CN1233629C - Sulfolipid compound with neural nourishing function and synthetic method and application thereof - Google Patents
Sulfolipid compound with neural nourishing function and synthetic method and application thereof Download PDFInfo
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- CN1233629C CN1233629C CN 02134155 CN02134155A CN1233629C CN 1233629 C CN1233629 C CN 1233629C CN 02134155 CN02134155 CN 02134155 CN 02134155 A CN02134155 A CN 02134155A CN 1233629 C CN1233629 C CN 1233629C
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Abstract
The present invention provides a compound of a general formula (I), which is an aromatic thioester compound with a neurotrophic function. The present invention also provides a synthetic method and an application as a medicine. The compound in the general formula (I) has a neurotrophic (NTF) function, namely obvious anaerobic protection activity to PC12 cells and cerebral cortex neurons.
Description
Technical field: the invention belongs to the pharmaceutical chemistry field; specifically: belong to aromatic series sulfur ester with neurotrophic effect; and its synthetic method and as the application method of medicine; particularly as the cerebral protective agent that resists pallium neurone anoxia-induced apoptosis; disordered brain function medicines such as prevention and treatment brain injury such as cerebral apoplexy and wallerian degeneration disease are especially improving cognitive ability and are improving in the medicine of learning and memory and use.
Background technology: particularly the survival of cholinergic neuron and injury protection rise and make important effect nerve growth factor to the cell of nervus centralis.Nerve growth factor is considered to the medicine of most promising treatment senile dementia (AD type).But nerve growth factor is protein, and they one are to be difficult to by hemato encephalic barrier, the 2nd, before reaching target spot, be decomposed easily.Therefore, seek the nerve growth factor of non-protein or intend the focus that the nerve growth factor micromolecular compound is this area research with neurotrophic effect.
In natural product, there is a large amount of sulfur esters to exist, because the specificity of its structure, some compound has special biological activity, can treat parkinsonism (Hamilton, G.S., Li, J.H. as compound (I), Chem.Abstr.1999,131,351237).
(+)-Lactacystin is separated from the substratum of Streptomyces sp.OM-6159 and the novelty identified contains pyrrolidone-2 class flower compound (Omura, the S. of thioester group in the early 1990s by people such as S.Omura; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi, R.; Tanaka, H.; Sasaki, Y.J.Antibiot.1991,44,113-116.), it has the non-albumen god of neurotrophic effect
Through the somatomedin characteristic.Carried out the complete synthesis research of (+)-Lactacystin in recent years abroad and carried out a large amount of pharmacology and the research work of medicine preclinical phase, in the hope of developing into the newtype drug of anti-senile dementia disease.
We find in the study on the synthesis of the simplification analogue of carrying out (+)-Lactacystin: synthetic aromatic series sulfur ester is not significantly urged Differentiation (nerve growth factor NGF has tangible Differentiation) to the PC12 cell, but has the provide protection that the PC12 cell hypoxia is damaged equally with NGF.
The objective of the invention is to: based on the structure singularity of this compounds, novelty and to the remarkable hypoxia protection effect of neurocyte, provide a kind of sulfur ester with neurotrophic effect and other synthetic method and application.
Summary of the invention: have the sulfur ester of neurotrophic effect, the general formula of this compound is:
In the formula, R1 represents hydrogen, kharophen (NHAc), R2 represents hydrogen, carboxyl and methyl esters thereof, ethyl ester, kharophen (NHAc), Ar represents (1) phenyl, substituted-phenyl, substituted-phenyl comprises the neighbour, between, the fluorine of para-orientation, chlorine, bromine atoms and hydroxyl, methoxyl group, oxyethyl group, N, the N-dimethylamino, (2) naphthalene nucleus (α position and β position), replace naphthalene nucleus, replace naphthalene nucleus and comprise 4,5,6,7,8 substituted hydroxies, methoxyl group, oxyethyl group, fluorine, chlorine, bromine atoms, (3) five-membered ring comprise furan nucleus (α position and β position), thiphene ring (α position and β position) and substituted hydroxy thereof, methoxyl group, oxyethyl group, fluorine, chlorine, the bromine atoms derivative; R1, R2 alternate c atoms are whole isomer of R configuration, S configuration and raceme (situation that has chiral carbon).Specifically: the structural formula of this compound can be respectively following structure:
This synthetic method with sulfur ester of neurotrophic effect, pass through with BOPCl[Bis (2-oxo-3-oxazolidinyl) phosphinic Chloride by aromatic carboxylic acid and compounds containing thiol groups] be dewatering agent, under the effect of triethylamine, reaction generates the compound of described general formula (I); Specifically: synthetic method can be under nitrogen protection, and aromatic carboxylic acid and compounds containing thiol groups room temperature reaction in anhydrous methylene chloride promptly got general formula (I) compound in 5～8 hours.Application method with sulfur ester of neurotrophic effect is that compound with described general formula (I) is as medicinal application; Described general formula (I) compound suitable form of administration can be changed into, if necessary, auxilliary agent and the vehicle of adding of inertia can be used; Can also be with the compound of general formula (I) as neurocyte particularly agent of pallium neurone hypoxia protection or cerebral protective agent; With the compound of described general formula (I) as the application in disordered brain function medicines such as brain injury such as preparation prevention and treatment cerebral apoplexy and wallerian degeneration disease, particularly preventing and treating in the medicine that improves cognitive ability and improve learning and memory and use, the method for its application can be existing ordinary method.
In order to reach better effect, the present invention is preferably as follows technical scheme:
With the anhydrous methylene chloride is solvent, in nitrogen protection, after fragrant acid or beta-aromatic vinylformic acid, sulfhydryl compound and dewatering agent BOPCl mixing, drips the organic bases triethylamine, after stirring reaction 5-10 hour, promptly generates the compound of general formula (I) under the room temperature.Reaction is chemical pure or analytical pure with the reagent triethylamine, must not deal with and can directly use.Methylene dichloride steams after the hydrolith drying and can use, and the characteristics of this method are: the reaction conditions gentleness, method is simple, is suitable for the expansion scale, can be used for producing in batches.
The characteristics of said synthesis route are: according to route of synthesis provided by the invention, can select different material as required, construct a series of sulfur esters easily; Synthetic method provided by the invention, the reaction conditions gentleness is being grasped simplely, is suitable for the expansion scale, is easy to realize the suitability for industrialized production purpose.
The method of synthetic sulfur ester provided by the invention, document (E.J.Corey andGregory A.Reichard, J.Am.Chem.Soc., 1992,114,10677-10678) report once was used for the synthetic of (+)-Lactacystin, and promptly aliphatic sulfur ester is synthetic.Utilize present method to carry out aromatic series sulfur ester synthesizing shown in general formula (I), do not appear in the newspapers.
Utilize method provided by the invention and approach synthetic sulfur ester [shown in general formula (I)], be special, the novel compound of structure, its activity research particularly to the hypoxia protection activity research of neurone (pallium cell), does not appear in the newspapers as yet.
Compound by technological method synthetic general formula of the present invention (I) has PCl2 cell and the neuronic hypoxia protection effect of pallium, as compound 1 (seeing embodiment 1) hypoxia protection of PCl2 cell there is remarkable activity, be that dosage is when being 5 μ g/ml, survival rate is 22.66%, and control group only is 5.44%; And for example, compound 5 (seeing embodiment 5) is remarkable to the neuronic hypoxia protection effect of pallium, and when promptly dosage was 10 μ g/ml, survival rate was 57.57%, and control group only is 41.39%.
The present invention has proposed to contain the medicine of general formula of the present invention (I) compound simultaneously, and described compound is converted into suitable form of administration, uses inert auxiliary and vehicle promptly to can be made into medicine where necessary.Application general formula (I) compound has been proposed simultaneously as neurotrophic agents, the application in preparation prevention and treatment disordered brain function medicine.Pharmaceutical composition of the present invention can be ointment, gel, paste, creme, sprays, lotion, suspension agent, activeconstituents solution or emulsion, syrup, particle or the pulvis in water or non-diluent water.
Use general formula of the present invention (I) compound as medicine, the formulation that can adopt is the lid human relations form of administration of habitually practising, for example: ointment, tablet, pill, capsule, suppository emulsion, input liquid and injection liquid, these preparations use traditional additive and vehicle to make by well-known method.The medicine that makes thus as required can be by the part, non-enteron aisle, the oral administration that waits.
By tablet, drageeing, capsule and the pill that medicinal compositions of the present invention forms, can hold common dressing, coating and protectiveness matrix, it can contain opalizer.They can be made into such composition, make they over a period to come with activeconstituents only or preferentially special in vivo part discharge.Dressing, parcel and protectiveness matrix can be with making as poly material or wax and so on.
Also available one or more the above-mentioned thinners of activeconstituents are made the microcapsule packet form together, any currently known methods that medicinal compositions or medicine production can be used in this technology carries out, for example one or more activeconstituentss and one or more mixing diluents are formed medicinal compositions, again composition is made medicine.
Find by the experiment that the present invention did; general formula (I) compound is as cerebral protective agent; the disordered brain function that brain injury such as cerebral ischemia, anoxic and wallerian degeneration disease etc. are caused has protection and prophylactic effect, and this effect is applicable to that clinical prevention and treatment are low because of cerebral apoplexy, learning and memory that anoxic and exitotoxicity damage cause neuronal damage to cause, a little less than the cognitive ability and disease such as dementia.
Bioactive experimental result with the following representation compound of synthetic of the present invention confirms biological activity effect of the present invention below:
1. the provide protection that the PCl2 cell hypoxia is damaged:
Method
Drug dose: 5 μ g/ml, NGF are 20ng/ml;
The anoxic time: 12 hours;
The PC12 cell cultures time: 9 days.Experimental result sees Table 1
The provide protection of table 1 pair PC12 cell hypoxia damage is observed
(X±s n＝30)
| Group | Cell count (visual field) | Survival rate (%) |
| Normal oxygen group control group NGF embodiment 1 embodiment 2 embodiment 3 | 72.60±19.28 3.95±3.46 20.35±5.48 ** 16.45±5.26 ** 7.89±3.72 ** 7.20±5.43 * | 100.00 5.44 28.03 22.66 10.88 9.92 |
Compare with control group
*P＜0.05
*P＜0.01
2. to the neuronic provide protection of rat layer in the vitro culture after the anoxia _ reoxygenation
Material and method
1) the pallium neurone is cultivated
Get nascent Wistar rat, under aseptic condition, isolate pallium, with (37 ℃ of 0.125% tryptic digestions, 30min.) disperse after, make the cell suspension of 5 * 105/ml density, be inoculated in the 35mm plastic culture device that scribbles the calf hide glue, every ware 2ml places 36 ℃, contains 10%CO2
With cultivate in the incubator (U.S. FORMA) of air.Nutrient solution is by 9.4g/L Eagle ' sMEM, and 0.05L/L horse serum, 0.01L/LN3 make up liquid and glutamine 0.10g/L forms.In cultivating 3d, in nutrient solution, add cell division inhibitor cytosine arabinoside 3mg/L respectively to suppress the hyper-proliferative of non-neurocyte, change fresh medium behind the effect 48h, change liquid later on weekly 2 times, change half fresh medium at every turn.Until cultivating 12d.
2. anoxic-reoxygenation experiment
Cultivate the cortical neuron of 12d.Be divided into normal group by experiment, control group, each group of trial-product (embodiment 4-8).12h added 50 μ g, 20 μ g and 10 μ g respectively before trial-product was respectively organized anoxic in nutrient solution; Normal group and control group add the equivalent dimethyl sulfoxide (DMSO).Then control group and trial-product are respectively organized in constant temperature (36 ℃) encloses container that neurone moves to 2000cm3 simultaneously, fill continuously with oxygenless gas (90%N2,10%CO2), under anoxia condition, after cultivating 6h, take out, put reoxygenation cultivation 24h in the incubator that contains 10%CO2 and air again.The normal group neurone continues to cultivate 24h under normal condition.
3. the observation of morphology and neuronal survival number
Neuronic metamorphosis when observing normal group, control group and trial-product (embodiment 4-8) respectively and respectively organize after the anoxia _ reoxygenation 24h with inverted phase contrast microscope, and inverted phase contrast microscope (400 *) down every ware (neurone of being counted must have halation by the survived neuronal in the adjacent visual field of Z word sequential counting (the 0.16mm2/ visual field), length has projection, and it is not painted to contaminate 3min through the 3g/L trypan blue) count and make comparisons.20 visuals field of every ware cell observation, each experimental observation 2 ware cell, experiment repeats 2 times.
Three. the result
Trial-product (embodiment 4-8) be 10 μ g/mL than suitable concentration.
When dosage was 50 μ g/mL, the rat layer neurone of vitro culture had obvious provide protection (seeing Table 2) after 4 pairs of anoxia _ reoxygenation of embodiment.When dosage was 20 μ g/mL, the rat layer neurone of vitro culture had obvious provide protection (seeing Table 3) after 5 pairs of anoxia _ reoxygenation of embodiment 4 and embodiment.When dosage is 10 μ g/mL, embodiment 4-8 to anoxia _ reoxygenation after the rat layer neurone of vitro culture have obvious provide protection (seeing Table 4).
The neuronic provide protection of rat layer in the vitro culture after the table 2 pair anoxia _ reoxygenation
(X ± s n=80/ visual field)
| Group | Neuron number (visual field) | Survival rate (%) |
| Normal oxygen group control group embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 | 31.95±5.27 13.73±2.77 17.00±3.81 ** 13.75±2.20 15.45±4.31 12.55±2.04 14.85±2.32 | 100.00 42.93 53.21 43.03 48.36 39.28 46.48 |
*Compare with control group P＜0.01
The neuronic provide protection of rat layer in the vitro culture after the table 3 pair anoxia _ reoxygenation
(X ± s n=80/ visual field)
| Group | Neuron number (visual field) | Survival rate (%) |
| Normal oxygen group control group embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 | 32.90±4.96 12.92±3.09 18.79±3.99 ** 16.80±2.62 ** 14.31±5.54 15.88±3.42 14.51±2.14 | 100.00 39.27 57.11 51.06 43.49 48.27 44.10 |
*Compare with control group P＜0.01
The neuronic provide protection of rat layer in the vitro culture behind the table 4 pair anoxic reoxygenation
(X ± s n=80/ visual field)
| Group | Neuron number (visual field) | Survival rate (%) |
| Normal oxygen group control group embodiment 4 embodiment 5 embodiment 6 embodiment 7 embodiment 8 | 33.70±6.23 13.95±3.65 17.30±2.74 ** 17.90±3.28 ** 18.85±3.50 ** 21.75±4.42 ** 22.35±2.83 ** | 100.00 41.39 51.34 53.12 55.93 64.54 66.32 |
*Compare with control group P＜0.01
Compared with prior art, beneficial effect of the present invention is:
1. sulfur ester provided by the invention is special, the novel compound of structure.
2. route of synthesis provided by the invention can be selected different material as required, constructs a series of aromatic series sulfur esters easily.
3. synthetic method provided by the invention, the reaction conditions gentleness is being grasped simplely, is suitable for the expansion scale, is easy to realize the suitability for industrialized production purpose.
4. the aromatic series sulfur ester that the present invention relates to [shown in general formula (I)]; its activity is particularly to the hypoxia protection activity research of neurone (pallium cell); do not appear in the newspapers as yet; the described compound of general formula (I) is as cerebral protective agent; the disordered brain function that brain injury such as cerebral ischemia, anoxic and wallerian degeneration disease etc. are caused has protection and prophylactic effect, and this effect is applicable to that clinical prevention and treatment are low because of cerebral apoplexy, learning and memory that anoxic and exitotoxicity damage cause neuronal damage to cause, a little less than the cognitive ability and disease such as dementia.
Embodiment:
Below given preferred embodiment, be intended to further illustrate compound of the present invention and synthetic method thereof, and and the scope of non-limiting compound of giving an example, the technological method that proposes in the also also non-limiting claim of the present invention that is to say by the described method of these embodiment to make general formula (I) compound at an easy rate.
Embodiments of the invention 1: compound title: 3,4,5-trimethoxybenzoic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: with 3,4,5-trimethoxybenzoic acid 30mg (0.142mmol), 3-mercaptopropionic acid ethyl ester 19mg (0.142mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 46.9mg (0.184mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml) three, under magnetic agitation, room temperature, add Et3N30 μ L (0.213mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 37mg product, and productive rate is 80.4%.
Colourless thick liquid
Spectroscopic data IR maxcm-1 (CHCl3): 3025,1730,1660,1587,1502,1464,1416,1322,1205,1107; 1HNMR (400MHz, CDCl3) δ ppm:7.22 (2H, s, Ar-H), 4.19 (2H, q, J1=7.2Hz, J2=14.4Hz, CO2CH2), 3.92 (9H, m, OCH3 * 3), 3.32 (2H, t, J=6.8Hz, SCH2), 2.73 (2H, t, J=6.8Hz, CH2CO), 1.28 (3H, t, J=7.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:190.3 (s), 171.5 (s), 152.9 (s * 2), 142.5 (s), 131.8 (s), 104.3 (d * 2), 60.7 (q * 2), 60.1 (t), 56.1 (q), 34.3 (t), 24.1 (t), 14.0 (q); EI-M (m/z): 328[M]+, 300,283,257,228,195,179,167,152,137,122,109.
Embodiments of the invention 2: compound title: 3,4-dimethoxy cinnamic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: according to embodiment 1, with 3,4-Dimethoxyphenyl acrylic acid 50mg (0.240mmol), 3-mercaptopropionic acid ethyl ester 32mg (0.240mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 76mg (0.300mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml) three, under magnetic agitation, room temperature, add Et3N51 μ L (0.360mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 64mg product, and productive rate is 82.1%.
Clear crystal (petrol ether/ethyl acetate), mp51.0-52.0 ℃
Spectroscopic data: IRKBr υ maxcm-1:3019,1733,1662,1590,1514,1464,1437,1354,1267,1234,1135; 1HNMR (400MHz, CDCl3) δ ppm:7.56 (1H, d, J=15.6Hz, ArCH=), 7.05～7.14 (3H, m, Ar-H), 6.58 (1H, d, J=15.6Hz, SCOCH=), 4.17 (2H, q, J1=7.2Hz, J2=14.4Hz, COOCH2), (3.93 6H, m, OCH3 * 2), 3.52 (2H, t, J=6.8Hz, SCH2), 2.69 (2H, t, J=5.6Hz, CH2CO2), 1.27 (3H, t, J=7.2Hz, CH3CH2); 13CNMR (100.6MHz, CDCl3) δ ppm:189.1 (s), 171.6 (s), 151.4 (s), 149.1 (s), 140.8 (d), 126.7 (s), 123.2 (d), 122.5 (d), 110.9 (d), 109.6 (d), 60.7 (t), 55.9 (q), 55.8 (q), 34.5 (t), 23.8 (t), 14.1 (q); EI-MS (m/z): 324,296,279,266,224,191,163,148,133,119.
Embodiments of the invention 3: the name of compound is called: 3,4, and 5-elemicin acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: according to embodiment 1, with 3,4,5-trimethoxyphenyl acrylic acid 100mg (0.45mmol), 3-mercaptopropionic acid ethyl ester 63mg (0.470mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 143mg (0.560mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N94 μ L (0.680mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 83mg product, and productive rate is 52.2%.
Clear crystal (petroleum ether/ethyl ether), mp47.0-48.5 ℃
Spectroscopic data: IRKBr υ maxcm-1:3029,1728,1668,1629,1591,1498,1459,1404,1289,1245,1086; 1HNMR (400MHz, CDCl3) δ ppm:7.534 (1H, d, J=15.6Hz, ArCH=), 6.761 (2H, s, Ar-H), 6.611 (1H, d, J=16.0Hz ,=CHCO), 4.166 (2H, q, J1=7.0Hz, J2=14Hz, H-16), 3.894 (9H, s, CH3O), 3.261 (2H, t, J=6.8Hz, SCH2), 2.701 (2H, t, J=6.8Hz, CH2CO), 1.276 (3H, t, J=7.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:189.1 (s), 171.7 (s), 153.4 (s), 140.8 (d * 2), 129.4 (s), 123.9 (d), 105.4 (d), 60.9 (q), 60.8 (t), 56.1 (q), 34.5 (t), 23.9 (t), 14.2 (q); EI-MS (m/z): 354[M]+, 309,236,221,190,178,163.
Embodiments of the invention 4: compound name is called: 2-furancarboxylic acid-(3-sulfydryl ethyl propenoate)-thioesters, and structural formula is:
Preparation method: according to embodiment 1, furancarboxylic acid 50mg (0.446mmol), 3-mercaptopropionic acid ethyl ester 59.8mg (0.446mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 147mg (0.579mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N93.8 μ L (0.669mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 54mg product, and productive rate is 52.9%.
Colourless thick liquid
Spectroscopic data: IR maxcm-1 (CHCl3): 3024,1723,1651,1568,1469,1375,1349,1253,1228,1204,1160; 1HNMR (400MHz, CDCl3) δ ppm:7.59 (1H, d, J=0.4Hz, Ar-H), 7.20 (1H, t, J=0.4Hz, Ar-H), 6.55 (1H, p, J=1.2Hz, Ar-H), 4.16 (2H, p, J=12.8Hz, J2=12.4Hz, CO2CH2), 3.30 (2H, t, J=7.2Hz, SCH2), 2.72 (2H, t, J=6.8Hz, CH2CO), 1.27 (3H, t, J=6.8Hz, CH2CH3); 13CNMR (100MHz, CDCl3) δ ppm:179.9 (s), 171.5 (s), 150.5 (s), 146.2 (d), 115.2 (d), 112.2 (d), 60.7 (t), 34.4 (t), 23.0 (t), 14.0 (q); EI-MS (m/z): 228[M]+, 182,149,135,126,95,57.
Embodiments of the invention 5: compound title: anisic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: according to embodiment 1,4-methoxybenzoic acid 50mg (0.329mmol), 3-mercaptopropionic acid ethyl ester 44mg (0.329mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 108mg (0.428mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N69 μ L (0.494mmol) and continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 50mg product, and productive rate is 56.8%.
Colourless thick liquid
Spectroscopic data: IR maxcm-1 (CHCl3): 3029,1730,1655,1630,1508,1260,1227,1168,1031,915; 1HNMR (400MHz, CDCl3) δ ppm:7.93 (2H, d, J=7.6Hz, Ar-H), 6.92 (2H, d, J=7.6Hz, Ar-H), 4.17 (2H, q, J1=7.2Hz, J2=10.0Hz, CO2CH2), 3.86 (3H, s, OCH3), 3.298H, t, J=5.6Hz, SCH2), 2.73 (2H, t, J=6.0Hz, CH2CO), 1.27 (3H, t, J=7.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:189.9 (s), 171.8 (s), 163.7 (s), 129.6 (s), 129.3 (d * 2), 113.7 (d * 2), 60.7 (t), 55.4 (q), 34.6 (t), 23.8 (t), 14.1 (q); EI-MS (m/z): 268[M]+, 239,223,149,135,107,92,77.
Embodiments of the invention 6: compound title: 3,5-dimethoxybenzoic acid-(N-mucolyticum)-thioesters, concrete structural formula:
Preparation method: according to embodiment 1, with 3,5-mesitylenic acid 68mg (0.336mmol), N-mucolyticum 40mg (0.336mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 111mg (0.423mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N71 μ L (0.504mmol) and continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 80mg product, productive rate is 83.5%,
Clear crystal (petrol ether/ethyl acetate), mp107.5-109.0 ℃
Spectroscopic data: IRKBr υ maxcm-1:3025,1678,1651,1590,1541,1515,1470,1420,1261,1146,1047; 1HNMR (400MHz, CDCl3) δ ppm:7.08 (2H, s, Ar-H), 6.66 (1H, s, Ar-H), 6.50 (1H, s, NH), 3.83 (6H, s, CH3O), 3.52 (2H, d, 5.6Hz, CH2), 3.22 (2H, t, J=6.0, SCH2), 2.00 (3H, s, COCH3); 13CNMR (100.6MHz, CDCl3) δ ppm:191.9 (s), 170.9 (s), 60.6 (s * 2), 138.4 (s), 105.8 (d), 104.8 (d * 2), 55.5 (q * 2), 39.5 (t), 28.5 (t), 22.9 (q); EI-MS (m/z): 283[M]+, 240,224,198,165,137,122,107,92,97.
Embodiments of the invention 7: compound title: 3,5-dimethoxybenzoic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: according to embodiment 1, with 3,5-dimethoxybenzoic acid 250mg (0.275mmol), 3-mercaptopropionic acid ethyl ester 37mg (0.275mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 91mg (0.378mmol) burns at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml) is miscible
In the bottle, add Et3N58 μ L (0.413mmol) under magnetic agitation, room temperature, continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 51mg product, and productive rate is 62.2%.
Colourless thick liquid
Spectroscopic data: IR maxcm-1 (CHCl3): 3029,1729,1662,1595,1465,1437,1349,1298,1224,1205,1159; 1HNMR (400MHz, CDCl3) δ ppm:7.03 (2H, s, Ar-H), 6.60 (1H, s, Ar-H), 4.12 (2H, p, J=7.2Hz, J2=14.4Hz), 3.77 (6H, s, CH3O), 3.25 (2H, t, J=6.8Hz, SCH3), 2.67 (2H, t, J=7.2Hz, CH2CO), 1.22 (3H, t, J=7.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:191.3 (s), 171.6 (s), 160.7 (s * 2), 138.6 (s), 105.8 (d), 104.7 (d * 2), 60.7 (t), 55.5 (q * 2), 34.3 (t), 24.1 (t), 14.1 (q); EI-MS (m/z): 298[M]+, 253,165,137,122,107.
Embodiments of the invention 8: the title of compound is: 1-naphthoic acid-(3-sulfydryl ethyl propenoate)-thioesters, and structural formula:
Preparation method: according to embodiment 1, α-Nai formic acid 50mg (0.291mmol), 3-mercaptopropionic acid ethyl ester 40mg (0.291mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 96mg (0.378mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N61 μ L (0.437mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 78mg product, and productive rate is 92.8%.
Colourless thick liquid
Spectroscopic data: IR υ maxcm-1 (CHCl3): 3012,1730,1655,1509,1371,1251,1027,1173,1060; 1HNMR (400MHz, CDCl3) δ ppm:8.52～8.24 (7H, m, Ar-H), 4.17 (2H, q, J1=7.2Hz, J2=14.0Hz, CO2CH2), 3.36 (2H, t, J=6.4Hz, SCH2), 2.78Hz (2H, t, J=7.2Hz, CH2CO), 1.24 (3H, t, J=4.8Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:193.8 (s), 171.7 (s), 135.0 (s), 133.7 (s), 133.0 (d), 129.1 (s), 128.3 (d), 128.0 (d), 127.8 (d), 126.6 (d), 125.1 (d), 124.4 (d), 60.8 (t), 34.4 (t), 24.9 (t), 14.2 (q); EI-MS (m/z): 288[M]+, 243,213,187,155,127,115,101,87.
Embodiments of the invention 9: compound title: anisic acid-(N-mucolyticum)-thioesters, structural formula particularly:
Preparation method: according to embodiment 1,4-methoxybenzoic acid 56mg (0.370mmol), N-ethyl ester half Guang ammonia 40mg (0.336mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 111mg (0.423mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N71 μ L (0.504mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 49mg product, and productive rate is 57.6%.
Clear crystal (petrol ether/ethyl acetate), mp110.5-112.0 ℃
Spectroscopic data: IR KBr υ maxcm-1:3021,1660,1602,1514,1311,1263,1169,917,833; 1HNMR (400MHz, CDCl3) δ ppm:7.93 (1H, d, J=2.8Hz, Ar-H), 6.93 (1H, d, J=4.0Hz, Ar-H), 6.50 (1H, s, NH), 4.87 (3H, s, OCH3), 3.52 (2H, m, CH2N), 3.20 (2H, t, J=6.4Hz, SCH2), 1.89 (3H, s, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:190.5 (s), 170.5 (s), 163.8 (s * 2), 129.3 (d * 2), 113.7 (d * 2), 55.4 (q), 39.6 (t), 28.2 (t), 23.0 (q); EI-MS (m/z): 253[M]+194,168,152,135,107,92,77.
Embodiments of the invention 10: compound title: 3,4,5-trimethoxybenzoic acid-(N-mucolyticum)-thioesters, structural formula:
Preparation method: according to embodiment 1, with 3,4,5-trimethoxybenzoic acid 78mg (0.370mmol), N-ethyl ester half Guang ammonia 40mg (0.2336mol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 111mg (0.437mmol) are miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N71 μ L (0.504mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 70mg product, and productive rate is 66.7%.
Clear crystal (petroleum ether/ethyl ether), mp108-110 ℃
Spectroscopic data: IR KBr υ maxcm-1:3021,1590,1497,1464,1415,1327,1157,1124; 1HNMR (400Hz, CDCl3) δ ppm:7.21 ((2H, s, Ar-H), 6.71 (1H, s, NH), 3.93 (9H, s, OCH3 * 3), 3.53 (2H, m, CH2N), 3.23 (2H, t, J=6.0Hz, SCH2), 2.05 (3H, s, COCH3); 13CNMR (100.6MHz, CDCl3) δ ppm:191.0 (s), 171.6 (s), 163.1 (s), 152.8 (s * 2), 142.6 (s), 131.6 (s), 104.4 (d * 2), 60.8 (q), 56.1 (q), 39.6 (t), 28.3 (t), 22.7 (q); EI-MS (m/z): 313[M]+, 270,256,195,179,167,152,137,122,109.
Embodiments of the invention 11: the title of compound: 3-pyridine carboxylic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: according to embodiment 1,3-pyridine carboxylic acid 50mg (0.406mmol), 3-mercaptopropionic acid ethyl ester 54mg (0.406mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 134mg (0.528mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N85 μ L (0.609mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 65mg product, and productive rate is 67%.
Colourless thick liquid
Spectroscopic data: IR maxcm-1 (CHCl3): 3023,1730,1666,1586,1419,1399,1234; 1HNMR (400MHz, CDCl3) δ ppm:7.43～9.17 (4H, m, Ar-H), 4.19 (2H, q, J1=6.8Hz, J2=11.2Hz, CO2CH2), 3.38 (2H, t, J=6.8Hz, SCH2), 2.77 (2H, t, J=10.8Hz, CH2CO2), 1.29 (3H, t, J=7.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:189.9 (s), 171.3 (s), 153.7 (d), 148.2 (d), 134.3 (d), 132.1 (s), 123.3 (d), 60.7 (t), 34.0 (t), 23.9 (t), 13.9 (q); EI-MS (m/z): 239[M+], 211,194,165,139,106,78.
Embodiments of the invention 12: compound title: phenylformic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: according to embodiment 1, phenylformic acid 50mg (0.347mmol), 3-mercaptopropionic acid ethyl ester 46mg (0.347mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 114.6mg (0.451mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N95 μ L (0.676mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 90mg product, and productive rate is 92.8%.
Colourless thick liquid
Spectroscopic data: IRmaxcm-1 (CHCl3): 1728,1668,1449,1374,1349,1229,1201,1017,910; 1HNMR (400MHz, CDCl3) δ ppm:7.36～7.89 (5H, m, Ar-H), 4.10 (2H, q, J1=7.2Hz, J2=14.4Hz, CO2CH2), 3.26 (2H, t, J=7.6Hz, SCH2), 2.67 (2H, t, J=6.8Hz, CH2CO), 1.20 (3H, t, J=7.6Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:191.4 (s), 171.6 (s), 136.7 (s), 133.4 (d), 128.5 (d * 2), 127.0 (d * 2), 60.7 (t), 34.3 (t), 23.9 (t), 14.1 (q); EI-MS (m/z): 238[M]+, 209,193,164,138,105,77.
Embodiments of the invention 13: compound title: to (N, N-dimethylamino) phenylformic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula:
Preparation method: according to embodiment 1, with 4-[N, the N-dimethyl] phenylformic acid 50mg (0.303mmol), 3-mercaptopropionic acid ethyl ester 40.6mg (0.303mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 100mg (0.394mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N63 μ L (0.454mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 34mg product, and productive rate is 40%.
Clear crystal (petrol ether/ethyl acetate), mp52.0-53.5 ℃
Spectroscopic data: IRKBr υ maxcm-1:3023,1722,1651,1596,1525,1448,1373,1244,1223,1168; 1HNMR (400MHz, CDCl3) δ ppm:7.85 (2H, d, J=4.8Hz, Ar-H), 6.61 (2H, d, J=5.2Hz, Ar-H), 4.16 (2H, q, J1=7.2Hz, J2=14.4Hz, CO2CH2), 3.27 (2H, t, J=6.4Hz, SCH2), 3.04 (6H, s, CH3N), 2.70 (2H, t, J=6.8Hz, CH2CO), 1.25 (3H, t, J=7.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:189.4 (s), 171.2 (s), 153.6 (s), 129.3 (d * 2), 124.3 (s), 110.5 (d * 2), 60.6 (t), 39.9 (q * 2), 34.8 (t), 23.5 (t), 14.2 (q); EI-MS (m/z): 281[M]+, 236,208,181,148,119,105,91,77.
Embodiments of the invention 14: compound title: 0-chloro-benzoic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula particularly:
Preparation method: according to embodiment 1,2-chloro-benzoic acid 50mg (0.319mmol), 3-mercaptopropionic acid ethyl ester 42.8mg (0.319mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 105mg (0.415mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N65 μ L (0.479mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 57mg product, and productive rate is 65.6%.
Colourless thick liquid
Spectroscopic data: IR maxcm-1 (CHCl3): 3023,1730,1677,1580,1465,1375,1227,1201,1063; 1HNMR (400MHz, CDCl3) δ ppm:7.30～7.65 (4H, m, Ar-H), 4.18 (2H, q, J1=7.2Hz, J2=14.4Hz, CO2CH2), 3.32 (2H, t, J=7.2Hz, SCH2), 2.76 (2H, t, J=6.8Hz, CH2CO2), 1.28 (3H, t, J=7.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:191.5 (s), 171.5 (s), 137.0 (s), 132.3 (d), 130.8 (d), 130.7 (s), 129.1 (d), 126.6 (d), 60.7 (t), 34.1 (t), 24.8 (t), 14.1 (q); EI-MS (m/z): 272[M]+, 227,172,139,111.
Embodiments of the invention 15: compound title: 0-chloro-benzoic acid-(N-mucolyticum)-thioesters, structural formula:
Preparation method: according to embodiment 1,2-chloro-benzoic acid 43mg (0.277mmol), N-ethyl ester half Guang ammonia 30mg (0.252mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 83mg (0.328mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N53 μ L (0.378mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 61mg product, and productive rate is 95.3%.
Colourless thick liquid
Spectroscopic data: IRmaxcm-1 (CHCl3): 3452,3018,2927,1673,1589,1518,1467,1434,1373,1265,1212,1064; 1HNMR (400MHz, CDCl3) δ ppm:7.33～7.65 (4H, m, Ar-H), 6.55 (1H, s, NH), 3.55 (2H, m, CH2N), 3.24 (2H, t, J=6.8Hz, SCH2), 2.00 (3H, s, COCH3); 13CNMR (100.6MHz, CDCl3) δ ppm:192.2 (s), 170.5 (s), 136.9 (s), 132.4 (d), 130.7 (d), 130.4 (s), 129.1 (d), 126.7 (d), 39.2 (t), 29.3 (t), 23.0 (q); EI-MS (m/z): 256[M-1]+, 198,171,139,111.
Embodiments of the invention 16: compound title: 3,4,5-trimethoxybenzoic acid-(N-acetyl cysteine methyl esters)-thioesters, concrete structural formula:
Preparation method: according to embodiment 1, with 2,3,4-trimethoxybenzoic acid 155mg (0.734mmol), N-acetylcystein methyl esters 156mg (0.881mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 233mg (0.917mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N154 μ L (1.101mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 100mg product, and productive rate is 58.1%.
Clear crystal (petroleum ether-ethyl acetate), mp169.0-170.5 ℃
Spectroscopic data: IRmaxcm-1 (CHCl3): 3685,3017,1711,1598,1578,1522,1476,1423,1363,1227,1016; 1HNMR (400MHz, CDCl3) δ ppm:7.21 (2H, s, Ar-H), 6.35 (1H, d, J=7.2Hz, NH), 4.90 (1H, m, CHCO), 3.92 (9H, m, OCH3 * 3), 3.79 (3H, s, COOCH3), 3.57 (2H, m, SCH2), 2.02 (3H, s, COCH3); 13CNMR (100.6MHz, CDCl3) δ ppm:190.2 (s), 170.7 (s), 169.9 (s), 153.1 (s * 2), 143.0 (s), 131.4 (s), 104.7 (d * 2), 60.0 (q), 56.3 (q * 2), 52.8 (q), 52.2 (d), 30.8 (t), 23.1 (q); EI-MS (m/z): 371[M]+, 355,327,312,281,253,228,195,167,152,137,122.
Embodiments of the invention 17: compound name is called: 2,3,4 trimethoxybenzoic acid-(3-sulfydryl ethyl propenoate)-thioesters, and structural formula:
Preparation method: according to embodiment 1, with 2,3,4-trimethoxybenzoic acid 30mg (0.142mmol), 3-mercaptopropionic acid ethyl ester 19mg (0.142mmol) and two (2-oxo-3-oxane base) phosphoryl chloride (BOPCl) 46.9mg (0.184mmol) is miscible in flask at the bottom of three mouthfuls of gardens with anhydrous CH2Cl2 (5ml), under magnetic agitation, room temperature, add Et3N30 μ L (0.213mmol), continue 12 hours (TLC detection reaction process) of reaction, behind ethyl acetate extraction, column chromatography for separation gets the 34mg product, and productive rate is 73.9%.
Colourless thick liquid
Spectroscopic data: IRmaxcm-1 (CHCl3): 3021,1729,1690,1591,1503,1549,1421,1382,1349,1227,1130; 1HNMR (400MHz, CDCl3) δ ppm:7.61 (1H, d, J=8.8Hz, Ar-H), 6.72 (1H, d, J=8.8Hz, Ar-H), 4.16 (2H, q, J1=5.2Hz, J2=12.4Hz, CO2CH2), 3.92 (9H, m, OCH3 * 3), 3.25 (2H, t, J=5.2Hz, SCH2), 2.72 (2H, t, J=6.4Hz, CH2CO), 1.27 (3H, t, J=5.2Hz, CH2CH3); 13CNMR (100.6MHz, CDCl3) δ ppm:189.0 (s), 171.9 (s), 157.5 (s), 153.6 (s), 142.2 (s), 124.8 (d), 124.0 (s), 106.8 (d), 61.4 (q), 60.8 (q), 60.1 (t), 56.1 (q), 34.4 (t), 24.2 (t), 14.1 (q); EI-M S (m/z):
328[M]+，283，226，195，180，152，137，109。
Synthetic method and raw material etc. more than are provided; in application process this compound is become pharmaceutical composition according to the making of existing conventional method patient's administration is got final product, described pharmaceutical composition can be ointment, gel, paste, creme, sprays, lotion, suspension agent, activeconstituents solution or emulsion, syrup, particle or the pulvis etc. in water or non-diluent water.As: ointment, tablet, pill, capsule, suppository emulsion, input liquid and injection liquid, these preparations use traditional additive and vehicle to make by well-known method, the medicine that makes thus as required can be by the part, non-enteron aisle, the oral administration that waits; The tablet, drageeing, capsule and the pill that form by medicinal compositions of the present invention, can hold common dressing, coating and protectiveness matrix, it can contain opalizer, they can be made into such composition, make they over a period to come with activeconstituents only or preferentially special in vivo part discharge, the dressing of use, parcel and protectiveness matrix can be with making as poly material or wax and so on; Also available one or more the above-mentioned thinners of activeconstituents are made the microcapsule packet form together, any currently known methods that medicinal compositions or medicine production can be used in this technology carries out, for example one or more activeconstituentss and one or more mixing diluents are formed medicinal compositions, again composition is made medicine.Can be used as neurocyte particularly the agent of pallium neurone hypoxia protection or cerebral protective agent, it can be applied in disordered brain function medicines such as brain injury such as preparation prevention and treatment cerebral apoplexy and wallerian degeneration disease, particularly can improve cognitive ability and improve in the medicine of learning and memory obtaining important use in prevention and treatment.
Claims (13)
1, a kind of sulfur ester with neurotrophic effect, it is characterized in that: the general formula of this compound is:
N=0 or 1
In the formula, R
1Represent hydrogen or kharophen, R
2Represent hydrogen, carboxyl, methoxycarbonyl, ethoxy carbonyl or kharophen, the phenyl of Ar representative (1) phenyl or replacement, substituting group is fluorine, chlorine, bromine, hydroxyl, methoxyl group, oxyethyl group or N, the N-dimethylamino, (2) α-or betanaphthyl, or the naphthyl that replaces, substituting group is hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine or bromine, or (3) quinary heterocyclic radical, it is α-or β-furyl, α-or β-thienyl, the furyl of replacement or thienyl of replacement, substituting group is hydroxyl, methoxyl group, oxyethyl group, fluorine, chlorine or bromine, works as R
1And R
2When representing the different group of non-hydrogen atom respectively, R
1And R
2The carbon atom that replaces is R configuration or S configuration.
2, according to the described sulfur ester of claim 1 with neurotrophic effect, it is characterized in that this compound is 3,4,5-trimethoxybenzoic acid-(3-sulfydryl ethyl propenoate)-thioesters, structural formula is:
3, according to the described sulfur ester of claim 1 with neurotrophic effect, it is characterized in that this compound is 2-furancarboxylic acid-(3-sulfydryl ethyl propenoate)-thioesters,
Structural formula is:
4, according to the described sulfur ester of claim 1 with neurotrophic effect, it is characterized in that this compound is anisic acid-(3-sulfydryl ethyl propenoate)-thioesters,
Structural formula is:
5, according to the described sulfur ester of claim 1 with neurotrophic effect, it is characterized in that this compound is 3,5-dimethoxybenzoic acid-(N-mucolyticum)-thioesters,
Structural formula is:
6, according to the described sulfur ester of claim 1 with neurotrophic effect, it is characterized in that this compound is 3,5-dimethoxybenzoic acid-(3-sulfydryl ethyl propenoate)-thioesters,
Structural formula is:
7, according to the described sulfur ester of claim 1 with neurotrophic effect,
It is characterized in that this compound is 1-naphthoic acid-(3-sulfydryl ethyl propenoate)-thioesters,
Structural formula is:
8, as having the synthetic method of the sulfur ester of neurotrophic effect as described among the claim 1-7 any one, it is characterized in that: by aromatic carboxylic acid and compounds containing thiol groups by being dewatering agent with two (2-oxo-3-oxazolidinyl) phosphonyl chloride, under the effect of triethylamine, synthetic general formula (I) compound
9, the synthetic method with sulfur ester of neurotrophic effect according to claim 8; it is characterized in that: under nitrogen protection, aromatic carboxylic acid and compounds containing thiol groups room temperature reaction in anhydrous methylene chloride promptly got general formula (I) compound in 5～8 hours.
10, as having the application of the sulfur ester of neurotrophic effect as described among the claim 1-7 any one, it is characterized in that: general formula (I) compound
Be applied in the medicine of prevention and treatment disease of brain.
11, according to the described application of claim 10, it is characterized in that: described compound is changed into suitable form of administration, can use auxilliary agent and the vehicle of adding of inertia in the form of administration with sulfur ester of neurotrophic effect.
12, according to claim 10 or 11 described application, it is characterized in that: use described compound as agent of neurone hypoxia protection or cerebral protective agent with sulfur ester of neurotrophic effect.
13, according to claim 10 or 11 described application with sulfur ester of neurotrophic effect, it is characterized in that: described general formula (I) compound is used to prepare the medicine of prevention and treatment brain injury and disordered brain function disease, or is used to prevent and treat the medicine that improves cognitive ability and improve learning and memory.
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| KR101651605B1 (en) * | 2015-12-10 | 2016-08-26 | 대봉엘에스 주식회사 | Novel phenolic acid derivatives, and uses of the same |
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| US10358414B2 (en) | 2013-11-08 | 2019-07-23 | Promentis Pharmaceuticals, Inc. | Substituted N-acetyl-L-cysteine derivatives and related compounds |
| US10961187B2 (en) | 2013-11-08 | 2021-03-30 | Promentis Pharmaceuticals, Inc. | Substituted N-acetyl-L-cysteine derivatives and related compounds |
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