CN103142569B - 2,6-diisopropyl benzoic acid and derivant thereof are as the application of neuroprotective - Google Patents
2,6-diisopropyl benzoic acid and derivant thereof are as the application of neuroprotective Download PDFInfo
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- CN103142569B CN103142569B CN201310061349.1A CN201310061349A CN103142569B CN 103142569 B CN103142569 B CN 103142569B CN 201310061349 A CN201310061349 A CN 201310061349A CN 103142569 B CN103142569 B CN 103142569B
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- diisopropyl
- benzoic acid
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- MWWNHUVCHNJZPF-UHFFFAOYSA-N CC(C)c1c(C)c(C(C)C)ccc1 Chemical compound CC(C)c1c(C)c(C(C)C)ccc1 MWWNHUVCHNJZPF-UHFFFAOYSA-N 0.000 description 3
- 0 CCC(C)c1c(*C)c(C(C)C)ccc1 Chemical compound CCC(C)c1c(*C)c(C(C)C)ccc1 0.000 description 2
- MLSDURGAASAJBV-UHFFFAOYSA-N CC(C)C1=C(CO)C(C(C)C)=CCC1 Chemical compound CC(C)C1=C(CO)C(C(C)C)=CCC1 MLSDURGAASAJBV-UHFFFAOYSA-N 0.000 description 1
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Abstract
2,6-diisopropyl benzoic acid and derivant thereof, as the application of neuroprotective, are compound specifically
for the preparation of the application in nerve protection medicine, wherein R is carboxyl, methylol, carboxymethyl, ethoxy.The neuronal damage of compound in the present invention to glutamate induction has stronger protective effect.
Description
Technical field
The invention belongs to pharmaceutical field, provide class 2, a 6-diisopropyl benzoic acid and derivant thereof preparing the application in nerve protection medicine.
Background technology
Neuroprotective is a focus of cerebral infarction medicine development.At present, for numerous protection reagent of the different link exploitation of cerebral infarction cascade reaction, except free radical scavenger Edaravone, be all that animal is effective, clinical invalid or poor effect, or can not be applied to clinical because of serious side effects.Therefore, the exploitation of novel nerve protective agent and screening are the emphasis of research at present.
Research shows, plays an important role in the cell injury that glutamic acid causes in cerebral ischemia, and when cerebral ischemia occurs, a large amount of releases of glutamic acid can cause the death of neuronal cell.The damage of neurocyte causes lactic acid dehydrogenase (LDH) to be discharged into extracellular, can evaluate the protective effect of medicine to neuronal cell by the rate that spills measuring Drug inhibition LDH.
Based on glutamic acid stimulate neuronal cell lactic acid dehydrogenase (LDH) releasing theory to the selection result of compound, the present invention finds that class 2, a 6-diisopropyl benzoic acid and derivant thereof have protective effect to neuronal cell.
Summary of the invention
The technical problem solved: provide class 2, a 6-diisopropyl benzoic acid and derivant thereof preparing the application in nerve protection medicine.
Technical scheme:
Compound
for the preparation of the application in nerve protection medicine, wherein R is carboxyl, methylol, carboxymethyl or ethoxy.
The application of above-claimed cpd in neuroprotective.
The salt of the pharmaceutically acceptable alkali of the compound as shown in general formula (I), the salt of alkali is potassium salt, sodium salt.
The application in nerve protection medicine prepared by the salt of the compound as shown in general formula (I) and pharmaceutically acceptable alkali.
Compound in the present invention is known compound, its synthesis can according to or the method for reference literature synthesize.
By following synthesis, the synthesis of the compound that the present invention relates to can illustrate that route represents.
Synthesis signal route:
Beneficial effect:
The neuronal damage of compound in the present invention to glutamate induction has stronger protective effect.
Accompanying drawing explanation
The anti-apoplexy effect of Fig. 1: 2,6-diisopropyl benzoic acid (1).
Detailed description of the invention
The following examples can make those skilled in the art comprehensively can understand the present invention, but do not limit the present invention in any way.
The synthesis of embodiment 12,6-diisopropyl iodobenzene
Measure 2,6-diisopropyl aniline 3.2mL (15.8mmol) is in 100mL tri-neck round-bottomed flask, add 30mL water, concentrated hydrochloric acid 15mL is added under the mechanical agitation of limit, after adding, under ice-water bath, drip with constant pressure funnel the aqueous solution that sodium nitrite 1.18g (17.4mmol) is dissolved in 4mL, at 4 DEG C, react 1h again.Take iodine 4.40g (21.28mmol) and potassium iodide 6.04g (36mmol) and to be dissolved in 10mL frozen water obtaining mixed liquor.Mixed liquor is dropped in reaction system, after 30min, add water 40mL, dichloromethane 100mL, ambient temperature overnight, add hydration sodium thiosulfate 6.30g (25.4mmol), stirring reaction 20min.Elimination black precipitate, solution separatory funnel separatory, aqueous phase chloroform (60mL × 2 time) extraction, merges organic facies, washs, saturated common salt water washing, anhydrous magnesium sulfate drying with 10%wt hypo solution 50mL.Elimination desiccant, boils off solvent, carries out column chromatography (petroleum ether: ethyl acetate=200:1, volume ratio) obtain flaxen liquid 1.54g, productive rate 34% with silicagel column.
1HNMR(CDCl
3,300MHZ):1.21-1.24(s,12H),3.37-3.43(m,1H),3.44-3.51(m,1H),7.04-7.06(s,1H),7.11-7.13(s,1H),7.17-7.23(m,1H).
The synthesis of embodiment 22,6-diisopropyl benzoic acid (1)
Get 2,6-diisopropyl iodobenzene 1.44g (5mmol) in 100mL three-necked bottle, add anhydrous tetrahydro furan 3mL, fully replace with nitrogen in biexhaust pipe system.Be coolant with acetone, with liquid nitrogen, reaction system dropped to-78 DEG C.Drip the n-butyllithium solution 5mL (10mmol) of 2mol/L under stirring with syringe, after injection, keep-78 DEG C to react 1h.Temperature is risen to room temperature, after half an hour, passes into CO
2reaction 20h.Add 2N hydrochloric acid solution 5mL, stir rear extracted with diethyl ether, merge organic facies, solvent evaporated.Residue 2NNaOH solution 5mL dissolves, and uses washed with diethylether.Aqueous phase 2N hydrochloric acid solution 10mL neutralizes, and with extracted with diethyl ether, combining extraction liquid, anhydrous sodium sulfate drying, filter, evaporate to dryness obtains white crystal 0.54g, productive rate 54%.
1HNMR(CDCl
3,300MHZ):1.28(s,12H),2.82-2.96(m,2H),7.16-7.20(s,2H),7.26-7.36(m,1H),13.05(s,1H).
The synthesis of embodiment 32,6-diisopropyl benzyl alcohol (2)
The solution that 2,6-diisopropyl benzoic acid 2.1g (10mol) is dissolved in 10mLTHF is added dropwise to LiAlH
40.57g is at the solution of 20mLTHF.After adding, backflow 2h.After letting cool, add 10%wtNH
4cl solution 20mL, with EtOAc extraction, saturated common salt water washing, anhydrous sodium sulfate drying, filters, concentrated, obtains solid 1.83g, productive rate 95%.
1HNMR(CDCl
3,500MHZ):1.28(s,12H),2.92-3.12(m,2H),4.79(s,2H),6.86-7.05(m,3H).
The synthesis of embodiment 42,6-diisopropyl phenethanol (3)
Get 2,6-diisopropyl iodobenzene 2.88g (10mmol) in 100mL three-necked bottle, add anhydrous tetrahydro furan 3mL, fully replace with nitrogen in biexhaust pipe system.Be coolant with acetone, with liquid nitrogen, reaction system dropped to-78 DEG C.Drip the n-butyllithium solution 10mL (20mmol) of 2mol/L under stirring with syringe, after injection, keep-78 DEG C to react 1h.Temperature is risen to-10 DEG C, oxirane 7mL (0.14mol) is dissolved in the solution instillation reactant liquor of 20mL dry tetrahydrofuran, drips off rear stirred overnight at room temperature.Next day, add saturated ammonium chloride solution 50mL, add dilute hydrochloric acid (1: 1 volume with water dilution) 100mL, be extracted with ethyl acetate (60mL × 3 time).Combining extraction liquid, saturated common salt water washing, anhydrous sodium sulfate drying, filters, evaporate to dryness, and residue over silica gel column chromatography (petroleum ether: ethyl acetate=200:1, volume ratio) obtains white cotton like solid 0.53g, productive rate 28%.
1HNMR(CDCl
3,500MHZ):1.22(d,12H,J=6.90Hz),2.82-2.96(m,2H),3.66-3.74(m,2H),3.89-3.95(m,2H),7.09-7.21(m,2H),7.26-7.36(m,1H).
The synthesis of embodiment 52,6-diisopropyl hyacinthin
2,6-diisopropyl phenethanol 1.36g (6.6mmol) is dissolved in 50mL dichloromethane, adds pyridinium chlorochromate 3.08g (14mmol).Stirring at room temperature 2 hours, steams except dichloromethane, uses 75mL diluted ethyl acetate, washing, saturated common salt is washed, anhydrous sodium sulfate drying, filters, concentrated, column chromatography (petroleum ether: ethyl acetate=50:1, volume ratio), obtains white solid 0.85g, productive rate 63%.Product is directly used in next step reaction.
The synthesis of embodiment 62,6-diisopropyl phenylacetic acid (4)
By 2,6-diisopropyl hyacinthin 0.82g (4.0mmol) is dissolved in the mixed solvent of the 50mL tert-butyl alcohol, 10mL oxolane, add under ice bath in the 36mL aqueous solution of 3.3g sodium dihydrogen phosphate (28mmol) and 2.4g sodium chlorite (80%, 21mmol).20min is stirred under ice bath, rise to stirring at room temperature 3 hours, in impouring saturated ammonium chloride solution 150mL, ethyl acetate 200mL extracts, wash twice, saturated common salt washing twice, anhydrous sodium sulfate drying filters, concentrated, column chromatography (petroleum ether: ethyl acetate=8:1, volume ratio), obtain white solid 0.42g, productive rate 48%.
1HNMR(CDCl
3,500MHz):0.95-1.20(m,12H),2.85-3.15(m,2H),3.74(s,2H),7.10-7.30(m,3H).
The protective effect that in embodiment 7 embodiment, target compound damages for glutamate induction primary neuronal cell
Experimental principle:
This experiment adopts lactic acid dehydrogenase (Lactatedehydrogenase, LDH) algoscopy.LDH is present in cell, and the outer content of normal condition lower eyelid is less, and when cell damage is hindered, LDH can be discharged into outside born of the same parents, and the rate that spills therefore detecting LDH can judge that cell damage hinders degree.LDH can generate acetone acid by catalysis lactic acid, and acetone acid and 2,4 dinitrophenyl hydrazine react and generate acetone acid dinitrophenylhydrazone, in brownish red in alkaline solution, can obtain enzyme activity by colorimetric.
The extraction of mouse cortex primary neuron:
Get the pregnant mice of ICR that pregnant age is 15-16 days, after cervical dislocation, uterus is separated with Placenta Hominis, successively the tire Mus of taking-up is placed in bromogeramine solution, 75% alcohol disinfecting of 0.1%.Left hand fixes tire Mus, and cranium is separated by right hand ophthalmic tweezers, exposes cerebral hemisphere, with ophthalmic tweezers careful gripping both sides cerebral cortex, is placed in the plate being placed with 10mLD-hanks.After all taking, peel off meninges and be placed in the plate that another one is placed with 10mLD-hanks, and then draw 5mLD-hanks washing once.With curved tweezer, cortex is shredded, take out the pancreatin (2mL0.25% pancreatin+2mLD-hanks) being placed in 0.125% of 37 DEG C of incubators and be added to plate, transfer in small beaker, after mixing, in incubator, digest 10min.After taking out from incubator, add 5mLDMEM+10%wtFBS and stop digestion, after piping and druming mixing, be transferred in centrifuge tube, 1500rpm, centrifugal 5min.Supernatant discarded, then add 4mLDMEM+10%wtFBS, after piping and druming mixing, recentrifuge, 1500rpm, 5min.Discarded by supernatant, add 2mL neuronal culture (98mLNeurobasalMedium, 2mLB27,50 μm of ol/lL-glutamine400 μ L, penicillin 50 μ L, streptomycin 50 μ L), piping and druming makes cell dispersal, crosses 400 mesh sieves.After diluting 10 times, carry out cell counting, then inoculate, 300 μ L are inoculated in the 24 every holes of orifice plate, and labelling is placed in incubator well and cultivates.Change culture medium after one day, siphon away 120 μ L, then add 450 μ L.Within 4th day, again change liquid, siphon away 200 μ L, then add 300 μ L.7th day, glutamic acid modeling.
Glutamate injury model:
First the 24 every holes of orifice plate are settled to 300 μ L, then every hole administration 0.3 μ L, each drug level establishes 3 parallel holes, after half an hour, every hole again give Glu3 μ L and Gly3 μ L, period observation of cell state, after half an hour, full dose changes liquid, collects culture medium (born of the same parents are outer) after being placed in incubator 8h.After washing twice with PBS again, add 300 μ L distilled waters, then collect (in born of the same parents) afterwards 3 times in-80 DEG C of multigelations.-20 DEG C of preservations.
LDH spills the mensuration of rate:
Table 1 spills the operating procedure that rate measures
Again mix after adding NaOH solution, sample is joined 96 orifice plates respectively, every hole 200 μ L, in microplate reader, then measure each hole absorbance during 440nm.
Spill the outer measured value of rate=born of the same parents/(in the outer measured value+born of the same parents of born of the same parents measured value) × 100%
Evaluation of result foundation:
According to following formulae discovery compound to the suppression ratio of the neuronal cell injury of glutamate induction:
Suppression ratio=(glutamic acid group spills rate-compound group and spills rate)/(glutamic acid group spills rate-matched group and spills rate) × 100%
The suppression ratio of compound is the meansigma methods of three parallel hole measured values.
Result:
Table 2LDH spills suppression ratio
Above-mentioned test shows: the primary neuronal cell damage of compound 1 ~ 4 pair of glutamate induction has protective effect, and wherein 2,6-diisopropyl benzoic acid (1) are 10 of test
-7~ 10
-5stronger neuroprotective is had, 10 in M concentration range
-5during M, its LDH discharges suppression ratio up to 36.8%.Our research also finds, menthylformic acid (5) and bornyl amine (6) have neurotoxicity in the concentration range of test.
Embodiment 82,6-diisopropyl benzoic acid (1) neuroprotective on animal model
The preparation of cerebral ischemic model:
Internal carotid artery line brush is adopted to prepare middle cerebral artery occlusion (Middlecerebralartery, MCAO) cerebral ischemia re-pouring model.Animal is with after 10% chloral hydrate (4.0mL/kg) anesthesia, dorsal position is fixed on operating-table, sterilization skin, cervical region medisection, be separated right carotid, external carotid artery, internal carotid artery, peel off vagus nerve gently, ligation also cuts off external carotid artery, follow internal carotid artery forward, tie wings arteria palatina.Folder closes common carotid artery proximal part, make a kerf from the far-end of the ligature of external carotid artery, inserting external diameter is the nylon wire of 0.285mm, and top is through polishing and lubricated, internal carotid artery is entered through common carotid artery bifurcated, then (be about 20mm from crotch) till being slowly inserted into light resistance, block all blood confessions of middle cerebral artery, cerebral ischemia is after 2.0 hours, extract nylon wire gently, recover blood for also at once by tail vein injection medicine, sew up skin of neck, sterilization.Rat hot plate is used to maintain Rat-rectum temperature 37.0 ± 0.5 DEG C in whole operation process.
The evaluation of neuroprotective:
The chloral hydrate anesthesia of animal 10%wt after recovery blood was for 24 hours, broken end gets brain, remove olfactory bulb, cerebellum and low brain stem, with normal saline flushing brain surface bloodstain, suck remained on surface water mark, 7min is placed in-80 DEG C, coronal section is made vertically downward in sight line crossing plane immediately after taking-up, and cut a slice every 2mm backward, brain sheet is placed in PBS(0.2mol/L, pH7.4 ~ 7.8) freshly prepared TTC(20g/L) in dye liquor in 37 DEG C of incubation 90min, normal cerebral tissue dyes peony, ischemic tissue of brain is then in pale asphyxia, after normal saline flushing, rapidly brain sheet is arranged from front to back in order, blot remained on surface water mark, take pictures.The infarct size of comparison model group and administration group, evaluates the neuroprotective of medicine.
Experimental result is shown in accompanying drawing 1, and after result display 2,6-diisopropyl benzoic acid (1) 1mg/Kg intravenously administrable, the cerebral infarction dead band of mice is obviously reduced than the infarct size of model group.
Claims (1)
1. compound
for the preparation of the application in nerve protection medicine, wherein R is carboxyl or methylol.
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| 异丙酚对脑缺血缺氧性损伤保护作用的分子机制;何爱霞，等;《国外医学麻醉学与复苏分册》;20051231;第26卷(第6期);355-358 * |
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