CN101100416A - Small molecule inhibitor for preventing Alzheimer's disease Abeta polypeptide from fiberizing and its preparation method, pharmaceutical composition and application - Google Patents
Small molecule inhibitor for preventing Alzheimer's disease Abeta polypeptide from fiberizing and its preparation method, pharmaceutical composition and application Download PDFInfo
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Abstract
A compound for inhibiting beta-starch protein aggregation and fibrillation or its medicinal accepted slat, composition, its production and use in prevention and treatment of Alzheimer's disease are disclosed. The compound or medicinal accepted slat combines with Alpha-beta polypeptide and inhibits Alpha-beta polypeptide aggregation and fibrillation.
Description
Technical field
The present invention relates to the pharmaceutical chemistry field, relate in particular to the inhibitor of the amyloid-beta relevant (A β) with Alzheimer's disease.More specifically, the present invention relates to gathering and Fibrotic compound (general formula I) with symmetrical structure or its pharmacy acceptable salt and preparation method thereof of novel the suppressed amyloid-beta of a class; The invention still further relates to the pharmaceutical composition that comprises this compounds or its pharmacy acceptable salt, and this compound or its pharmacy acceptable salt and the application of pharmaceutical composition in the medicine of preparation prevention and treatment Alzheimer's disease thereof.
Background technology
In the dull-witted case of typical intractable, 50%～70% be Alzheimer (Alzheimer ' s Disease, AD).It is a kind of degeneration of brain, and encephalatrophy is arranged more, especially the atrophy of brain frontal cortex cortex.The general male sex 65 years old, women at 55 years old with sequela.Fall ill just absent minded in early days, be losing one's memory, slowly develop into poverty of thought, behavior naivety, emotional lability, computing power poor, do not understand others, then be unable to leave the bed at last, completely lose viability.Along with the aging of social population, at present the AD sickness rate is in rising trend, and according to statistics, the world today has more than 5,000 ten thousand the elderlys to suffer from various degree dementia.In the U.S., suffer from more 4,000,000 people of AD number at present, the annual cost that directly or indirectly is used for the treatment of the senile dementia disease has reached 9,000,000,000 dollars.Along with China has entered astogeny society, the senile dementia problem is one of social unavoidable outstanding problem that is faced in China too now.Therefore the good medicine of seeking treatment AD has been subjected to the especially great attention of developed country of various countries, becomes the task of top priority.
From the seventies in 20th century, people promptly begin to develop the medicine of treatment AD, and originally, research direction mainly concentrates on the relation of vagusstoff and AD; Mainly be the influence of research anticholinesterase to AD the eighties; But the cholinergic nerve function reduction is the variation than the later stage, therefore in theory, and can not be with anticholinesterase from stage performance early to the therapeutic action of AD.The nineties, research not only has acetyl choline receptor agonists, has also comprised oestrogenic hormon, antiphlogistic drug, has influenced the medicine of Radical Metabolism and the medicine of inhibition amyloid beta deposition.At present, the medicine that commercially available some are used for the treatment of AD nearly all can only be some symptoms of alleviating AD, temporarily improves patient's AD memory and attention.Therefore, up to the present, the clinical treatment of AD remains a global problem of demanding urgently breaking through.
The reason that causes AD patient's dementia is because the death of the neuronal cell that causes because of high-caliber " senile plaque " and " nerve fiber disorder " in some zone of human brain.The item key that Alzheimer takes place is to form insoluble amyloid-beta (A β peptide) in the cerebrovascular, and the unusual generation of A β and deposition are considered to cause neuronal damage and the one of the main reasons of losing.
A β is 39-43 the amino acid polypeptide that is formed by β and gamma-secretase catalytic hydrolysis by amyloid-beta precursor APP (Amyloid precursor protein), and its main form is A β 40 and A β 42.Result of study shows that the generation of A β is the early stage the most key factor of AD morbidity.Early stage in AD morbidity, the excessive generation meeting of A β 42 directly causes stacked on its pathology, and excessive A β 42 is difficult to be eliminated, so under A β under the effect of some agglomerative factors 42 can deposition.In theory, as long as the expression of blocking-up APP can be avoided the generation of A β and then can reach the purpose of treatment AD, yet, because the non-A β fragment of APP itself and APP has some other important physical function, and, in actual mechanical process, transcribing of a specific target gene of blocking-up is quite difficult.So people are based upon a difficult problem of capturing treatment AD on hydrolysis that how to stop APP rather than the expression of the blocking APP.The catalytic hydrolysis of APP can carry out along two main paties: alpha-secretase enzymatic pathway and beta-secretase approach.Under normal circumstances (alpha-secretase enzymatic pathway), APP is become the APP fragment α-APPs and the C83 peptide of solubility by the alpha-secretase enzyme at the inner catalytic hydrolysis of A β sequence, and the result has stoped the generation of A β; Under improper situation (beta-secretase approach), APP is cut APP fragment β-APPs and the C99 peptide that catalytic hydrolysis becomes solubility by beta-secretase in the N-of A β end-grain cutting, and it is complete A β that the latter is then cut metabolism by gamma-secretase in the C-of A β end-grain cutting.This shows that beta-secretase is the rate-limiting enzyme that produces A β, is APP is become A β by catalytic hydrolysis prerequisite.
Before A beta polypeptides molecule cut down from APP, 12～14 amino-acid residues of its C-end were in cytolemma, and it is folding to be the alpha-helix form; 28 residues of its N-end are exposed to outside the film structure the unknown.After A beta polypeptides molecule is cut down from APP by beta-secretase and gamma-secretase, the spiral folded form of C-end will be opened.In vivo, A beta polypeptides molecule may be gathered into fiber via 1. random structure (RC) → beta sheet or the 2. approach of alpha-helix → beta sheet.External, the conformation of A beta polypeptides molecule changes and difference with residing solution environmental.In the aqueous solution, it exists with the form that random structure, beta sheet and alpha-helix mix conformation.In the aqueous solution of the SDS of the analogue membrane environment aqueous solution or fluorinated alohol, the A beta polypeptides exists with the alpha-helix conformation form.Molecular dynamics simulation and experiment show, A beta polypeptides molecular folding, is gathered into fiber, contain the stable intermediate conformation of alpha-helix through some.The design drug molecule combines with the A beta polypeptides, stablizes its intermediate conformation, just can stop gathering and the further fibrosis of A β.
The nucleus magnetic resonance structure shows that the A beta polypeptides is folded into two sections α-Luo Xuanjiegous in TFE, SDS and HFIP, has the Loop district of a flexibility to be connected between these two sections alpha-helixs.The length of the alpha-helix that the A beta polypeptides forms in these solution has nothing in common with each other, and illustrates that A beta polypeptides structure is flexible, and depends on residing solution environmental.Because nuclear magnetic resonance experiment solutions employed and physiological environment difference are very big, so can not directly use these structures of A beta polypeptides to design inhibitor molecules.
In addition, the gathering of A beta polypeptides needs configuration metal ions Zn
2+, Cu
2+Participation.Some A beta polypeptides inhibitor such as Clioquinol and these metal ion a flat iron plate for making cakes close, and sedimentary A β also can stop the gathering of A beta monomers molecule in the solubilized brain.At present, Clioquinol uses with vitamin B12, has entered phase ii clinical trial.Other most of A beta inhibitors of having reported because of toxicity, in vivo easily by proteasome degradation, can see through problem such as hemato encephalic barrier and enter clinical trial, also need further chemical structure transformation and optimization.The present invention is a target with the stable intermediate conformation in the A βZhe Die process, utilizes the computer virtual screening, has designed and synthesized out the Fibrotic micromolecular inhibitor of prevention A beta polypeptides that a class has brand-new chemical backbone.
Summary of the invention
The present invention is initial conformation with the nucleus magnetic resonance structure (PDB number is 1BA4) of A β 40 polypeptide in the SDS aqueous solution, Biopolymer module among the utilization Sybyl6.8 is to A β 40 peptide molecule hydrogenation and Kollman-all-atom electric charge, adopt Gromac software that peptide molecule is carried out molecular dynamics simulation, study its conformational change.We find that the rock steady structure form that the A beta polypeptides can alpha-helix/beta sheet exists (Xu, Y.Shen, J., Luo, X., Zhu, W., Chen, K., Ma, J., and Jiang, H. (2005) Conformational transition of amyloid beta-peptide.Proc Natl Acad Sci USA 102,5403-7.).The stable middle conformation that contains alpha-helix/beta sheet with resulting A β 40 polypeptide of molecular dynamics simulation is a target spot, adopt molecular docking database virtual screening technology, from SPECS company (http://www.specs.net/) compound database, screen active compound.The micromolecular inhibitor of designing as shown in Figure 1, is attached on the A beta polypeptides, stablizes the monomer structure under its non-state of aggregation, stops it to form fibrosis.
The inventor adopts autoMS and the sphgen program in the DOCK4.0 software package that the whole molecular surface of the stable intermediate structure of the alpha-helix/beta sheet of A β 40 peptide molecules is explained, the ball collection of describing molecular surface is combined, as the targeted activity site of screening.Determine the computer capacity of GRID program then, character such as the hydrophobicity of calculating molecular surface, electrostatic interaction, model ylid bloom action on A β 40 peptide molecule surface mesh lattice points, preserve gridden data, so that in the molecular docking process, accelerate the computing velocity that marking is estimated.Compound in the SPECS compound database is placed in the avtive spot with the DOCK4.0 program, and the main screening parameter of DOCK4.0 is set at: each round-robin conformation number (configuration per circle): 30; Anchor point direction (anchor orientation): 50; Energy-optimised (energy minimization): 100; Energy-optimised cycle number (energy minimization circle): 1, adopt combining of contact marking and chemistry marking evaluation function assessing compound and A β 40 peptide molecules.We get preceding 1000 and have the preferably compound of marking, carry out bioactivity screening.
Therefore, the objective of the invention is to, the compound or its pharmacy acceptable salt that provide a class to have following general formula I symmetrical structure, this compounds stops the gathering and the fibrosis of A beta polypeptides by combining with Alzheimer's disease Abeta polypeptide (comprising A β 40, A β 42).
Another object of the present invention provides the preparation method of above-mentioned compound of Formula I.
Also purpose of the present invention provides the pharmaceutical composition that comprises compound of Formula I or its pharmacy acceptable salt.
A further object of the present invention provides compound of Formula I or its pharmacy acceptable salt in the i.e. application in the medicine of anti-degenerative brain disorder of preparation prevention and treatment Alzheimer's disease.
The invention provides compound or its pharmacy acceptable salt with following general formula I symmetrical structure:
Wherein:
W
(wherein, n=1 or 2);
Y is O, NH or S;
R
1Can be aromatic base,
Wherein, Z is OH, SH or NH
2
R
4And R
5Respectively be the saturated or unsaturated alkyl of hydrogen, C1-C6 straight or branched, saturated or unsaturated cycloalkyl group, aromatic base or 5-7 unit heterocyclic radical; Described aromatic base can be phenyl, substituted-phenyl, naphthyl or xenyl, the fragrant heterocycle of 5-7 unit, wherein said substituted-phenyl can comprise 1～4 substituting group, and this substituting group can be selected among halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl and the C1-C4 acyl group; The first heterocyclic radical of described 5-7 contains 1-3 heteroatoms that is selected from oxygen, sulphur and nitrogen; and optional contain one or more substituting groups that are selected from halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl, C1-C4 acyl group and aromatic base, described 5-7 unit heterocyclic radical can with R
4Or R
5In phenyl and close;
R
2And R
3Respectively be saturated or unsaturated alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl, C1-C4 acyl group, C3-C7 cyclic hydrocarbon radical, benzyl, aromatic base or the 5-7 unit heterocyclic radical of hydrogen, halogen, C1-C6 straight or branched;
Described halogen is fluorine, chlorine, bromine or iodine;
Described aromatic base can be phenyl, substituted-phenyl, naphthyl or xenyl, the fragrant heterocycle of 5-7 unit; Wherein said substituted-phenyl can comprise 1～4 substituting group, and this substituting group can be selected among halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl and the C1-C4 acyl group;
The first heterocyclic radical of described 5-7 contains 1-3 heteroatoms that is selected from oxygen, sulphur and nitrogen, and optional containing one or more substituting groups that are selected from halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl, C1-C4 acyl group and aromatic base, described 5-7 unit heterocyclic radical can and close with phenyl in the parent nucleus;
The pharmacy acceptable salt of compound of Formula I provided by the invention, can enumerate particularly with organic acid such as propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate or citric acid or acidic amino acids such as aspartic acid, L-glutamic acid and form behind the esters again the salt that forms with mineral alkali, as sodium, potassium, calcium, aluminium salt and ammonium salt; Or the salt that forms with organic bases, as methylamine salt, ethylamine salt, ethanolamine salt etc.; Or form the salt of mineral acids such as hydrochloric acid behind the esters, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid with basic aminoacidss such as Methionin, arginine, ornithine, or with organic acid salt such as formic acid, acetate, picric acid, methylsulfonic acid, ethyl sulfonic acid.
Compound preferred embodiment is compound or its pharmacy acceptable salt with following structure shown in the general formula I of the present invention:
In the formula (I), W is
Y is O; R
1Be phenyl or substituted-phenyl;
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
Second preferred embodiment of compound shown in the general formula I of the present invention is compound or its pharmacy acceptable salt with following structure:
In the formula (I), W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
Wherein, R
4Be selected from methyl, morphine quinoline base, methylpiperazine base, phenyl and substituted-phenyl; Z is a hydroxyl.
The 3rd preferred embodiment of compound shown in the general formula I of the present invention is compound or its pharmacy acceptable salt with following structure:
In the formula (I), W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
R
5Be selected from phenyl, substituted-phenyl, thienyl and furyl;
The 4th preferred embodiment of compound shown in the general formula I of the present invention is compound or its pharmacy acceptable salt with following structure:
In the formula (I), W is
Y is NH; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
R
4Be selected from methyl, morphine quinoline base, methylpiperazine base, phenyl and substituted-phenyl;
The 5th preferred embodiment of compound shown in the general formula I of the present invention is compound or its pharmacy acceptable salt with following structure:
In the formula (I), W is
Y is O; R
1Be phenyl or substituted-phenyl;
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
The 6th preferred embodiment of compound shown in the general formula I of the present invention is compound or its pharmacy acceptable salt with following structure:
In the formula (I), W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
R
5Be selected from phenyl, substituted-phenyl, thienyl, furyl;
The 7th preferred embodiment of compound shown in the general formula I of the present invention is compound or its pharmacy acceptable salt with following structure:
In the formula (I), W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
R
5Be selected from phenyl, substituted-phenyl, thienyl, furyl;
The 8th preferred embodiment of compound shown in the general formula I of the present invention is compound or its pharmacy acceptable salt with following structure:
In the formula (I), W is-CH
2-; Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl;
R
3Be selected from hydrogen, halogen, methyl and ethyl;
R
5Be selected from phenyl, substituted-phenyl, thienyl, furyl;
The invention provides compound shown in the general formula I and intermediates preparation thereof, wherein R
1, R
2, R
3, W, Y definition as mentioned above:
Described method comprises the steps:
(1) compound (II) under concentrated hydrochloric acid catalysis with W
1Reaction gets compound (III);
Wherein, W
1Can be acetone, 1,1,1,3,3,3-Perfluoroacetone, naphthenone etc.
(2) in dichloromethane solvent, compound (III) and halogen X
2And hydroperoxidation, getting compound (IV), wherein middle X is a halogen atom;
(3) compound (IV) and R
1The X halide reaction gets compound of Formula I;
Or
(1) compound (II) under concentrated hydrochloric acid catalysis with W
1Reaction gets compound (III);
Wherein, W
1Can be acetone, 1,1,1,3,3,3-Perfluoroacetone, naphthenone etc.
(2) compound (III) and R
1The X halide reaction gets compound of Formula I.
In preferred compound of the present invention, wherein
Be Br, R
3Be hydrogen, R
4During for morphine quinoline base, its concrete synthetic route is as follows:
Pharmaceutical composition of the present invention contains compound or its pharmacy acceptable salt of the above-mentioned general formula I for the treatment of significant quantity, and contains one or more pharmaceutically acceptable carriers.This medicinal compositions can also further comprise odorant agent, flavouring agent etc.
Its ideal ratio of pharmaceutical composition provided by the present invention is, compound of Formula I or its pharmacy acceptable salt account for 65%～99.5% of gross weight as activeconstituents, rest part is the 0.5-35% that accounts for gross weight, or 1-20% more preferably, or be preferably pharmaceutically acceptable carrier, diluent or solution or the salts solution of 1-10%.
Compound provided by the present invention or its pharmacy acceptable salt and pharmaceutical composition can be used in a variety of forms, as tablet, capsule, pulvis, syrup, solution shape, suspension and aerosol etc., and may reside in suitable solid or liquid support or the diluent and the suitable disinfector injecting or instil of being used for.
The various formulations of compound of the present invention or its pharmacy acceptable salt and pharmaceutical composition can be according to conventional preparation method's preparation of pharmaceutical field.
Compound of the present invention or its pharmacy acceptable salt and pharmaceutical composition can comprise humans and animals to the clinical use of Mammals, can through port, the route of administration of nose, skin, lung or gi tract etc.Most preferably be oral.Best preferred per daily dose is the 0.01-200mg/kg body weight, disposable taking, or 0.01-100mg/kg body weight part vic.Which kind of instructions of taking that don't work, individual's optimal dose should be decided according to concrete treatment.Generally be from low dose, increase dosage gradually until find optimal dosage.
Description of drawings
Fig. 1 illustrates that the organic molecule inhibitor is attached on the A beta polypeptides, stops it to form beta sheet and fibrosis;
Fig. 2 illustrates combining of Compound D C-AB1 and A beta polypeptides, wherein A) A β 40 peptide molecules that are used for virtual screening contain the rock steady structure of alpha-helix/beta sheet; B) the micromolecular inhibitor DC-AB1 that designs is incorporated into the C-end beta sheet zone of A β 40 peptide molecules; C) DC-AB1 and the concrete mode of action of A β 40 polypeptide amino acid residue bonded;
Fig. 3 illustrates that Compound D C-AB1 suppresses the fibrosis of A β 42 polypeptide in the mode of concentration dependence;
Fig. 4 illustrates that 20 hours experiment confirm: DC-AB1 of hatching of 37 ℃ have suppressed the Fibrotic formation of A beta polypeptides, data I, II, III, IV, V are that 2.5 μ L, 200 μ M A β 42 mix with 0 μ L, 10 μ L, 20 μ L, 30 μ L, 40 μ L 10mM DC-AB1 respectively, the fluorescence intensity that measures after 20 hours.
Fig. 5 A) A β 42 is not when having Compound D C-AB1 to exist, under 37 ℃ of environment, hatch 6 days after, the image of being seen under atomic force microscope can clearly be seen that A β 42 assembles to have formed fiber; B) A β 42 is with Compound D C-AB1 is hatched 6 days under 37 ℃ of environment after, and the image of being seen under atomic force microscope can find out significantly that Compound D C-AB1 has suppressed the formation of A β 42 fibers.
Fig. 6 uses electrophoretic analysis DC-AB1 to A β 42 Fibrotic restraining effect.
Fig. 7 adopts the circular dichroism spectrometry to observe Compound D C-AB1 to combine the variation that causes that A β 40 conformations take place afterwards with A β 40 polypeptide.
Embodiment
In following embodiment, will further illustrate the present invention.These embodiment only are used to illustrate the present invention, but do not limit the present invention in any way.All parameters among the embodiment and remaining explanation unless otherwise indicated, all are the explanation foundation with the quality.
2, the preparation of 2-two [3,5-two bromo-4-(2-hydroxyl) propoxy-phenyl] propane
1.1.1 2, the preparation (method one) of 2-two (4-hydroxy phenyl) propane
1.16 gram (0.02 mole) acetone and 5.64g. (0.06 mole) phenol are placed the flask of 100mL, and stirring adds the 12mL concentrated hydrochloric acid, and feeds the exsiccant hydrogen chloride gas, stopped reaction after one week of reaction.Add water, break solid reactant into pieces, boil off excessive phenol, suction filtration obtains almost to become white solid, and drying is used the 20mL ethyl alcohol recrystallization then, gets product as white needles 4.1 grams (productive rate 90%), fusing point 151-153 ℃ (151 ℃ of bibliographical informations).
1.1.2 2, the preparation (method two) of 2-two (4-hydroxy phenyl) propane
With 0.02 mole phenol and 0.02 mole 2,2-diethyl sulfenyl propane places the 100mL flask, stirs, and feeds hydrogen chloride gas, at room temperature continues reaction 6.5 hours; Then, stopped reaction, distillation, drying gets crude product, uses the 20mL ethyl alcohol recrystallization then, gets 2,2-two (4-hydroxy phenyl) propane (productive rate about 53%).
1.2 2, the preparation of 2-two (3,5-two bromo-4-hydroxy phenyls) propane
With 0.02 mole 2,2-two (4-hydroxy phenyl) propane dissolves in the 20mL methylene dichloride, adds 0.02 mole 30% H
2O
2, slowly drip the dichloromethane solution of 10mL0.02 mole bromine water again with dropping funnel, drip and finish stirring at normal temperature 20 hours; Add 50mL water,, merge organic layer and use MgSO with methylene dichloride (20mL * 3) extraction
4Drying is filtered, after filtrate concentrates, silica gel column chromatography separate (sherwood oil: ethyl acetate: methylene dichloride=4: 1: 1 (volume ratio), product 2,2-two (3,5-two bromo-4-hydroxy phenyls) propane, yield is about 96%, fusing point 180-182 ℃.
1.3 2, the preparation of 2-two [3,5-two bromo-4-(2-hydroxyl) propoxy-phenyl] propane
With 2 of the 1-chloro-2-propanol of 10mmol and 5mmol, 2-two (3,5-two bromo-4-hydroxy phenyls) propane places the flask of 100mL, adds the 50mL dehydrated alcohol, refluxes 4 hours; Stopped reaction boils off solvent then, adds 20ml water, extracts with methylene dichloride (20ml * 3), merges organic layer and uses MgSO
4Drying is filtered, and after filtrate concentrated, (sherwood oil: ethyl acetate: methylene dichloride=2: 1: 1 (volume ratio) got product 2,2-two [3,5-two bromo-4-(2-hydroxyl) propoxy-phenyl] propane in the silica gel column chromatography separation.
1HNMR(CDCl
3)ppm：δ1.24(s，3H，CH
3)，δ1.26(s，3H，CH
3)，δ3.85(m，2H，CH)，δ4.11(m，2H，CH
2)，δ4.24(m，2H，CH
2)，δ7.09(s，4H，ArH).EI-MS?m/s?660[M+].
2, the preparation of 2-two [3,5-two bromo-4-furyls-2-methanoyl phenyl] propane
1-chloro-2-propanol in embodiment 1 step 1.3 is replaced to furans-2-formyl chloride, and all the other desired raw materials, reagent and preparation method get product 2,2-two [3,5-two bromo-4-furyls-2-methanoyl phenyl] propane with embodiment 1.
1HNMR(CDCl
3)ppm：δ1.68(s，6H，CH
3)，δ6.63(m，2H，ArH)，δ7.42(s，4H，ArH)，δ7.49(m，2H，ArH)，δ7.73(m，2H，ArH).EI-MS?m/s?732[M+].
2, the preparation of 2-two [3,5-two bromo-4-(5-bromo-furyl)-2-methanoyl phenyl] propane
1-chloro-2-propanol in embodiment 1 step 1.3 is replaced to 5-bromo-furans-2-formyl chloride, and all the other desired raw materials, reagent and preparation method get product 2,2-two [3,5-two bromo-4-(5-bromo-furyl)-2-methanoyl phenyl] propane with embodiment 1.
1HNMR(CDCl
3)ppm：δ1.71(s，6H，CH
3)，δ6.55(m，2H，ArH)，δ7.12(s，3H，ArH)，δ7.31(m，3H，ArH).EI-MS?m/s?889[M+].
Embodiment 4
2, the preparation of 2-two [3,5-two bromo-4-(2-hydroxyl-3-morphine quinoline base) propoxy-phenyl] propane
(a) preparation method of 1-chloro-3-morphine quinoline base-2-propyl alcohol
0.05 mole of morphine quinoline and 0.065 mole of 2-chloromethyloxirane are placed the flask of 100mL, add the 50mL dehydrated alcohol, connect drying installation, refluxed 24 hours; Underpressure distillation then removes and desolvates, and gets product, can be not treated, be directly used in next step reaction.
(b) 1-chloro-2-propanol in embodiment 1 step 1.3 is replaced to 1-chloro-3-morphine quinoline base-2-propyl alcohol that above-mentioned (a) method prepares, all the other desired raw materials, reagent and preparation method are with embodiment 1, get product 2,2-two [3,5-two bromo-4-(2-hydroxyl-3-morphine quinoline base) propoxy-phenyl] propane.
1HNMR(DMSO)ppm：δ1.65(s，6H)，δ2.45(m，8H)，δ3.55(s，4H)，δ3.95(s，8H)，δ4.10(m，2H)，δ4.75(s，4H)，δ7.49(s，4H).EI-MS?m/s?830[M+].
Embodiment 5:
2, the preparation of 2-two { 4-[4-(phthalimide-based) phenoxy group] phenyl } propane
(a) 2, the preparation of 2-two (4-hydroxy phenyl) propane
1.16 gram (0.02 mole) acetone and 5.64g. (0.06 mole) phenol are placed the flask of 100mL, and stirring adds the 12mL concentrated hydrochloric acid, and feeds the exsiccant hydrogen chloride gas, stopped reaction after one week of reaction.Add water, break solid reactant into pieces, boil off excessive phenol, suction filtration obtains almost to become white solid, and drying is used the 20mL ethyl alcohol recrystallization then, gets product as white needles 4.1 grams (productive rate 90%), fusing point 151-153 ℃ (151 ℃ of bibliographical informations).
(b) preparation of 4-(phthalimide-based) bromobenzene
0.1 mole Tetra hydro Phthalic anhydride and 0.1 mole of para-bromoaniline are dissolved in 20mLN, and in the dinethylformamide, reaction is 20 minutes under microwave catalysis, adds 20mL water, with dichloromethane extraction (20mL * 3), and saturated NaCl liquid washing, MgSO
4Drying, (ethyl acetate: sherwood oil=1: 6 (volume ratio) gets 4-(phthalimide-based) bromobenzene, yield 96% to column chromatography for separation.
(c) 2, the preparation of 2-two { 4-[4-(phthalimide-based) phenoxy group] phenyl } propane
With 2 of 4-(phthalimide-based) bromobenzene of 10mmol and 5mmol, 2-two (4-hydroxy phenyl) propane places the flask of 100mL, adds the 50mL dehydrated alcohol, refluxes 4 hours; Stopped reaction boils off solvent then, adds 20ml water, extracts with methylene dichloride (20ml * 3), merges organic layer and uses MgSO
4Drying is filtered, and after filtrate concentrated, silica gel column chromatography separated, and got product 2,2-two 4-[4-(phthalimide-based) phenoxy group] and phenyl } propane.
1HNMR(DMSO)ppm：δ1.65(s，6H)，δ7.50(m，24H).EI-MS?m/s?670[M+].
Embodiment 6:
2,2-two 4-[4-(phthalimide-based) phenoxy group] and phenyl }-1,1,1,3,3, the preparation of 3-HFC-236fa
Acetone is replaced to 1,1,1,3,3, the 3-Perfluoroacetone, all the other desired raw materials, reagent and preparation method get product 2 with embodiment 5,2-two 4-[4-(phthalimide-based) phenoxy group] and phenyl }-1,1,1,3,3, the 3-HFC-236fa.
Embodiment 7:
1, the preparation of 1-two [4-(3-anisole acyloxy)] Santosol 360
4-(phthalimide-based) bromobenzene is replaced to the 3-methoxy benzoyl chloride, acetone replaces to pimelinketone, all the other desired raw materials, reagent and preparation method with the step (a) of embodiment 5 and (c), product 1,1-two [4-(3-anisole acyloxy)] Santosol 360.
1HNMR(DMSO)ppm：δ1.60(m，6H)，δ2.35(s，4H)，δ3.89(s，6H)，δ7.1(m，6H)，δ7.39(m，6H)，δ7.59(s，2H)，δ7.70(d，2H).EI-MS?m/s?536[M+].
Tentative embodiment:
The keying action pattern of Compound D C-AB1 (that is: 2,2-two [3,5-two bromo-4-(2-hydroxyl-3-morphine quinoline base) propoxy-phenyl] propane) and A β 40 polypeptide
The keying action of Compound D C-AB1 and A β 40 polypeptide as shown in Figure 2, this compound mainly is to combine with A beta polypeptides molecule with hydrophobic interaction.Two aromatic groups of DC-AB1 are attached to Val-24, Gly-29, Val-40 amino-acid residue and Tyr-10, the Phe-19 of A beta polypeptides molecule, the hydrophobic site place (as Fig. 2 C) that Phe-20 surrounds respectively), the morphine quinoline group of DC-AB1 is attached to the Val-40 of peptide molecule and the hydrophobic site place that Leu-34 surrounds.
The fluorescence spectrometry compound combines with the A beta polypeptides
Experimental principle:
The sulfo-thioflavin (Thioflavin T, ThT) with after fibrosis A beta polypeptides combines, its maximum emission wavelength is displaced to 482nm by 435nm, and the amount of fluorescence intensity and its bonded fibrosis A beta polypeptides has dependency.Compound and A beta polypeptides binding ability are strong more, that exist with free form in the solution, can Fibrotic A beta polypeptides also just few more, the sulfo-thioflavin is also just weak more in the fluorescent emission intensity of 482nm vicinity because of the binding fiber polypeptide, according to this principle, we can utilize fluorescence intensity to measure combining of compound and A beta polypeptides.
Experimental technique:
(available from U.S. Sigma-Aldrich company, production number A-9810) is dissolved among the DMSO with A β 42 polypeptide, is made into the solution of 200 μ M concentration.A β 42 solution are with 12, and the speed high speed centrifugation of 000rpm 10 minutes is got supernatant liquor and done experiment.Adopt micromolecular inhibitor DC-AB1 of the present invention to be dissolved among the DMSO, be made into a series of different concns of 0.1～10mM.
In 96 orifice plates, add the PBS damping fluid (pH=7.4) of 76 μ L and the compound of 2 μ L different concns, add 2 μ L200 μ M A β 42 again.After leaving standstill 1 hour under the room temperature, the 5 μ M sulfo-thioflavin solution that add 80 μ L in each hole (contain 50mM glycine-NaOH, pH=8.5).Left standstill under lucifuge, the room temperature 30 minutes, and used TECAN, Genios Pro
TMMicroplate reader is measured fluorescence intensity in 430nm excitation wavelength and 488nm transmitted wave strong point.As shown in Figure 3, Compound D C-AB1 stops A β 42 fibers to form with concentration dependence form.The concentration of A β 42 is 2.5 μ M in the reaction solution, and stoping the concentration of the required DC-AB1 of half concentration A β 42 fibrosiss is 35.6 μ M, promptly needs the compound of 14.24 times of amounts can stop the fibrosis of half concentration A β 42.
Compound D C-AB1 suppresses the formation of A β 42 polypeptide fibersization
DC-AB1 can also be by hatching experiment confirm in 20 hours for a long time to the restraining effect of A β 42 polypeptide fibersization.We mix 2.5 μ L, 200 μ M A β, 42 polypeptide solutions respectively with 0 μ L, 10 μ L, 20 μ L, 30 μ L, 40 μ L 10mM DC-AB1, adding PBS solution to final volume is 50 μ L.Reaction system was hatched in 37 ℃ water-bath 20 hours.Add 100 μ L, 7.5 μ M ThT (in PBS) again, measure intensity in 430nm excitation wavelength, 483nm place fluorescent emission.Experiment is carried out on Hitachi F-2500 luminoscope, and PMT is set to 700, and the reaction times is 0.08 second.As shown in Figure 4, under the situation that does not have inhibitor to exist, through 20 hours hatch, the fluorescence intensity that measures from A β 42 reaction systems approximately was 2,700 RFU (data I).Along with increasing of inhibitor DC-AB1 concentration in the reaction system, fluorescence intensity also decreases, to about 1,100RFU (data I I → V).Thereby illustrate that A β 42 fibers that form have reduced, the existence of DCAB1 has obviously suppressed the Fibrotic formation of A beta polypeptides.
Utilize atomic power electron microscopic observation Compound D C-AB1 to suppress A β 42 polypeptide fibersization
2.5 μ L 10mM DC-AB1 are mixed with 2.5 μ L, 200 μ M A β 42, and adding PBS damping fluid to the final volume that contains 20%TFE pH=7.4 is 50 μ L.In contrast, to add PBS damping fluid to the final volume that contains 20%TFE pH=7.4 be 50 μ L to 2.5 μ L, 200 μ M A β 42.These two samples were hatched 6 days under 37 ℃ of environment.From these two samples, get 3 μ L and be put on the sheet mica respectively, placed 5 minutes, dry up, usefulness tapping pattern is in Multimode Nano IIIa atomic force microscope (Veeco, Woodbury, NY) following form of observing A β 42 polypeptide.The resonant frequency of employed 7TESP probe is 280-290kHz, and sweep velocity is 1-3Hz.Fig. 5 A) be A β 42 when not having Compound D C-AB1 to exist, the image of being seen under atomic force microscope can clearly be seen that A β 42 assembles to have formed fiber.Fig. 5 B) be A β 42 after Compound D C-AB1 is hatched, the image of being seen.With Fig. 5 A) contrast, can find out significantly that Compound D C-AB1 has suppressed the formation of A β 42 fibers.
Compd A B1 is to the influence of A β 42 polypeptide aggregation states
3 μ l, 200 μ M A β 42 are mixed with 3 μ l 10mM DC-AB1, add PBS (20%TFE, pH=7.4) to final volume be 20 μ l.In contrast, 3 μ l, 200 μ M A β 42 add PBS (20%TFE, pH=7.4) to final volume be 20 μ l.With these two samples 37.Hatched 6 days under ℃ environment, with these two samples of 10% polyacrylamide gel (non-sex change glue) electrophoretic analysis, the result as shown in Figure 6.What add in first sample cell is freshly prepared A β 42 (not through hatching), can see that one is A β 42 monomeric black-tapes; What add in the 3rd sample cell is the sample that A β 42 is hatched separately when not having DC-AB1, does not see monomeric black-tape, illustrates that A β 42 has assembled fiber or the polymer for macromolecule; And what add in second sample cell is the sample that A β 42 is hatched when having DC-AB1 to exist, and can see that A β 42 still exists with the form from the monomer to the oligomer.From this electrophorogram, can be clear that DC-AB1 is to A β 42 Fibrotic restraining effect.
Circular dichroism spectrometry observation DC-AB1 combines the influence to its conformation with A β 40
Whether we can cause that A β 40 conformations change after also having studied Compound D C-AB1 and A β 40 combines with circular dichroism spectrum.The circular dichroism spectrum experiment is to record in 190-260nm range of wavelengths scope in the quartz sample pool of 0.1cm, and the background signal of water is therefrom deducted.Experiment be at room temperature on Jasco J-810 circular dichroism spectrometer, record (JASCO Corporation, Japan).Shown in figure seven, A β 40 in the aqueous solution with the mixed in molar ratio of Compound D C-AB1 with 1: 1, the CD of A β 40 spectrum changes as can be seen.This result is more obvious in the aqueous solution that contains 20%TFE (trifluoroethanol).A β 40 after adding 20%TFE, its alpha-helix conformation showed increased, this is because the hydrogen bond action of the removable beta sheet of this low polar solvent of TFE, and the α-Luo Xuanjiegou of stabilizing protein.And after the Compound D C-AB1 that adds equimolar amount, A β 40 formed alpha-helix content in 20%TFE obviously reduces, and the conformation of beta sheet increases, show that the two the lowest point peak 208nm, the 220nm that characterize alpha-helix conformation weaken, and occurred characterizing the characteristic peak of beta sheet conformation at the 216nm place.This further illustrates DC-AB1 and combines with A β 40, and depolymerization the alpha-helix of A β 40, impel its to form beta sheet.
The possibility of utilizing on the industry
The preparation method of compound of Formula I of the present invention has the reaction condition gentleness, abundant raw material is easy , the advantage such as operation and post processing be simple.
Compound of Formula I of the present invention at computer virtual screening and beta-secretase in conjunction with experiment In, show the effect of activation/inhibitory enzyme activity, can effectively treat and prevent Alzheimer Disease, children mental retardation disease, amnesia and other painstaking effort brain pipe diseases.
Toxicity of compound of the present invention is very low.
Therefore, compound of the present invention or its pharmaceutically acceptable salt can be used for preparation treatment or The medicine of associated diseases is regulated in prevention by secretase.
Claims (16)
1, a kind of compound or its pharmacy acceptable salt with following general formula I symmetrical structure:
Wherein:
W is
Or
Wherein, n=1 or 2;
Y is O, NH or S;
R
1For aromatic base,
Or
Wherein, Z is OH, SH or NH
2
R
4And R
5Respectively be the saturated or unsaturated alkyl of hydrogen, C1-C6 straight or branched, saturated or unsaturated cycloalkyl group, aromatic base or 5-7 unit heterocyclic radical; Described aromatic base is phenyl, substituted-phenyl, naphthyl or xenyl, the fragrant heterocycle of 5-7 unit, wherein said substituted-phenyl comprises 1～4 substituting group, and this substituting group is selected from halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl and C1-C4 acyl group; The first heterocyclic radical of described 5-7 contains 1-3 heteroatoms that is selected from oxygen, sulphur and nitrogen; and optional contain one or more substituting groups that are selected from halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl, C1-C4 acyl group and aromatic base, described 5-7 unit heterocyclic radical can with R
4Or R
5In phenyl and close;
R
2And R
3Respectively be saturated or unsaturated alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl, C1-C4 acyl group, C3-C7 cyclic hydrocarbon radical, benzyl, aromatic base or the 5-7 unit heterocyclic radical of hydrogen, halogen, C1-C6 straight or branched; Described halogen is fluorine, chlorine, bromine or iodine; Described aromatic base is phenyl, substituted-phenyl, naphthyl or xenyl, the fragrant heterocycle of 5-7 unit; Wherein said substituted-phenyl comprises 1～4 substituting group, and this substituting group is selected from halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl and C1-C4 acyl group; The first heterocyclic radical of described 5-7 contains 1-3 heteroatoms that is selected from oxygen, sulphur and nitrogen; and optional containing one or more substituting groups that are selected from halogen, C1-C6 straight or branched alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoromethyl, trifluoromethoxy, carboxyl, C1-C4 alkoxyl group, sulfydryl, C1-C4 acyl group and aromatic base, described 5-7 unit heterocyclic radical can and close with the phenyl of parent nucleus.
2, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is
Y is O; R
1Be phenyl or substituted-phenyl; R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl.
3, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl; Wherein, R
4Be selected from methyl, morphine quinoline base, methylpiperazine base, phenyl and substituted-phenyl; Z is a hydroxyl.
4, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl; R wherein
5Be selected from phenyl, substituted-phenyl, thienyl and furyl.
5, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is
Y is NH; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl; R
4Be selected from methyl, morphine quinoline base, methylpiperazine base, phenyl and substituted-phenyl.
6, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is
Y is O; R
1Be phenyl or substituted-phenyl; R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl.
7, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl; R wherein
5Be selected from phenyl, substituted-phenyl, thienyl and furyl.
8, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is
Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl; R wherein
5Be selected from phenyl, substituted-phenyl, thienyl and furyl.
9, compound according to claim 1 or its pharmacy acceptable salt is characterized in that, W is-CH
2-; Y is O; R
1For
R
2Be selected from hydrogen, halogen, methyl and ethyl; R
3Be selected from hydrogen, halogen, methyl and ethyl; R wherein
5Be selected from phenyl, substituted-phenyl, thienyl and furyl.
10, compound according to claim 1 or its pharmacy acceptable salt, it is characterized in that, described compound is 2,2-two [3,5-two bromo-4-(2-hydroxyl) propoxy-phenyl] propane, 2,2-two [3,5-two bromo-4-furyls-2-methanoyl phenyl] propane, 2,2-two [3,5-two bromo-4-(5-bromo-furyl)-2-methanoyl phenyl] propane, 2,2-two [3,5-two bromo-4-(2-hydroxyl-3-morphine quinoline base) propoxy-phenyl] propane, 2,2-two 4-[4-(phthalimide-based) phenoxy group] and phenyl } propane, 2,2-two 4-[4-(phthalimide-based) phenoxy group] and phenyl }-1,1,1,3,3,3-HFC-236fa or 1,1-two [4-(3-anisole acyloxy)] Santosol 360.
11, according to each described compound of claim 1～10 or its pharmacy acceptable salt, it is characterized in that described pharmacy acceptable salt is that described compound and propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate or citric acid organic acid or aspartic acid, L-glutamic acid acidic amino acid form behind the ester sodium salt, sylvite, calcium salt, aluminium salt or the ammonium salt that forms with mineral alkali again; Or the methylamine salt, ethylamine salt or the ethanolamine salt that form with organic bases; Or form hydrochloride, hydrobromate, hydrofluoride, vitriol, nitrate, phosphoric acid salt, formate, acetate, picrate, mesylate or esilate behind the ester with Methionin, arginine, ornithine basic aminoacids.
12, a kind of method for preparing each described compound of Formula I of claim 1～10, wherein R
1, R
2, R
3, W, Y definition according to claim 1:
Described method comprises the steps:
(1) compound (II) under concentrated hydrochloric acid catalysis with W
1Reaction gets compound (III);
Wherein, W
1Can be acetone, 1,1,1,3,3,3-Perfluoroacetone or naphthenone;
(2) in dichloromethane solvent, compound (III) and halogen X
2And hydroperoxidation, get compound (IV), wherein X is a halogen atom;
(3) compound (IV) and R
1The X halide reaction gets compound of Formula I;
Or
(1) compound (II) under concentrated hydrochloric acid catalysis with W
1Reaction gets compound (III);
Wherein, W
1Can be acetone, 1,1,1,3,3,3-Perfluoroacetone or naphthenone;
(2) compound (III) and R
1The X halide reaction gets compound of Formula I.
13, a kind of pharmaceutical composition is characterized in that, said composition contains each described compound of claim 1～11 or its pharmacy acceptable salt for the treatment of significant quantity.
14, pharmaceutical composition according to claim 13 is characterized in that, described compound or its pharmacy acceptable salt account for 65%～99.5% of this pharmaceutical composition gross weight.
According to claim 13 or 14 described pharmaceutical compositions, it is characterized in that 15, said composition further comprises one or more pharmaceutically acceptable carriers, odorant agent, flavouring agent, vehicle or diluent.
16, each described compound of a kind of claim 1～11 or its pharmacy acceptable salt prevent and/or treat application in the medicine of Alzheimer's disease in preparation.
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| PCT/CN2007/001518 WO2008006276A1 (en) | 2006-07-03 | 2007-05-09 | THE SMALL MOLECULE INHIBITOR WHICH CAN INHIBIT THE AβPOLYPEPTIDE FIBROSIS OF ALZHEIMER'S DISEASE, THEIR PREPAREATION METHODS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF |
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| CN1260303C (en) * | 2004-08-13 | 2006-06-21 | 大连理工大学 | Red anthraquinone dispersion dye |
| JP4455404B2 (en) * | 2004-09-10 | 2010-04-21 | キヤノン株式会社 | Method for manufacturing electrophotographic photosensitive member, electrophotographic photosensitive member, process cartridge, and electrophotographic apparatus |
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| CN102706839A (en) * | 2011-01-31 | 2012-10-03 | 香港科技大学 | Water-soluble aie illuminant and purpose of the illuminant in detecting and delaying starch sample fibering of starch sample protein |
| CN102706839B (en) * | 2011-01-31 | 2015-08-12 | 香港科技大学 | Water-soluble AIE luminous agent and detect and postpone amyloid protein amyloid fiber in purposes |
| CN106632144A (en) * | 2016-10-31 | 2017-05-10 | 浙江省医学科学院 | Cyclopropane compound as well as preparation method and application thereof |
| CN106632144B (en) * | 2016-10-31 | 2019-02-26 | 浙江省医学科学院 | A kind of cyclopropanes compound and its preparation method and application |
| CN110396064A (en) * | 2019-07-25 | 2019-11-01 | 南京大学 | The application of methanesulfonamide derivatives and preparation method thereof and prevention and treatment Alzheimer disease |
| CN110396064B (en) * | 2019-07-25 | 2020-07-10 | 南京大学 | Methanesulfonamide derivative, preparation method thereof and application of methanesulfonamide derivative in prevention and treatment of Alzheimer disease |
| CN110963985A (en) * | 2019-12-27 | 2020-04-07 | 珠海派锐尔新材料有限公司 | Preparation method of 4, 4' - (hexafluoroisopropylidene) diphthalic anhydride |
| CN112778094A (en) * | 2021-02-02 | 2021-05-11 | 山东迈特新材料科技有限公司 | Preparation process of high-purity tetrabromobisphenol A |
| CN112778094B (en) * | 2021-02-02 | 2023-02-17 | 山东迈特新材料科技有限公司 | Preparation process of high-purity tetrabromobisphenol A |
| CN113008850A (en) * | 2021-02-07 | 2021-06-22 | 首都医科大学宣武医院 | Application of diagnosing Alzheimer disease and device for diagnosing Alzheimer disease |
| CN113008850B (en) * | 2021-02-07 | 2022-02-25 | 首都医科大学宣武医院 | Application of diagnosing Alzheimer disease and device for diagnosing Alzheimer disease |
| WO2023036868A1 (en) | 2021-09-10 | 2023-03-16 | Reuter Chemische Apparatebau E.K. | (het)aryl substituted bisphenol compounds and thermoplastic resins |
Also Published As
| Publication number | Publication date |
|---|---|
| CN101100416B (en) | 2011-02-16 |
| WO2008006276A1 (en) | 2008-01-17 |
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