CN101817761B - Benzoate derivatives, preparation method and application - Google Patents

Benzoate derivatives, preparation method and application Download PDF

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CN101817761B
CN101817761B CN201010103089.6A CN201010103089A CN101817761B CN 101817761 B CN101817761 B CN 101817761B CN 201010103089 A CN201010103089 A CN 201010103089A CN 101817761 B CN101817761 B CN 101817761B
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benzoate derivatives
compound
acid
benzene
senile dementia
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CN101817761A (en
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戚建华
罗燕
向兰
高丽娟
孙恺悦
李金优
韩峰
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Hangzhou Ivy Leaf Medical Technology Co Ltd
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Zhejiang University ZJU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

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Abstract

The invention provides benzoate derivatives. A series of benzoate derivatives are synthesized through a chemical method, comprising ester compounds, (sulfur) ether compounds and amide compounds, wherein most synthesized compounds have new chemical structures, and proved through in vitro cell activity experiments, the synthesized benzoate derivatives have obvious activities similar to nerve growth factors (NGF). Proved through an in vitro animal experiment, 2,3-dyhydroxy benzoic acid tetradecyl ester which is a new synthesized compound has the effect of enhancing the memory of senile mice, thus the benzoate derivative can be applied to preparing medicaments for preventing and treating senile dementia neurodegenerative diseases, particularly to preparing medicaments for treating the neurodegenerative diseases such as the Alzheimer's diseases (AD), and the like. The invention opens up a new medical application of the benzoate derivatives, has reasonable preparation method and simple and convenient operation and provides new treatment medicaments for preventing and treating the neurodegenerative diseases such as the senile dementia, and the like.

Description

Benzoate derivatives and preparation method and application
Technical field
The invention belongs to compounds process for production thereof and application, relate to the preparation method of benzoate derivatives, and the application of this compounds in the nerve degenerative diseases such as prevention and treatment senile dementia.
Background technology
Senile dementia is broadly divided into three major types type: the dementia of Alzheimer's disease (Alzheimer ' s disease, be called for short AD), vascular dementia and other types.Along with increasing of the aged, the morbidity of senile dementia obviously raises, and has become the 4th major cause that causes grownup's death, is only second to heart trouble, cancer, apoplexy.China's patients with Alzheimer disease is estimated to exceed 5,000,000, accounts for 1/4 of the total case load in the world; And along with the quickening of China's aging population process, this numeral will be more huge, bring great impact to social stability and development.According to statistics, the sickness rate over-65s of Aged in China dementia disease is within 5%, 70 years old, to be within 10%, 80 years old, to be 30% above above, to 85 years old above up to 40%.After 20 years, middle-aged people of today will step into the elderly's ranks, and dementia patient's quantity will sharply increase, and the elderly's health also will be related to the stable and development of entire society.Therefore, research and develop effective prophylactic treatment senile dementia medicine and become whole world medical problem in the urgent need to address.
In senile dementia three macrotaxonomies, AD is that sickness rate is the highest, is also most important a kind of dementia form disease.AD is a kind of nerve degenerative diseases, taking memory and Cognitive function damage as main clinical disease, when serious, can cause can't take care of oneself.The definite pathomechanism of AD it be unclear that, and at present main academic viewpoint has following several: 1. beta-amyloyd polypeptide (A β) toxicity and deposition; 2. cholinergic disappearance theory; 3. nerve retrograde affection (Neurodegeneration); 4. other many factors, as transgenation theory, oxidative stress theory.
A β deposition and toxicity are one of principal elements of A Shi dementia morbidity.The abnormal adjusting of the app gene in neurone causes the gathering of toxicity A β in neurocyte, causes the cascade reaction of pathological change, and then causes the degeneration of neurocyte.Both at home and abroad the focus of research concentrate on reduce A β generation, suppress A beta peptide aggregation, thereby the configuration that changes A β reduces its neurotoxicity, had at present several drugs to enter clinical trial.
The medicament categories of present stage treatment AD is a lot of, mainly contain cholinergic agent, wherein acetylcholinesterase (Acetylcholinesterase, AChE) inhibitor, the medicine of main listing has tacrine (tacrine), rivastigmine (rivastigmine), selagine (huperzine A), E2020 (donepezil) etc.; β, gamma secretase Depressant; Brain metabolism regulators, as vincamine, nimodipine, cinnarizine; Affect the medicine of Radical Metabolism, if vitamins C is in conjunction with vitamin-E etc.But these AD medicines are mainly symptomatic treatments, can not delay the progress of the AD course of disease, and reduce gradually with PD curative effect of medication, there is serious side effects simultaneously, old friends turn to sight the research and development of new anti senile dementia drug.Find medicine and method for the AD cause of disease, become focus and the difficult point of current research.
Research shows, neurotrophic factor has important impact to the lysis of neurodevelopment and Adult Nervous System.In neurodegeneration animal model, find that nerve growth factor (nerve growthfactor, NGF) can stop or reduce neuronic regression.NGF is first neurotrophic factor that the mankind find, is also most important neurotrophic factor; It is the biologically active polypeptides that there is important regulating and controlling effect the aspects such as a kind of growth, growth, differentiation and function maintenance to neurocyte; Treatment to sacred diseases such as neuratorphy, neurodegeneration, wound reparations has unusual effect.Research discovery, NGF to a certain degree can stop AD progress, and it promotes that nerve growth and neuroprotective are long-term study hotspots.But it is a polypeptide being made up of more than 100 amino acid; Due to reasons such as molecular weight are large and polarity is strong, can not pass through hemato encephalic barrier (Blood Brain Barrier), and be difficult to the factors such as extensive preparation, limited to its practical clinical, NGF does not also find better methods for the treatment of except operation in brain is directly offerd medicine.Therefore, find and there is similar NGF activity (NGF mimics) and maybe can strengthen its activity (NGFenhancer) and can just naturally become study hotspot by the low molecular compound of hemato encephalic barrier.Due to PC12 cell (Pheochromocytoma cells, from Clonal Rat Pheochromocytoma, clone obtains), there is the general feature of neurocyte and the feature that can go down to posterity, under the effect of NGF, cell can stop division, grow projection, change into neuron cell.Therefore be, a good model at the function PC12 cell of cellular and molecular level research NGF.At present, there is NGF mimics in the phase iii clinical trial stage.
Recently, the separation and purification from Chinese medicine rough gentian of this study group obtains a class 2,3-dyhydroxyl parabens new compound, and new discovery its there is the good NGF mimics biological activity of anti-senile dementia.Up to now, not yet there is research worker from natural product, to find such material, do not have this compounds to there is the relevant report of the similar NGF activity of anti-senile dementia.Only has bibliographical information chemosynthesis and compound its structural similitude (aliphatic chain contains carbon number lower than 11), European patent (EP 1 930 002 A1) has been described the application of benzoate compounds (1) aspect treatment and prophylaxis of viral infections, the described benzoic acid derivative of Chinese patent (CN1411339A) is mainly used in antibacterial, as foodstuff additive etc.
In formula, R is C 1-11alkyl; R 1, R 2, R 3, R 4and R 5independently hydroxyl or hydrogen, R 1, R 2, R 3, R 4and R 5one of them is hydroxyl, and two or more are hydroxyl, but except Whitfield's ointment; Optimum when carbonatoms is 1-3.
Acetylsalicylic acid (Aspirin has another name called acetylsalicylic acid), with 2 of natural acquisition, 3-dyhydroxyl parabens compound has similar parent nucleus, be classical small molecules NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), there is stronger antipyretic, analgesia, anti-inflammatory, anti rheumatism action.Aspirin has unique effects to anticoagulant, can stop thrombosis, with it prevent and treat cerebral apoplexy, coronary heart disease etc., all can receive certain effect.In recent years, along with the research that deepens continuously to NSAIDs pharmacological action, its novel clinical use is also constantly excavated.Epidemiological study demonstration, the danger that the old man of frequent Aspirin suffers from AD and cognitive disorder obviously reduces, and prompting NSAIDs has the potential using value for the treatment of AD.Research thinks that this possible mechanism is: acetylsalicylic acid can be prevented and treated the inflammatory process of AD and can directly regulate the metabolism of A β.
Aspirin is the active testing of screening model PC 12 cell systems in vitro, find that it does not have obvious similar NGF activity, from Chinese medicine rough gentian, separation and purification obtains natural 2, although the parent nucleus of 3-dyhydroxyl parabens compound is similar to the structure of Aspirin, but can cause a high proportion of PC12 cell generation nervous process to extend phenomenon, show naturally 2,3-resorcylic acid ester has good similar NGF activity, has the value of exploitation anti-senile dementia prophylactic treatment medicine.As primer, design and synthesize a series of benzoate derivatives with 2,3-resorcylic acid ester cpds, extensively carry out its external activity research, find the structure activity relationship of such material.There is potential more excellent activity and/or more hypotoxic compound if can find, and can be used for the nerve degenerative diseases such as prevention and treatment senile dementia, will have important practical significance.
Summary of the invention
The object of this invention is to provide benzoate derivatives, comprise ester compound, (sulphur) ether compound and amides, there is following general structure:
In formula:
R is the straight or branched alkyl, particularly C of carbonatoms from 1 to 30 12～C 22;
R 1it is the one in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl, alkoxyl group or substituted-phenyl;
R 2it is the one in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or alkoxyl group;
R 3it is the one in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl, alkoxyl group or substituted-phenyl;
R 4it is the one in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or alkoxyl group;
R 5it is the one in hydrogen, hydroxyl, carboxyl, ester group, fluorine, chlorine, bromine, iodine, sulfydryl, amino, cyano group, nitro, sulfonic group, trifluoromethyl, propenyl, alkyl or alkoxyl group;
X is O, N or CH 2in one;
Y is O, S or CH 2in one;
Another object of the present invention is to provide the preparation method of benzoate derivatives, realizes by following steps:
(1) preparation method of ester compound (formula I, II, IV, V, X=O), first by acid and alcohol or the appropriate dissolution with solvents of phenol, coldly cause 0 DEG C, stir and drip dewatering agent down, then be raised to room temperature or reflux state reaction 1～2 day, follow the tracks of and react with thin-layer chromatography, after reaction finishes, steam solvent, then obtain ester compound through purification by silica gel column chromatography.Acid used is the straight or branched lipid acid of (replacement) phenylformic acid, (replacement) naphthoic acid or carbonatoms from 1 to 30; Alcohol used is the straight or branched fatty alcohol of carbonatoms from 1 to 30; Phenol used is (replacement) phenol or (replacement) naphthols; Dewatering agent is selected the one in the vitriol oil, DIC or dicyclohexylcarbodiimide; Solvent is selected protic solvent methyl alcohol, ethanol or tetrahydrofuran (THF), or selects non-protonic solvent methylene dichloride, chloroform, benzene,toluene,xylene, methyl-sulphoxide or acetonitrile; In reaction, acid is 1: 1 to 1: 20 with the mol ratio of alcohol, and acid is 1: 0.2 to 1: 3 with the mol ratio of dewatering agent.
(2) preparation method (formula III, Y=O, S) of (sulphur) ether compound, first by phenol and the appropriate dissolution with solvents of alkali, under agitation drip halides, room temperature to 80 DEG C reaction 1～2 day, follows the tracks of and reacts with thin-layer chromatography again, after reaction finishes, system is poured in a large amount of distilled water, filtered, then water, 10% sodium hydroxide repeatedly washs, and aftertreatment obtains (sulphur) ether compound.Phenol used is thiophenol, (replacement) phenol or (replacement) naphthols; Halides used is that the straight or branched alkyl chloride of carbonatoms from 1 to 30 is for thing, bromo-derivative or iodo thing; Solvent is selected protic solvent methyl alcohol, ethanol or tetrahydrofuran (THF), or selects non-protonic solvent methylene dichloride, chloroform, benzene,toluene,xylene, methyl-sulphoxide or acetonitrile; Alkali used is sodium hydroxide, potassium hydroxide, salt of wormwood or sodium hydride; In reaction, the mol ratio of phenol and halides is 1: 1 to 1: 10, and the mol ratio of phenol and alkali is 1: 1 to 1: 5.
(3) preparation method of amides (formula I, II, IV, V, X=N), under protection of inert gas, in appropriate dry methylene dichloride, stirs lower drip dry sulfur oxychloride or oxalyl chloride, room temperature reaction 1 day by acid-soluble.After reaction finishes, underpressure distillation eliminates excessive sulfur oxychloride or oxalyl chloride, repeatedly washs and obtains acyl chlorides with dry methylene dichloride.Again acyl chlorides is dissolved with appropriate dry methylene dichloride, stir the lower dichloromethane solution that drips amine and triethylamine, room temperature reaction 2～5 hours.After reaction finishes, with deionized water, 1 mole of every liter of sodium hydroxide solution, 1 mole of every liter of hydrochloric acid soln washing, anhydrous magnesium sulfate drying, concentrated, finally wash to obtain amides with normal hexane; Rare gas element used is nitrogen or argon gas; Acid used is the lipid acid of the straight or branched of (replacement) phenylformic acid, (replacement) naphthoic acid or carbonatoms from 1 to 30; Amine used is the aliphatic amide of the straight or branched of (replacement) aniline, (replacement) naphthylamines or carbonatoms from 1 to 30; Acid is 1: 2 to 1: 10 with the mol ratio of sulfur oxychloride or oxalyl chloride, and the mol ratio of acyl chlorides and amine is 1: 1 to 1: 5.
Another object of the present invention is to provide the application of benzoate derivatives formula (I～V) in preparation prevention and treatment senile dementia nerve degenerative diseases medicine.It is mainly the application in the nerve degenerative diseases medicines such as preparation treatment Alzheimer's disease (AD).
The present invention further also provides a kind of pharmaceutical composition that prevents the nerve degenerative diseases such as senile dementia, the benzoate compounds shown in (I～V) that this pharmaceutical composition contains physiology significant quantity and derivative thereof and pharmaceutically acceptable carrier or thinner.
Pharmaceutically acceptable carrier described here refers to the pharmaceutical carrier of pharmaceutical field routine, and in this way etc., weighting agent is as starch, sucrose, Microcrystalline Cellulose etc. for such as thinner, vehicle; Tackiness agent is as starch slurry, hydroxypropylcellulose, gelatin, polyoxyethylene glycol etc.; Wetting agent is as Magnesium Stearate, micropowder silica gel, polyethylene glycols etc.; Absorption enhancer gathers sorb fat, Yelkin TTS etc., and tensio-active agent poloxamer, smooth, the poly-sorb fat of lipid acid sorb etc. can also add other assistant agent as flavouring agent, sweeting agent etc. in addition in composition.
Benzoate compounds of the present invention and derivative thereof can be with unit dosage form administrations, and route of administration can be enteron aisle and non-enteron aisle, comprise oral, muscle, subcutaneous and nasal cavity.
Compound administration approach of the present invention can be intravenously administrable.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection and acupoint injection therapy.
The various formulations of pharmaceutical composition of the present invention can according to the conventional production method preparation of pharmaceutical field, for example, make activeconstituents mix with one or more carriers, are then made into required formulation.
Form of administration can be tablet, capsule, dispersible tablet, oral liquid, infusion solutions, little pin, freeze-dried powder, ointment, liniment or suppository.
Preparation method of the present invention is reasonable in design, easy and simple to handle, synthetic compound major part has new chemical structure, and confirm that by cell in vitro activity experiment the benzoate derivatives of synthesized has the activity of very significant similar nerve growth factor, particularly interior animal experiment confirms synthetic new compound 2, 3-resorcylic acid 14 fat have the effect that strengthens Aged Mice memory, therefore benzoate derivatives can be applied in preparation prevention and treatment senile dementia nerve degenerative diseases medicine, especially the application in the nerve degenerative diseases medicines such as preparation treatment Alzheimer's disease (AD).The present invention has opened up the new pharmaceutical use of benzoate derivatives.For the nerve degenerative diseases such as prevention and treatment senile dementia provide new medicine.
Brief description of the drawings
Fig. 1 adds the considerable change of Compound I-6 PC 12 cellular neural projections after 48 hours.
The variation that Fig. 2 adds the nervous process differentiation rate of Compound I-6 PC 12 cells after 48 hours to increase with dosage.
The variation that Fig. 3 adds the nervous process differentiation rate of Compound I-8, I-12, I-14, I-15, I-16 and I-18 PC 12 cells after 48 hours to increase with dosage.
The variation that Fig. 4 adds the nervous process differentiation rate of Compound I I-1, III-1, IV-2 and V-1 PC 12 cells after 48 hours to increase with dosage.
Fig. 5 injects the rear mouse in Compound I-6 and always enters arm number and the alternately variation of action rate.
Embodiment
Again foregoing of the present invention is described in further detail by embodiment and the accompanying drawing of being prepared by such some particular compound to example below, but this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example, all technology realizing based on foregoing of the present invention all belong to scope of the present invention.
Embodiment 1
Compound I-1:2,3-dihydric ethyl benzoate
By (154mg, 1mmol) 2,3-resorcylic acid, 10ml ethanol is placed in 25ml round-bottomed flask, is chilled to 0 DEG C, drips 2～3 vitriol oils, return stirring 24h.Follow the tracks of and react with thin-layer chromatography (developping agent: n-hexane/ethyl acetate, 5/1, V/V), after reaction stops, steam ethanol, obtain thick product 390mg, silica gel column chromatography (developping agent: n-hexane/ethyl acetate, 5/1, V/V), obtain white solid 180mg, yield: 99%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.12(dd，1H，J＝1.0，7.5Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.66(s，1H，benzene?3-OH)，4.41(q，2H，J＝7.0Hz)，1.42(t，3H，J＝7.0Hz)；MS(m/z)：182[M] +.
Compound I-2:2,3-resorcylic acid pentyl ester
Synthetic method is with compound I-1, reaction feed intake into: (154mg, 1mmol) 2,3-resorcylic acid, 10ml amylalcohol, obtain white solid 170mg, yield: 76%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.12(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.65(s，1H，benzene?3-OH)，4.41(t，2H，J＝7.0Hz)，1.78(m，2H)，1.33～1.38(m，4H)，0.90(t，3H，J＝7.0Hz)；MS(m/z)：224[M] +.
Compound I-3:2,3-resorcylic acid monooctyl ester
Synthetic method is with compound I-1, reaction feed intake into: (154mg, 1mmol) 2,3-resorcylic acid, 10ml octanol, obtain white solid 128mg, yield: 48%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.64(s，1H，benzene?3-OH)，4.35(t，2H，J＝7.0Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.38(m，8H)，0.89(t，3H，J＝7.0Hz)；MS(m/z)：266[M] +.
Compound I-4:2,3-resorcylic acid ester in the last of the ten Heavenly stems
By (154mg, 1mmol) 2,3-resorcylic acid, (316mg, 2mmol) nonylcarbinol, 10ml tetrahydrofuran (THF) is placed in 25ml round-bottomed flask, is chilled to 0 DEG C, add (145mg, 0.7mmol) dicyclohexylcarbodiimide, stirring at room temperature 24h.Follow the tracks of and react with thin-layer chromatography (developping agent: n-hexane/ethyl acetate, 2/1, V/V).After reaction stops, steaming solvent, resistates acetic acid ethyl dissolution, filter, filtrate, is filtered through anhydrous sodium sulfate drying with 5% citric acid solution, saturated sodium bicarbonate solution, washing, ester layer, concentrated by rotary evaporation obtains head product 440mg, silica gel column chromatography (developping agent: n-hexane/ethyl acetate, 2/1, V/V), obtain white solid 41mg, yield: 14%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.09(dd，1H，J＝1.5，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.65(s，1H，benzene3-OH)，4.35(t，2H，J＝7.0Hz)，1.78(m，2H)，1.44(m，2H)，1.27～1.35(m，12H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：294[M] +.
Compound I-5:2,3-resorcylic acid dodecane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,3-resorcylic acid, (372mg, 2mmol) dodecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 180mg, yield: 56%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.38(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.64(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，16H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：322[M] +.
Compound I-6:2,3-resorcylic acid tetradecane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,3-resorcylic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 150mg, yield: 43%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.5Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：350[M] +.
Compound I-7:2,3-resorcylic acid n-Hexadecane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,3-resorcylic acid, (484mg, 2mmol) cetyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 178mg, yield: 47%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.65(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.25～1.35(m，24H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：378[M] +.
Compound I-8:2,3-resorcylic acid octadecane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,3-resorcylic acid, (540mg, 2mmol) Stearyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 170mg, yield: 42%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.25～1.35(m，28H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：406[M] +.
Compound I-9:2,3-resorcylic acid eicosane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,3-resorcylic acid, (896mg, 3mmol) eicosanol, (206mg, 1mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 104mg, yield: 24%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝0.5，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.34(t，2H，J＝6.5Hz)，1.78(m，2H)，1.43(m，2H)，1.25～1.35(m，32H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：434[M] +.
Compound I-10:2,3-resorcylic acid docosane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,3-resorcylic acid, (653mg, 2mmol) V-1326, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 102mg, yield: 22%. 1H?NMR(500MHz，CDCl 3)δ：11.01(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.0Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.34(t，2H，J＝6.5Hz)，1.78(m，2H)，1.43(m，2H)，1.25～1.35(m，36H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：462[M] +.
Compound I-11:2,3-resorcylic acid triacontane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,3-resorcylic acid, (1.32g, 3mmol) triacontanol price quote, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 20ml tetrahydrofuran (THF), obtains white solid 75mg, yield: 13%. 1H?NMR(500MHz，CDCl 3)δ：11.00(s，1H，benzene?2-OH)，7.37(dd，1H，J＝1.5，8.5Hz，benzene?H-6)，7.10(dd，1H，J＝1.0，8.0Hz，benzene?H-4)，6.80(t，1H，J＝8.0Hz，benzene?H-5)，5.63(s，1H，benzene?3-OH)，4.34(t，2H，J＝6.5Hz)，1.77(m，2H)，1.45(m，2H)，1.25～1.35(m，52H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：575[M] +.
Compound I-12:2,6-resorcylic acid tetradecane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,6-resorcylic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 66mg, yield: 19%. 1H?NMR(500MHz，CDCl 3)δ：9.79(s，2H)，7.32(t，1H，J＝8.5Hz)，6.48(d，2H，J＝8.5Hz)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：350[M] +.
Compound I-13:2,6-resorcylic acid eicosane ester
Synthetic method is with compound I-4, reaction feeds intake as (154mg, 1mmol) 2,6-resorcylic acid, (597mg, 2mmol) eicosanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 104mg, yield: 24%. 1H?NMR(500MHz，CDCl 3)δ：9.79(s，2H)，7.31(t，1H，J＝8.5Hz)，6.48(d，2H，J＝8.5Hz)，4.50(t，2H，J＝6.5Hz)，1.83(m，2H)，1.43(m，2H)，1.25～1.35(m，32H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：434[M] +.
Compound I-14:2-hydroxy-benzoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feeds intake as (138mg, 1mmol) 2 hydroxybenzoic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtain white solid 164mg, yield: 49%. 1H?NMR(500MHz，CDCl 3)δ：10.88(s，1H)，7.37(m，1H)，7.10(m，1H)，6.91(m，1H)，6.80(t，1H，J＝8.0Hz)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：334[M] +.
Compound I-15:3-hydroxy-benzoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feeds intake as (138mg, 1mmol) 3-hydroxy-benzoic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtain white solid 174mg, yield: 52%. 1H?NMR(500MHz，CDCl 3)δ：9.76(s，1H)，7.57(m，1H)，7.37(m，1H)，7.25(m，1H)，7.01(m，1H)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：334[M] +.
Compound I-16:2,3-dimethoxybenzoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feeds intake as (182mg, 1mmol) 2,3-dimethoxybenzoic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 162mg, yield: 43%. 1H?NMR(500MHz，CDCl 3)δ：7.08(t，1H，J＝7.5Hz)，6.95(dd，1H，J＝1.5，8.0Hz)，6.79(dd，1H，J＝1.0，7.0Hz)，4.35(t，2H，J＝6.5Hz)，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，J＝7.0Hz)；MS(m/z)：378[M] +.
Compound I-17:2,3-dimethoxybenzoic acid octadecane ester
Synthetic method is with compound I-4, reaction feeds intake as (182mg, 1mmol) 2,3-dimethoxybenzoic acid, (540mg, 2mmol) Stearyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 170mg, yield: 39%. 1H?NMR(500MHz，CDCl 3)δ：7.06(t，1H，J＝8.0Hz)，6.93(dd，1H，J＝1.5，8.0Hz)，6.77(dd，1H，J＝1.5，8.0Hz)，4.35(t，2H，J＝6.5Hz)，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，J＝7.0Hz)；MS(m/z)：434[M] +.
Compound I-18:2,3-dimethoxy-N-tetradecyl benzamide
By (1.1g, 6mmol) 2,3-dimethoxybenzoic acid, (7ml, 0.09mol) sulfur oxychloride is placed in 25ml round-bottomed flask, stirring at room temperature 24h under nitrogen protection.After reaction stops, underpressure distillation eliminates excessive sulfur oxychloride, repeatedly washs with dry methylene dichloride, obtains acyl chlorides.Under nitrogen protection, (0.5g, 2.5mmol) acyl chlorides is dissolved with a small amount of dry methylene dichloride; again (640mg; 3mmol) tetradecylamine, (0.9ml, 9mmol) triethylamine is dissolved in respectively the methylene dichloride that 10ml is dry and splashes into successively.Stirring at room temperature 2h, after reaction stops, using deionized water, 1 mole of every liter of sodium hydroxide solution, deionized water, 1 mole of every liter of hydrochloric acid soln, deionization to wash.Anhydrous magnesium sulfate drying, concentrated, normal hexane washing obtains white solid 219mg, yield: 58%. 1H?NMR(500MHz，CDCl 3)δ：7.94(bt，1H)，7.57(dd，1H，J＝1.5，8.0Hz)，7.09(dd，1H，J＝1.5，8.0Hz)，6.85(t，1H，J＝8.0Hz)，3.82(bs，6H)，3.37(q，2H，J＝5.8Hz)，1.58(m，2H)，1.17～1.35(m，22H)，0.86(t，3H，J＝7.0Hz)；MS(m/z)：377[M] +.
Compound I-19:2,3-dihydroxyl-N-tetradecyl benzamide
Under nitrogen protection, Compound I-19 (188mg, 0.5mmol) is dissolved in to the methylene dichloride that 30ml is dry, drip (2ml) boron tribromide, absorb the hydrogen bromide generating, stirring at room temperature three days with the sodium hydroxide solution of 1 mole every liter.After reaction finishes, slowly drip frozen water cancellation, steam solvent, more repeatedly wash with methyl alcohol, obtain gray solid 140mg, yield: 40%. 1H?NMR(500MHz，DMSO-d 6)δ：12.71(s，1H)，8.58(s，1H)，8.05(bt，1H)，7.35(dd，1H，J＝1.5，8.5Hz)，6.98(dd，1H，J＝1.0，8.0Hz)，6.75(t，1H，J＝8.0Hz)，3.25～3.38(m，2H)，1.71(m，2H)，1.18～1.35(m，22H)，0.86(t，3H，J＝7.0Hz)；MS(m/z)：349[M] +.
Compound I-20:2-chloro-benzoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feeds intake as (156mg, 1mmol) 2-chloro-benzoic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtain white solid 150mg, yield: 43%. 1H?NMR(500MHz，CDCl 3)δ：7.65(m，1H)，7.30(m，2H)，7.08(m，1H)，4.35(t，2H，J＝6.5Hz)，1.78(m，2H)，1.44(m，2H)，1.26～1.35(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：352[M] +.
Embodiment 2
Compound I I-1:1,2-phenylene 20 acid esters
Synthetic method is with compound I-4, and reaction feeds intake as (110mg, 1mmol) o-phenol, (310mg, 1mmol) arachic acid, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 391mg, yield: 56%. 1H?NMR(500MHz，CDCl 3)δ：7.13～7.16(t，1H，J＝7.5Hz)，7.09～7.11(d，1H，J＝7.5Hz)，7.02～7.04(d，1H，J＝7.5Hz)，6.92～6.95(t，1H，J＝7.5Hz)，2.63(t，2H，J＝6.5Hz)，2.42(t，2H，J＝6.5Hz)，1.96～1.99(m，12H)，1.17～1.42(m，60H)，0.89(bs，6H)；MS(m/z)：699[M] +.
Embodiment 3
Compound III-1:1, two (tetradecyloxyaniline) benzene of 4-
Under nitrogen protection, (110mg, 1mmol) Resorcinol, (280mg, 5mmol) potassium hydroxide, 10ml DMF are placed in to 25ml round-bottomed flask, drip (830mg, 3mmol) bromotetradecane.Stirred overnight at room temperature, after reaction stops, pouring system in a large amount of distilled water into, and yellow solid is separated out on upper strata, filter, and water, 10% sodium hydroxide washs to obtain product 111mg, yield: 22%. 1H?NMR(500MHz，CDCl 3)δ：6.76(bs，4H)，3.75～3.80(t，4H，J＝6.5Hz)，1.82(m，4H)，1.25～1.33(m，44H)，0.85(t，6H，J＝7.0Hz)；MS(m/z)：502[M] +.
Embodiment 4
Compound IV-1:1-hydroxy-2-naphthoic acid tetradecane ester
Synthetic method is with compound I-4, reaction feeds intake as (188mg, 1mmol) 1-hydroxy-2-naphthoic acid, (428mg, 2mmol) tetradecanol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtain white solid 184mg, yield: 48%. 1H?NMR(500MHz，CDCl 3)δ：12.09(s，1H)，8.41(d，1H，J＝8.5Hz)，7.76～7.79(m，2H)，7.59～7.62(m，1H)，7.51～7.54(m，1H)，7.28(d，1H，J＝9.0Hz)，4.39(t，2H，J＝6.5Hz)，1.82(m，2H)，1.47(m，2H)，1.25～1.38(m，20H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：384[M] +.
Compound IV-2:1-hydroxy-2-naphthoic acid octadecane ester
Synthetic method is with compound I-4, reaction feeds intake as (188mg, 1mmol) 1-hydroxy-2-naphthoic acid, (270mg, 1mmol) Stearyl alcohol, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtain white solid 198mg, yield: 45%. 1H?NMR(500MHz，CDCl 3)δ：12.09(s，1H)，8.41(d，1H，J＝8.5Hz)，7.75～7.79(m，2H)，7.59～7.63(m，1H)，7.51～7.54(m，1H)，7.28(d，1H，J＝9.0Hz)，4.39(t，2H，J＝6.5Hz)，1.82(m，2H)，1.47(m，2H)，1.25～1.38(m，28H)，0.88(t，3H，J＝7.0Hz)；MS(m/z)：440[M] +.
Embodiment 5
Compound V-1:1-naphthyl myristinate
Synthetic method is with compound I-4, and reaction feeds intake as (144mg, 1mmol) naphthols, (228mg, 1mmol) tetradecanoic acid, (250mg, 1.2mmol) dicyclohexylcarbodiimide, 15ml tetrahydrofuran (THF), obtains white solid 258mg, yield: 70%. 1H?NMR(500MHz，CDCl 3)δ：8.39(d，1H，J＝8.5Hz)，7.77～7.82(m，2H)，7.59～7.62(m，2H)，7.49～7.51(m，1H)，7.28(m，1H)，2.32(t，2H，J＝6.5Hz)，1.76～1.88(m，6H)，1.14～1.32(m，18H)，0.88(s，3H)；MS(m/z)：368[M] +.
Embodiment 6
Biological Activity Identification: in neurodegeneration animal model, research finds that NGF can stop or reduce neuronic regression, to a certain degree can stop AD progress, has the nerve growth of promotion and neuroprotective.Because PC12 cell has the general feature of neurocyte, under the effect of NGF, PC12 cell can stop division, grows projection, changes into neuron cell.Therefore, can cause PC12 cell transformation to become the compound of neuron cell to there is the using value of the nerve degenerative diseases such as prevention and treatment senile dementia.
Experimental technique:
1) cultivation of PC 12 cells: connect 20 × 10 4 individual PC 12 cells, in the culture dish of 100mm, containing 10ml DMEM substratum (wherein containing 10% horse serum, 5% foetal calf serum), are changed a subculture, after three days subcultures two days later.First with PBS, cell is washed to twice, then add 10ml PBS in culture dish, at 37 DEG C, 5%CO 2incubator in cultivate 10 minutes, purge, transfers to the disposable centrifuge tube of 15ml, on centrifugal rear blood counting chamber, counts.The 24 every holes of porocyte culture plate first add 1ml to contain the DMEM substratum of serum, and after cell counting, every hole connects 2 × 10 4individual cell, CO 2incubator is cultivated application of sample after 24 hours.
2) active testing: with the negative contrast of DMSO, the positive contrast of NGF 40ng, is configured to Compound I-6 the DMSO solution of different concns.After former every hole of 24 porocyte plates substratum being replaced containing the DMEM solution (not containing serum) of 1%DMSO and sample with 1ml, put into 37 DEG C, 5%CO 2incubator in cultivate.Under inverted microscope every 24 hours, continuous 6 days observation of cell metamorphosis, record cytodifferentiation rate NA (nervous process is longer than the ratio of total cell number under the cell number of one times of cell space diameter and the visual field), approximately 100 cells under each visual field, choose at random 3 places, and statistics mapping.
Fig. 1: add the considerable change of Compound I-6 nervous process of PC 12 cells after 48 hours, the negative contrast of A:1%DMSO; B:NGF 40ng/ml, positive contrast; C: Compound I-6, concentration, 1 μ M; )
Fig. 2: the variation that adds the nervous process differentiation rate of Compound I-6 PC 12 cells after 48 hours to increase with dosage, C: negative control 1%DMSO, the concentration unit of I-6: μ M;
Fig. 3: the variation that adds the nervous process differentiation rate of Compound I-8, I-12, I-14, I-15, I-16 and I-18 PC12 cell after 48 hours to increase with dosage, C: negative control 1%DMSO, the concentration unit of compound: μ M;
Fig. 4: the variation that adds the nervous process differentiation rate of Compound I I-1, III-1, IV-2 and V-1 PC 12 cells after 48 hours to increase with dosage, C: negative control 1%DMSO, the concentration unit of compound: μ M).
3) experimental result: found that, under the concentration of 0.03-10 μ M, 48 compounds of as a child testing afterwards all demonstrate NGF-mimics activity.Compound I-6 are under the condition of optimal concentration 1 μ M, and the nervous process that this compound induction PC 12 cells produce can exceed the projection of NGF induction.
Embodiment 7
Experimentation on animals: Compound I-6 (2,3-resorcylic acid tetradecane ester) improves the investigation of effect to aged mouse short-term memory
1) acute poisoning test: by 4 week age 20 of ICR male mices be divided at random control group, 100mg/kg treatment group.By Compound I-6 that are dissolved in 1%Tween-80 according to dosage disposable celiac be injected in animal body, Continuous Observation one week, the mental status of observing animal every day, measures body weight and food ration.Compound drops into mouse limbs after 10 minutes and occurs crispaturaing, and amount of exercise reduces.After 1 hour, full recovery is normal.In one week, mouse is without death condition, and food ration is without considerable change, but body weight change obviously reduces.The heart, liver, spleen, kidney and white adipose tissue weight and observe there was no significant difference.
2) test of pesticide effectiveness: 18 of the ICR male mices at 12 monthly ages are divided into control group at random, 1mg/kg treatment group and 10mg/kg treatment group.Do control group with the young ICR mouse in 4 week age simultaneously, inject corresponding dosage every day and be dissolved in Compound I-6 of Tween-80.Offer medicine 11 days, measure the variation of food ration and body weight every day, within 12 days, utilize the improvement situation of Y labyrinth test compounds to short-term memory effect.Test-results shows the Mouse Weight variation of 1mg/kg treatment group and food ration and the comparison of aged mouse control group, all no significant difference.Always enter arm number and alternately action rate increase (Fig. 5, the rear mouse in injection Compound I-6 always enters arm number and the alternately variation of action rate, P < 0.05).10mg/kg treatment group food ration, always enters arm number and alternately action rate is without considerable change, and body weight obviously reduces.This result shows that this compound is improved effect to the short-term memory of aged mouse.There is certain side effect in 10mg/kg dosage.

Claims (5)

1. a benzoate derivatives, has following general structure:
Figure 114117DEST_PATH_IMAGE001
In formula:
R is that carbonatoms is 14 straight or branched alkyl;
R 1, R 2for hydroxyl, R 3, R 4, R 5for hydrogen;
X is O.
2. a benzoate derivatives, has following general structure:
Figure 624733DEST_PATH_IMAGE002
In formula:
R is that carbonatoms is 18 straight or branched alkyl;
R 1, R 2for hydroxyl, R 3, R 4, R 5for hydrogen;
X is O.
3. the application of the benzoate derivatives of any one in the nerve degenerative diseases medicine of preparation prevention and treatment senile dementia in claim 1-2.
4. the application of the benzoate derivatives of any one in the nerve degenerative diseases medicine of preparation treatment Alzheimer's disease in claim 1-2.
5. the preparation method of the benzoate derivatives of any one in claim 1-2, is characterized in that, realizes by following steps:
First, by acid and alcohol dissolution with solvents, be chilled to 0 DEG C, stir and lower drip dewatering agent, then be raised to room temperature or reflux state reaction 1 ~ 2 day, follow the tracks of reaction with thin-layer chromatography, after reaction finishes, steam solvent, then obtain benzoate compounds through purification by silica gel column chromatography; Acid used is 2,3-resorcylic acid; It is 14 and 18 straight or branched fatty alcohol that alcohol used is selected from carbonatoms; Dewatering agent is selected the one in the vitriol oil, DIC or dicyclohexylcarbodiimide; Solvent is selected protic solvent tetrahydrofuran (THF), in reaction acid and the mol ratio of alcohol be 1:1 to 1:20, acid is that 1:0.2 is to 1:3 with the mol ratio of dewatering agent.
6. the application of benzoate derivatives in the nerve degenerative diseases medicine of preparation prevention and treatment senile dementia, is characterized in that, described benzoate derivatives has following general structure:
Figure 873311DEST_PATH_IMAGE003
In formula:
R is the straight or branched alkyl of carbonatoms from 12 to 22;
R 1, R 2, R 3, R 4, R 5be selected from respectively hydrogen, hydroxyl, and R 1, R 2, R 3, R 4, R 5in have two hydroxyls in consecutive position at least;
X is O.
7. the application of benzoate derivatives in the nerve degenerative diseases medicine of preparation prevention and treatment senile dementia, is characterized in that, described benzoate derivatives has following general structure:
Figure 612728DEST_PATH_IMAGE004
In formula:
R is the straight or branched alkyl of carbonatoms from 12 to 22;
R 1, R 2, R 3, R 4, R 5be selected from respectively hydrogen, hydroxyl, and R 1, R 2, R 3, R 4, R 5in have and only have two hydroxyls in consecutive position;
X is O.
8. the application of any one in claim 6-7, the nerve degenerative diseases that it is characterized in that senile dementia is Alzheimer's disease.
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