CN103118677A - Uses of benzoate and its derivatives - Google Patents

Abstract

The uses of benzoate and its derivatives for anti-aging of brain, and for preventing and treating the neurodegenerative diseases such as the senile dementia and the like are provided in the present invention. A series of benzoate and its derivatives are synthesized through a chemical method in the present invention. Proved through cell activity experiments in vitro, the synthesized benzoate and its derivatives have distinguished activities similar to nerve growth factors. Proved through an animal experiment, benzoate and its derivatives do not induce toxic reaction during long term oral or celiac administration, they are able to cross the blood-brain barrier and promote the regeneration of cerebral neuron.

Description

The application of benzoic ether and its derivative

The application of benzoic ether and its derivative

Technical field

The invention belongs to pharmaceutical field, it is related to the application of benzoic ether and its derivative in the nervous system disease and the old disease of Anti-endotoxin activity.

Background technology

With the aging of social population, the illness rate of nerve degenerative diseases, especially senile dementia is significantly raised, it has also become the 4th main cause for causing adult dead.The particularly quickening of China human mortality aging, current patients with Alzheimer disease, including Alzheimer's disease（Alzheimer's disease are said) and blood vessel nature feeble-mindedness, number accounts for the 1/4 of the total case in the world more than 5,000,000.Due to lacking effective prevention and treatment measure so that senile dementia brings serious influence to social stability with development.Therefore, effective new drug of the nerve degenerative diseases such as exploitation prevention and treatment senile dementia is current whole world medical problem in the urgent need to address.Book

The major target class of conventional treatment senile dementia disease drug clinical at present is cholinergic nerve system, such as acetylcholine, acetylcholinesteraseinhibitors inhibitors：Tacrine（Tacrine), rivastigmine（Rivastigmine), huperzine（Huperzine A), donepezil（Donepezil) etc..But these medicines can only partly substitute cholinergic nerve system function, temporarily improve cognitive function, can not prevent and delay the progress of nerve retrograde affection.Moreover, long-term taking curative effect is gradually reduced, there is side effect.Therefore, old and prevention nerve retrograde affection the novel drugs of exploitation Anti-endotoxin activity, it has also become the focus studied at present.

It is to cause the main cause of cognition dysfunction that the nerve cell death and nervous function of brain, which decline,.In recent years research is it was demonstrated that the newborn neuron of adult brain（Nerve regneration）It can replace and repair due to the neuron loss that natural aging or lesion are caused, to safeguarding that the 26S Proteasome Structure and Function of brain plays the effect of key.Nerve growth factor（Nerve growth factor, NGF) it is a kind of biologically active polypeptide to having important regulating and controlling to act in terms of the growth of nerve, development, differentiation and function holding found earliest, it is most important neurotrophic factor.Particularly during the nervous system disease, neurotrophic factor has important protective effect to nerve cell and nerve regneration.Neurotrophic factor can prevent or reduce neural Wei Shrink, neurodegeneration, promote post-traumatic CO2 laser weld.However, it is the protein being made up of more than 100 amino acid；Due to the reason such as molecular weight is big and polarity is strong, it is impossible to be the bottleneck for limiting nerve growth factor clinical practice by blood-brain barrier, do not find more preferable treatment method also in addition to intracerebral operation is directly offerd medicine at present.Therefore, nerve growth factor is found to intend like thing（NGF mimi_CS), nerve growth factor reinforcing agent（NGF enhancer) and nerve growth factor primer（NGF inducer) it is considered as the new target drone that research prevents and treats nerve degenerative diseases.

Chinese herbal medicine is the material base of Chinese pharmacology, is the cornucopia of natural activity organic compound.There is the traditional Chinese medical science civilization of thousands of years in China, and vast territory and abundant resources, the genunie medicinal materials for having many preciousnesses, because the utilization of Chinese material medicine resource is more convenient, also just particularly significant to its new composition and new active research.Research shows that Chinese medicine has significant curative effect to senile dementia, wherein foremost is the huperzine of alkaloid one extracted from Huperzia serrata（Huperzine A), it is the medicine of the Anti-alzheimer's disease with independent intellectual property right of institute of materia medica of Chinese Academy of Sciences exploitation.Mainly there is acetylcholine esterase inhibition activity, reduce glutamic acid and induce nerve cell death, the neurotoxicity and antioxidation of anti-beta-amyloyd polypeptide.

Rough gentian, alias：Andrographis paniculata, courage grass.Spring, the excavation of season in autumn two, cleaning, drying.Nature and flavor, it is bitter, tremble with fear.Return liver, courage Through.Introduced in 2005 editions pharmacopeia, the major function of rough gentian：Heat-clearing and damp-drying drug, purging the liver of pathogenic fire courage fire.For jaundice with damp-heat pathogen, swelling of vulva pruritus vulvae, with, persistent erection, eczema itch, hot eyes, deafness, hypochondriac pain, bitter taste, convulsion.The identification of its biological activity system set up using PC12 cells, obtain more than ten kinds with notable similar Nerve Growth Factor Activity 2 are isolated and purified from the extract of Gentiana rigescens Gmtiana rigescens Franch. drying root and rhizome, 3- dyhydroxyl parabens noval chemical compounds, it is named as gentisides o on this basis, has synthesized a series of benzoic ethers and its derivative（Detailed in Example 1), it is found that benzoic ether and its derivative have the growth promoting function of similar nerve growth factor.Particularly, the ester of 2,3- dihydroxy-benzoic acids 14（Be named as ABG-001) the processing of Ι μ Μ low concentrations, it is shown that it is significant to promote nerve growth effect（Detailed in Example 2-1).So far, not yet there are benzoate compounds that there is the relevant report of similar NGF activity of anti-senile dementia.

The content of the invention

In view of the above-mentioned deficiencies in the prior art, it is an object of the present invention to provide the preparation method and application of benzoic ether and its derivative.The purpose of the present invention is achieved through the following technical solutions：The application of a kind of benzoic ether and its derivative in prevention and treatment nerve degenerative diseases and the old medicine of Anti-endotoxin activity is prepared, the benzoic ether and its derivative have following structure formula：

Wherein, R is carbon number from 1 to 30 straight chain, side chain, saturation and unsaturated alkyl, cycloaliphatic ring or their derivative； 〜R₅Separately it is selected from hydrogen, hydroxyl, carboxyl, aldehyde radical, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, amide groups, cyano group, nitro, sulfonic group, trifluoromethyl, acrylic, alkyl, alkoxy, substituted benzyl, substituted-phenyl, aryl, heteroaryl, glycosyl and amino acid residue；X is selected from C (0) 0, OC (0), C (0) NH, NHC (0), C (0), CH₂, S standing grain Jie 0.

Further, the R is carbon number from 6 to 22 straight chain, side chain, saturation and unsaturated alkyl, cycloaliphatic ring or their derivative.

Further, the benzoic ether and its derivative are： 2,3- dihydric ethyl benzoates, 2,3- dihydroxy-benzoic acid pentyl esters, 2,3- dihydroxy-benzoic acid monooctyl esters, 2,3- dihydroxy-benzoic acid last of the ten Heavenly stems esters, 2,3- dihydroxy-benzoic acid dodecane esters, 2,3- dihydroxy-benzoic acid tetradecane esters, 2,3- dihydroxy-benzoic acid hexadecane esters, 2,3- dihydroxy-benzoic acid octadecane esters, 2,3- dihydroxy-benzoic acid eicosane esters, 2,3- dihydroxy-benzoic acid docosane esters, 2,3- dihydroxy-benzoic acid melissane esters, 2,6- dihydroxy-benzoic acid tetradecane esters, 2,6- dihydroxy-benzoic acid eicosane esters, 2,4- dihydroxy-benzoic acid tetradecane esters, 3,4- dihydroxy-benzoic acid tetradecane esters, 3, 4,5- trihydroxybenzoic acid tetradecane esters,2 hydroxybenzoic acid tetradecane ester,3- hydroxybenzoic acid tetradecane esters, 2,3- dimethoxybenzoic acid tetradecane esters, 2,3- dimethoxybenzoic acid octadecane esters,2- hydroxy 3-methoxybenzene formic acid tetradecane esters,2- chlorobenzoic acid tetradecane esters, 2,3- dihydroxy-N- myristyl benzamides, 2,3- dihydroxy-N- octyl group benzamides, 2,3- dihydroxy-N- dodecyl benzamides, 2,3- dihydroxy-N- cetyl benzamides, 2,3- dihydroxy-N- octadecyl benzamides, 2,3- dimethoxy-N- myristyl benzamides, 3,4- dihydroxy-N- myristyl benzamides, 3, 4,5- trihydroxy-N- myristyl benzamides, N- (3,4- Dimethoxyphenyls) 14（Alkane) acid amides, N- (3,4- Dihydroxyphenyl) 14（Wash) acid amides, 1- (3; 4- Dimethoxyphenyls) tetradecane -1- ketone, 1- (3; 4- dihydroxyphenyls) tetradecane -1- ketone, 3- (tetradecyloxyaniline carbonyl) -1; 2- phenyl diacetate, 3- (myristyl formoxyl) -1; 2- phenyl diacetate, 5- (tetradecyloxyaniline carbonyl) benzene -1; 2; 3- triacetates, 5- (myristyl formoxyl) benzene -1; 2; 3- triacetates, 1; the acid esters of 2- phenylene 20,2,3- dihydroxyphenyls 14（Alkane) hydrochlorate, 3- (tetradecane oxygen) benzene -1,2- glycol.

The beneficial effects of the present invention are：（1) 2,3- dyhydroxyl parabens compounds（ABG-001) oral or intraperitoneal administration finds no toxic action, and the compound can enter intracerebral quickly through blood-brain barrier, adjusts cerebral nervous system function；（2) Animal pharmacology experiments result is proved, of the present invention 2,3- dyhydroxyl parabens compounds can promote neuron regeneration, the aging of anti-brain, the neurotoxicity for preventing β starch polypeptides, the reduction acetylcholine esterase active of adult brain, the effect with prevention and treatment senile dementia and Anti-endotoxin activity always.

Brief description of the drawings

Fig. 1 is the dosage dependence figure that compound ABG-001 promotes the elongation of PC12 cellular neurals projection；

Fig. 2 is addition ABG-001, the microphoto of the cellular neural projections of PC 12 after 48 hours, wherein, a is 1% DMSO, is negative control；B is the ng/ml of NGF 40, is positive control；C is ABG-001 (1 μ Μ)_;

Fig. 3 represents that ABG-001 plays the role of to intend nerve growth factor, wherein,（A) it is the expression figure of hippocampal neural growth factor, (b) is the quantity figure of newborn neuron；

Fig. 4 represents that ABG-001 treatments can promote nerve regneration and migration after cerebral ischemia；

Fig. 5 represents that ABG-001 can be by blood-brain barrier；

Fig. 6 represents that ABG-001 can promote nerve regneration of growing up by blood-brain barrier, wherein,（A) it is the quantity figure of newborn neuron,（B) it is newborn neuron projection length figure,（C) it is the differentiation figure of newborn neuron；

Fig. 7 represents that ABG-001 has the effect of Anti-endotoxin activity always, wherein,（A) it is the quantity figure of newborn neuron,（B), (c) and（D) it is Morris water maze test figures,（e)、 （0th, (g) and（H) it is the oxidative stress biochemical indicator figure of mouse；Fig. 8 represents that ABG-001 has the effect of Anti-endotoxin activity always, wherein,（A) arm number of times is always entered for Y labyrinths,

(b) arm rate is alternately entered for Y labyrinths,（C) and（D) it is the resolving ability figure of novelty；

Fig. 9 is that Α β are damaged and Α β damage Morris water maze test figures after ABG-001 treatments；

Figure 10 represents that ABG-001 treatments can improve Α β infringements（APP/PS1 mouse）Nerve regneration, wherein,（A) it is the quantity figure of newborn neuron,（B) it is the projection length figure of newborn nerve,（C) it is acetylcholinesterase（AChE) activity figure.Embodiment

2,3- dyhydroxyl parabens compounds can cause a high proportion of PC12 cells to occur nervous process elongation phenomenon, show that 2,3- dihydroxy-benzoic acids ester has good similar NGF activity, the value with exploitation anti-senile dementia prophylactic treatment medicine.With 2,3- dihydroxy-benzoic acid ester compounds as primer, a series of benzoate derivatives are designed and synthesized, carries out the research of its external activity extensively, finds the structure-activity relationship of such material.It if the compound with potential more excellent activity and/or more hypotoxicity can be found, and can be used to preventing and treating the nervus retrogressions such as senile dementia and the old disease of Anti-endotoxin activity, will have important practical significance.

Benzoate derivatives of the present invention, the structure of the compound can be represented with formula I：

I

In formula：R be carbon number from 1 to 30 straight chain or side chain or saturation and unsaturated alkyl or cycloaliphatic ring or their derivative, particularly C₆〜C_{22 ;}

〜R₅Separately it is selected from hydrogen, hydroxyl, carboxyl, aldehyde radical, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, amide groups, cyano group, nitro, sulfonic group, trifluoromethyl, acrylic, alkyl, alkoxy, substituted benzyl, substituted-phenyl, aryl, heteroaryl, glycosyl and amino acid residue；

X is selected from C (0) 0, OC (0), C (0) NH, NHC (0), C (0), CH₂, S and 0.

The preparation method of benzoic ether and its derivative of the present invention, is realized by following steps：

1) when X is the preparation method of c (o) o or oc (o) ester type compound：First acid is completely dissolved with alcohol or phenol with solvent, cold to cause 0 °C, stirring is lower to be added dropwise dehydrating agent, is raised again to room temperature reaction 12 days, is tracked and reacted with thin-layer chromatography.After reaction terminates, solvent is steamed, is post-processed, then ester type compound is purified to obtain through silica gel column chromatography.Acid be substituted benzoic acid or carbon number from 1 to 30 straight chain or side chain or saturation and unsaturated alkyl or cycloaliphatic ring or their derivative, particularly C₆〜C₂₂Aliphatic acid；Alcohol be carbon number from 1 to 30 straight chain or side chain or saturation and unsaturated alkyl or cycloaliphatic ring or their derivative, particularly C₆〜C₂₂Fatty alcohol；Phenol is fortified phenol；Dehydrating agent is the concentrated sulfuric acid, DIC or dicyclohexylcarbodiimide；Solvent is protonic solvent methanol, ethanol or tetrahydrofuran, or non-protonic solvent dichloromethane, chloroform, benzene,toluene,xylene, dimethyl sulfoxide or acetonitrile；The mol ratio of acid and alcohol is 1:1〜1 :20, the sour mol ratio with dehydrating agent is 1:0.2〜1 :3.

2) when X is the preparation method of C (0) NH or NHC (O) amides compound：By acid, amine is dissolved with the dry solvent of hydroxybenzotriazole, and cold to cause 0 °C, the lower Jia Ru Shrink mixture of stirring is reacted at room temperature 25 days.After reaction terminates, solvent evaporated, residue ethyl acetate dissolves, successively with saturated sodium bicarbonate solution, water washing, and anhydrous magnesium sulfate dries , Nong Shrink, then purifies to obtain acid amides through silica gel column chromatography.Acid is substituted benzoic acid or carbon number from 1 to 30 straight or branched, saturated or undersaturated aliphatic acid；Amine be substituted aniline or carbon number from 1 to 30 straight or branched, saturation or undersaturated fatty amine.The mol ratio of acid and amine is 1:1〜1 :The mol ratio of 5, Suan Yu Shrink mixture is 1:1〜1 :5.

3) when X is the preparation method of C (O) ketone compounds：Under inert gas shielding, the magnesium metal of activation is added in absolute ether, the diethyl ether solution of brominated alkanes is added dropwise.Continue the diethyl ether solution of instillation brominated alkanes, back flow reaction 1 hour after grignard reaction starts.Then under inert gas shielding, 0 °C, the grignard reagent prepared is added drop-wise in the diethyl ether solution of aldehyde, is warmed to room temperature reaction 2 hours.Question response is finished, by cold 0 °C of the cause of reaction solution, it is slowly added into 1 mole of every liter of hydrochloric acid solution, with ether extractive reaction liquid, organic phase is successively with 1 mole of every liter of watery hydrochloric acid, saturated sodium bicarbonate solution, saturated common salt water washing, anhydrous magnesium sulfate dries , Nong Shrink, then purifies to obtain alcohol compound through silica gel column chromatography.Inert gas is nitrogen or argon gas；Solvent is absolute ether or tetrahydrofuran；Aldehyde is substituted benzaldehyde；Brominated alkanes are carbon numbers from 1 to 30 straight or branched, saturation or undersaturated brominated alkanes；Reaction temperature can be from -80 degree to 50 degree；The mol ratio of brominated alkanes and magnesium is 1:1〜1 :10； The mol ratio of brominated alkanes and substituted benzaldehyde is 1:1〜1 :10.

Alcohol compound is completely dissolved with solvent, it is slowly added to oxidant, reaction is finished, Jian Ya Nong Shrink, the dense Shrink liquid of gained is diluted with ethyl acetate, successively with 1 mole of every liter of watery hydrochloric acid, saturated sodium bicarbonate solution, saturated common salt water washing, and anhydrous magnesium sulfate is dried; dense Shrink, then purifies to obtain ketone compounds through silica gel column chromatography.Solvent can be tetrahydrofuran, dichloromethane, acetone, chloroform, dimethyl sulfoxide or acetonitrile；Oxidant can be chromium trioxide, manganese dioxide, dimethyl sulfoxide, periodate or N-methyl morpholine oxide.The mol ratio of alcohol and oxidant is 1:1〜1 :10.

4) when X is the preparation method of 0 ether compound：I.e. under inert gas shielding, phenol is dissolved in dry tetrahydrofuran, stirring is lower to add alcohol, triphenylphosphine, diethyl azodiformate, reacts at room temperature 1 24 hours.After reaction terminates, solvent is removed under reduced pressure.Ethyl acetate dilutes dense Shrink liquid, with deionized water, saturated common salt water washing, and anhydrous magnesium sulfate is dried, and subtracts the dense Shrink organic phases of pressure, and the dense Shrink liquid of gained purifies to obtain ether compound through silica gel column chromatography again.Phenol is fortified phenol, substituted naphthol；Alcohol is carbon number from 1 to 30 straight or branched, saturation or unsaturated fatty alcohol；Azo-reagents can be diethyl azodiformate, azoformic acid dipropyl, diisopropyl azodiformate, tert-butyl azodicarboxylate or azoformic acid dibenzyl ester；Phosphine reagent can be triphenylphosphine, tri isopropyl phosphine, three p-methylphenyl phosphines, triethyl phosphine, tributylphosphine or tricyclohexyl phosphine;Solvent is protonic solvent methanol or ethanol, or non-protonic solvent tetrahydrofuran, dichloromethane, chloroform, benzene,toluene,xylene, dimethyl sulfoxide or acetonitrile；The mol ratio of phenol and alcohol is 1:20, the mol ratio of phenol and Azo-reagents is 1_:0.2〜1 :20；The mol ratio of phenol and phosphine reagent is 1:0.2〜1 :20.

The purpose of the present invention is the application of benzoic ether and its derivative in treatment Alzheimer's disease and the old disease medicament of Anti-endotoxin activity is prepared.

The present invention further also provide it is a kind of treat Anti-alzheimer's disease disease and the old pharmaceutical composition of Anti-endotoxin activity, the pharmaceutical composition contains the benzoic ether and its derivative of physiology effective dose（) and pharmaceutically acceptable carrier or diluent I.Shown benzoic ether and its derivative（I) the weight ratio in medicine is the % of 0.1 % 90.

Pharmaceutically acceptable carrier described here refers to the conventional pharmaceutical carrier of pharmaceutical field, such as diluent, excipient in this way, filler such as starch, sucrose, microcrystalline cellulose etc.；Adhesive such as starch slurry, hydroxypropylcellulose, gelatin, polyethylene glycol etc.；Wetting agent such as magnesium stearate, superfine silica gel powder, polyethylene glycols etc.；The poly- sorb fat of sorbefacient, lecithin etc., surfactant poloxamer, fatty acid sorbitan, poly- sorb fat etc., it can in addition contain add other assistant agents such as flavouring agent, sweetener etc. in the composition.

Benzoate derivatives of the present invention can be administered in a unit, and method of administration can be enteron aisle and non-bowel, including oral, muscle and subcutaneous.Compound method of administration is alternatively intravenously administrable.Injection includes intravenous injection, intramuscular injection, hypodermic injection and acupoint injection therapy.

The various formulations of the pharmaceutical composition of the present invention can be prepared according to the conventional production process of pharmaceutical field, for example, active component is mixed with one or more carriers, be then made into required formulation.

Form of administration can be solid pharmaceutical preparation, capsule or liquid preparation, including tablet, capsule, dispersible tablet, oral liquid, big transfusion, small pin, freeze-dried powder.

Benzoic ether and its derivative of the present invention have the activity of significant similar nerve growth factor, and the effect with neuroprotection and Anti-endotoxin activity always can be applied in the nerve degenerative diseases such as prevention senile dementia and Anti-endotoxin activity are old.The benzoate compounds of the present invention show significant NGF in the in-vitro screening model PC12 cells of senile dementia Mimics activity.Using such compound as primer, optimize structure, the new drug development for nerve degenerative diseases such as prevention and treatment senile dementias carries out basic research, will have important practical significance.

Benzoic ether and its derivative of the present invention can be by blood-brain barriers, with dynamical neurotrophic effect.Benzoic ether and its derivative of the present invention have the aging of anti-brain, and prevent and treat the effect of senile dementia.The above below by way of the embodiment and accompanying drawing to such some particular compound preparating example again to the present invention is described in further detail, but this should not be interpreted as to the scope of above-mentioned theme of the invention and be only limitted to following examples, all technologies realized based on the above of the present invention belong to the scope of the present invention.

Embodiment 1

Compound 1-1:2,3- dihydric ethyl benzoates

Will（154 mg, l mmol) 2,3- dihydroxy-benzoic acids, 10 ml ethanol are placed in 25 ml round-bottomed flasks, cold to cause 0 °C, are added dropwise 23 and are dripped the concentrated sulfuric acid, the h of return stirring 24.Use thin-layer chromatography（Solvent：Just oneself washes/ethyl acetate, 5/1, V/V) tracking reaction, after reaction stops, ethanol is steamed, the mg of crude product 390, silica gel column chromatography is obtained（Solvent：Just oneself washes/ethyl acetate, 5/1, V/V), obtain the mg of white solid 180.1H NMR (500 MHz, CDC1₃) δ:11.00 (s, 1H, benzene 2-OH), 7.38 (dd, 1 Η, /=1.5,8.0 Hz, benzene H-6), 7.12 (dd, 1H, /=1.0,7.5 Hz, benzene H-4), 6.80 (t, 1H, J=8.0 Hz, benzene H-5), 5.66 (s, 1H, benzene 3-OH), 4.41 (q, 2H, the Hz of J=7.0), 1.42 (t, 3H, J=7.0 Hz); HRMS: m/z [M+H]+ calcd for C₉H_u0₄ ⁺: 183.0652, found: 183.0639.

Compound I -2:2,3- dihydroxy-benzoic acid pentyl esters

Synthetic method with compound 1-1, reaction feed intake for：（154 mg, l mmol) 2,3- dihydroxy-benzoic acids, 10 ml amylalcohols, obtain white solid 170 mg o 1H NMR (500 MHz, CDC1₃) δ:11.00 (s, 1H), 7.38 (dd, 1H, J=1.5,8.0 Hz), 7.12 (dd, 1H, /=1.0,8.0 Hz), 6.80 (t, 1H, /=8.0 Hz), 5.65 (s, 1H), 4.41 (t, 2H, the Hz of /=7.0), 1.78 (m, 2H), 1.33 1.38 (m, 4H), 0.90 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:170.4,148.9,145.1,120.5,119.7,119.1,112.7,65.7,28.2,28.1,22.3,13.9 ppm; IR (KBr) v:3458,2931,2865,1674,1469,1309,1268,1067,754 cm¹; HRMS: m/z [M+H]+ calcd for C₁₂H₁₇0₄ ⁺: 225.1121 , found: 225.1104.

Compound I -3:2,3- dihydroxy-benzoic acid monooctyl esters

Synthetic method with compound 1-1, reaction feed intake for：（154 mg, l mmol) 2,3- dihydroxy-benzoic acids, 10 ml octanols, obtain white solid 128 mg o 1H NMR (500 MHz, CDC1₃) δ:11.01 (s, 1 Η), 7.38 (dd, 1 Η, /=1.5,8.0 Hz), 7.10 (dd, 1H, /=1.0,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.64 (s, 1H), 4.35 (t, 2H, /=7.0 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.38 (m, 8H), 0.89 (t, 3H, /=7.0 Hz); HRMS: m/z [M+H]+ calcd for C₁₅H₂₃0₄ ⁺: 267.1591 , found: 267.1590.

Compound I -4:2,3- dihydroxy-benzoic acid last of the ten Heavenly stems esters

Will（154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（316 mg, 2 mmol) Decanol, 10 ml tetrahydrofurans are placed in 25 ml round-bottomed flasks, cold to cause 0 °C, are added（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 24 h are stirred at room temperature.Use thin-layer chromatography（Solvent：Just oneself washes/ethyl acetate, 2/1, V/V) tracking reaction.After reaction stops, solvent is steamed, residue ethyl acetate dissolves, filtering, filtrate is with 5% citric acid solution, saturated sodium bicarbonate solution, washing, and ester layer is through anhydrous sodium sulfate drying, filtering, Xuan Zheng Nong Shrink obtain the mg of head product 440, silica gel column chromatography（Solvent：Just oneself washes/ethyl acetate, and 2/1, V/V), white solid 132mg is obtained.1HNMR(500 MHz, CDC1₃) δ:11.01 (s, 1H), 7.37 (dd, 1 Η, /=1.5,8.0 Hz), 7.09 (dd, 1H, /=1.5,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.65 (s, 1H), 4.35 (t, 2H, /=7.0 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.27 1.35 (m, 12H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDCI3) δ:170.8,148.9,145.0,120.5,120.0,119.6,119.1,65.7,31.9,29.5,29.3,29.2,28.5,27.6,25.9,22.7,14.1 ppm; IR (KBr) v: 3478, 2926, 2885, 1667, 1469, 1309, 1267, 1067, 753 cm"¹; HRMS: m/z [M+H]+ calcd for C₁₇H₂₇0₄ ⁺: 295.1904, found: 295.1910.

Compound I -5:2,3- dihydroxy-benzoic acid dodecane esters

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（372 mg, 2 mmol) dodecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 180mg. 1H NMR (500 MHz, CDC1₃) δ:11.01 (s, 1 Η), 7.38 (dd, 1 Η, /=1.5,8.0 Hz), 7.10 (dd, 1 Η, /=1.0,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.64 (s, 1H), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.35 (m, 16H), 0.88 (t, 3H, /=7.0 Hz); HRMS: m/z [M+H]+ calcd for C₁₉H₃₁0₄ ⁺: 323.2217, found: 323.2236.

Compound I -6:2,3- dihydroxy-benzoic acid tetradecane esters

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 150mg. 1H NMR (500 MHz, CDC1₃) δ:11.01 (s, 1 Η), 7.37 (dd, 1 Η, /=1.5,8.5 Hz), 7.10 (dd, 1 Η, /=1.0,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.63 (s, 1H), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.35 (m, 20H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:170.4,148.9,145.0,120.5,119.6,119.1,112.6,65.7,31.9,29.7 29.6,29.5,29.4,29.2,28.5,25.9,22.7,14.1 ppm; IR (KBr) v: 3485, 2917, 2849, 1669, 1467, 1310, 1267, 1157, 1067, 759 cm"¹; HRMS: m/z [M+H]+ calcd for C₂₁H₃₅0₄ ⁺: 351.2530, found: 351.2536.

Compound I -7:2,3- dihydroxy-benzoic acid hexadecane esters

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（484 mg, 2 mmol) hexadecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 178 mg. 1H NMR (500 MHz, CDC1₃) δ:11.01 (s, 1 Η), 7.37 (dd, 1 Η, /=1.5,8.0 Hz), 7.10 (dd, 1 Η, /=1.0,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.65 (s, 1H), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.25 1.35 (m, 24H), 0.88 (t, 3H, /=7.0 Hz); HRMS: m/z [M+H]+ calcd for C₂₃H₃₉0₄ ⁺: 379.2843, found: 379.2848.

Compound I -8:2,3- dihydroxy-benzoic acid octadecane esters

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（540 mg, 2 mmol) octadecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 170mg. 1H NMR (500 MHz, CDC1₃) δ:11.01 (s, 1 Η), 7.37 (dd, 1 Η, /=1.5,8.0 Hz), 7.10 (dd, 1 Η, /=1.0,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.63 (s, 1H), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.25 1.35 (m, 28H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:170.4,148.9,145.1,120.5,119.6,119.1,112.7,65.7,31.9,29.7 29.6,29.5,29.4,29.2,28.5,25.9,22.7,14.1 ppm; IR (KBr) v: 3473, 2917, 2850, 1665, 1467, 1266, 1159, 1064, 799, 762 cm—¹; HRMS: mJz [M+H]+ calcd for C₂₅H₄₃0₄ ⁺: 407.3156, found: 407.3192.

Compound I -9:2,3- dihydroxy-benzoic acid eicosane esters

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（896 mg, 3 mmol) eicosanol,（206 mg, 1 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 104 mg. 1H NMR (500 MHz, CDC1₃) δ:11.00 (s, 1 Η), 7.37 (dd, 1 Η, /=1.5,8.0 Hz), 7.10 (dd, 1 Η, /=0.5,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.63 (s, 1H), 4.34 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.43 (m, 2H), 1.25 1.35 (m, 32H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:170.4,148.9,145.0,120.5,119.6,119.1,112.7,65.7,31.9,29.7 29.6,29.5,29.4,29.2,28.5,25.9,22.7,14.1 ppm; IR (KBr) v: 3403, 2919, 2850, 1675, 1467, 1313, 1254, 1159, 1067, 752 cm—¹; HRMS: mJz [M+H]+ calcd for C₂₇H₄₇0₄ ⁺: 435.3469, found: 435.3489.

Compound I -10:2,3- dihydroxy-benzoic acid docosane esters

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（653 mg, 2 mmol) tadenan,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 102 mg. 1H NMR (500 MHz, CDC1₃) δ:11.01 (s, 1H), 7.37 (dd, 1 Η, /=1.5,8.0 Hz), 7.10 (dd, 1 Η, /=1.0,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.63 (s, 1H), 4.34 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.43 (m, 2H), 1.25 1.35 (m, 36H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:170.4,148.9,145.1,120.5,119.6,119.1,112.7,65.7,31.9,29.7 29.6,29.5,29.4,29.2,28.5,25.9,22.7,14.1 ppm; IR (KBr) v: 3397, 2918, 2849, 1675, 1469, 1312, 1256, 1158, 1065, 750 cm"¹; HRMS: m/z [M+H]+ calcd for C₂₉H₅₁0₄ ⁺: 463.3782, found: 463.3790.

Compound I -11:2,3- dihydroxy-benzoic acid melissane esters

Synthetic method with compound I -4, reaction feed intake for：（154 mg, l mmol) 2,3- dihydroxy-benzoic acids,（1.32 g, 3 mmol) triacontanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 20 ml tetrahydrofurans, acquisition white solid 75 mg. 1H NMR (500 MHz, CDC1₃) δ:11.00 (s, 1H), 7.37 (dd, 1 Η, /=1.5,8.5 Hz), 7.10 (dd, 1 Η, /=1.0,8.0 Hz), 6.80 (t, 1H, the Hz of /=8.0), 5.63 (s, 1H), 4.34 (t, 2H, /=6.5 Hz), 1.77 (m, 2H), 1.45 (m, 2H), 1.25 1.35 (m, 52H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:164.5,149.4,145.0,120.5,119.6,119.1,112.6,65.7,34.9,31.9,29.7 29.5,29.4,29.2,28.5,25.9,25.4,24.7,22.7,14.1 ppm; IR (KBr) v:3484,2920,2848,1665,1468,1313,1262,1162,1076,801 cm-¹; MS (m z): 575 [M]⁺.

Compound I -12:2,6-DHBA tetradecane ester

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,6-DHBA,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 66 mg. 1H NMR (500 MHz, CDC1₃) δ:9.79 (s, 2H), 7.32 (t, 1H, the Hz of J=8.5), 6.48 (d, 2H, J=8.5 Hz), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.35 (m, 20H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:169.8,149.3,145.4,160.9,136.5,108.2,100.1,66.7,53.4,31.9,29.6 29.7,29.5,29.4,29.3,29.1,28.5,25.9,22.7,14.1 ppm; IR (KBr) v:3472,2919,2849,1669,1630, 1576,1465,1327,1293,1156,1067,782 cm "¹; HRMS: m/z [M+H]+ calcd for C₂₁H₃₅0₄ ⁺: 351.2530, found: 351.2516.

Compound I -13:2,6-DHBA eicosane ester

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,6- dihydroxy-benzoic acids,（597 mg, 2 mmol) eicosanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 104 mg. 1H NMR (500 MHz, CDC1₃) δ:9.79 (s, 2 Η), 7.31 (t, 1H, the Hz of /=8.5), 6.48 (d, 2H, /=8.5 Hz), 4.50 (t, 2H, /=6.5 Hz), 1.83 (m, 2H), 1.43 (m, 2H), 1.25 1.35 (m, 32H), 0.88 (t, 3H, /=7.0 Hz); MS (m/z): 434 [M]⁺.

Compound I -14:2,4- dihydroxy-benzoic acid tetradecane esters

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,4- dihydroxy-benzoic acids,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 158 mg. 1H NMR (500 MHz, CDC1₃) δ:11.06 (s, 1H), 7.74 (d, /=8.5 Hz, 1H), 7.54 (m, 1H), 6.38 (m, 1H), 5.39 (s, 1H), 4.30 (t, /=6.5 Hz, 2H), 1.76 (m, 2H), 1.41 (m, 2H), 1.25 1.35 (m, 20H), 0.88 (t, /=7.0 Hz, 3H) ppm; HRMS: m/z [M+H]+ calcd for C₂₁H₃₅0₄ ⁺: 351.2530, found: 351.2557.

Compound I -15:PCA tetradecane ester

Synthetic method with compound I -4, reaction feed intake for：(154 mg, 1 mmol) 2,4- dihydroxy-benzoic acids,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 180 mg. 1H NMR (500 MHz, CDC1₃) δ:7.59 (d, J=2.0 Hz, 1H), 7.57 (dd, J=2.0,8.0 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.26 (t, /=6.5 Hz, 2H), 1.73 (m, 2H), 1.42 (m, 2H), 1.25 1.37 (m, 20H), 0.89 (t, /=7.0 Hz, 3H) ppm; HRMS: m/z [M+H]+ calcd for C₂₁H₃₅0₄ ⁺: 351.2530, found: 351.2551.

Compound I -16:Gallic Acid tetradecane ester

Synthetic method with compound I -4, reaction feed intake for：(170 mg, 1 mmol) Gallic Acid,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 176 mg. 1H NMR (500 MHz, CDC1₃) δ:7.24 (s, 2H), 4.24 (t, /=6.5 Hz, 2H), 1.72 (m, 2H), 1.41 (m, 2H), 1.25 1.35 (m, 20H), 0.88 (t, J=7.0 Hz, 3H) ppm; HRMS: m/z [M+H]+ calcd for C₂₁H₃₅0₅ ⁺: 367.2479, found: 367.2473.

Compound I -17:2 hydroxybenzoic acid tetradecane ester

Synthetic method with compound I -4, reaction feed intake for：（138 mg, 1 mmol) 2 hydroxybenzoic acid,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 164 mg. 1H NMR (500 MHz, CDC1₃) δ:10.88 (s, 1H), 7.37 (m, 1H), 7.10 (m, 1H), 6.91 (m, 1H), 6.80 (t, 1H, J=8.0 Hz), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.35 (m, 20H), 0.88 (t, 3H, /=7.0 Hz); HRMS: m/z [M+H]+ calcd for C₂₁H₃₅0₃ ⁺: 335.2581 , found: 335.2564.

Compound I -18:3- hydroxybenzoic acid tetradecane esters

Synthetic method with compound I -4, reaction feed intake for：（138 mg, 1 mmol) 3- hydroxybenzoic acids,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 174 mg. 1H NMR (500 MHz, CDC1₃) δ:7.57 (m, 1H), 7.37 (m, 1H), 7.25 (m, 1H), 7.01 (m, 1H), 5. 67 (s, 1H), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.35 (m, 20H), 0.88 (t, 3H, /=7.0

Hz); MS (m/z): 334 [M]⁺.

Compound I -19:2,3- dimethoxybenzoic acid tetradecane esters

Synthetic method with compound I -4, reaction feed intake for：（182 mg, l mmol) 2,3- dimethoxybenzoic acids,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 162 mg. 1H NMR (500 MHz, CDC1₃) δ:7.08 (t, 1 Η, /=7.5 Hz), 6.95 (dd, 1H, /=1.5,8.0 Hz), 6.79 (dd, 1H_:/=1.0,7.0 Hz), 4.35 (t, the Hz of 2H, J=6.5), 3.92 (s, 3H), 3.88 (s, 3H), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.35 (m, 20H), 0.88 (t, 3H, /=7.0 Hz);¹³C NMR (125 MHz, CDC1₃) δ:166.4,153.5,148.9,126.6,123.8,122.2,115.6,65.3,61.5,56.0,31.9,29.7 29.6,29.5,29.3,29.2,28.7,26.0,22.7,14.1 ppm; IR (KBr) v:2926,2855,1726,1587,1474,1266,1148,1062,754 cm "¹; HRMS: m/z [ +H]⁺ calcd for C₂₃H₃₉0₄ ⁺: 379.2843, found: 379.2865.

Compound I -20:2,3- dimethoxybenzoic acid octadecane esters

Synthetic method with compound I -4, reaction feed intake for：（182 mg, l mmol) 2,3- dimethoxybenzoic acids,（540 mg, 2 mmol) octadecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 170 mg. 1H NMR (500 MHz, CDC1₃) δ:7.06 (t, 1H, /=8.0 Hz), 6.93 (dd, 1H, /=1.5,8.0 Hz), 6.77 (dd, 1H_:/=1.5,8.0 Hz), 4.35 (t, the Hz of 2H, J=6.5), 3.92 (s, 3H), 3.88 (s, 3H), 1.78 (m, 2H), 1.44 (m, 2H), 1.25 1.35 (m, 28H), 0.88 (t, 3H, /=7.0 Hz); MS (m z): 434 [M]+.

Compound I -21:2- hydroxy 3-methoxybenzene formic acid tetradecane esters

Synthetic method with compound I -4, reaction feed intake for：（168 mg, 1 mmol) 2- hydroxy 3-methoxybenzenes formic acid, 428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition yellow liquid 109 mgo 1H NMR (500 MHz, CDC1₃) δ:11.12 (s, 1H), 7.44 (dd, /=1.5,8.5 Hz, 1H), 7.04 (dd, 1H, J=1.5,8.0 Hz, 1H), 6.83 (t, /=8.0 Hz, 1H), 4.34 (t, /=6.5 Hz, 2H), 3.91 (s, 3H), 1.77 (m, 2H), 1.44 (m, 2H), 1.25 1.36 (m, 20H), 0.88 (t, J=7.0 Hz, 3H) ppm;¹³C NMR (125 MHz, CDC1₃) δ:170.5,152.1,148.5,121.0,118.4,116.4,112.9,65.6,56.2,31.9,29.7 29.6,29.5,29.3,29.2,28.5,25.9,22.7,14.1 ppm; IR (KBr) v:3080,2923,2849,1667,1587,1466,1341,1242,1167,1062,767 cm¹; HRMS: m/z [M+H]+ calcd for C₂₂H₃₇0₄ ⁺: 365.2686, found: 365.2654.

Compound I -22:2- chlorobenzoic acid tetradecane esters

Synthetic method with compound I -4, reaction feed intake for：（156 mg, 1 mmol) 2- chlorobenzoic acids,（428 mg, 2 mmol) tetradecanol,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 150 mg. 1H NMR (500 MHz, CDC1₃) δ:7.65 (m, 1H), 7.30 (m, 2H), 7.08 (m, 1H), 4.35 (t, 2H, /=6.5 Hz), 1.78 (m, 2H), 1.44 (m, 2H), 1.26 1.35 (m, 20H), 0.88 (t, 3H, /=7.0 Hz); MS (m z): 352 [M]+.

Compound I -23:2,3- dihydroxy-N- myristyl benzamides

Will（154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（253 mg, 1.1 mmol) tetradecylamine, 10 ml tetrahydrofurans are placed in 25 ml round-bottomed flasks, cold to cause 0 °C, are added（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 4 h are stirred at room temperature.Use thin-layer chromatography（Solvent：Just oneself washes/ethyl acetate, 3/1, V/V) tracking reaction.After reaction stops, solvent is steamed, residue ethyl acetate dissolves, filtered, filtrate is molten with saturated sodium bicarbonate Liquid, washing, ester layer obtain the mg of head product 440 through anhydrous sodium sulfate drying, filtering, Xuan Zheng Nong Shrink, and silica gel column chromatography obtains the mg of white solid 265.¹L^NMR (500MHz, CDC1₃) δ:12.81 (s, 1H), 7.04 (dd, /=1.0,8.0 Hz, 1H), 6.87 (dd, /=1.0,8.0 Hz, 1H), 6.76 (t, /=8.0 Hz, 1H), 6.30 (s, 1H), 5.78 (s, 1H), 3.44 (m, 2H), 1.62 (m, 2H), 1.25 1.40 (m, 22H), 0.88 (t, /=7.5 Hz, 3H) ppm;¹³C NMR (125 MHz, CDC1₃) δ:169.9,149.1,146.0,118.5,117.9,115.7,114.0,39.7,31.9,29.7 29.6,29.5,29.4,29.3,29.2,26.9,22.7,14.1 ppm; IR (KBr) v:3482,3389,3268,2920,2850,1639,1586,1546,1462,1338,1270,1236,1176,1077,723,746 cm "¹; HRMS: m/z [M+Na]+ calcd for C₂₁H₃₅N0₃Na⁺: 372.2509, found:372.2499. compound I -24:2,3- dihydroxy-N- octyl group benzamides

Synthetic method with compound I -23, reaction feed intake for：（154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（185 mg, 1 mmol) octylame,（135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 158 mgo 1HNMR (500 MHz, CDC1₃) δ:12.81 (s, 1 Η), 7.04 (d, /=8.0 Hz, 1H), 6.86 (d, /=8.5 Hz, 1H), 6.76 (t, /=8.0 Hz, 1H), 6.31 (s, 1H), 5.78 (s, 1H), 3.44 (q, J=7.0 Hz, 2H), 1.63 (m, 2H), 1.27 1.39 (m, 10H), 0.88 (t, /=7.0 Hz, 3H); MS (m/z):265 [M]+compounds I -25:2,3- dihydroxy-N- dodecyl benzamides

Synthetic method with compound I -23, reaction feed intake for：(154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（428 mg, 2 mmol) dodecyl amine, (135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 158 mg. 1H NMR (500 MHz, CDC1₃) δ:12.81 (s, 1H, Ph2-OH), 7.04 (dd, /=1.0,8.0 Hz, 1H), 6.87 (dd, /=1.0,8.5 Hz, 1H), 6.75 (t, /=8.0 Hz, 1H), 6.32 (s, 1H), 5.80 (s, 1H), 3.44 (q, /=7.0 Hz, 2H), 1.62 (m, 2H), 1.25 1.40 (m, 10H), 0.88 (t, /=7.0 Hz, 3H); MS (m/z): 321 [M]⁺.

Compound I -26:2,3- dihydroxy-N- cetyl benzamides

Synthetic method with compound I -23, reaction feed intake for：（154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（241 mg, 1 mmol) cetylamine, (135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 308 mg. 1H NMR (500 MHz, CDC1₃) δ:12.81 (s, 1H, Ph2-OH), 7.04 (dd, /=1.0,8.0 Hz, 1H), 6.86 (dd, /=1.0,8.5 Hz, 1H), 6.75 (t, /=8.0 Hz, 1H), 6.30 (s, 1H), 5.77 (s, 1H), 3.44 (q, J=6.5 Hz, 2H), 1.61 (m, 2H), 1.25 1.40 (m, 10H), 0.88 (t, /=7.0 Hz, 3H); MS (m/z): 377 [M]⁺.

Compound I -27:2,3- dihydroxy-N- octadecyl benzamides

Synthetic method with compound I -23, reaction feed intake for：（154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（269 mg, 1 mmol) octadecylamine, (135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 340mg. 1H NMR (500 MHz, CDC1₃) δ:12.81 (s, 1H, Ph2-OH), 7.04 (the Hz of dd, J=1.0,8.0,1H), 6.87 (dd, /=1.0,8.0 Hz, 1H), 6.76 (t, /=8.0 Hz, 1H), 6.30 (s, 1H), 5.77 (s, 1H), 3.44 (q, /=6.5 Hz, 2H), 1.63 (m, 2H), 1.25 1.38 (m, 30H), 0.88 (t, /=7.5 Hz, 3H); MS (m/z): 405 [M]⁺.

Compound I -28:2,3- dimethoxy-N- myristyl benzamides

Synthetic method with compound I -23, reaction feed intake for：（182 mg, 1 mmol) 2,3- dimethoxybenzoic acids,（230mg, l Mmol) tetradecylamine,（135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（250 mg, 1.2mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 305 mg.1H NMR (500 MHz, CDC1₃) δ:7.97 (s, 1 Η, Ν Η), 7.68 (dd, /=1.0,8.0 Hz, 1 Η), 7.14 (t, /=8.0 Hz, 1H), 7.02 (dd, /=1.0,8.0 Hz, 1H); MS (mz): 377 [M]⁺.

Compound I -29:3,4- dihydroxy-N- myristyl benzamides

Synthetic method with compound I -23, reaction feed intake for：（154 mg, 1 mmol) 2,3- dihydroxy-benzoic acids,（230 mg, 1 mmol) tetradecylamine,（135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 297 mg. 1H NMR (500 MHz, CDC1₃) δ:7.66 (d, /=2.0 Hz, 1H), 7.09 (dd, /=2.0,8.0 Hz, 1H), 6.88 (d, /=8.0 Hz, 1H), 6.12 (s, 1H), 3.43 (m, 2H), 1.93 (m, 2H), 1.25 1.39 (m, 22H), 0.88 (t, /=7.0 Hz, 3H) ppm;¹³C NMR (125 MHz, CDC1₃) δ:167.9,148.0,144.1,118.8,115.5,115.7,114.0,40.3,31.9,29.7 29.6,29.5,29.3,27.0,22.7,14.1 ppm; IR (KBr) v: 3494, 3382, 3182, 2921, 2851, 1587, 1517, 1467, 1439, 1294, 1169, 1106, 769 cm—¹; HRMS: mJz [M+H]+ calcd for C₂₁H₃₆N0₃ ⁺: 350.2690, found: 350.2683.

Compound I -30:3,4,5- trihydroxy-N- myristyl benzamides

Synthetic method with compound I -23, reaction feed intake for：（170 mg, 1 mmol) Gallic Acid,（230 mg, 1 mmol) tetradecylamine,（135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（250 mg, 1.2 mmol) dicyclohexylcarbodiimide, 15 ml tetrahydrofurans, acquisition white solid 314 mg. 1HNMR (500 MHz, CDC1₃) S:7.34 7.37 (m, 3H), 3.65 (t, /=8.0 Hz, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.52 (m, 2H), 1.21 1.31 (m, 22H), 0.88 (t, /=7.0 Hz, 3H); MS (m/z): 365 [M]⁺.

Compound I -31:(washing) acid amides of N- (3,4- Dimethoxyphenyl) 14

Synthetic method with compound I -23, reaction feed intake for：（312mg, 2mmol) 3,4- dimethoxyanilines,（465 mg, 2 mmol) tetradecanoic acid, (135 mg, 1 mmol) I-hydroxybenzotriazole hydrate,（450 mg, 2.2 mmol) dicyclohexylcarbodiimide, 30 ml tetrahydrofurans, acquisition white solid 560mg. 1H NMR (500 MHz, CDC1₃) δ:7.40 (d, /=2.0 Hz, 1H), 7.05 (s, 1H), 6.82 (dd, /=2.0,8.5 Hz, 1H), 6.80 (s, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.33 (t, /=7.5 Hz, 2H), 1.72 (m, 2H), 1.25 1.40 (m, 20H), 0.88 (t, J=7.0 Hz, 3H) ppm; MS (m/z):363 [M]+compounds I -32:(washing) acid amides of N- (3,4- dihydroxyphenyl) 14

(150 mg, 0.41 mmol) compound 1-31 is dissolved in 10 ml dichloromethane, Boron tribromide (0.3 ml, 3 mmol) is added dropwise under zero degree, completion of dropping is warmed to room temperature, and is stirred overnight.After reaction terminates, it is quenched under zero degree with methanol, decompression steams solvent, the extraction of residue ethyl acetate, water washing, anhydrous sodium sulfate drying.Silica gel column chromatography (solvent：Petrol ether/ethyl acetate, 8/1, V/V) obtain white solid 118 mgo 1H NMR (500 MHz, CDC1₃) δ:7.29 (d, /=2.0 Hz, 1H), 7.15 (s, 1H), 6.79 (d, /=8.5 Hz, 1H), 6.40 (dd, /=2.5,8.5 Hz, 1H), 5.30 (s, 2H), 2.38 (t, /=7.5 Hz, 2H), 1.74 (m, 2H), 1.26 1.40 (m, 20H), 0.88 (t, /=7.0 Hz, 3H) ppm; MS (mz): 335 [M]+.

Compound I -33:L- (3, the 4- Dimethoxyphenyl) tetradecane -1- ketone

By tetradecanoic acid（2.28g, 0.01 mol) 30 ml thionyl chlorides are dissolved in, backflow under a nitrogen is stayed overnight, excessive S0C1₂Vacuum distillation is eliminated, and obtains myristyl acyl chlorides.The ml of 1,2- dimethoxy benzene 2 is dissolved in 20 ml carbon disulfide, and A1C1 is added portionwise under stirring₃(1.4 g, 10 mmol) are stirred for 15 minutes after adding, and acyl chlorides is added dropwise, and continue to stir 4 hours.Reaction is finished, and will be reacted Liquid is poured into 30 ml frozen water until reddish brown decoloration.Ethyl acetate is extracted, anhydrous sodium sulfate drying, filtering , Nong Shrink.Silica gel column chromatography (solvent：Petrol ether/ethyl acetate, 10/1, V/V) obtain the g of white solid 2.6.1H NMR (500 MHz, CDCl₃) δ:7.58 (the Hz of dd, J=2.0,8.5,1H), 7.53 (the Hz of d, J=2.0,1H), 6.88 (the Hz of d, J=8.5,1H), 6.92 (the Hz of d, J=8.5,1H), 3.95 (s, 3H), 3.94 (s, 3H), 2.92 (t, /=7.5 Hz, 2H), 1.72 (m, 2H), 1.25 1.40 (m, 20H), 0.88 (t, /=6.5 Hz, 3H) ppm; HRMS: m/z [M+H]+ calcd for C₂₂H₃₇0₃ ⁺: 349.2737, found:349.2715. compound I -34:L- (3, the 4- dihydroxyphenyl) tetradecane -1- ketone

(348mg, 1 mmol) compound 1-33 is dissolved in 20 ml dichloromethane, Boron tribromide (0.6 ml, 6 mmol) is added dropwise under zero degree, completion of dropping is warmed to room temperature, and is stirred overnight.After reaction terminates, it is quenched under zero degree with methanol, decompression steams solvent, the extraction of residue ethyl acetate, water washing, anhydrous sodium sulfate drying.Silica gel column chromatography (solvent：Petrol ether/ethyl acetate, 8/1, V/V) obtain white solid 65mg. 1H NMR (500 MHz, CDC1₃) δ:7.67 (d, /=2.0 Hz, 1H), 7.50 (dd, /=2.0,8.5 Hz, 1H), 6.92 (d, /=8.5 Hz, 1H), 6.17 (s, 1H), 5.87 (s, 1H), 2.90 (t, /=7.5 Hz, 2H), 1.71 (m, 2H), 1.25 1.37 (m, 20H), 0.88 (t, J=6.5 Hz, 3H) ppm; HRMS: m/z [ +H]⁺ calcd for C₂₀H₃₃O₃ ⁺: 321.2424, found: 321.2434.

Compound I -35:3- (tetradecyloxyaniline carbonyl) -1,2- phenyl diacetates

By (140 mg, 0.4 mmol) compound I -6, (49 mg, 0.4 mmol) 4-dimethylaminopyridine DMAP is dissolved in the pyridine of 4ml dryings, and stirring is lower to be added dropwise 1ml acetic anhydride, and 5h is stirred at room temperature.Reaction is finished, and is extracted with ethyl acetate, and 1M HC1, water washing, anhydrous sodium sulfate drying are used successively.Silica gel column chromatography（Solvent：Just oneself washes/ethyl acetate, 5/1, V/V) white solid 130mgo 1H NMR (500 MHz, CDC1₃) δ:7.90 (dd, /=1.0,7.5 Hz, 1H), 7.37 (dd, /=1.0,8.0 Hz, 1H), 7.32 (t, /=8.0 Hz, 1H), 4.26 (t, /=6.5 Hz, 2H), 2.34 (s, 3H), 2.32 (s, 3H), 1.72 (m, 2H), 1.40 (m, 2H), 1.26 1.33 (m, 20H), 0.88 (t, /=7.0 Hz, 3H);¹³C NMR (125 MHz, CDC1₃) δ:168.4,168.2,163.9,143.5,142.6,128.9,127.6,126.0,125.2,65.6,31.9,29.6 29.7,29.5,29.4,28.6,25.9,22.7,20.6,14.1; IR (KBr) v: 2919, 2850, 1775, 1710, 1463, 1375, 1306, 1294, 1197, 1106, 761 cm—¹; HRMS: m/z [ +H]⁺ calcd for C₂₅H₃₉0₆ ⁺: 435.2741 , found: 435.2752.

Compound I -36:3- (myristyl formoxyl) -1,2- phenyl diacetates

Synthetic method with compound 1-35, reaction feed intake for：（100 mg, 0.29 mmol) compound 1-23, (37 mg, 0.3 mmol) DMAP, (0.6 ml) acetic anhydride, 2 ml dry pyridines obtain weak yellow liquid 1 10 mg. 1H NMR (500 MHz, CDC1₃) δ:7.34 7.37 (m, 3H), 3.65 (t, /=8.0 Hz, 2H), 2.26 (s, 3H), 2.24 (s, 3H), 1.52 (m, 2H), 1.21 1.31 (m, 22H), 0.88 (t, /=7.0 Hz, 3H); MS (m/z): 434 [M]⁺.

Compound I -37:5- (tetradecyloxyaniline carbonyl) benzene -1,2,3- triacetates

Synthetic method with compound I -35, reaction feed intake for：（28 mg, 0.076 mmol) compound I -17, (12 mg, 0.1 mmol) DMAP, (0.3 ml) acetic anhydride, 1 ml dry pyridines, acquisition white solid 29 mg. 1H NMR (500 MHz, CDC1₃) δ:7.80 (s, 3 Η), 4.31 (t, /=6.5 Hz, 2H), 2.32 (s, 9H), 1.75 (m, 2H), 1.21 1.31 (m, 22H), 0.88 (t, J=7.0 Hz, 3H); MS (m/z): 492 [M]+.

Compound I -38:5- (myristyl formoxyl) benzene -1,2,3- triacetates

Synthetic method with compound I -35, reaction feed intake for：Compound I -31 (100 mg, 0.27 mmol) (37 mg, 0.3 mmol) DMAP, acetic anhydride (0.6 ml), 2 ml dry pyridines obtain the mg of white solid 1 13. 1H NMR (500 MHz, CDC1₃) δ:7.53 (s, 2H), 6.04 (s, 1H), 3.42 (q, /=6.5 Hz, 2H), 2.32 (s, 9H), 1.59 (m, 2H), 1.27 1.39 (m, 22H), 0.89 (t, /=7.0 Hz, 3H); MS (m z): 491 [M]⁺.

Compound I -39:The acid esters of 1,2- phenylene 20

Synthetic method with compound I -4, reaction feed intake for：O-phenol（110 mg, 1 mmol), arachic acid（310 mg, 1 mmol), dicyclohexylcarbodiimide（250 mg, 1.2 mmol), 15 ml tetrahydrofurans obtain the mg of white solid 391. 1H NMR (500 MHz, CDC1₃) δ:7.13 7.16 (t, 1H, /=7.5 Hz), 7.09 7.11 (d, 1H, /=7.5 Hz), 7.02 7.04 (d, 1H, J=1.5 Hz), 6.92 6.95 (t, 1H, /=7.5 Hz), 2.63 (t, 2H, /=6.5 Hz), 2.42 (t, 2H, the Hz of /=6.5), 1.96 1.99 (m, 12H), 1.17 1.42 (m, 60H), 0.89 (bs, 6H); MS (m z): 699 [M]+.

Compound I -40:2,3- dihydroxyphenyl 14 (alkane) hydrochlorates

Synthetic method with compound I -4, reaction feed intake for：Adjacent trisphenol (126 mg, 1 mmol), tetradecanoic acid (456 mg, 2 mmol), dicyclohexylcarbodiimide（250 mg, 1.2 mmol), 15 ml tetrahydrofurans obtain the mg of white solid 120. 1H NMR (500 MHz, CDCI3) δ:6.82 (m, 1H), 6.61 (dd, J=3.0,7.0 Hz, 1H), 6.57 (d, /=8.0 Hz, 1H), 5.74 (s, 1H), 5.30 (s, 1H), 2.64 (m, 2H), 1.77 (m, 2H), 1.41 (m, 2H), 1.26 1.35 (m, 18H), 0.88 (t, /=6.5 Hz, 3H) ppm;¹³C NMR (125 MHz, CDC1₃) δ:173.2,148.0,146.9,126.8,121.1,113.4,112.8,109.7,34.4,34.1,31.9,29.6 29.7,29.4,29.3,29.2,29.0,24.9,22.7,14.1 ppm; IR (KBr) v: 3551 , 3341 , 2920, 2848, 1735, 1604, 1473, 1413, 1273, 1142 cm"¹; HRMS: mJz [M+H]+ calcd for C₂₀H₃₃O₄ ⁺: 337.2373, found: 337.2361.

Compound I -41:3- (tetradecane oxygen) benzene -1,2- glycol

By adjacent triphenol（200 mg, 1.58 mmol), tetradecyl alchohol（339 mg, 1.58 mmol), triphenyl phosphorus（414 mg, 1.58 mmol) it is added in anhydrous tetrahydro furan, diethyl azodiformate is added dropwise under ice bath（275 mg, 1.58 mmol), room temperature reaction is stayed overnight, and reaction is finished, and removes solvent , Nong Shrink fluid columns chromatography (solvent under reduced pressure：Petrol ether/ethyl acetate, 20/1, VA, obtain the mg of light red solid 220.1H NMR (500 MHz, CDC1₃) δ:6.73 (t, /=6.5 Hz, 1H), 6.58 (dd, /=1.0,8.0 Hz, 1H), 6.45 (dd, /=1.0,8.5 Hz, 1H), 5.41 (s, 1H), 5.29 (s, 1H), 4.02 (t, /=6.5 Hz, 2H), 1.80 (m, 2H), 1.44 (m, 2H), 1.26 1.36 (m, 20H), 0.88 (t, /=6.5 Hz, 3H) ppm;¹³C NMR (125 MHz, CDC1₃) δ:146.4,144.1,132.7,119.7,108.6,104.1,69.2,31.9,29.6 29.7,29.4,29.3,26.0,22.7,14.1 ppm; IR (KBr) v: 3444, 3373, 2922, 2851 , 1627, 1526, 1471 , 1234, 1178, 1071 , 765, 717 cm—¹; HRMS: mJz [M+H]+ calcd for C₂。H₃₅0₃ ⁺: 323.2581 , found: 323.2560.

Embodiment 2, benzoate derivatives have the effect of nerve growth factor

2-1：

Research finds that NGF can prevent or reduce the regression of neuron, with promotion nerve growth and neuroprotection.Because the cells of PC 12 have the general features of nerve cell, PC12 cells can stop division in the presence of NGF, grow projection, change into neuron cell.Accordingly, it is capable to cause PC12 cell transformations that there is the application value prevented and treat the nerve degenerative diseases such as senile dementia into the compound of neuron cell.

Experimental implementation：

1) culture of the cells of PC 12：Meet 20x l0⁴The individual cells of PC 12 are in 100 mm culture dish, the DMEM culture mediums of ml containing lO（Wherein contain 10% horse serum, 5% hyclone）, a subculture was changed two days later, after three days subcultures.First use PBS washes cell twice, 10 ml PBS is added in culture dish, in 37 °C, 5% C0₂Incubator in culture 10 minutes, purging, be transferred to 15 ml disposable centrifuge tube, after centrifugation on blood counting chamber count.24 porocyte culture plates first add DMEM culture mediums of the l ml containing serum per hole, after cell count, and 2 are connect per hole><10⁴Individual cell, C0₂Incubator culture is loaded after 24 hours.

2) active testing：Using DMSO as negative control, the ng of NGF 40 are positive control, and compound I is configured to the DMSO solution of various concentrations.With DMEM solution of 1 ml containing 1% DMSO and sample（Without serum）After the former culture medium in every hole of 24 porocyte plates is replaced, 37 V, 5% C0 are put into₂Incubator in cultivate.Every 24 hours, observation cellular morphology change in continuous 6 days under inverted microscope, the nervous process differentiation rate of cell is recorded（Nervous process is longer than total cell number purpose ratio under the cell number of one times of cell space diameter and the visual field), about 100 cells under each visual field are randomly selected at 3, averaged, and count mapping analysis.

) experimental result：

The series compound I of table 1. after 48 hours the cells of optium concentration PC 12 nervous process differentiation rate compound optium concentration（μ Μ) nervous process point

I -1 10 37

I -2 3 35

I -3 3 73

I -4 1 80

I -5 1 82

I -6(ABG-001) 1 87

I -7 1 82

I -8 3 82

I -9 10 79

I -10 10 70

I -11 30 61

I -12 3 27

I -13 3 25

I -14 1 36

I -15 3 83

I -16 0.3 80

I -17 3 32

I -18 3 28

I -19 10 30

I -20 10 33

I -21 1 32

I -22 3 27 I -23 0.03 61

I -24 0.03 58

I -25 0.1 35

I -26 0.1 50

I -27 0.1 39

-28 0.1 49

-29 1 73

-30 0.3 53

-31 3 30

-32 3 57

-33 1 84

-34 3 15

-35 0.3 71

-36 0.3 68

-37 0.3 70

-38 0.3 65

-39 3 40

-40 3 37

-41 0.3 44

Negative control（DMSO) 1% 10

Positive control (NGF) 40ng/ml 83

Preliminary pharmacological test result is shown：The connected mode of long alkyl chains, species, position and the number of benzene ring substituents, phenyl ring and side chain has a major impact to the cellular neural projection activity of PC 12.The nervous process differentiation rate of wherein compound 1-4,1-5, I -6 (ABG-001), I -7, I -8, I -9, I -10, I -15, I -16 in the cells of optium concentration PC 12 after 48 hours is suitable or higher with positive control NGF, and these compounds have the meaning further researched and developed.

Fig. 1 is to add compound ABG-001, and the nervous process differentiation rate of the cells of PC 12 is with the increased change of dosage after 48 hours, C in figure:1% DMS0 is negative control；NGF C40ng/ml) it is positive control, compound ABG-001 concentration unit μ Μ.

Fig. 2 is to add compound ABG-001, the microphoto of the cellular neural projections of PC 12 after 48 hours, schemes a, and 1% DMSO is negative control；Scheme b, the ng/ml of NGF 40 are positive control；Scheme c, compound ABG-001 concentration is 1 μ Μ. 2-2：

1,25 (Ο Η)₂Vitamine D3 is by activating it by physical efficiency inducing neural growth factor（NGF expression).Our research finds that compared with brood wild-type mice, let- hydroxylases strike DNA murine and NGF expression reduction and hippocampal neural aregeneratory occur.Supplement l, 25 (OH)₂Vitamine D3 or NGF can improve the nerve regneration that let- hydroxylases strike DNA murine.

Test main material：The experimental animal model lacked from 12 week old targeting knock out let- '-hydroxylase genes mouse as adult NGF.（Develop cooperatively with Canada McGill University this research department） Experimental implementation：12 week old let- hydroxylases strike DNA murine and give B U intraperitoneal injections.And fixed brain tissue is irrigated through left ventricle with 4% paraformaldehyde after 10 days, BrdU immunostainings are carried out, newborn neuron is marked.ABG-001 is dissolved in

In 99.5% ethanol, then it is administered orally with normal saline dilution.

Experimental result（Fig. 3):With NGF treatment groups（Intracerebroventricular administration）Compare, ABG-001 intraperitoneal administrations can effectively improve the nerve regneration function that let- hydroxylases strike DNA murine；From Fig. 3 (a), compared with wild-type mice (+/+) compare, let- hydroxylases strike DNA murine（-/-) hippocampus nerve growth factor（NGF substantially reduction) is expressed；From Fig. 3 (b), compared with wild-type mice, hydroxylase strikes the reduction of DNA murine hippocampus neonatal neuron survival.NGF is treated（The ventricles of the brain are administered）The neonatal neuron survival that hydroxylase strikes DNA murine can be improved.Compared with NGF treatment groups, ABG-001 treatments（Intraperitoneal administration）The nerve regneration obstacle caused by NGF lacks can effectively be improved.

2-3：

Start in hippocampal dentate submicron particle area within the 3rd day after brain Temporary ischemia（SGZ) there is cell propagation increase, the peaks for 7-10 days, then declines.In recent years research finds that the newborn nerve cell of cerebral ischemia induction is most dead in 1-2 weeks after birth.Although cerebral ischemia can activate NSC, the nerve regneration of stimulation of endogenous, but the limited amount of precursor propagation, and the newborn nerve cell migration of regulation, differentiation, survival, neuron reparation and Synaptic formation the factor it is also not enough, the effect of itself reparation neurologic impairment can not be reached by regenerating after cerebral ischemia endogenous neural.Therefore, the death of newborn nerve cell how is reduced, promotes it to be migrated to ischemic necrosis stove, is induced to differentiate into functional neuron, play endogenous neurogenesis effect has turned into the focus that current ischemic brain damage is studied.The propagation of NSC, migration, differentiation are regulated and controled by many inside and outside environmental factor interactions.Although mechanism of nerve regeneration is still unclear at present after cerebral ischemia, the nerve regneration that neurotrophic factor gene knocks out after mouse cerebral ischemia substantially weakens, and intraventricular injection neurotrophic factor can promote stem cells hyperplasia, promotes newborn nerve cell number increase.

Test main material：Sprague-Dawley (SD) rat（Male and each 10 of female）, body weight 200g 250g, purchased from Jiangsu Province's Experimental Animal Center.

Experimental implementation：10% chloraldurate intraperitoneal anesthesia, ligation right carotid and external carotid artery, internal carotid distal end is closed with artery clamp folder, and fishing line is inserted into internal carotid distal end, is implemented arteria cerebri media and is blocked for 60 minutes（Middle cerebral artery occlusion abbreviation MCAO in figure), prepare focal cerebral ischemia mouse model（With electric blanket to keep experimental animal rectal temperature at 37 ± 0.5 degree）.The ABG-001 (0.5-1.0mg/kg) for proceeding by continuous 14 days for 48 hours after cerebral ischemia is injected intraperitoneally.Give within the 3rd day after cerebral ischemia BrdU injections.And irrigate fixed brain tissue through left ventricle with 4% paraformaldehyde in 28 days after cerebral ischemia, BrdU immunostainings are carried out, newborn neuron is marked.

Experimental result（Fig. 4):ABG-001 administrations can promote the survival and the migration to brain damage area corpus straitum of newborn neuron after cerebral ischemia, and be easy to recover the nervous function after ischemic brain damage.

Theoretically analysis and preliminary experimental result illustrate that other compounds in all embodiments 1 also have the effect similar to ABG-001.

The ABG-001 acute high doses of embodiment 3 are oral, Long-term Oral and intraperitoneal administration do not occur toxic reaction

Test main material：ICR mouse（Body weight 22g 25g, male and each 5 of female, purchased from Zhejiang University's Experimental Animal Center.

Experimental implementation：ABG-001 is relatively insoluble in water.（1) ABG-001 is dissolved in 99.5% ethanol, then adds 1% Tween 80, with normal saline dilution to concentration（2%) ultimate density of ethanol is less than.Oral medication 5g/kg.（2) abdominal channels are administered, and ABG-001 is dissolved in into dimethyl sulfoxide（), DMSO then with normal saline dilution to concentration（DMSO ultimate densities are below 1%）；

Acute poisoning test：By 4 week old ICR male mices 20, male and female half and half are randomly divided into control group, 5g/kg treatment groups.The compound ABG-001 for being dissolved in l%Tween-80 is orally taken medicine 5g/kg, the state of mind of Continuous Observation one week, daily observation animal determines body weight and food ration.There are Juan Shrink in mouse limb after compound is put into 10 minutes, and amount of exercise is reduced.After 1 hour, full recovery is normal.Mouse is without death condition in one week, and food ration is significantly reduced without significant change, but changes of weight.The heart, liver, spleen, kidney and white adipose tissue weight and observe that there was no significant difference.

Experimental result：

(1) table 2 is shown, compared with saline control group, and increased weight/reduction does not occur in ABG-001 treatment groups animal（Including each organ weights）, also do not breathe（50 60 beats/min）, heart rate（305 400 beats/min）, mean arterial pressure（Exception 210mmHg), and the phenomenon such as lethargic sleep, manic, motor behavior exception.

Table 2:ICR mouse blood biochemical indicators（Every group early=10 ,=10;ABG-001=5g/kg gavages)

|

GLO

TP ALB ^

B ALT AST TBIL DBIL CHE

Group (g/L (g/L A/G

(g/L (U/L) (U/L) (umol/L) (umol/L) (U/L) ) )

)

56.86 40.20 16.66 2.42 31.00

It is early right 1.62 0.82 9350.80 Shi Shishishishi

Clear ± 0.34 ± 0.09 ± 156.32

0.43 0.37 0.32 0.06 2.28

57.54 39.00 18.54 2.12 33.40

Early 111.40 1.62 0.96 10075.40 Shi Shishishishi

5g/kg ± 15.80 ± 0.16 ± 0.08 ±411.98

1.24 1.30 0.98 0.14 1.44

57.40 36.50 20.90 1.75 37.75

Very little 88.75 1.48 0.87 6081.50 Shi Shishishishi

Clear ± 12.16 ± 0.33 ± 0.11 ± 184.27

2.11 0.86 1.33 0.09 2.49

54.68 18.68 1.94 32.00

75.40 1.64 0.91 5974.60 Shi Shishishi

5g/kg ±2.34 ± 0.27 ± 0.04 ± 153.90

In 0.88 0.24 0.07 1.10 tables 2, TP (total proteins）, ALB (albumin）, GLOB (globulin）, ALT (ALTs）, AST (glutamic-oxalacetic transamineases）, TBIL (total bilirubins）, DBIL (bilirubin directs）, CHE (acetylcholinesterases）(2) compared with saline control group, exception of the ABG-001 5g/kg groups without display blood biochemical analysis index（Table 3), point out the functions such as liver, kidney, blood forming organ not to be compromised.

Table 3:ICR mouse weights and each organ coefficient（Every group 10 ,=5, early=5; ABG-001=5g/kg) Group body weight（G) heart（%) liver（%) kidney（%) spleen（It is %) fatty（%)

24.64 0.685 2.102 0.684 3.185

Control group

±0.38 ±0.086 ±0.148 ±0.078 ±0.260

23.67 0.607 7.904 2.200 0.698 2.129

5g/kg group ± 0.86 ± 0.044 ± 0.289 ± 0.110 ± 0.036 ± 0.105

20.30 0.658 6.669 1.681 0.607 2.848 early control groups

± 0.56 ± 0.031 ± 0.205 ± 0.046 ± 0.038 ± 0.384 early 19.12 0.726 6.373 1.756 0.701 2.095

5g/kg group ± 1.41 ± 0.037 ± 0.234 ± 0.047 ± 0.039 ± 0.405 organ coefficient=internal organs weight/body weight（%)

Chronic toxicity test:ABG-001 carries out the intraperitoneal injection of continuous 60 days（10 mg/kg/ days）, or oral administration（10 mg/kg/ days）（Saline administration is as a control group）Afterwards, body weight is detected.With 10% chloraldurate intraperitoneal anesthesia, recording respiration, heart rate and mean arterial pressure.Then the detection of blood progress hematology and blood biochemical analysis index etc. is taken from left ventricle.And take out the histological observation of each internal organs progress.

Experimental result：

(1) table 4 is shown, compared with saline control group, and increased weight/reduction does not occur in ABG-001 treatment groups animal（Including each organ weights）.Also do not breathe（50 60 beats/min）, heart rate（305 400 beats/min）, mean arterial pressure（Exception 210mmHg), and the phenomenon such as lethargic sleep, manic, motor behavior exception.

Table 4:Mouse weight and each organ coefficient（Every group=10 ,=10;ABG-001=10mg/kg gavages）Group body weight（G) lung（%) heart（%) liver（%) kidney（%) spleen（%)

36.50 0.71 0.502 5.093 1.302 0.419 control groups

± 2.84 ± 0.21 ± 0.10 ± 0.32 ± 0.20 ± 0.12 solvent 33.20 0.82 0.605 5.128 1.235 0.405

(gavage）± 2.72 ± 0.24 ± 0.19 ± 0.43 ± 0.17 ± 0.09 solvent 36.22 0.78 0.524 4.912 1.193 0.368

(abdominal cavity) ± 2.47 ± 0.12 ± 0.16 ± 0.55 ± 0.18 ± 0.14 ABG-001

35.83 0.87 0.482 5.243 1.203 0.390 (gavages）

±2.11 ±0.28 ±0.22 ±0.67 ±0.32 ±0.07 lOmg/kg

ABG-001

32.30 0.80 0.523 5.031 1.133 0.371 (abdominal cavities）

± 3.42 ± 0.19 ± 0.15 ± 0.37 ± 0.15 ± 0.09 5mg/kg organ coefficients=internal organs weight/body weight

(2) compared with saline control group, chronic ABG-001 administration groups do not show blood biochemical analysis index（Table 5) exception, point out liver, kidney, the function such as blood forming organ not to be compromised.

Table 5:The biochemical index of mouse major blood（Every group=10 ,=10; ABG-001=^:10mg/kg gavages）

GLO

TP ALB ALT TBIL DBIL

B AST CHE

Group (g/ (g/L A/G (U/L (umol (umol/L

(g/L (U/L) (U/L)

L) ) ) /L) )

)

57.2 38.5 17.7 32.2 85.4 7863.2

2.14 1.71

82952 0.71 4 control group ± 0.0 ± 0.2

±0.6 ±0.5 ±0.9 ±1.4 ±15. ±0.10 ±120.6

8 4

9 8 2 3 2 7

56.2 39.9 19.1 32.8 111. 8017.4

2.01 1.58

Solvent 3445 41 0.92 0

±0.0 ±0.1

(turn over） ±1.0 ±0.9 ±1.2 ±1.4 ±17. ±0.08 ±168.5

7 9

4 7 1 4 10 4

57.1 36.5 18.4 33.6 75.7 7684.3

1.91 1.63

Solvent 07318 0.85 8

±0.1 ±0.2

(abdominal cavity) ± 1.1 ± 0.6 ± 0.8 ± 1.9 ± 14. ± 0.09 ± 176.5

3 6

1 7 1 9 72 9

ABG-00 55.7 38.2 20.0 33.0 85.6 8344.7

2.04 1.70

1 (gavage） 8 5 2 4 3 0.91 5

±0.0 ±0.1

10mg/k ±0.6 ±1.0 ±1.0 ±1.0 ±11. ±0.05 ±191.8

8 9

g 0 2 4 3 41 3

56.8 37.4 18.3 32.1 89.4 7976.4

ABG-00 1.88 1.51

9 3 5 9 7 0.89 3

1 (abdominal cavity） ±0.0 ±0.3

±1.1 ±0.7 ±0.8 ±1.5 ±15. ±0.09 ±143.0

5mg/kg 9 5

In 7274 98 6 tables 5, TP (total proteins）, ALB (albumin）, GLOB (globulin）, ALT (phenylalanine ammonia group-transfers Enzyme）, AST (glutamic-oxalacetic transamineases）, TBIL (total bilirubins）, DBIL (bilirubin directs）, CHE (acetylcholinesterases）.Theoretically analysis and preliminary experimental result illustrate that other compounds in all embodiments 1 also have the effect similar to ABG-001.The ABG-001 of embodiment 4 can pass through blood-brain barrier（Fig. 5)

Test main material：Sprague-Dawley (SD) rat（Male and each 10 of female）, body weight 200g 250g, purchased from Jiangsu Province's Experimental Animal Center.

Experimental implementation：10% chloraldurate intraperitoneal anesthesia, record microelectrode according to after 0.3mm, foretells at 1.0mm sunset, the coordinates of 2.5 mm depth inserts CA1 pyramidal cell at hippocampus layer, the spontaneity discharge frequency of record hippocampus CA1 nerve cell.After basic value stable recording 20 minutes, ABG-001 carries out intraperitoneal administration, continuous record 1-2 hours.Analyze whether ABG-001 can adjust the excitability of hippocampal neurons through blood-brain barrier.

Experimental result（Fig. 5):ABG-001 (0.5-lmg/kg) is injected intraperitoneally 20-30 minutes afterwards, spontaneity discharge frequency, which occurs, in hippocampus CA1 nerve cell substantially to be increased, and continue more than 2 hours, point out ABG-001 that the excitability of nerve cell by blood-brain barrier, can be adjusted.

Theoretically analysis and preliminary experimental result illustrate that other compounds in all embodiments 1 also have the effect similar to ABG-001.Embodiment 5, ABG-001 can promote the regeneration of brain neuron by blood-brain barrier（Fig. 6)

In 1988, Erikssion etc. was marked with a division cells with BrdU (5-bromodeoxyuridine), finds the NSC of adult mammal hippocampus and can be divided into the nerve to occur of nerve cell one.The newborn neuron of adult hippocampal dentate fascia Neng Yu CA3 areas neuron similar to ripe granular cell sets up synaptic contact and occurs synaptic plasticity.The nerve to occur of adult can replace due to the neuronal death that natural aging or lesion are caused, and the integrality of brain function and structure is safeguarded to greatest extent.Research has shown that the neonatal cell member of old brain is reduced（Nerve regeneratl fails）It is relevant with Age-related cognitive hypofunction.This experiment primary part observation ABG-001 is to nerve to occur（Mainly include nerve stem cell proliferation, survival, differentiation）Effect.

Test main material：2 monthly age kunming mices（Male and each 40 of female）, body weight 25g 30g, purchased from Jiangsu Province's Experimental Animal Center.

Experimental implementation：1. BrdU (5- bromodeoxyuridine nucleosides is used）The cell of m period is marked, ABG-001 administrations are carried out within continuous 14 days after B U injections（0.5mg/kg/d).Then 48 hour, days and 28 days methods with SABC detect that the BrdU in hippocampus DG areas is positive after BrdU first administrations respectively（BrdU⁺) cell, to determine ABG-001 cell proliferations（24 hour age-BrdU⁺Cell）, survival（7 day age-BrdU⁺Cell）And maturation（28 day age-BrdU⁺Cell）Influence.2. neuronal specificity nucleoprotein is used（) and Deiter's cells NeuN（GFAP immunostaining), influences of the observation ABG-001 to newborn Neural Differentiation.3. Doublecortin (DCX) immunostaining, influences of the observation ABG-001 to newborn neuron enation are used.ABG-001 is administered：ABG-001 is dissolved in 99.5% ethanol or dimethyl sulfoxide, is then injected intraperitoneally with tea oil dilution, or be administered orally with normal saline dilution.

Experimental result（Fig. 6):ABG-001 is oral or intraperitoneal administration can promote the propagation of hippocampal dentate NSC（A), the enation of newborn neuron is promoted（B), stem cell Differentiating Into Neurons are promoted（C), prompting ABG-001 has god Through trophism.

Theoretically analysis and preliminary experimental result illustrate that other compounds in all embodiments 1 also have the effect similar to ABG-001.Embodiment 6, ABG-001 have the effect of Anti-endotoxin activity always（Fig. 7)

6-1：

Mammal obtains galactolipin from lactose, and lactose hydrolyzes generation glucose and galactolipin in vivo, and galactolipin is then digested into rapidly glucose in liver.Excessive galactolipin is reduced into galactitol under AR enzymatic.Galactitol is end product of metabolism, it is impossible to is further divided metabolism and accumulates, and increases the osmotic pressure of cell, causes cellular swelling, dysfunction and metabolic disorder, ultimately result in body aging.Substantial amounts of research report, D-gal galactolipins induction aged animal model.The D-gal retrogressions such as slow, projection comes off, the death rate increases that make rat embryo brain neuron occur growing.D-gal causes the fibroblastic external division algebraically of induced lung to reduce, and G2-M phases Leukopenia, the increase of G-G1 phases cell in diploid fibroblast division cycle, cell proliferation rate slow down.D-gal suppresses cell development and reduces division number of times, accelerates cell ageing.

Test main material：2 monthly age kunming mices（Male and each 30 of female）, body weight 25g 30g, purchased from Jiangsu Province's Experimental Animal Center.

Experimental implementation：D-gal galactolipins（100mg/kg/ days）The intraperitoneal injection of progress 60 days.After 6 weeks, mouse is slow in action, and hair color is gloomy, and body is thin and weak, obvious aging sign is presented, it was demonstrated that aging model is successfully established.After D-gal galactolipins are injected 20 days, ABG-001 is proceeded by oral（0.1st, 5.0,10.0 mg/kg/ days）Or intraperitoneal injection（0.1st, 0.5,5 mg/kg/ days）.When D-gal is injected 30 days, continuous 4 times of BrdU (5- bromodeoxyuridine nucleosides, 50.0 mg/kg) injections are given, are spaced 6 hours.Then respectively 28 days after BrdU administrations, fixed brain tissue is irrigated through left ventricle with 4% paraformaldehyde, BrdU immunostainings is carried out, marks newborn neuron.Detect that the BrdU in hippocampus DG areas is positive（BrdU⁺) cell, to determine that ABG-001 is survived and ripe to neonatal cell（28 day age-BrdU⁺Cell）Influence.With Doublecortin (DCX) immunostaining, influences of the observation ABG-001 to newborn neuron enation.Mouse was put to death in the 2nd day after last dose, hippocampus is taken out and cerebral cortex determines glutathione peroxidase (glutathione peroxidase, GSH2Px), superoxide dismutase（Superoxide dismutase, SOD), monoamine oxidase (monoamine oxidase, MAO) standing grain mouthful TAC（Total anti-oxidation competence, T-ACO) etc. aging biochemical indicator.

Experimental result（Fig. 7):(1) D-gal galactolipins long term injections can significantly reduce the quantity of newborn neuron, damage the enation of newborn neuron（a) ；(2) motor function of D-gal galactolipins-mouse aging is without obvious abnormal（B), but Spatial learning and memory function is substantially reduced；（3) ABG-001 treatments can improve survival and the enation obstacle of newborn neuron caused by D-gal（a) ；(4) ABG-001 treatments can improve the memory function of brain aging mouse（C) and（d) ；(5) the oxidative stress biochemical indicator of mouse（Every group early=10,3=10；ABG-001=10mg/kg gavages）Show that TAC improves unobvious（E), (f), (g) and（h) .Test main material：SAM R1 (6 week old male, each 18）With SAM P8 (9 week old male, each 18）It is purchased from affiliated hospital of Medical University Of Tianjin first.SAM P8 mouse are a kind of quick aging animal models. Experimental implementation：SAM P8 September age mouse are randomized into 3 groups, control group（The physiological saline of 1% Tween 80）, low dosage（Lmg/kg) group and high dose（3mg/kg) group, every group 6.Another sunset is foretold, the week old mouse of SAM R1 six as normal aging mouse young control.The physiological saline or ABG-001 of 1% Tween 80, continuous two weeks is injected intraperitoneally in each group daily.The detection of learning and memory and spatial memory function.（1) Y-maze is tested：Spontaneous alternative behavior can be assessed with Y-maze experiments.Y-maze is that black Y shape trisection radiant type is got lost case, is made up of 3 support arms and a bonding pad, three arms, 120 ° of angle with each other, it is upper wide 8 centimetres per 38.5 centimetres of brachium, it is lower wide 3.5 centimetres, it is high 12 centimetres, three arms can an optional arm be starting arm.Every mouse discharges from the end for fixing an arm, makes mouse freely movable 8 minutes, and record enters the order of arm every time.Continuously enter three different arm arms for three times and be decided to be and alternately enter arm（Such as：ABC, ACB, BAC, BCA, CAB, CBA).Alternately enter being calculated as arm rate：1 one（2) χ 100% of errors number/total degree 1.Enter arm number of times in addition, total and can also determine.(2) novelty distinguishes experiment：Novelty distinguishes that experiment is that the ability being familiar with novelty is distinguished according to rodent.Using to device be white uncovered box（The long wide X of X are high：18 centimetres of 40x20x）.First, what object is not let alone in box, mouse is discharged from identical location point every time, allows adapt to environment, referred to as laundering period, totally two days within its free movable 5 minutes.It is within 3rd day to be familiar with phase and test phase.It is familiar with the phase：First it is put into after two same objects, mouse is put into, freely activity 5 minutes, be less than 2 centimetres away from object with mouse nose or lie prone worthwhile for exploratory behavior in identified object, records respectively and the time is probed into two same objects.The test phase：Two different objects are changed in interval after 1 hour（One of them is and is familiar with phase identical object（0, another is novelty (n)), allow its freely activity 5 minute, and record mouse probing into time f and time n is probed into novelty to familiar objects.It is familiar with phase and test phase to put by random digit two kinds of objects of combination and position.The calculation formula of cognitive index be the time n/ that probes into novelty always probe into time n+f.

Experimental result（Fig. 8):(1) compared with SAM R1 mouse, always entering arm number of times and alternately entering arm rate for SAM P8 mouse does not substantially change（a);(2) receive high dose or low dosage ABG-001 processing SAM P8 mouse compared with the SAM R1 mouse and SAM P8 mouse do not treated learning and memory function be remarkably reinforced（b);(3) compared with SAM R1 mouse, SAM P8 mouse substantially reduce to the resolving ability of novelty（c);(4) ABG-001 processing energy concentration dependent recovers resolving ability of the SAM P8 mouse to novelty（d).

Theoretically analysis and preliminary experimental result illustrate that other compounds in all embodiments 1 also have the effect similar to ABG-001.Embodiment 7, ABG-001 have the effect of prevention and treatment senile dementia（Fig. 9)

74

Test main material：Sprague-Dawley (SD) rat（Male and each 20 of female）, body weight 200g 250g, purchased from Jiangsu Province's Experimental Animal Center.1. stereotaxic technique is used, by osmotic pump (osmotic minipump: Alzet 2002;Alze, CA) connection implantation catheter（Cannula), and be fixed on one side telocoele (0.3mm, right side lmm, deep 2.5mm after bregma).By Α β_{( 1}_ 42) continuous 2 weeks（100pM/day) it is fed into telocoele.By observing Α β deposition, spatial memory function and Cholinergic, to verify whether AD models succeed.

Experimental implementation： Αβ_{( 1}_ 42) irrigate after proceed by within the 2nd day continuous 14 days ABG-001 (0.5-1.0mg/kg) intraperitoneal injection.In Α β α -4_{2 )}Carry out water maze test within the 7th day after perfusion, check spatial memory function.The movement locus of rat is recorded, calculating is gone up on the stage incubation period.In Α β_α_₄₂₎15 days after perfusion, fixed brain tissue is irrigated through left ventricle with 4% paraformaldehyde. After FFPE, hippocampus serial section is done.After 1% Toluidine blue staining, the density of measurement hippocampus CA1 area survival cones (pyramidal cell layer per mm length in granular cell number）.

Experimental result Fig. 9: Αβ_α_₄₂₎Perfusion causes about 60% hippocampus CA1 area neuronal death to be lost, and causes escape latency to extend, and points out the reduction of spatial cognition function.ABG-001 treatments can significantly reduce Α β_α_₄₂₎Dementia rats hippocampal neurons are dead, improve the Spatial memory function of Α β rats.

ABG-001 treatments can improve the brain endogenous nerve regneration obstacle of Alzheimer disease (AD)

The NSC of Adult Mammals hippocampal dentate can be divided into nerve cell referred to as nerve to occur.The nerve to occur of adult is considered to replace and repaired due to the neuron loss that natural aging or lesion are caused, and the 26S Proteasome Structure and Function of brain is safeguarded to greatest extent.Alzheimer disease (Alzheimer's disease, AD) is a kind of nervous system degenerative disease being characterized with progressive cognition dysfunction.Whether newborn neuron can substitute the neuron of lesion, improve AD cognition dysfunction and turned into the novel targets that AD is studied.Research finds that the neuronotropic differentiation ratio of precursor of AD cerebral hippocampals is significantly reduced, and the survival rate of synkaingenesis neuron is significantly reduced, and the enation of newborn neuron is abnormal.These researchs have confirmed that the nerve regeneration of AD brains is by serious infringement, and it is probably one of important pathomechanism of AD cognitive functions progressive decline to point out nerve regneration obstacle.

Test main material：APP/PS1 transgenosis AD mouse（10 monthly age male and female mouse）（It is purchased from Nanjing University's zootype center）.Experimental implementation：With BrdU (5- bromodeoxyuridine nucleosides）The cell of m period is marked, ABG-001 administrations are carried out within continuous 14 days after B U injections（0.5mg/kg/ days）.Then 28 days methods with SABC detect that the BrdU in hippocampus DG areas is positive after BrdU first administrations respectively（BrdU⁺) cell.Pass through neuronal specificity nucleoprotein（) and Deiter's cells NeuN（GFAP immunostaining), influences of the observation ABG-001 to newborn Neural Differentiation.Doublecortin (DCX) in the growth course of central nervous system neural precursor transition process particular expression, DCX as neuronal precursor mark can for study neuronal precursor propagation and migration.The growth of newborn Neuronal processes can be observed by being dyed by DCX.Mouse was put to death in the 2nd day after last dose, hippocampus is taken out and determines acetylcholinesterase（AChE it is) active.

Experimental result（Figure 10):Compared with wild-type mice, 28 day age-BrdU+ cell of APP/PS1 adult mouse dentate gyrus shows 50% reduction（a);Newborn neuron number of projection and length are significantly reduced（b).ABG-001 treatments can improve APP/PS1 mouse 28 day age-B U+ cells and substantially reduce（A) growth of nervous process, is protected（B), prompting ABG-001 has the effect for improving AD neurogenesis and cognition dysfunction.The acetylcholinesterase of APP/PS Hippocampus of Mice（AChE) activity has slight increase, and ABG-001 treatments can substantially lower AD hippocampus of mice acetylcholinesterases（AChE it is) active (c).

Theoretically analysis and preliminary experimental result illustrate that other compounds in all embodiments 1 also have the effect similar to ABG-001.The preparation method of embodiment 8, ABG-001 tablets

Prescription：

ABG-001 100g

Starch 40g Microcrystalline cellulose 80g

Magnesium stearate 3.0g

Hydroxypropyl methyl cellulose（E-30) (40% solution）In right amount

It is made 1000

Preparation method：4% is prepared through propyl methocel（E-30) solution, it is standby.Weighing 10g starch, to put 105 °C of dryings 5 hours standby.Weigh 20 g starch and recipe quantity invents ABG-001, microcrystalline cellulose, and 80 mesh sieves were crushed in mixing.With 4% through propyl methocel（E-30) solution pelletizes material softwood, in the % of moisture content 3 of 50 °C of 60 °C of dryings into particle or so with 20 mesh sieves.20 mesh sieve whole grains are crossed, the dried starch of recipe quantity is added（105 °C of dryings 5 hours）, magnesium stearate, it is mixed eventually, survey intermediates content, stator weight；Tabletting.

The preparation method of embodiment 9, ABG-001 parenteral solutions

Prescription：

ABG-001 10g

Propane diols 500mL

Water for injection 500mL

LOOOmL is made

Preparation method：Weigh the ABG-001 and propane diols of recipe quantity, plus the mL of water for injection 500, stirring and dissolving；0.1 % activated carbons are added into above-mentioned solution, are stirred, are placed 15 minutes, 5 microns of titanium rods take off charcoal, then the miillpore filter refined filtration through 45 microns of 0, of filter cartridge and 22 microns of 0,；Embedding is in 10 ml ampoule bottles, and 100 °C of flowing steams sterilize 45 minutes, produce invented ABG-001 parenteral solution.

Claims (1)

1. Claims

   1st, the application of a kind of benzoic ether and its derivative in the medicine for preparing prevention and treatment nerve degenerative diseases, it is characterised in that the benzoic acid following structure formula：

   Wherein, R is carbon number from 1 to 30 straight chain, side chain, saturation and unsaturated protective embankment base, cycloaliphatic ring or their derivative；Separately it is selected from hydrogen, hydroxyl, carboxyl, aldehyde radical, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, amide groups, cyano group, nitro, sulfonic group, trifluoromethyl, acrylic, protective embankment base, protective embankment epoxide, substituted benzyl, substituted-phenyl, aryl, heteroaryl, glycosyl or amino acid residue；X is selected from C (0) 0, OC (0), C (0) NH, NHC (0), C (0), CH₂, S or 0.

   2nd, application according to claim 1, it is characterised in that the R is carbon number from 6 to 22 straight chain, side chain, saturation and unsaturated protective embankment base, cycloaliphatic ring or their derivative.

   3rd, application according to claim 1, it is characterised in that the benzoic ether and its derivative are： 2,3- dihydric ethyl benzoates, 2,3- dihydroxy-benzoic acid pentyl esters, 2,3- dihydroxy-benzoic acid monooctyl esters, 2,3- dihydroxy-benzoic acid last of the ten Heavenly stems esters, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 12, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 14, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 16, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 18, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 20, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 22, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 30, 2,The protective embankment ester of 6- dihydroxy-benzoic acids 14, 2,The protective embankment ester of 6- dihydroxy-benzoic acids 20, 2,The protective embankment ester of 4- dihydroxy-benzoic acids 14, 3,The protective embankment ester of 4- dihydroxy-benzoic acids 14, 3, 4,The protective embankment ester of 5- trihydroxybenzoic acids 14,The protective embankment ester of 2 hydroxybenzoic acid 14,The protective embankment ester of 3- hydroxybenzoic acids 14, 2,The protective embankment ester of 3- dimethoxybenzoic acids 14, 2,The protective embankment ester of 3- dimethoxybenzoic acids 18,The protective embankment ester of 2- hydroxy 3-methoxybenzenes formic acid 14,The protective embankment ester of 2- chlorobenzoic acids 14, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 14, 2,3- dihydroxy-N- octyl group benzamides, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 12, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 16, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 18, 2,The protective embankment yl-benzamides of 3- dimethoxys-N- 14, 3,The protective embankment yl-benzamides of 4- dihydroxy ^- 14, 3, 4,The protective embankment yl-benzamides of 5- trihydroxies-N- 14, N- (3,4- Dimethoxyphenyls) 14 (protective embankment) acid amides, N- (3,4- dihydroxyphenyls) 14 (protective embankment) acid amides, 1- (3,4- Dimethoxyphenyls) 14 protective embankment -1- ketone, 1- (3,4- dihydroxyphenyls) 14 protective embankment -1- ketone,3- (14 protective embankment Epoxide carbonyl) -1,2- phenyl diacetates,3- (14 protective embankment base formoxyl) -1,2- phenyl diacetates,5- (14 protective embankment Epoxide carbonyls）Benzene -1,2,3- triacetates, 5- (14 protective embankment base formoxyls）Benzene -1,2,3- triacetates, 1,2- phenylene 20 Acid esters, 2,3- dihydroxyphenyls 14 (protective embankment) hydrochlorate, 3- (14 protective embankment oxygen) benzene -1,2- glycol.

   4th, the application of a kind of benzoic ether and its derivative in prevention and the old medicine for the treatment of Anti-endotoxin activity is prepared, it is characterised in that the benzoic ether and its derivative have following structure formula：

   Wherein, R is carbon number from 1 to 30 straight chain, side chain, saturation and unsaturated protective embankment base, cycloaliphatic ring or their derivative；Separately it is selected from hydrogen, hydroxyl, carboxyl, aldehyde radical, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, amide groups, cyano group, nitro, sulfonic group, trifluoromethyl, acrylic, protective embankment base, protective embankment epoxide, substituted benzyl, substituted-phenyl, aryl, heteroaryl, glycosyl or amino acid residue；X is selected from C (0) 0, OC (0), C (0) NH, NHC (0), C (0), CH₂, S or 0.

   5th, application according to claim 4, it is characterised in that the R is carbon number from 6 to 22 straight chain, side chain, saturation and unsaturated protective embankment base, cycloaliphatic ring or their derivative.

   6th, application according to claim 4, it is characterised in that the benzoic ether and its derivative are： 2,3- dihydric ethyl benzoates, 2,3- dihydroxy-benzoic acid pentyl esters, 2,3- dihydroxy-benzoic acid monooctyl esters, 2,3- dihydroxy-benzoic acid last of the ten Heavenly stems esters, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 12, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 14, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 16, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 18, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 20, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 22, 2,The protective embankment ester of 3- dihydroxy-benzoic acids 30, 2,The protective embankment ester of 6- dihydroxy-benzoic acids 14, 2,The protective embankment ester of 6- dihydroxy-benzoic acids 20, 2,The protective embankment ester of 4- dihydroxy-benzoic acids 14, 3,The protective embankment ester of 4- dihydroxy-benzoic acids 14, 3, 4,The protective embankment ester of 5- trihydroxybenzoic acids 14,The protective embankment ester of 2 hydroxybenzoic acid 14,The protective embankment ester of 3- hydroxybenzoic acids 14, 2,The protective embankment ester of 3- dimethoxybenzoic acids 14, 2,The protective embankment ester of 3- dimethoxybenzoic acids 18,The protective embankment ester of 2- hydroxy 3-methoxybenzenes formic acid 14,The protective embankment ester of 2- chlorobenzoic acids 14, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 14, 2,3- dihydroxy-N- octyl group benzamides, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 12, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 16, 2,The protective embankment yl-benzamides of 3- dihydroxy-N- 18, 2,The protective embankment yl-benzamides of 3- dimethoxys-N- 14, 3,The protective embankment yl-benzamides of 4- dihydroxy ^- 14, 3, 4,The protective embankment yl-benzamides of 5- trihydroxies-N- 14, N- (3,4- Dimethoxyphenyls) 14 (protective embankment) acid amides, N- (3,4- dihydroxyphenyls) 14 (protective embankment) acid amides, 1- (3,4- Dimethoxyphenyls) 14 protective embankment -1- ketone, 1- (3,4- dihydroxyphenyls) 14 protective embankment -1- ketone,3- (14 protective embankment Epoxide carbonyl) -1,2- phenyl diacetates,3- (14 protective embankment base formoxyl) -1,2- phenyl diacetates,5- (14 protective embankment Epoxide carbonyls）Benzene -1,2,3- triacetates, 5- (14 protective embankment base formoxyls）Benzene -1,2,3- triacetates, the acid esters of 1,2- phenylene 20,2,3- dihydroxyphenyls 14 (protective embankment) hydrochlorate, 3- (14 protective embankment oxygen) benzene -1,2- glycol.