CN103006631B - Application of N-benzyl fatty acyl amide compound to preparation of neuroprotective drugs - Google Patents
Application of N-benzyl fatty acyl amide compound to preparation of neuroprotective drugs Download PDFInfo
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- CN103006631B CN103006631B CN201210591732.3A CN201210591732A CN103006631B CN 103006631 B CN103006631 B CN 103006631B CN 201210591732 A CN201210591732 A CN 201210591732A CN 103006631 B CN103006631 B CN 103006631B
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Abstract
The invention discloses an application of an N-benzyl fatty acyl amide compound to preparation of neuroprotective drugs. In a structural formula in the specification, R1 is H or hydroxy or C1-4 alkoxy and R2 is C7-C23 saturated or unsaturated fatty alkyl. The compound can serve as a neuroprotective agent and is used for preparing drugs for treating nerve diseases such as cerebral ischemia, cerebral injury, multiple sclerosis, Alzheimer disease and Parkinson disease.
Description
Technical field
The present invention relates to a kind of N-benzyl fatty acyl amide compound and preparing the application in nerve protection medicine, this compound is likely used to the sacred diseases such as treatment cerebral ischemia, brain injury, multiple sclerosis, Alzheimer, parkinson disease.
Background technology
Neurocyte is the main body of central nervous system, neuronal damage is the main cause of many sacred diseases, nerve injury, infection, the degeneration such as apoplexy, multiple sclerosis, Alzheimer, parkinson disease, all because neuron suffers damage, cause part or all of function of nervous system to lose.Therefore, neuroprotective unit is a point of penetration of the multiple sacred disease for the treatment of effectively.
In nervous system, Endocannabinoids plays an important role to neuronic survival.N-N-Arachidonylethanolamine (anandamide, AEA) is shown below
being the endocannabinoid of separated qualification the earliest, is also neurotransmitter important in brain, not only participates in the protection of various acute nerve injury model, and also has protective effect to multiple neurodegenerative diseases.
Except endogenous AEA, in vivo and in vitro shows, AEA analog also has neuroprotective widely.Up to now, the AEA analog studying system is the most fatty acyl amino acids, is shown below,
wherein R' is saturated or unsaturated alkyl, and R is amino acid residue.They are combined into from different aminoacid by saturated or unsaturated fatty acid.Natural fat amic acid finds in the microbial bodies such as Campylobacter, Recent study confirm, also there is this compounds in mammalian body, and find its biological function and AEA similar.Chinese patent CN1974545B discloses a class fatty amide compounds and is preparing the application in the neurological disease drugs such as treatment cerebral ischemia, apoplexy, Alzheimer, parkinson disease as neuroprotective.
N-benzyl fatty acyl amide compound is the characteristic chemical composition in the plant Maca of South America, and its structure is similar to AEA, and compound is different from being basic structure with fatty acyl aminoacid disclosed in patent CN1974545B.(the documents: McCollom M M such as McCollom M M; Villinski JR; Gafner S; etal.Analysis of macamides in samples of Maca (Lepidium meyenii) by HPLC-UV-MS/MS.Phytochemical Analysis; 2005; 16:463 – 469) report the synthetic method of this type of material, and before making the present invention, there is not the report of compound of the present invention for neuroprotective aspect.
Summary of the invention
The technical problem to be solved in the present invention is to provide above-mentioned N-benzyl fatty acyl amide compound and is preparing the application in nerve protection medicine.
Above-mentioned N-benzyl fatty acyl amide compound structure is as follows:
Wherein, R
1for H or hydroxyl or C1-4 alkoxyl, R
2for the saturated of C7-C23 or unsaturated aliphatic hydrocarbyl moiety.
The Effect study that the N-benzyl fatty acyl amide compound of through type of the present invention (I) damages isolated rat brain sheet Anoxia (OGD); and the of short duration Forebrain Ischemia of pallasiomy and intraluminal middle cerebral artery occlusion in rats are blocked to the research of Reperfu-sion neuroprotective; confirmation formula (I) compound has axoneure prolection; can be used for preparing nerve protection medicine, to treat or to prevent the sacred diseases such as cerebral ischemia, brain injury, multiple sclerosis, Alzheimer, parkinson disease.
N-benzyl fatty acyl amide compound shown in general formula (I) can form pharmaceutically useful addition salts with organic acid or mineral acid.
The present invention is also provided as the pharmaceutical composition of neuroprotective, wherein comprises the compound described in general formula (I) of effective dose or the salt of general formula (I) described compound, can also comprise one or more pharmaceutically acceptable carriers.
Above-mentioned pharmaceutically acceptable carrier is nontoxic and the performance curative effect of mutual-through type (I) compound does not have adverse effect.Examples of such carriers can be the usual getable any solid excipient in this area, liquid excipient, semisolid excipient or gaseous excipient.Solid excipient comprises starch, cellulose, Pulvis Talci, glucose, lactose, sucrose, gelatin, Fructus Hordei Germinatus, rice, flour, Chalk, silica gel, magnesium stearate, sodium stearate, glyceryl stearate acyl ester, sodium chloride, dried skim milk etc.Liquid and semisolid excipient comprise glycerol, propylene glycol, water, ethanol and various oil, as Oleum Arachidis hypogaeae semen, Oleum Glycines, mineral oil, Semen Sesami wet goods.Other adjuvant can also be added in addition in the composition as flavouring agent, sweeting agent etc.
Compound administration mode of the present invention can be oral, muscle, vein or subcutaneous injection, or systemic administration (such as transdermal, snuffing enter or suppository).
The actual amount of application of compound of the present invention depends on many factors, as the seriousness of disease to be treated, the age for the treatment of target and relative health, route of administration and mode, and other factors.The effective dose of compound in treatment of general formula (I) is 0.03-30mg/kg body weight every day, can use according to practical situation one or many.
The various dosage forms of pharmaceutical composition of the present invention can be prepared according to the conventional method of pharmaceutical field.As made compound (I) mix with one or more carriers, be then made into required dosage form, as tablet, pill, capsule, semisolid, powder, slow release formulation, solution, suspension, ingredients, aerosol etc.
Accompanying drawing explanation
The protective effect that Fig. 1 different N-benzyl fatty acyl amide compound preconditioning on rat brain sheet OGD damages.
The protective effect of the N-benzyl fatty acyl amide compound preconditioning on rat brain sheet OGD damage of Fig. 2 variable concentrations.
The pretreatment of Fig. 3 N-benzyl palmitamide is on the impact of Forebrain Ischemia and Reperfusion hippocampal CAl district neuron survival rate.
The pretreatment of Fig. 4 N-benzyl palmitamide affects block diagram to Forebrain Ischemia and Reperfusion hippocampal CAl district neuron survival rate.
Fig. 5 N-benzyl palmitamide is on the impact of Focal Cerebral Ischemia-Reperfusion in Rats infarction of brain area.
Fig. 6 N-benzyl palmitamide affects block diagram to Focal Cerebral Ischemia-Reperfusion in Rats infarction of brain area.
Detailed description of the invention
Embodiment 1
The synthesis of N-benzyl fatty acyl amide compound, synthetic route is as follows
Fatty acid and thionyl chloride reflux obtain fat acyl chloride.Benzene methanamine or benzenemethanamine derivatives are dissolved in pyridine, slowly drip the fat acyl chloride obtained, stirring reaction 1h.Through extraction, recrystallization etc., obtained N-benzyl fatty acyl amide compound.
Be prepared as follows altogether N-benzyl fatty acyl amide compound, the structure of obtained compound is respectively:
1.N-benzyl palmitamide:
2.N-(3-methoxybenzyl) palmitamide:
3.N-benzyl kemanide S:
4.N-(3-methoxybenzyl) kemanide S
5.N-benzyl oleamide
6.N-(3-methoxybenzyl) oleamide
Wherein the nuclear-magnetism of compound 1 and mass spectrometric data are:
1H-NMR(CDCl
3)δ(ppm)：7.30(5H，m，H-3′to H-7′)，5.74(1H，s，N-H)，4.44(2H，d，J=5.7Hz，H2-1′)，2.21(2H，t，J=7.7Hz，H2-2)，2.00(4H，m，H2-8，H2-11)，1.66(2H，m，H2-3)，1.29(20H，m，H2-4to H2-7，H2-12to H2-17)，0.88(3H，t，J=6.6Hz，H3-18)；
13C-NMR(CDCl
3)δ(ppm)：172.89(C-1)，138.45(C-2′)129.99(C-10)，129.73(C-9)，128.68(C-4′，C-6′)，127.80(C-3′，C-7′)，127.46(C-5′)，43.58(C-1′)，36.78(C-2)，31.88(C-16)，29.12-29.75(C-4to C-7and C-12to C-15)，27.21(C-11)，27.16(C-8)，25.74(C-3)；ESI-HRMSm/z346.3142(calculated for C23H39NO，[M+H]+，346.3104).
Prove that it is N-benzyl palmitamide.
Embodiment 2
The protective effect that N-benzyl fatty acyl amide compound damages isolated rat brain sheet Anoxia (OGD)
1. the preparation of brain sheet
Before experiment, estimation of cerebrospinal fluid flow in normal volunteers (nACSF) is divided into two parts, under room temperature (25 DEG C) He in ice bath (0 DEG C), passes into mixture of oxygen 1 hour respectively, make it saturated for subsequent use.Rat breaks end, and rapidly takes out full brain, immerses in ice nACSF subsequently, takes out after 1 minute, along coronalplane cut and equating akrencephalon and brain in end, 502 glue are pasted onto on vibratome bracket, and with the whole cerebral tissue of ice nACSF dipping bath, mixed oxygen continues to pass into.Cut 400 μm of thick brain sheets fast, with the thick mouth suction pipe of surface finish, brain sheet is moved to surface plate, immerse in the saturated ice nACSFF of mixture of oxygen, separate rapidly cortex and hippocampal tissue, with thick mouth suction pipe, cortex and hippocampal slices are moved in the small beaker of built-in nylon guard subsequently, it is made to be bathed in the saturated nACSF of mixture of oxygen, at room temperature recover to hatch 90 minutes, hatch in process and avoid brain sheet to shake by bubble, and mutually cover between brain sheet, extrude, hatch and terminate hindbrain sheet for subsequent experimental.
2. experiment grouping and administration
Random taking-up cortex brain sheet, moves in the saturated nACSF of 37 DEG C of mixed oxygen after at room temperature recovering to hatch 90 minutes and hatches 30 minutes again, subsequently row OGD injury experiment respectively: 1. matched group: continue to hatch in the nACSF that 37 DEG C of mixed oxygen is saturated; 2. damage group: brain sheet moves into mixing nitrogen (95%N
2+ 5%CO
2) saturated (replace the glucose in nACSF with the sucrose of 10mmol/L) without in glucose artificial cerebrospinal fluid, hatch 10 minutes, then recover nACSF and normally hatch 2 hours; 3. administration group: in damage first 30 minutes, damage and recover normally to hatch in 2 hours periods Incubating Solution and add the different N-benzyl fatty acyl amide compound of 10 μm of ol/L and the N-benzyl palmitamide of variable concentrations respectively.After hatching end, the capable TTC of all brain sheets (2,3,5-diphenyl tetrazolium chloride) dyes.
Brain sheet is hatched in the nACSF that end immerses subsequently containing 2%TTC, lucifuge dyeing in 37 DEG C of water baths, and period shakes gently, to prevent adhered to one another between brain sheet or to be pasted onto on bottle wall, affect brain sheet and dyes.Take out brain sheet after 30 minutes, with normal saline rinsing twice, filter paper sucks surface moisture, weigh weight in wet base, add extract (ethanol: DMSO=1:1v/v) with the ratio of 1g:20ml, then extracting 24 hours, period shake is for several times, complete to ensure the extracting of all brain sheets.After lucifuge extracting terminates, add on 96 orifice plates by the amount in 200ul/ hole by extract, microplate reader measures the absorbance (A value) of each hole at 490nm Podbielniak place.Computation organization's damage percentage as follows:
Tissue injury's percentage rate=(1-A
490 damages/ ~ A
490 contrasts) × 100%
The protective effect that 3.N-benzyl fatty acyl amide compound preconditioning on rat brain sheet OGD damages
Recover normally to hatch 2 hours after brain sheet OGD damages 10 minutes, brain sheet TTC dye levels reduces, tissue injury's percentage rate is 58.6 ± 0.91%, give N-benzyl fatty acyl amide compound in advance and brain sheet is hatched, various N-benzyl fatty acyl amide compound cumulative reduces tissue injury's percentage rate (see Fig. 1) of brain sheet.
N-benzyl palmitamide all can reduce tissue injury's percentage rate of brain sheet when its concentration is 0.1,1,3,10,30 μm of ol/L, when being 3 μm of ol/L and 10 μm of ol/L with concentration, effect the most obviously (see Fig. 2).Fig. 4 abscissa represents the variable concentrations of N-benzyl fatty acyl amide compound, and vertical coordinate represents corresponding tissue injury's percentage ratio, and * represents p<0.05, and * * represents p<0.01.
Embodiment 3
N-benzyl fatty acyl amide compound is to the protective effect of of short duration Forebrain Ischemia and Reperfusion pallasiomy neuronal damage
1. animal grouping
Bull mongolian gerbils is preoperative raises 1 ~ 2 day in 22 ~ 25 DEG C of environment, and operation consent curfew eats, and arbitrarily intakes.Be divided into sham operated rats, model group and administration group 3 groups at random.
2. modelling
Bilateral common carotid arteries blocked method is adopted to make the of short duration forebrain ischemia-reperfusion injury model of pallasiomy.Pallasiomy is pressed the anesthesia of 350mg/kg dosage lumbar injection 10% chloral hydrate solution, ventricumbent position is fixed.Model group is dissociated bilateral carotid arteries, give arteriole folder close 5 minutes+unclamping arteriole folder recovers cerebral blood flow.Sham operated rats is only free exposes bilateral carotid arteries, will not close by arteriole folder.Administration group in the preoperative three days and folder close first 30 minutes of bilateral carotid arteries respectively and postoperative 4 days by 3mg/kg dosage vena femoralis injection test medicine (N-benzyl palmitamide).
3. structure observation
Neuron count: postoperative 4th day of the of short duration Forebrain Ischemia and Reperfusion of pallasiomy, lumbar injection 350mg/kg10% chloral hydrate solution anesthesia pallasiomy, opens breast, fixing with 4% neutral formalin perfusion through ascending aorta.After getting optic chiasma, 1 ~ 4mm brain block carries out paraffin embedding, carries out coronalplane section, and the section of getting dentate gyrus and the mutual bag plane of Hippocampus is bonded on kiss-coating slide, slice thick 10 μm.Cut into slices through Nissel dyeing, under 200 times of light microscopics, count in the unit length of Hippocampus CAl stage casing 100 neuron number of surviving.
4. experimental result
Postoperative 4th day of the of short duration Forebrain Ischemia and Reperfusion of pallasiomy, takes out the capable tissue slice of brain and observes the neuronic survival condition in Hippocampus CAl district.Compared with sham operated rats, model group, administration group hippocampal CAl district survived neuronal number all obviously reduce at ischemia-reperfusion for postoperative 4 days.Administration group after pallasiomy Forebrain Ischemia and Reperfusion 4 days Hippocampus CAl district survived neuronal obviously more than model group (see Fig. 3,4, p<0.05).
Embodiment 4
N-benzyl fatty acyl amide compound is to the protective effect of Focal Cerebral Ischemia Reperfusion rat model neuron apoptosis
1. animal grouping and administration
Experimental rat is divided into 3 groups at random by body weight, i.e. sham operated rats, model group, administration group, administration group is three days and preoperative l hour lumbar injection N-benzyl palmitamide 3mg/kg in the preoperative, and sham operated rats and model group lumbar injection isometric(al) DMSO, after administration, 1h performs a surgical operation.
2. Focal Ischemia-Reperfusion in Rats model preparation
Middle cerebral artery occlusion method (middle cerebral artery occlusion, MCAO) is adopted to prepare rat brain re-perfusion model.Rat dorsal position after anesthesia is fixed, be separated right common carotid artery (CCA), RICA (ICA) and external carotid artery (ECA), ligation ECA and CCA, folder closes ICA distal end, to divide and place makes a kerf in ECA and ICA, insert a head end and be heated into smooth, spherical, front end is the nylon wire of 0.25mm through the diameter of poly-D-lysine process, then the bulldog clamp that folder closes ICA is unclamped, slightly withdraw after continuing to insert nylon wire to slightly resistance, line insertion depth is about 18.5 ± 0.5mm, cause MCA entrance block and cause cerebral ischemia, about lcm is stayed outside nylon wire, suture muscles skin, lumbar injection gentamycin sulfate 2ml, the end of a thread is lifted gently to there being resistance after 2 hours, realize filling with again.Model Success Flag: occur after Animal Anesthesia is clear-headed that ischemia side Homer ' s levies and offside take forelimb as the hemiplegia of hands.Sham operated rats only ligation right carotid, does not make otch, not bolt.
3. histological observation
TTC Determination Staining Infarction volume: postoperative latter 24 hours, broken end gets brain, and remove olfactory bulb, cerebellum and low brain stem, remainder is crown is cut into 5.Rapidly brain sheet is placed in 2%TTC dye liquor, 37 DEG C of lucifuge temperature are incubated 30 minutes (hatch in process shake beat one's brains sheet make it dyeing fully), take out to be placed in 10% formalin and keep in Dark Place.Take pictures after 24 hours and input computer, (red color area is normal cerebral tissue to calculate infarct size with AUTO--CAD image processing software, white area is infarcted region), each brain sheet infarct size sum is multiplied by thickness (2mm) for total Infarction volume.Volume × 100% of Infarction volume percentage ratio=infarct cerebral volume/contralateral hemisphere.
4. experimental result
After TTC dyeing, model group and administration group rat cortex and striatum infarcted region be pale asphyxia, and non-ischemic region takes on a red color, consistent with the brain district that MCA arranges, and illustrate that model successfully.Sham operated rats has no infarct, model group and administration group rat all have infarct in various degree, and administration group Infarction volume percentage ratio is significantly less than model group (see Fig. 5,6), difference has statistical significance (p<0.05).
Embodiment 5
The preparation of medicinal composition tablets of the present invention
Adopt hydrophilic adjuvant (hydroxypropyl cellulose and starch), suitable diluent is added in active component, again by the micronization processes of co-grinding method, medical surfaces is made to cover one deck water wetted material, particulate homogenous disperses, its dissolution characteristics can be improved, contribute to the bioavailability improving medicine.Then mixture tabletting is seen, the heavy 100mg of every sheet, my 70mg of active component content.A concrete formula is as follows:
Embodiment 6
The preparation of medicament composition capsule of the present invention
Mixed with auxiliary agent by active component, sieve, mix homogeneously in the container examined, the mixture obtained is loaded hard gelatin capsule, the heavy 200mg of each capsule, active component content is 30mg.A concrete formula is as follows:
N-benzyl palmitamide 30mg
Lactose 168mg
Magnesium stearate 2mg
Claims (1)
1. N-benzyl fatty acyl amide compound is preparing the application in nerve protection medicine, and described N-benzyl fatty acyl amide compound is N-benzyl palmitamide, N-(3-methoxybenzyl) palmitamide, N-benzyl kemanide S, N-(3-methoxybenzyl) kemanide S, N-benzyl oleamide or N-(3-methoxybenzyl) oleamide.
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| CN103585138B (en) * | 2013-11-19 | 2015-03-25 | 武汉华士特工业生物技术开发有限公司 | Application of natural maca amide compound to preparation of bone mineral density improving products |
| CN106902102A (en) * | 2017-02-22 | 2017-06-30 | 武汉华士特工业生物技术开发有限公司 | Application of the macamide class compound in treatment irregular menstruation medicine is prepared |
| CN111153827B (en) * | 2020-01-17 | 2023-05-16 | 广东药科大学 | Preparation method and application of benzylamine omega-3 unsaturated fatty acid |
| CN115616216A (en) * | 2021-07-15 | 2023-01-17 | 华南理工大学 | Use of an agent that inhibits or blocks the interaction between FAAH and NLRP3 |
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| CN1974545A (en) * | 2005-11-29 | 2007-06-06 | 上海第二医科大学 | Long chain fatty acyl amide compound and its application |
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| CN1974545A (en) * | 2005-11-29 | 2007-06-06 | 上海第二医科大学 | Long chain fatty acyl amide compound and its application |
Non-Patent Citations (1)
| Title |
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| Analysis of macamides in samples of Maca (Lepidium meyenii) by HPLC-UV-MS/MS;Megan M. 等;《PHYTOCHEMICAL ANALYSIS》;20051231;第16卷;463-469 * |
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