhage.
It is preferred that, the cerebral apoplexy, which includes cerebral thrombus, cerebral embolism, cerebral infarction, transient ischemic attack, heart arrest, leads
Cause cerebral apoplexy caused by the one or more in cerebral ischemia, cerebral hemorrhage and cerebral arteriovenous malformation.
In the present invention, the dosage of the compound of formula I is 0.05mg/kg~90mg/kg.
It is preferred that, compound of formula I is 1,2- bis- [(3,5,6- trimethylpyrazine -2- bases) methyl] disulfide.
A kind of medicine, it is characterised in that including compound of formula I and pharmaceutically acceptable auxiliary material；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-
BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
It is preferred that, the formulation of the preparation is oral formulations, injection, suppository, inhalant or may be directly applied to brain and lacks
The formulation at blood position.
It is preferred that, the formulation of the preparation is capsule, micro-capsule, tablet, granule, pill, dispersion powders, liquid preparation,
Soft extract, suspending agent, syrup, gel, aerosol, patch, liposome, oral liquid, intravenous fluid or intramuscular injection.
The preparation method of structural compounds is shown in Formulas I of the present invention：By compound A and thiocarbamide in manganese dioxide and
Reacted under PEG existence conditions, compound of formula I is made；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-
BrPh、3-FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh；
The compound A is 1- bromos ligustrazine, benzyl bromine, 4- (bromomethyl) methyl benzoate, 2- bromobenzyls bromine, 3- bromobenzyls
Bromine, 4- bromobenzyls bromine, 3- fluorobenzyl bromides, 4- fluorobenzyl bromides, 2- nitrobenzyls bromine, 3- nitrobenzyls bromine, 4- nitrobenzyls bromine, 4- bromine chlorides, 4- first
Base benzyl bromine or 4- cyano group benzyl bromines.
The reaction is carried out in the basic conditions.The present invention obtains alkaline environment using sodium carbonate condition.
The mol ratio of the compound A and thiocarbamide are 0.97:1.45.
The mol ratio of the sodium carbonate and thiocarbamide is 1:1.
The manganese dioxide and compound A mol ratio are 1:1.
The PEG is PEG200；Preferably wet-PEG200；Specifically, in the wet-PEG200, PEG200 and H2O
Volume ratio be 10:1.
The reaction temperature is 40 DEG C, stirring reaction 3h.
It is made after compound of formula I, in addition to the step of purifying.Specifically, purifying includes：Reaction product is extracted with ethyl acetate
Take, extract is after water washing, drying, suction filtration, column chromatography (eluant, eluent [petroleum ether：Ethyl acetate (v:V)=10:1]) obtain
Compound of formula I.
The invention provides two fragrant methylene disulfide compounds, and research shows that these compounds can pass through
Number of ways plays a part of preventing cerebral apoplexy.Experimental result, the two fragrant methylene disulfide class chemical combination that the present invention is provided
Thing, the effect on cell model with neurotoxicity caused by suppression excessive glutamate；Also there is suppression hydrogen peroxide to cause
Neurotoxicity effect；The effect of platelet aggregation-against；And the work of brain infarction area can be reduced in mouse MCAO model
With.These results show that this kind of two fragrant methylene disulfide compounds that the present invention is provided can be directed to a variety of diseases of cerebral apoplexy
Reason mechanism has the effect of prevention and/or treatment.
Brief description of the drawings
Fig. 1-a show LYY-I1The influence of the hippocampus neurons in mice cell survival rate damaged to glutamate induction；Fig. 1-b show
The influence for the hippocampus neurons in mice cell survival rate that ligustrazine is damaged to glutamate induction；Wherein * * show compared with glutamic acid group
There is pole significant difference, P<0.01；
Fig. 2-a show LYY-I1The influence of the hippocampus neurons in mice cell survival rate damaged to hydrogen peroxide-induced；Fig. 2-b
Show the influence for the hippocampus neurons in mice cell survival rate that ligustrazine is damaged to hydrogen peroxide-induced；Wherein * * show and hydrogen peroxide
Group, which is compared, has pole significant difference, P<0.01；
Fig. 3 shows LYY-I1Influence to platelet aggregation rate；Wherein：* show there is significant difference, P compared with ADP groups<
0.05；* shows has pole significant difference, P compared with ADP groups<0.01；
Fig. 4 shows the Reperfu- sion 3h pneumoretroperitoneums administration 0.22mmol/kg LYY-I in mouse MCAO model1Cerebral infarction volume
Percentage, wherein * show there is significant difference compared with solvent group, P<0.05；*, which shows compared with solvent group, has pole significance difference
It is different, P<0.01.
Embodiment
The invention provides two fragrant methylene disulfide compounds and preparation method and application, art technology
Personnel can use for reference present disclosure, be suitably modified technological parameter realization.In particular, all similar replacements and change
Dynamic apparent to those skilled in the art, they are considered as being included in the present invention.The present invention method and should
With being described by preferred embodiment, related personnel substantially can be not departing from present invention, in spirit and scope
Methods herein and application are modified or suitably change is with combining, to realize and apply the technology of the present invention.
With reference to embodiment, the present invention is expanded on further：
Embodiment 1 1,2- bis- [(3,5,6- trimethylpyrazine -2- bases) methyl] disulfide (LYY- Ι1)
1- bromos ligustrazine (0.210g, 0.97mmol), thiocarbamide (0.111g, 1.45mmol), sodium carbonate (0.154g,
1.45mmol), manganese dioxide (0.084g, 0.97mmol) is added in 100mL reaction bulbs, adds wet-PEG200 (20mL)
(PEG200：H2O=10:1) 40 DEG C, stirring reaction 3h, are heated to.Room temperature is cooled to, water (20mL), ethyl acetate is added
(20mL) is extracted three times, and water (50mL) is washed three times, and anhydrous magnesium sulfate is dried, suction filtration, column chromatography [eluent petroleum ether：Acetic acid
Ethyl ester (v:V)=10:1], yellow solid is obtained.Yield 45%.Mp:73~75 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):3.99(s,4H,CH2),2.54(s,6H,CH3),2.49(s,12H,
CH3).
13C-NMR(600MHz,CDCl3),δ(ppm):150.17,148.94,148.64,146.61,42.67,21.62,
21.40,21.09.
HR-MS:[M+H]+,Calcd:335.1364,Found:335.1360.
1,2- benzyldithio toluenes (the LYY- Ι of embodiment 22)
Reference compound LYY- Ι1Synthetic method prepared by benzyl bromine and thiocarbamide, obtain white solid.Yield 57%.Mp:64
~68 DEG C.
1H NMR(400MHz,CDCl3,δ(ppm):7.35-7.32(m,2H,ArH),7.32-7.28(m,4H,ArH),
7.24 (dd, J=5.8,4.3Hz, 4H, ArH), 3.60 (s, 4H, CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):137.60,129.65,128.72,127.66,43.03.
HR-MS:[M+H]+,Calcd:247.0615,Found:247.0611.
Double (methylene) dibenzoic acid methyl esters (the LYY- Ι of the 4,4'- disulphanes diyl of embodiment 33)
Reference compound LYY- Ι1Synthetic method prepared by 4- (bromomethyl) methyl benzoates and thiocarbamide, obtain white solid
Body.Yield 51%.Mp:81~85 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):8.01-7.97 (m, 4H, ArH), 7.28 (d, J=8.3Hz, 4H,
ArH),3.92(s,6H,OCH3),3.62(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):166.80,142.61,129.86,129.41,129.35,
52.21,42.91.
HR-MS:[M+H]+,Calcd:363.0725,Found:363.0724.
(2- bromobenzyls) disulfide (the LYY- Ι of 4 1,2- of embodiment bis-4)
Reference compound LYY- Ι1Synthetic method prepared by 2- bromobenzyls bromine and thiocarbamide, obtain white solid.Yield 36%.
Mp:93~96 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):7.56 (d, J=7.8Hz, 2H, ArH), 7.29-7.26 (m, 4H,
ArH),7.16-7.11(m,2H,ArH),3.80(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):136.66,133.06,131.63,129.11,127.35,
124.56,43.74.
HR-MS:[M+H]+,Calcd:402.8825,Found:402.8819.
(3- bromobenzyls) disulfide (the LYY- Ι of 5 1,2- of embodiment bis-5)
Reference compound LYY- Ι1Synthetic method prepared by 3- bromobenzyls bromine and thiocarbamide, obtain faint yellow solid.Yield 41%.
Mp:57~60 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):7.44-7.39 (m, 2H, ArH), 7.38 (dd, J=7.7,1.8Hz,
2H,ArH),7.23-7.17(m,2H,ArH),7.17-7.13(m,2H,ArH),3.55(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):139.53,132.32,130.57,130.07,127.98,
122.43,42.54.
HR-MS:[M+H]+,Calcd:402.8825,Found:402.8811.
(4- bromobenzyls) disulfide (the LYY- Ι of 6 1,2- of embodiment bis-6)
Reference compound LYY- Ι1Synthetic method prepared by 4- bromobenzyls bromine and thiocarbamide, obtain white solid.Yield 33%.
Mp:91~95 DEG C.
1H NMR(600MHz,CDCl3),δ(ppm):7.45 (d, J=8.2Hz, 4H, ArH), 7.09 (d, J=8.3Hz,
4H,ArH),3.56(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):136.30,131.62,130.99,121.47,42.53.
HR-MS:[M+H]+,Calcd:402.8825,Found:402.8817.
(3- luorobenzyls) disulfide (the LYY- Ι of 7 1,2- of embodiment bis-7)
Reference compound LYY- Ι1Synthetic method prepared by 3- fluorobenzyl bromides and thiocarbamide, obtain yellow liquid.Yield 37%.
1H NMR(400MHz,CDCl3),δ(ppm):7.32-7.26 (m, 2H, ArH), 7.01 (d, J=7.7Hz, 2H,
), ArH 6.95 (ddd, J=9.2,4.8,2.1Hz, 4H, ArH), 3.59 (s, 4H, CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):163.53,139.80,129.99,125.01,116.13,
114.50,42.72.
HR-MS:[M+H]+,Calcd:283.0427,Found:283.0435.
(4- luorobenzyls) disulfide (the LYY- Ι of 8 1,2- of embodiment bis-8)
Reference compound LYY- Ι1Synthetic method prepared by 4- fluorobenzyl bromides and thiocarbamide, obtain white solid.Yield 28%.
Mp:67~71 DEG C.
1H NMR(400Hz,CDCl3),δ(ppm):7.22-7.20 (m, 2H, ArH), 7.19 (d, J=5.5Hz, 2H,
), ArH 7.02 (d, J=8.2Hz, 2H, ArH), 7.01 (d, J=8.6Hz, 2H, ArH), 3.59 (s, 4H, CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):163.02,133.09,130.86,115.30,42.40.
HR-MS:[M+H]+,Calcd:283.0427,Found:283.0432.
(2- nitrobenzyls) disulfide (the LYY- Ι of 9 1,2- of embodiment bis-9)
Reference compound LYY- Ι1Synthetic method prepared by 2- nitrobenzyls bromine and thiocarbamide, obtain white solid.Yield 21%.
Mp:108~111 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):8.20-8.02(m,4H,ArH),7.59-7.50(m,4H,ArH),
3.72(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):148.25,139.27,135.25,129.58,124.08,
122.60,42.08.
HR-MS:[M+H]+,Calcd:337.0317,Found:337.0323.
(3- nitrobenzyls) disulfide (the LYY- Ι of 10 1,2- of embodiment bis-10)
Reference compound LYY- Ι1Synthetic method prepared by 3- nitrobenzyls bromine and thiocarbamide, obtain white solid.Yield 47%.
Mp:97~101 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):8.15 (dd, J=7.8,1.4Hz, 2H, ArH), 8.07 (s, 2H,
), ArH 7.58 (d, J=7.6Hz, 2H, ArH), 7.53 (t, J=7.7Hz, 2H, ArH), 3.72 (s, 4H, CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):148.24,139.27,135.26,129.58,124.08,
122.60,42.08.
HR-MS:[M+H]+,Calcd:337.0317,Found:337.0312.
(4- nitrobenzyls) disulfide (the LYY- Ι of 11 1,2- of embodiment bis-11)
Reference compound LYY- Ι1Synthetic method prepared by 4- nitrobenzyls bromine and thiocarbamide, obtain white solid.Yield 24%.
Mp:141~145 DEG C.
1H NMR(600MHz,CDCl3),δ(ppm):8.19 (d, J=8.6Hz, 4H, ArH), 7.43 (dd, J=12.9,
6.3Hz,4H,ArH),3.68(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):129.71,129.63,123.85,123.74,35.18.
HR-MS:[M+H]+,Calcd:337.0317,Found:337.0309.
(4- chlorobenzyls) disulfide (the LYY- Ι of 12 1,2- of embodiment bis-12)
Reference compound LYY- Ι1Synthetic method prepared by 4- bromine chlorides and thiocarbamide, obtain white solid.Yield 29%.
Mp:33~40 DEG C.
1H NMR(600MHz,CDCl3),δ(ppm):7.27 (t, J=7.9Hz, 4H, ArH), 7.19 (d, J=8.3Hz,
4H,ArH),3.54(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):136.34,130.63,130.25,128.62,34.84.
HR-MS:[M+H]+,Calcd:314.9836,Found:314.9828.
(4- methyl-benzyls) disulfide (the LYY- Ι of 13 1,2- of embodiment bis-13)
Reference compound LYY- Ι1Synthetic method prepared by 4- methyl benzyl bromines and thiocarbamide, obtain white solid.Yield 34%.
Mp:52~55 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):7.14-7.12(m,4H,ArH),7.12-7.10(m,4H,ArH),
3.60(s,4H,CH2),2.33(s,6H,CH3).
13C-NMR(600MHz,CDCl3),δ(ppm):137.11,134.28,129.28,129.15,43.04,21.16.
HR-MS:[M+H]+,Calcd:275.0928,Found:275.0924.
(4- cyanobenzyls) disulfide (the LYY- Ι of 14 1,2- of embodiment bis-14)
Reference compound LYY- Ι1Synthetic method prepared by 4- cyano group benzyl bromines and thiocarbamide, obtain yellow solid.Yield 34%.
Mp:136~139 DEG C.
1H NMR(400MHz,CDCl3),δ(ppm):7.63 (d, J=8.2Hz, 4H, ArH), 7.33 (d, J=8.2Hz,
4H,ArH),3.64(s,4H,CH2).
13C-NMR(600MHz,CDCl3),δ(ppm):142.65,132.31,129.96,118.51,111.45,42.58.
HR-MS:[M+H]+,Calcd:297.0520,Found:297.0513.
The 2,2- of embodiment 15 [(3- hydroxy-4-hydroxymethyl methyl -2- methyl -5- pyridine radicals)-methyl] disulphide (LYY-I15)
Pyritinol hydrochloride (0.200g, 0.5mmol) is soluble in water, and saturated aqueous sodium carbonate is added dropwise, and separates out white solid
Body, yield 70%.
1H NMR(400MHz,CDCl3),δ(ppm):δ8.35(s,2H,OH),7.70(s,2H,ArH),4.76(s,4H,
OCH2),3.83(s,4H,CH2),2.34(s,6H,CH3).
13C-NMR(600MHz,CDCl3),δ(ppm):δ151.05,147.12,140.97,132.05,128.86,
56.98,36.83,19.84.
HR-MS:[M+H]+,Calcd.:369.0938,Found:369.0940.
The guarantor for the hippocampus neurons in mice HT-22 cell lines that embodiment 16LYY-I classes compound is damaged to glutamate induction
Shield is acted on
Test method reference literature [Cheng J, et al.Neurochemistry International, 2013,62
(8):1072–1078.]。
Sample DMSO dissolves.Experiment is divided into blank control group, glutamic acid group, sample sets.Glutamic acid group adds 5mM paddy
Propylhomoserin；The glutamic acid and final concentration that sample sets add 5mM simultaneously are respectively 1,5,10,50,100 μM of LYY-I1-15Or Ligusticum wallichii
Piperazine；Blank control group adds the DMSO of same volume.After dosing 24 hours, survivaling cell is detected with mtt assay.Every group of carry out is put down for three times
Row experiment, the results are shown in Table 1.
Table 1LYY-I classes compound damages the influence of HT22 cell survival rates to glutamate induction
* shows compared with glutamic acid group there is significant difference, P<0.01
5mM glutamic acid can induce HT22 cellular damages, survival rate<30%.From the result of table 1, final concentration of 1~100 μ
The compound that M embodiment 1~15 is synthesized can significantly increase HT22 cell survival rates (P caused by glutamic acid<0.05,P<
0.01) neural cell injury, is reduced.It effectively protects 10~100 μM of concentration range, and it is 10 to detect minimum effective protection concentration
μM.Wherein LYY-I1The protective effect for damaging HT22 cells to glutamate induction is most strong, and at 10~100 μM, cell survival rate reaches
To 91.77~95.40%, there is significant difference (P with other compound phase ratios<0.01)；But ligustrazine under same concentration
There is no the effect of anti-glutamate toxicity, see Fig. 1.
Embodiment 17LYY-I1The protective effect for the hippocampus neurons in mice HT-22 cell lines damaged to hydrogen peroxide-induced
Test method reference literature [ChenZ, et al.Cancer Letters, 2013,336 (2):281-289.].
Experiment is divided into blank control group, hydrogen peroxide group and sample sets.Hydrogen peroxide group is added at 100 μM of hydrogen peroxide
Reason；Sample sets add simultaneously 100 μM of hydrogen peroxide and final concentration be respectively 1,5,10,50,100 μM of LYY-I1Or Ligusticum wallichii
Piperazine；Control group adds the DMSO of same volume.After dosing 24 hours, survivaling cell is detected with mtt assay.Every group in triplicate, experiment
As a result Fig. 2 is seen.
Shown by Fig. 2, in H2O2Group, the survival rate position 15.23% of HT-22 cells, illustrates 100 μM of H2O2Cause HT-
The damage of 22 cells.Through 50,100 μM of LYY-I1Processing, the survival rate of HT-22 cells is remarkably decreased (P<0.01), explanation
LYY-I1With removing H2O2The Free Radical of generation, to H2O2The HT-22 cells of damage have good protection effect.But it is same
Ligustrazine does not remove H under sample concentration2O2Free Radical.
Embodiment 18LYY-I1To the antagonism of ADP induced rat platelet aggregations
Experimental method reference literature [Paul Jurasz, et al.PLoS One, 2013；8(3):e59281.].
Experiment is divided into ADP (adenosine diphosphate) group, LYY-I1Group (plus ADP and 0.1,0.5,1mMLYY-I1), ligustrazine group
(plus ADP and 0.1,0.5,1mM ligustrazines), each group is all provided with 3 parallel pipes.Blood platelet is derived from SD rats.In platelet aggregation instrument
The upper maximum aggregation rate (PAGm) for determining each group.
Shown by Fig. 3, ADP groups maximum platelet aggregation rate is 78.77%.As addition 0.1,0.5,1mMLYY-I1Processing
When, maximum platelet aggregation rate is remarkably decreased (P<0.05, P<0.01) LYY-I, is pointed out1Lived with good platelet aggregation-against
Property.But ligustrazine does not have antiplatelet aggregative activity under same concentration.
Embodiment 19LYY-I1Cerebral protection in mouse brain in artery occlusion model
ICR mouse, male, 30 ± 2.0g of body weight, purchased from Chinese Academy of Sciences's Shanghai Experimental Animal Center.2,3,5- chlorinated triphenyl bases
Tetrazole (TTC) (Sigma).
Experiment artery occlusion (MCAO) model in mouse brain is carried out, and is divided into LYY-I1Group and solvent control group.Every group 8
Mouse.Solvent group injects the corn oil containing 25%DMSO.LYY-I1Group is after ischemia-reperfusion 3h, intraperitoneal administration present invention system
The 0.22mmol/kg LYY-I of work1.Mouse is put to death after ischemia-reperfusion 24h, with TTC Determination Staining cerebral infarction area sizes.
Fig. 4 is mouse cerebral infarction volume percentage after Reperfu- sion 24h in MCAO.By the visible artery occlusion 24h in the brain of Fig. 4 results
Afterwards, compared with solvent group mouse, LYY-I is injected after mouse ischemia-reperfusion 3h1Significantly reduce cortex, corpus straitum and cerebral hemisphere
Infarction volume, shows LYY-I1Blocking the Ischemia Brain Damage caused to arteria cerebri media has significant protective effect.
It the above is only the preferred embodiment of the present invention, it is noted that come for those skilled in the art
Say, under the premise without departing from the principles of the invention, some improvements and modifications can also be made, these improvements and modifications also should be regarded as
Protection scope of the present invention.
Claims (10)
1. structural compounds shown in Formulas I：
Wherein, Ar is 3,5,6-trimethylpyrazinyl or 4-COOCH3-Ph。
2. application of the structural compounds shown in Formulas I in the preparation for preparing protection neuronal cell；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-
FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
3. application of the structural compounds shown in Formulas I in the preparation for suppressing platelet aggregation is prepared；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-
FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
4. application of the structural compounds shown in Formulas I in the preparation for preparing preventing and treating cerebral ischemia re-pouring Brain Injury After；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-
FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
5. application of the structural compounds shown in Formulas I in the preparation for preparing preventing and treating cerebral apoplexy；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-
FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
6. application according to claim 5, it is characterised in that the cerebral apoplexy is the cerebral apoplexy caused by cerebral vessels embolism
And/or cerebral apoplexy caused by cerebral hemorrhage.
7. the application according to any one of claim 2~6, it is characterised in that the dosage of the compound of formula I is
0.05mg/kg~90mg/kg.
8. the application according to any one of claim 2~6, it is characterised in that the Ar is 3,5,6-
trimethylpyrazinyl。
9. a kind of medicine, it is characterised in that including compound of formula I and pharmaceutically acceptable auxiliary material；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-
FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh.
10. the preparation method of structural compounds shown in Formulas I, it is characterised in that by compound A and thiocarbamide in manganese dioxide and PEG
Reacted under existence condition, compound of formula I is made；
Wherein, Ar is 3,5,6-trimethylpyrazinyl, Ph, 4-COOCH3-Ph、2-BrPh、3-BrPh、4-BrPh、3-
FPh、4-FPh、2-NO2Ph、3-NO2Ph、4-NO2Ph、4-ClPh、4-CH3Ph or 4-CNPh；
The compound A is 1- bromos ligustrazine, benzyl bromine, 4- (bromomethyl) methyl benzoate, 2- bromobenzyls bromine, 3- bromobenzyls bromine, 4-
Bromobenzyl bromine, 3- fluorobenzyl bromides, 4- fluorobenzyl bromides, 2- nitrobenzyls bromine, 3- nitrobenzyls bromine, 4- nitrobenzyls bromine, 4- bromine chlorides, 4- methyl benzyl bromines
Or 4- cyano group benzyl bromines.
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