CN106608824B - Aromatic acid ester compound and preparation method and application thereof - Google Patents
Aromatic acid ester compound and preparation method and application thereof Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/84—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring of monocyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of a six-membered aromatic ring
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
Abstract
The invention belongs to the technical field of drug synthesis, and relates to an aromatic acid ester compound with a general formula I, a preparation method and application thereof in pharmacy.
Description
Technical Field
The invention belongs to the technical field of drug synthesis, and relates to an aromatic acid ester compound, a preparation method and application thereof in pharmacy, in particular to application of the aromatic acid ester compound serving as a drug for treating NGF-related diseases, especially neurodegenerative diseases such as Alzheimer Disease (AD).
Background
The prior art discloses that Alzheimer's Disease (AD) is a neurodegenerative disease characterized mainly by progressive decline in memory and cognitive function, the main clinical symptoms of which are memory impairment, cognitive impairment and mental abnormalities. In clinical practice, patients usually have progressive disease, gradually lose independent living ability and die due to concurrent infection. Studies have shown that the condition is typically characterized neuropathologically by deposition of β -amyloidogenic protein (Α β) plaques, neuronal loss and neurofibrillary tangles. Studies have shown that AD is an age-related disease, and how much of the population composition of elderly people affects the prevalence, with dementia prevalence above 65 years of age being 2% -7% more. According to the related statistical data, the incidence rate of the Chinese Alzheimer disease is 4.8% above 65 years old, and the incidence rate is increased along with the increase of the age. According to the current population development trend prediction, the proportion of population over 65 years old in China to the total population is up to 30% by 2050, and if corresponding measures are not taken for prevention and control, the number of AD patients is increased sharply. The survival time of the patient after the disease is developed is longer, no effective treatment medicine exists at present, and the main intervention measure of clinical practice for women is to reduce various symptoms in the disease process as much as possible, delay the further development of AD and have larger side effect; the drugs for intervening and treating AD at the present stage mainly comprise acetylcholinesterase inhibitors, such as tacrine, rivastigmine tartrate, huperzine A, donepezil and the like; brain metabolism regulators, such as vincamine, nimodipine, and cinnarizine; drugs that affect free radical metabolism, such as vitamin C in combination with vitamin E; therefore, it has the consequence of causing a great mental and economic stress on the patients and relatives, as well as being linked to a varying degree to the stability of the whole society. Therefore, research and development of effective drugs for preventing and treating AD have become medical problems which need to be solved urgently in the field worldwide, and will generate significant medical scientific research value and economic and social benefits.
Research shows that Nerve Growth Factor (NGF) is a bioactive polypeptide consisting of 118 amino acids, has important regulation effects on the growth, development, differentiation, function maintenance and other aspects of neurons, has important influence on the disease process of nerve development and adult nervous system, and clinical experimental results of phase I and phase II of AD gene treatment show that the treatment method has better effect than common anti-AD drugs; however, the drawbacks of plasma instability, low bioavailability and inability to cross the blood brain barrier remain, limiting the direct administration of NGF. Therefore, the search for small molecule compounds with NGF activity (NGFmimics) and capable of passing the blood brain barrier has been one of the hot spots in anti-AD studies.
Based on the current state of the art, the inventors of the present application propose to provide novel arylate ester compounds and their use as drugs for the treatment of NGF-related diseases, in particular neurodegenerative diseases such as Alzheimer's Disease (AD).
As the prior art related to the present invention,
1，Huang,E.J.；Reichardt,L.F.,NEUROTROPHINS:Roles in Neuronal Development and Function1.Annual Review of Neuroscience 2001,24(1),677-736；
2，Chao,M.V.,Neurotrophins and their receptors:A convergence point for many signalling pathways.Nat Rev Neurosci 2003,4(4),299-309；
3，Tuszynski,M.H.；Thal,L.；Pay,M.；Salmon,D.P.；Bakay,R.；Patel,P.；Blesch,A.；Vahlsing,H.L.；Ho,G.；Tong,G.,A phase 1clinical trial of nerve growth factorgene therapy for Alzheimer disease.Nature medicine 2005,11(5),551-555.；
4，Longo,F.M.；Yang,T.；Knowles,J.K.；Xie,Y.；Moore,L.A.；Massa,S.M.,Small molecule neurotrophin receptor ligands:novel strategies for targetingAlzheimer's disease mechanisms.Current Alzheimer Research 2007,4(5),503-506；
5，Wilson,R.M.；Danishefsky,S.J.,Applications of total synthesis to problems in neurodegeneration:Fascinating chemistry along the way.Accounts of chemical research 2006,39(8),539-549.；
6，Qi,J.；Luo,Y.；Gao,L.,Structural diversity of neuritogenic substances and their application perspective.Mini reviews in medicinal chemistry 2011,11(8),658-677；
7，Xu,J.；Lacoske,M.H.；Theodorakis,E.A.,Neurotrophic natural products:chemistry and biology.Angewandte Chemie International Edition 2014,53(4),956-987；
8，More,S.V.；Koppula,S.；Kim,I.-S.；Kumar,H.；Kim,B.-W.；Choi,D.-K.,The role of bioactive compounds on the promotion of neurite outgrowth.Molecules2012,17(6),6728-6753.。
disclosure of Invention
One of the purposes of the invention is to provide an aromatic ester compound with a structure shown in a general formula I, wherein the compound has obvious nerve growth factor NGF-like activity, so that the compound plays a role in preventing and treating neurodegenerative diseases such as Alzheimer Disease (AD) and the like.
The second object of the present invention is to provide a process for preparing the compound represented by the general formula I.
The invention also aims to provide a pharmaceutical composition containing the compound shown in the general formula I.
The invention also aims to provide application of the compound shown in the general formula I in preparing a medicament for preventing and treating Alzheimer disease.
Specifically, the invention provides a compound shown as the following general formula I:
in the formula, ring A represents a five-membered or six-membered aromatic ring containing a substituent or not, and an aromatic heterocycle containing a nitrogen atom, an oxygen atom and a sulfur atom containing a substituent or not;
b represents a five-membered or six-membered aromatic ring, and an aromatic heterocycle containing nitrogen, oxygen and sulfur atoms, or an alkylene;
m represents an integer of 0 to 5, and n represents an integer of 0 to 15.
The invention provides a compound as shown in a general formula I, wherein the compound is shown in the specificationSelected from the group consisting of:
the invention provides a compound as shown in a general formula I, wherein the compound isSelected from the group consisting of:
the invention provides a compound as shown in a general formula I, wherein the compound isSelected from the group consisting of:
the preparation method of the compound of the general formula I is realized by the following steps:
dissolving acid and alcohol or phenol with a solvent, dropwise adding a condensing agent under ice bath, heating to room temperature or heating for reaction for 1 day, tracking the reaction by using a thin-layer chromatography, evaporating the solvent after the reaction is finished, and purifying by using a silica gel column chromatography to obtain an ester compound;
in the preparation method, the acid is 2, 3-dihydroxy benzoic acid or five-membered or six-membered aromatic acid containing heteroatom;
the alcohol is para-alkyl substituted aromatic alcohol or C1-20 linear fatty alcohol;
the phenol used is para-alkyl substituted phenol;
the condensing agent is N, N' -dicyclohexylcarbodiimide; the solvent is acetonitrile or tetrahydrofuran.
The invention provides a pharmaceutical composition containing a compound shown in a general formula I;
the pharmaceutical composition comprises a therapeutically effective amount of the compound of the general formula I and one or more pharmaceutically acceptable carriers, including excipients or diluents;
in the pharmaceutical composition, the compound accounts for 20-99% of the total weight of the pharmaceutical composition;
the pharmaceutical composition may further comprise an odorant, a flavorant.
In the present invention, preferred compounds have the following structure:
the compound prepared by the invention is subjected to in vitro cell activity tests, and the results prove that the compound has remarkable nerve growth factor NGF-like activity, and the preferable compounds I-1, I-2 and I-4 in the invention have very remarkable nerve growth factor NGF-like activity. Furthermore, the aromatic acid ester compound can be used for preparing medicines for preventing and treating neurodegenerative diseases such as Alzheimer disease and the like.
The invention has the advantages that:
the preparation method is reasonable in design and easy to synthesize, most of synthesized compounds have new chemical structures, the synthesized compounds are proved to have obvious nerve growth factor NGF-like activity through in vitro cell activity tests, and the compounds are preferably compounds I-1, I-2 and I-4;
the invention provides a new therapeutic drug for preventing and treating neurodegenerative diseases such as Alzheimer disease and the like; the aromatic acid ester compound can be used for preparing medicines for preventing and treating neurodegenerative diseases such as Alzheimer disease and the like.
Drawings
FIG. 1 shows the significant changes in neurites from PC-12 cells after 48h of addition of compounds I-1, I-2 and I-4, where A is blank, B is 40ng/mL NGF, C is 1. mu. M I-1 and D is 1. mu. M I-4.
FIG. 2 shows neurite differentiation rates of PC-12 cells after 48 hours of addition of Compounds I-1, I-2, I-3, and I-4, wherein the concentration of NGF was 40 ng/mL; concentration of I-1, I-2, I-3, I-4: 1 μ M.
The above-mentioned contents of the present invention are further described in detail by the following embodiments of several examples of the preparation of such compounds and the accompanying drawings, but it should not be understood that the scope of the above-mentioned subject matter of the present invention is limited to the following examples, and all the technologies realized based on the above-mentioned contents of the present invention belong to the scope of the present invention.
Detailed Description
Example 1: synthesis of Compound I-1, 2, 3-Dihydroxybenzoic acid p-sunflower phenol ester
N2Under the protection of gas, 2, 3-dihydroxy benzoic acid (77mg,0.5mmol) is dissolved in 10ml of dry acetonitrile, N' -dicyclohexylcarbodiimide (155mg,0.75mmol) is added, stirring is carried out at 50 ℃ for 1h, then 4-decyl phenol (117mg,0.5mmol) and DMAP (6mg,0.05mmol) are added, stirring is carried out overnight at 65 ℃, the solvent is evaporated under reduced pressure, 50ml of ethyl acetate is added into the residue, filtering is carried out, the filtrate is washed by 1mol/L hydrochloric acid, saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution for three times respectively, drying is carried out by anhydrous sodium sulfate, concentration is carried out under reduced pressure, the residue is chromatographed by silica gel column to obtain 100mg of white solid, and the yield is 54%;1H NMR(DMSO-d6,400MHz):δ10.68(s,1H),7.61(d,1H,J＝8.0Hz),7.25(d,2H,J＝8.0Hz),7.19(d,1H,J＝8.0Hz),7.10(d,2H,J＝8.0Hz),6.94-6.85(m,1H),5.70(s,1H),2.63(t,2H,J＝7.2Hz),1.67-1.58(m,2H),1.39-1.27(m,14H),0.88(t,3H,J＝6.4Hz).ESI-MS(m/z):[M+Na]+＝393.0(Calcd:370.2)。
example 2: synthesis of Compound I-2, 2, 3-Dihydroxybenzoic acid p-nonyl benzyl ester
The synthesis method is similar to the preparation method of the compound I-1, and 94mg of white solid is obtained with the yield of 51 percent;1H NMR(DMSO-d6,400MHz):δ10.92(s,1H),7.41(dd,1H,J＝8.4Hz,1.6Hz),7.35(d,2H,J＝7.6Hz),7.21(d,2H,J＝8.0Hz),7.10(dd,1H,J＝8.4Hz,1.6Hz),6.78(t,1H,J＝8.0Hz),5.67(s,1H),5.35(s,2H),2.62(2H,t,J＝8.0Hz),1.61(m,2H),1.30-1.26(m,12H),0.88(t,3H,J＝6.4Hz).ESI-MS(m/z):[M+Na]+＝393.0(Calcd:370.2).。
example 3: synthesis of Compound I-p-decyl-benzyl 3, 2, 3-dihydroxybenzoate
The synthesis method is similar to the preparation method of the compound I-1, and white solid 81mg is obtained with the yield of 42 percent;1H NMR(DMSO-d6,400MHz):δ10.92(s,1H),7.40-7.34(m,3H),7.22-7.11(m,3H),6.82-6.73(m,1H),5.68(s,1H),5.35(s,2H),2.67-2.55(m,2H),1.70-1.53(m,2H),1.39-1.14(m,14H),0.88(t,3H,J＝6.4Hz).ESI-MS(m/z):[M+Na]+＝407.0(Calcd:384.2).。
example 4: synthesis of Compound I-4, 2, 3-dihydroxyquinoline-4-carboxylic acid tetradecyl ester
Step 1 synthesis of (E) -2- (2-benzenesulfonylhydrazide) acetic acid, reaction formula is as follows:
adding 50% glyoxylic acid hydrate (7.4g and 50mmol) into 50ml of water, heating to 60 ℃, adding 25ml of hydrochloric acid solution (2.5mol/L) of p-toluenesulfonyl hydrazide (9.3g and 50mmol) into the mixture, reacting at 60 ℃ for 2 hours, cooling to room temperature, placing the mixture in a refrigerator overnight, separating out a large amount of solid, filtering, washing a filter cake with ice water to obtain a crude product, drying, and recrystallizing the crude product with ethyl acetate/carbon tetrachloride (1:2) to obtain 9.1g of white crystals with the yield of 75%;
step 2 synthesis of (E) -2- (2-benzenesulfonylhydrazide) acetic acid chloride, reaction formula is as follows:
N2(E) -2- (2-benzenesulfonylhydrazide) acetic acid (2.30g,9.4mmol) was added to 20mL of dry toluene under a gas blanket, sulfoxide chloride (1.37mL,18.8mmol) was added thereto, the mixture was refluxed for 2 hours, cooled to room temperature, and then the solvent was distilled off to give 2.0g of a crude productProduct, used in the next step directly;
step 3, synthesizing the tetradecyl diazoacetate, wherein the reaction formula is as follows:
N2under the protection of gas, (E) -2- (2-benzenesulfonylhydrazide) acetic acid chloride (2.00g,7.6mmol) was added to 50mL of dry dichloromethane, tetradecanol (1.64g, 7.6mmol) was added under ice bath conditions, a solution of triethylamine (2.14mL,15.2mmol) in dichloromethane was slowly dropped thereinto, the mixture was stirred at 0 ℃ for 1 hour, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography to give 0.96g of a yellow liquid with a yield of 45%;1H NMR(400MHz,CDCl3):δ＝4.71(s,1H),4.12(t,J＝6.4Hz,2H),1.64-1.58(m,2H),1.29-1.24(m,22H),0.86(t,J＝7.2Hz,3H).；
step 4.2, 3-dihydroxy quinoline-4-formic tetradecyl ester synthesis, the reaction formula is as follows:
N2under the protection of gas, adding isatin (100mg,0.73mmol), diethylamine (0.15mL,1.4mmol) and tetradecyl diazoacetate (0.40g,1.40mmol) into 15mL ethanol, stirring at room temperature for 64h, evaporating the solvent, adding 1mol/L hydrochloric acid (75mL) into the residue, stirring at room temperature for 40h, filtering to obtain a yellow solid, and performing silica gel column chromatography on the crude product to obtain 117mg of white solid with the yield of 40%;1HNMR(400MHz,CDCl3)δ＝11.48(s,1H),10.19(s,1H),8.11(d,J＝8.0Hz,1H),7.44-7.37(m,2H),7.30-7.28(m,1H),4.51(t,J＝6.8Hz,2H),1.90-1.83(m,2H),1.52-1.45(m,2H),1.39-1.25(m,20H),0.87(t,J＝7.2Hz,3H).ESI-MS(m/z):[M+H]+＝402.0(Calcd:401.2).。
example 5: in vitro bioactivity assay
This example follows the experimental principle: in a neurodegenerative disease change model, NGF can prevent or reduce the death of neurons, can prevent the occurrence and development of AD to a certain extent, and has the effects of promoting nerve growth and neuroprotection; by adopting a cell model PC12 cell model which is most widely applied at present and used for evaluating the NGF effect of compounds, PC12 cells can stop dividing, grow out processes and convert into neuron-like cells under the NGF effect; therefore, the compound capable of converting PC12 cells into neuron-like cells has application value in preventing and treating neurodegenerative diseases such as Alzheimer disease and the like;
the experimental method comprises the following steps:
20X 10 to4Culturing PC12 cells in culture bottle containing 10mL DMEM medium (containing 10% horse serum and 5% fetal calf serum), changing the medium once after two days, subculturing for three days, in vitro activity test, sucking out the medium, washing with PBS, digesting with pancreatin-EDTA, centrifuging, counting cells, adding 1mL DMEM medium containing serum into each well of 24-well cell culture plate, inoculating 2 × 10 cells into each well4Cells, incubated at 37 ℃ in 5% CO2Adding samples after the incubator is used for culturing for 24 hours,
serum-free DMEM medium containing 5 thousandth of DMSO is used as negative control, 40ng/mL of NGF is used as positive control, the compound is prepared into different concentrations by using the DMEM medium to carry out NGF-like activity test, 1mL of the solution is used for replacing the original culture medium of a 24-well cell plate, and the 24-well cell plate is placed at 37 ℃ and 5% CO2Culturing in an incubator, observing cell morphological change every 24h and continuously for 6 days under a phase contrast microscope, recording cell differentiation rate (the ratio of the number of cells with neurite being one time longer than the cell body diameter to the total number of cells under visual field), randomly selecting three positions in each hole, selecting 100 cells at least in each visual field, and performing statistical mapping;
the experimental results show that: at a concentration of 1-30 μ M, the compounds tested all showed NGF mimics activity after 48 h; compound I-1, I-4 induced the neurite differentiation rate of PC12 cells over the induction of 40ng/mL NGF at a concentration of 1. mu.M (as shown in FIG. 1, FIG. 2).
Claims (7)
1. An aromatic acid ester compound having one of the following structures:
wherein n represents an integer of 8 to 9.
2. The aromatic acid ester compound according to claim 1, wherein the compound is selected from the group consisting of:
3. use of a compound according to any one of claims 1-2 in the manufacture of a medicament for the treatment of alzheimer's disease.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 2, together with one or more pharmaceutically acceptable carriers.
5. The pharmaceutical composition of claim 4, wherein the compound is present in an amount of 20% to 99% by weight of the total pharmaceutical composition.
6. Pharmaceutical composition according to claim 4 or 5, characterized in that it further comprises one or more pharmaceutically acceptable carriers selected from odorants, excipients or diluents.
7. Use of the pharmaceutical composition according to any one of claims 4 to 6 for preparing a medicament for preventing and treating Alzheimer's disease.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010058314A1 (en) * | 2008-11-18 | 2010-05-27 | Pfizer Inc. | Hydroxyquinolin-2(1h)-ones and derivatives thereof |
| CN101774922A (en) * | 2010-01-29 | 2010-07-14 | 浙江大学 | 2,3-dyhydroxyl parabens compound as well as preparation and application thereof |
| CN101817761A (en) * | 2010-01-29 | 2010-09-01 | 浙江大学 | Benzoate derivatives, preparation method and application |
| CN102552233A (en) * | 2011-12-26 | 2012-07-11 | 暨南大学 | Application of methyl 3, 4-dihydroxybenzoate in preparation of medicaments for preventing and treating nerve degenerative diseases |
| CN103340880A (en) * | 2013-05-13 | 2013-10-09 | 杭州耐奇睿生物医药科技有限公司 | Application of 2,3-dihydroxy benzoic acid ester compound in preparation of foods and medicines for treating diabetes |
-
2015
- 2015-10-21 CN CN201510689879.XA patent/CN106608824B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010058314A1 (en) * | 2008-11-18 | 2010-05-27 | Pfizer Inc. | Hydroxyquinolin-2(1h)-ones and derivatives thereof |
| CN101774922A (en) * | 2010-01-29 | 2010-07-14 | 浙江大学 | 2,3-dyhydroxyl parabens compound as well as preparation and application thereof |
| CN101817761A (en) * | 2010-01-29 | 2010-09-01 | 浙江大学 | Benzoate derivatives, preparation method and application |
| CN102552233A (en) * | 2011-12-26 | 2012-07-11 | 暨南大学 | Application of methyl 3, 4-dihydroxybenzoate in preparation of medicaments for preventing and treating nerve degenerative diseases |
| CN103340880A (en) * | 2013-05-13 | 2013-10-09 | 杭州耐奇睿生物医药科技有限公司 | Application of 2,3-dihydroxy benzoic acid ester compound in preparation of foods and medicines for treating diabetes |
Non-Patent Citations (3)
| Title |
|---|
| 3-HYDROXY-QUINOLIN-2-ONES: INHIBITORS OF [3H]-GLYCINE BINDING TO THE SITEASSOCIATED WITH THE NMDA RECEPTOR;Sing-Yuen Sit 等;《Bioorganic & Medicinal Chemistry Letters》;19961231;第6卷(第5期);摘要、第499页第1段、第502页表1、第503页第2-4段 * |
| Structure–Activity Relationships of Neuritogenic Gentiside Derivatives;Yan Luo 等;《ChemMedChem》;20110810(第6期);第1986页表1、第1987页图1、第1988页图2-3 * |
| 具有拟NGF活性的苯甲酸酯类化合物的化学及生物学研究;高丽娟;《中国博士学位论文全文数据库（电子期刊）》;20150115;61-86 * |
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