CN105384691A - Preparation method and application of glutaminylcyclase (QC) inhibitor - Google Patents

Preparation method and application of glutaminylcyclase (QC) inhibitor Download PDF

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CN105384691A
CN105384691A CN201510701143.XA CN201510701143A CN105384691A CN 105384691 A CN105384691 A CN 105384691A CN 201510701143 A CN201510701143 A CN 201510701143A CN 105384691 A CN105384691 A CN 105384691A
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inhibitors
glutaminyl cyclase
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inhibitor
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CN105384691B (en
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吴海强
董瑶
邹永东
郑易之
李满满
刘志刚
贺震旦
余熙
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Shenzhen University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/61—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms

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Abstract

The invention discloses a preparation method and application of a glutaminylcyclase (QC) inhibitor. The preparation method comprises the of following steps that (1) raw materials of a unit A including a borate group, amino and R1 and raw materials of a unit B including a bromine substituent group and R2 serving as starting materials are subjected to a Suzuki coupling reaction to prepare a unit A and unit B coupled intermediate; (2) the unit A and unit B coupled intermediate and a dibromoalkyl chain serving as raw materials are subjected to an SN2 reaction to prepare an intermediate containing an alkyl chain; and (3) the intermediate containing the alkyl chain and imidazole or substituent-containing imidazole serving as raw materials are subjected to the SN2 reaction to prepare the QC inhibitor. The preparation method can be completed only by means of Suzuki coupling, SN2 reaction and the like, is simple and feasible in process route and high in yield, and is more suitable for large-scale preparation; and the QC inhibitor can be widely applied to development of new high-efficient QC inhibitor drugs, development of drugs, innovative drugs and diagnostic kits for alzheimer disease (AD) and other QC specifically highly expressed related diseases, and the like.

Description

A kind of preparation method of inhibitors of glutaminyl cyclase and application
Technical field
The present invention relates to medicinal chemistry art, particularly relate to a kind of preparation method and application of inhibitors of glutaminyl cyclase.
Background technology
Glutaminyl cyclase (Glutaminylcyclase, QC, EC2.3.2.5) is that one can hold glutamine residue intramolecular cyclization reaction to generate the enzyme of Pyrrolidonecarboxylic acid (pGlu) by the N such as catalytic polypeptide, albumen.1963, QC found first in tropical plants papaya (Caricapapaya) latex, and rear research confirms, QC all has distribution in plant, animal, microorganism.Mammals QC has well-conserved, and without any sequence homology between papaya QC, and with bacterium aminopeptidase, there is significant sequence homology, therefore animal and plant QC has different evolutionary source.In plant, the physiological function of QC is very not clear and definite, may have certain effect in plant defense pathogenic micro-organism process.QC in animal body has N such as changing albumen and holds chemical structure, regulates the important biomolecule functions such as activity, enhanced stability, and the keying action of QC increased activity in multiple major disease pathogeny is subject to the great attention of people day by day.
Alzheimer's disease (Alzheimer ' sdisease, AD) be a kind of common nerve degenerative diseases, be the principal mode of senile dementia, AD patient exceedes more than 65% of old dementia patients sum.With the development of population in the world aging, AD sickness rate and patient numbers raise rapidly, and epidemiology survey shows, and AD has become the third-largest worldwide health problem being only second to cardiovascular and cerebrovascular diseases and tumour.AD cardinal symptom comprises Progressive symmetric erythrokeratodermia memory and cognition dysfunction etc., has the features such as irreversible, high mortality, clinically at present there is no specific treatment medicine.
AD pathogenesis is comparatively complicated, people propose numerous hypothesis from different perspectives, comprise amyloid-beta (A β) cascade theory, Tau albumen tangles precipitation theory, oxidative stress theory, biological metal ionic homeostasis is unbalance theory, mitochondrial function exhaustion theory etc.But AD is definite, and pathomechanism does not still understand.Anti-AD Research progress of drugs based on above-mentioned academic hypothesis is slow.
Clinicopathological study confirms, the Hyperphosphorylationof Tau albumen entanglement etc. of the AD pathological characteristics A β precipitation that mainly brain neuroblastoma unit is outside and inside neurons.But in recent years, find with clinical study in multinomial body, with Elderly people human brain A β senile plaque precipitate unlike, the main component of AD patient's brain senile plaque precipitation is not A β, but the A β of variation, particularly N holds the pGlu-A β of glutamine residue molecule inner ring condensation, and especially pGlu-A β 42/pGlu-A β 40 etc., content is more than 50%.PGlu-A β has stronger neurotoxicity, faster aggregate and precipitate speed, stronger stability, and its generation is directly related with the generation of AD clinical symptom, be than A β occur more Zao, and AD to fall ill more special mark.
The deeply display further of correlative study, pGlu-A β is the product of QC enzyme catalysis, and Selective depression QC activity significantly can suppress the generation of pGlu-A β and the formation of senile plaque precipitation, and obviously improves the AD such as cognition, impaired memory function symptom.Meanwhile, research finds that AD patient brain QC specificity overexpression is that AD falls ill early stage significant pathology, before generation pGlu-A β, A β, can detect that the characteristic of QCRNA raises in peripheral blood.Visible, QC high expression level is the crucial promoting factor of AD morbidity, development, and QC is that AD pathology and causal anti-AD drug research open new research direction, and QC inhibitor is expected to become the strategic breakthrough mouth innovating anti-AD drug development.
In addition, QC all has specificity overexpression to the morbidity of the relevant complex disease of body inherent immunity functional disorder rheumatic arthritis, non-alcoholic hepatitis, cutaneous melanoma, lupus erythematosus syndromes etc. are multiple.QC inhibitor also can be used for the treatment of above-mentioned various diseases.
Current, the correlative study of QC inhibitor is relatively less.EP1713780B1, EP2091948B1, US7304086B2, US7371871B2, US7741354B2, US7892771B2, US8129160B2, US8188094B2, US8202897B2, US8227498B2, US20080214620A1, US200880286231A1, US20090269301A1 etc. patent discloses a class line style QC inhibitor molecules.Such QC inhibitor remains in certain weak point in structure and energy, and as single in precursor structure, poorly water-soluble, cross-film poor performance, limited activity, synthesis step are loaded down with trivial details.Therefore, further expansion QC inhibitor chemical structure diversity, the new QC inhibitor that design and synthesis druggability is higher, and study QC inhibitor to the therapeutic action of the diseases such as AD, rheumatic arthritis, non-alcoholic hepatitis, cutaneous melanoma, lupus erythematosus syndromes and mechanism, to QC high expression level related pathologies study mechanism, causal new drug research, QC target early diagnosis and therapy etc., all there is very important scientific meaning and using value.
Summary of the invention
In view of above-mentioned the deficiencies in the prior art; the object of the present invention is to provide a kind of preparation method and application of inhibitors of glutaminyl cyclase, being intended to solve existing QC inhibitor there is the problems such as precursor structure is single, poorly water-soluble, cross-film poor performance, limited activity, synthesis step are loaded down with trivial details in it.
Technical scheme of the present invention is as follows:
A preparation method for inhibitors of glutaminyl cyclase, the general structure of described inhibitors of glutaminyl cyclase is as follows: wherein, A unit is phenyl ring, six-membered Hetero-aromatic, five yuan of hetero-aromatic rings, seven yuan of aromatic rings, naphthalene, anthracene, naphthoquinones or many aromatic ring systems, R 1it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido, phosphate and substituent thereof;
Unit B is phenyl ring, six-membered Hetero-aromatic, five yuan of hetero-aromatic rings, seven yuan of aromatic rings, naphthalene, anthracene, naphthoquinones or many aromatic ring systems, R 2it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido, phosphate and substituent thereof;
In C unit, R on imidazole ring 3it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, amido and substituent thereof;
Wherein, preparation method comprises step:
(1) with boronate, amido and R 1a unit raw material and with bromine substituent and R 2unit B raw material initial, through Suzuki linked reaction, preparation A unit and the intermediate of unit B coupling;
(2) with the intermediate of A unit and unit B coupling and dibromo alkyl chain for raw material, through the intermediate of SN2 reaction preparation containing alkyl chain;
(3) with the intermediate containing alkyl chain and imidazoles or containing substituting group imidazoles for raw material, prepare inhibitors of glutaminyl cyclase through SN2 reaction.
An application for inhibitors of glutaminyl cyclase, wherein: described inhibitors of glutaminyl cyclase is applied in the anti-AD lead drug of QC target.
An application for inhibitors of glutaminyl cyclase, wherein: described inhibitors of glutaminyl cyclase is applied in the medicine for the treatment of QC specificity overexpression disease.
An application for inhibitors of glutaminyl cyclase, wherein: described inhibitors of glutaminyl cyclase is applied in QC diagnostic kit.
Beneficial effect: the preparation method in the present invention, it only needs Suzuki coupling, SN2 reaction etc. to complete, compared to existing technology, and operational path simple possible of the present invention, yield is high, is more suitable for extensive preparation; QC inhibitor of the present invention can be widely used in the exploitation etc. of the medicine of the QC specificity overexpression relative disease such as exploitation, AD of efficient QC inhibitor kind new medicine, original new drug and diagnostic kit.
Accompanying drawing explanation
Fig. 1 is QC enzyme inhibition activity test philosophy schematic diagram in the present invention.
Embodiment
The invention provides a kind of preparation method and application of inhibitors of glutaminyl cyclase, for making object of the present invention, technical scheme and effect clearly, clearly, the present invention is described in more detail below.Should be appreciated that specific embodiment described herein only in order to explain the present invention, be not intended to limit the present invention.
Inhibitors of glutaminyl cyclase of the present invention (QC inhibitor), its structural formula is as follows:
QC inhibitor of the present invention, it comprises three structural pharmacophore unit: A, B and C, wherein, A unit is phenyl ring, six-membered Hetero-aromatic (N, S, O), five yuan of hetero-aromatic rings (C, N, S, O), seven yuan of aromatic rings, naphthalene, anthracene, naphthoquinones or (mixing) many aromatic ring systems, R 1it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido, phosphate and substituent (such as the substituent of hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido or phosphate) thereof; R 1monosubstituted or different positions polysubstituted.
Unit B is phenyl ring, six-membered Hetero-aromatic (N, S, O), five yuan of hetero-aromatic rings (C, N, S, O), seven yuan of aromatic rings, naphthalene, anthracene, naphthoquinones or (mixing) many aromatic ring systems, R 2it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido, phosphate and substituent (such as the substituent of hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido or phosphate) thereof; R 2monosubstituted or different positions polysubstituted.
In C unit, R on imidazole ring 3it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, amido and substituent thereof.R 3monosubstituted or different positions polysubstituted.R 3the position of substitution 2,4 or 5 of imidazole ring.In C unit, carbon atom n=1-4 in alkyl chain, such as n is 1,2,3 or 4.
Further, unit B and C unit are ortho position, a position or contraposition in the link position of A unit.
Further, in same compound, A unit is identical with the mother nucleus structure of unit B or not identical, R 1and R 2structure identical or not identical.
QC inhibitor in the present invention pharmaceutically acceptable salt, comprises lithium salts, sodium salt, sylvite, magnesium salts, calcium salt, molysite, mantoquita, organic ammonium salt, hydrochloride, phosphoric acid salt, acetate, propionic salt, oxalate, Citrate trianion etc.
Preparation method of the present invention comprises step:
(1) with boronate, amido and R 1a unit raw material and with bromine substituent and R 2unit B raw material initial, through Suzuki linked reaction, preparation A unit and the intermediate of unit B coupling;
(2) with the intermediate of A unit and unit B coupling and dibromo alkyl chain for raw material, through the intermediate of SN2 reaction preparation containing alkyl chain;
(3) with the intermediate containing alkyl chain and imidazoles or containing substituting group imidazoles for raw material, prepare inhibitors of glutaminyl cyclase through SN2 reaction.
Then obtained QC inhibitor can be carried out Spectral Identification analysis after purification by silica gel column chromatography.
The invention provides a kind of application of inhibitors of glutaminyl cyclase, wherein: be applied to by described inhibitors of glutaminyl cyclase in the anti-AD lead drug of QC target.
Invention also provides a kind of Another Application of inhibitors of glutaminyl cyclase, wherein: be applied to by described inhibitors of glutaminyl cyclase in the medicine for the treatment of QC specificity overexpression disease (comprising rheumatic arthritis, non-alcoholic hepatitis, cutaneous melanoma, lupus erythematosus syndromes etc.).
Invention also provides a kind of Another Application of inhibitors of glutaminyl cyclase, wherein: be applied in QC diagnostic kit by described inhibitors of glutaminyl cyclase.
The synthesis of embodiment 1:N-(3-(1H-imidazoles-1-base) propyl group)-3', 4'-dimethoxy-[1,1'-biphenyl]-2-amine (MQI-1), its synthetic route is as follows:
A, 3', 4'-dimethoxy-[1,1'-biphenyl]-2-amine: by bromaniline (5.81mmol, 1 equivalent), 3,4-dimethoxyphenylboronic (6.98mmol, 1.2 equivalents) and [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride (II) dichloromethane complex (0.35mmol, 0.06 equivalent) is placed in 50ml round-bottomed flask, adds the dioxane of 10ml and the 2mol/LK of 10ml respectively 2cO 3solution, 100 DEG C, backflow 3h.Add saturated NaCl solution cancellation reaction, be cooled to room temperature, extraction into ethyl acetate three times, after merging, saturated NaCl solution is washed once, anhydrous Na 2sO 4drying, silica gel column chromatography collects product, and yield is 90%.
B, N-(3-bromopropyl)-3', 4'-dimethoxy-[1,1'-biphenyl]-2-amine: 3', 4'-dimethoxy-[1,1'-biphenyl]-2-amine (872.32umol, 1 equivalent), 1,3-dibromopropane (6.11mmol, 7 equivalents) be dissolved in 6ml anhydrous acetonitrile, add anhydrous K 2cO 3(1.74mmol, 2 equivalents) solid, stirring and refluxing is spent the night, and steaming desolventizes, and ethyl acetate and water extract three times, merges organic phase and washes once by saturated NaCl solution, anhydrous Na 2sO 4drying, silica gel column chromatography collects product, and yield is 48%.
C, N-(3-(1H-imidazoles-1-base) propyl group)-3', 4'-dimethoxy-[1,1'-biphenyl]-2-amine: imidazoles (285.51umol, 1 equivalent) is dissolved in 1ml anhydrous acetonitrile, adds dry K 2cO 3(285.51umol, 1 equivalent), stirring at normal temperature 15min, adds gained N-in above-mentioned b (3-bromopropyl)-3', 4'-dimethoxy-[1,1'-biphenyl] the 1ml anhydrous acetonitrile of-2-amine, backflow is spent the night, and steaming desolventizes, and ethyl acetate and water extract three times, merge organic phase and wash once by saturated NaCl solution, anhydrous Na 2sO 4drying, silica gel column chromatography collects product, and yield is 20%.
The synthesis of the fluoro-N-of embodiment 2:4'-(3-(4-methyl-1 H-imidazole-1-group) propyl group)-[1,1'-biphenyl]-2-amine (MQI-31), its synthetic route is as follows:
A, 4'-fluoro-[1,1'-biphenyl]-2-amine: by bromaniline (5.81mmol, 1 equivalent), 4-fluorobenzoic boric acid (6.98mmol, 1.2 equivalents) and [1,1 '-bis-(diphenylphosphine) ferrocene] palladium chloride (II) dichloromethane complex (0.35mmol, 0.06 equivalent) be placed in 50ml round-bottomed flask, solvent is 10ml dioxane and 10ml2mol/LK 2cO 3solution, stirs 3h by 100 DEG C, and add saturated NaCl solution cancellation reaction, extraction into ethyl acetate three times, after merging, saturated NaCl solution is washed once, anhydrous Na 2sO 4drying, silica gel column chromatography collects product, and yield is 94%.
B, N-(3-bromopropyl)-4'-fluorine [1,1'-biphenyl]-2-amine: 4'-fluoro-[1,1'-biphenyl]-2-amine (534.15umol, 1 equivalent) and 1,3-dibromopropane (3.74mmol, 7 equivalents) is dissolved in 4ml anhydrous acetonitrile, adds anhydrous K 2cO 3(1.74mmol, 2 equivalents) solid, stirring and refluxing is spent the night, and steaming desolventizes, and ethyl acetate and water extract three times, merges organic phase and washes once by saturated NaCl solution, anhydrous Na 2sO 4drying, silica gel column chromatography collects product, and yield is 45%.
The fluoro-N-of c, 4'-(3-(4-methyl-1 H-imidazole-1-group) propyl group)-[1,1'-biphenyl]-2-amine: 4-methylimidazole (324.48umol, 1 equivalent) is dissolved in 1ml anhydrous acetonitrile, adds anhydrous K 2cO 3(285.51umol, 1 equivalent), stirring at normal temperature 15min; Add the 1ml anhydrous acetonitrile of gained N-in above-mentioned b (3-bromopropyl)-4'-fluorine [1,1'-biphenyl]-2-amine, stirring and refluxing is spent the night, steaming desolventizes, ethyl acetate and water extract three times, merge organic phase and wash once by saturated NaCl solution, anhydrous Na 2sO 4drying, silica gel column chromatography collects product, and yield is 18%.
Embodiment 3:QC inhibitor is tested QC enzyme inhibition activity
QC enzyme inhibition activity test philosophy schematic diagram as shown in Figure 1.Enzyme is lived in testing and is carried out in 96 hole enzyme plates, adopt 200ulpH8.0Tris buffer system: 0.3mMNADH, 2.0mM fresh preparation Gln-Gln, 14mM α-ketoglutaric acid, 30U/ml glutamate dehydrogenase, 50mMTris, pH8.0 damping fluid, finally add the mixed solution of 0.28 μM of recombinant human QC albumen and different concns inhibitor, vibrate after 30 seconds with the absorption value change in 340nm wavelength place 15min of NADH during microplate reader detection of dynamic 25 DEG C, carry out a data gathering every 30s, according to test result, calculate inhibitor to QC enzyme inhibiting IC alive 50value, the test result for different Q C inhibitor is as shown in table 1, and wherein the structural formula of QC inhibitor is:
Table 1
The anti-AD effect of embodiment 4QC inhibitor
With double transgenic AD mouse (B6C3-Tg (APPswe, PSEN1dE9) 85Dbo/MmJNju) be animal pattern, select female 2 monthly age AD mouse, if medication group and control group, each 6, take MQI-1 as experimental drug, dosage 8.0mg/kg, abdominal injection, every administration in two days 1 time, control group is to equivalent buffered soln, and continuous use carried out Behaviors survey after 6 weeks.Nestconstruction Behaviors survey, the test paper group of equivalent is put at random in each cage, and be uniformly distributed, at interval after 24 hours, the situation of moving, pulverizing and nesting with test paper group that observed and recorded mouse is rolled into a ball test paper, result shows, the behavior of building again of medication group mouse obviously improves, and cognitive, memory function significantly strengthens.AD associated pathology is tested, and puts to death mouse, gets cerebral tissue, and saccharose gradient dewaters, and carry out hat dress frozen section after OCT embedding, then carry out WesternBlot and ThS staining analysis, result shows, after medication, the senile plaque precipitation of mouse brain obviously reduces.Comprehensive above-mentioned experiment, MQI-1 demonstrates significant anti-AD effect in Mice Body.
In sum, the preparation method in the present invention, it only needs Suzuki coupling, SN2 reaction etc. to complete, compared to existing technology, and operational path simple possible of the present invention, yield is high, is more suitable for extensive preparation; QC inhibitor of the present invention is remarkable to QC inhibit activities, the IC of part of compounds 50reach 4.72 μMs, be worth further optimization design, synthesis as lead compound, possess the very high potential that exploitation becomes novel, efficient QC.QC inhibitor of the present invention can be used for the exploitation etc. of the multiple exploitation with QC specificity overexpression relative disease causal treatment medicine such as AD, tumour, rheumatic arthritis, pathogeny and Study on Molecular Mechanism, early diagnosis and diagnostic kit.
Should be understood that, application of the present invention is not limited to above-mentioned citing, for those of ordinary skills, can be improved according to the above description or convert, and all these improve and convert the protection domain that all should belong to claims of the present invention.

Claims (4)

1. a preparation method for inhibitors of glutaminyl cyclase, the general structure of described inhibitors of glutaminyl cyclase is as follows: wherein, A unit is phenyl ring, six-membered Hetero-aromatic, five yuan of hetero-aromatic rings, seven yuan of aromatic rings, naphthalene, anthracene, naphthoquinones or many aromatic ring systems, R 1it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido, phosphate and substituent thereof;
Unit B is phenyl ring, six-membered Hetero-aromatic, five yuan of hetero-aromatic rings, seven yuan of aromatic rings, naphthalene, anthracene, naphthoquinones or many aromatic ring systems, R 2it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, carboxyl, nitro, sulfonic group, amido, phosphate and substituent thereof;
In C unit, R on imidazole ring 3it is the one in hydrogen, straight-chain alkyl, branched-chain alkyl, alkoxyl group, halogen, amido and substituent thereof;
It is characterized in that, preparation method comprises step:
(1) with boronate, amido and R 1a unit raw material and with bromine substituent and R 2unit B raw material initial, through Suzuki linked reaction, preparation A unit and the intermediate of unit B coupling;
(2) with the intermediate of A unit and unit B coupling and dibromo alkyl chain for raw material, through the intermediate of SN2 reaction preparation containing alkyl chain;
(3) with the intermediate containing alkyl chain and imidazoles or containing substituting group imidazoles for raw material, prepare inhibitors of glutaminyl cyclase through SN2 reaction.
2. an application for inhibitors of glutaminyl cyclase, is characterized in that: be applied to by described inhibitors of glutaminyl cyclase in the anti-AD lead drug of QC target.
3. an application for inhibitors of glutaminyl cyclase, is characterized in that: be applied to by described inhibitors of glutaminyl cyclase in the medicine for the treatment of QC specificity overexpression disease.
4. an application for inhibitors of glutaminyl cyclase, is characterized in that: be applied in QC diagnostic kit by described inhibitors of glutaminyl cyclase.
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CN108912051A (en) * 2018-08-23 2018-11-30 深圳大学 A kind of inhibitors of glutaminyl cyclase containing 4- imidazole radicals
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017071479A1 (en) * 2015-10-26 2017-05-04 深圳大学 Glutamine acyl cyclase inhibitor
CN106831713A (en) * 2017-01-13 2017-06-13 深圳大学 A kind of synthetic method of Mutiple Targets A β oligomerization inhibitor and application
CN106831712A (en) * 2017-01-13 2017-06-13 深圳大学 A kind of Mutiple Targets A β oligomerization inhibitor
CN106831713B (en) * 2017-01-13 2019-04-02 深圳大学 A kind of synthetic method and application of multiple target point A β oligomerization inhibitor
CN106831712B (en) * 2017-01-13 2019-04-02 深圳大学 A kind of multiple target point A β oligomerization inhibitor
CN108912051A (en) * 2018-08-23 2018-11-30 深圳大学 A kind of inhibitors of glutaminyl cyclase containing 4- imidazole radicals
CN108912051B (en) * 2018-08-23 2022-04-15 深圳大学 Glutaminyl cyclase inhibitor containing 4-imidazolyl
WO2021014437A1 (en) 2019-07-19 2021-01-28 Adama Makhteshim Ltd. Process for the preparation of biphenylamines
CN114805334A (en) * 2022-05-24 2022-07-29 深圳大学 QC and GSK-3 beta multi-target inhibitor and preparation method and application thereof

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