CN106749184B - 8-aminoquinoline-hydroxycarbazole heterozygotes, process for their preparation and pharmaceutical compositions containing them - Google Patents
8-aminoquinoline-hydroxycarbazole heterozygotes, process for their preparation and pharmaceutical compositions containing them Download PDFInfo
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- -1 8-aminoquinoline-hydroxycarbazole Chemical compound 0.000 title claims abstract description 6
- 238000000034 method Methods 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 title description 2
- 230000008569 process Effects 0.000 title description 2
- 239000003814 drug Substances 0.000 claims abstract description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 8
- 238000004440 column chromatography Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Natural products C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 claims description 5
- 239000012043 crude product Substances 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 239000002994 raw material Substances 0.000 claims description 5
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 3
- 239000001301 oxygen Substances 0.000 claims description 3
- 229910052760 oxygen Inorganic materials 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 2
- 239000012467 final product Substances 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 2
- 208000024827 Alzheimer disease Diseases 0.000 claims 2
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- 239000000725 suspension Substances 0.000 claims 1
- 239000003826 tablet Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 23
- JPVYNHNXODAKFH-UHFFFAOYSA-N Cu2+ Chemical compound [Cu+2] JPVYNHNXODAKFH-UHFFFAOYSA-N 0.000 abstract description 14
- 229910001431 copper ion Inorganic materials 0.000 abstract description 14
- 230000015572 biosynthetic process Effects 0.000 abstract description 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 210000002569 neuron Anatomy 0.000 abstract description 3
- 239000013522 chelant Substances 0.000 abstract description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
- 229910021645 metal ion Inorganic materials 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WREVVZMUNPAPOV-UHFFFAOYSA-N 8-aminoquinoline Chemical compound C1=CN=C2C(N)=CC=CC2=C1 WREVVZMUNPAPOV-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 229930195714 L-glutamate Natural products 0.000 description 4
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 230000006933 amyloid-beta aggregation Effects 0.000 description 3
- 238000012925 biological evaluation Methods 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 150000005012 8-aminoquinolines Chemical class 0.000 description 2
- 239000004956 Amodel Substances 0.000 description 2
- 208000037259 Amyloid Plaque Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- QCDFBFJGMNKBDO-UHFFFAOYSA-N Clioquinol Chemical compound C1=CN=C2C(O)=C(I)C=C(Cl)C2=C1 QCDFBFJGMNKBDO-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000030833 cell death Effects 0.000 description 2
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 2
- 239000002738 chelating agent Substances 0.000 description 2
- 238000009509 drug development Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
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- 235000002639 sodium chloride Nutrition 0.000 description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 2
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- 230000004083 survival effect Effects 0.000 description 2
- 102000013498 tau Proteins Human genes 0.000 description 2
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- 238000005406 washing Methods 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- 150000004325 8-hydroxyquinolines Chemical class 0.000 description 1
- UEOHATPGKDSULR-UHFFFAOYSA-N 9h-carbazol-4-ol Chemical compound N1C2=CC=CC=C2C2=C1C=CC=C2O UEOHATPGKDSULR-UHFFFAOYSA-N 0.000 description 1
- 238000010173 Alzheimer-disease mouse model Methods 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
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- 206010003694 Atrophy Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
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- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 102000004108 Neurotransmitter Receptors Human genes 0.000 description 1
- 108090000590 Neurotransmitter Receptors Proteins 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000007131 anti Alzheimer effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 230000037444 atrophy Effects 0.000 description 1
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- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000003710 cerebral cortex Anatomy 0.000 description 1
- 230000009920 chelation Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 229960005228 clioquinol Drugs 0.000 description 1
- 230000003920 cognitive function Effects 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
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- 230000036541 health Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 210000004295 hippocampal neuron Anatomy 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000006951 hyperphosphorylation Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- 230000007512 neuronal protection Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- YZPOQCQXOSEMAZ-UHFFFAOYSA-N pbt2 Chemical compound ClC1=CC(Cl)=C(O)C2=NC(CN(C)C)=CC=C21 YZPOQCQXOSEMAZ-UHFFFAOYSA-N 0.000 description 1
- 230000007505 plaque formation Effects 0.000 description 1
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- 230000001737 promoting effect Effects 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
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- 229920006395 saturated elastomer Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to synthesis of a series of 8-aminoquinoline-hydroxycarbazole heterozygotes. Can selectively chelate copper ions and simultaneously play a good role in protecting neurons, so that the copper ions become candidate compounds for developing medicaments for treating AD.
Description
Technical Field
The invention relates to synthesis of a series of 8-aminoquinoline-hydroxycarbazole heterozygotes. The structural formula is shown in figure 1 and formula (I). Can selectively chelate copper ions and simultaneously play a good neuroprotective role, so that the copper ions and the neuroprotective role become candidate compounds for developing medicaments for treating AD.
Background
The number of AD episodes is increasing year by year with the rapid increase of the aged population in the world, about 4680 million people suffer from AD, and the number of AD cases is expected to increase to 1.3 hundred million by 2050. the main pathological features of AD are diffuse atrophy of cerebral cortex, a large reduction of neurons, β -senile plaques formed by amyloid (SPs) and neurofibrillary nodules formed by hyperphosphorylation of tau (NFs). The pathogenesis of AD is not clear at present, and AD is generally considered to be a multi-etiology, multi-gene association and multi-node disease, and the existing hypothesis includes A β hypothesis, tau protein hypothesis, cholinergic hypothesis, deficiency of metal ions, and the like, but the hypothesis of any pathogenesis is not comprehensive.
Recent survey results reports show a variety of metal ions,the copper ion can inhibit the over-activation of excitatory neurotransmitter receptor N-Methyl-D-aspartic acid (NMDA), can promote A β aggregation and amyloid plaque formation, and has the effect of resisting oxidative damage.5-chloro-7-iodo-8-hydroxyquinoline (Clioquinol) can reduce the brain A β precipitation of an AD mouse model, improve the cognitive function of animals and improve the overall health condition, and becomes an anti-AD metal ion chelating agent for the first clinical research, the 8-hydroxyquinoline derivative PBT-2 can obviously reduce A β in the cerebrospinal fluid (CSF) of AD animals42The 8-aminoquinoline derivative PA1673 has high selectivity on copper ions and almost no chelation on zinc ions, can completely reverse the memory loss of mice injected or orally taken with A β, and is a feasible new AD drug development strategy for developing metal ion regulators for AD treatment based on 8-hydroxyquinoline and 8-aminoquinoline as core frameworks.
The research finds that the oxidative stress is caused by irregular active oxygen generated in vivo and further causes the death and loss of neurons, so that an exogenous antioxidant is found to be one of the directions in the research of AD therapeutic drugs.
Disclosure of Invention
Based on the research foundation, 8-aminoquinoline is a good selective copper ion chelating agent, and in vivo, 8-aminoquinoline derivatives can reduce divalent copper ions into monovalent copper ions, so that the divalent copper ions lose the binding capacity with A β, and the aggregation of A β is reduced.
The compounds of the invention are characterized by the presence of two main units: a carbazole moiety and an 8-aminoquinoline moiety. On one hand, the copper ions can be selectively chelated; on the other hand, the compound can simultaneously play a good neuronal protection role and improve AD symptoms, so that the compound becomes a candidate for drug development.
The present invention relates to compounds of formula (I) of figure 1 or tautomers, pharmaceutically acceptable salts, prodrugs or solvates thereof.
Wherein R is1＝H，F，Cl，Br；R2＝H，OH，OCH3；R1At the 5-, 6-, 7-or 8-position of the carbazole; r2At the 5 ' -position, 6 ' -position or 7 ' -position of quinoline; -O-CH2-the oxygen end of the carbazole is in the 1-, 2-, 3-or 4-position.
Unless otherwise indicated, the compounds of the present invention are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, having the structure except for replacing hydrogen with deuterium or tritium, or by13C or14C-enriched carbon atoms replacing carbon atoms, or15N-enriched nitrogen is a compound within the scope of the present invention.
FIG. 2 is a scheme illustrating a method of preparing the compounds of the present invention.
The preparation method comprises the following steps:
(1) dissolving the compound 1 in the figure 2 in acetonitrile, adding catalysts of potassium carbonate and epoxy chloropropane, heating and refluxing until the raw materials completely react, drying the solvent by spinning, extracting, and purifying by column chromatography to obtain an intermediate product 2;
(2) dissolving the intermediate product 2 in methanol, adding the compound 3, heating to 50 ℃ until the raw materials react completely, evaporating the solvent, and purifying the crude product by column chromatography to obtain the final product.
Drawings
FIG. 18 shows a general structural formula of aminoquinoline-hydroxycarbazole heterobody.
FIG. 28-aminoquinoline-hydroxycarbazole hybrid synthesis route.
FIG. 3 shows a specific synthetic route of P-Z-001.
FIG. 4 protective effect of the compound on L-glutamate induced HT22 cell death.
FIG. 5 is a graph of the UV-VIS absorption spectrum of the interaction of the compound P-Z-001 with metal ions (Cu, Fe, Zn) commonly found in organisms.
Examples
The following examples are provided to further illustrate the present invention and should not be construed as limiting the scope thereof.
Example 1: synthesis of Compound P-Z-001
FIG. 3 is a scheme illustrating the method of synthesizing P-Z-001.
Dissolving 4-hydroxycarbazole (1g, 5.5mmol) in 20m L acetonitrile, adding catalysts of potassium carbonate (1.52g, 11mmol) and epichlorohydrin (5.0m L, 6.4mmol), heating and refluxing until the raw materials are completely reacted, wherein the reaction time is about 24h, evaporating the solvent under reduced pressure, dissolving the residue in 50m L ethyl acetate, washing with water for 3 times, each time 20m L, separating an organic layer, washing with 20m L saturated common salt for 1 time, then adding anhydrous sodium sulfate for drying, and evaporating the solvent under reduced pressure to obtain a crude product, and purifying the crude product by column chromatography (dichloromethane: petroleum ether ═ 1: 1) to obtain a white solid product a (0.86g, 65%).1H NMR(400MHz，CDCl3)8.36(d，J＝7.9，0.9Hz，1H)，8.10(s，1H)，7.46-7.39(m，2H)，7.35(t，J＝8.0Hz，1H)，7.27(dd，J＝5.8，2.2Hz，1H)，4.49(dd，J＝11.0，3.3Hz，1H)，4.30(dd，J＝11.0，5.4Hz，1H)，3.59(dddd，J＝5.6，4.1，3.4，2.6Hz，1H)，3.03(dd，J＝5.0，4.1Hz，1H)，2.92(dd，J＝5.0，2.6Hz，1H)。13CNMR(100MHz，CDCl3)155.02，141.01，138.76，126.62，125.14，123.24，122.55，119.78，112.92，110.00，104.09，101.39，68.84，50.40，44.92.MS ESI：239.1。
The intermediate product a (300mg, 1.26mmol) was dissolved in 15m L methanol, 8-aminoquinoline (222mg, 1.5mmol) was added, the reaction was heated to 50 ℃ until the starting material was reacted completely, the reaction time was about 16h, the solvent was distilled off under reduced pressure to give a crude product, which was purified by column chromatography (petroleum ether: ethyl acetate: 10: 3) to give P-Z-001(298mg, 62%) as a pale yellow solid.1H NMR(400MHz，DMSO)11.26(s，1H)，8.73(d，J＝3.7Hz，1H)，8.28(d，J＝7.8Hz，1H)，8.20(d，J＝8.1Hz，1H)，7.49(dd，J＝8.2，4.2Hz，1H)，7.44(d，J＝8.1Hz，1H)，7.30(dq，J＝16.0，8.0，7.5Hz，3H)，7.12(t，J＝7.4Hz，1H)，7.06(dd，J＝8.0，4.0Hz，2H)，6.76(d，J＝7.7Hz，1H)，6.70(d，J＝7.9Hz，1H)，5.56(s，1H)，4.43-4.34(m，1H)，4.26(d，J＝5.1Hz，2H)，3.68(d，J＝10.2Hz，1H)，3.48(dd，J＝12.8，7.0Hz，1H)。13C NMR(100MHz，DMSO)155.31，147.42，145.11，141.60，139.40，138.03，136.45，128.78，128.22，126.95，125.03，122.99，122.20，122.17，119.06，113.85，112.05，110.84，104.90，104.45，100.95，70.79，68.05，55.38，46.57。
HRMS ESI(+)m/z calculated for C24H21N3O2[M+H]+：384.1713.Found：384.1707。
HPLC purity：98.4％。
Example 2: biological evaluation
Protective effect on L-glutamate induced HT22 cell death
Mouse hippocampal neuron cell line HT22 was cultured in DMEM complete medium containing 10% fetal calf serum at 37 deg.C and saturated humidity, and containing 5% CO by volume2Taking cells in logarithmic growth phase, digesting with 0.25% pancreatin, completely suspending the cells in a culture medium, counting by a cell counting plate under a microscope, and adjusting the cell concentration to 10 × 104Seed 96 well cell culture plates at 100. mu. L/well for overnight culture to allow cells to adhereAbsorbing the culture medium in a 96-well plate, dissolving a test compound by DMSO, diluting the test compound by complete culture medium, adding the test compound into the 96-well plate, 100 mu L/well, pre-incubating for 30min, adding 2 mu L100 mM L-glutamate, directly adding 2 mu L100 mM L-glutamate, incubating for 24h, adding 10 mu L5 mg/m L MTT into each well, incubating for 2h, discarding supernatant, adding DMSO 100 mu L/well, shaking to fully dissolve the product formazan, measuring the absorbance value of each well on a microplate reader, measuring the wavelength of 570nm, and promoting the survival rate of the cells by a formula compound to be 100 percent (A)Test compound-AModel set)/(AModel set-ABlank space) And calculating the cell survival rate.
Example 3: biological evaluation
Interaction with common metal ions in organisms
The method comprises the steps of setting up a single compound group to be detected and a blank group simultaneously, incubating the components for 30min at room temperature after uniformly mixing, scanning an ultraviolet absorption spectrogram of each experimental group in a range of 200-700nM on an ultraviolet spectrophotometer, and scanning an absorption point every 0.5nM, wherein the final concentration of the compound to be detected is 20 mu M, the final concentration of a metal ion solution is 20 mu M, firstly, 1M L absolute ethyl alcohol is added into a quartz cuvette to scan the baseleine, then, the absolute ethyl alcohol is scanned to serve as a solvent control group, secondly, the compound solution to be detected and the compound and metal ion solution group are scanned, and at least three independent experiments are carried out on each concentration.
Example 4: biological evaluation
Inhibition of copper ion-induced A β aggregation
Aβ1-42Dissolving in 1% ammonia water solution to obtain stock solution, subpackaging, and storing in-80 deg.C refrigerator, diluting A β stock solution with 20 μ M HEPES (containing 150 μ M NaCl), adding 10 μ L A β (final concentration of 25 μ M) into mixture of 10 μ L copper ion (final concentration of 25 μ M) and 10 μ L test compound (final concentration of 50 μ M), incubating at 37 deg.C for 24 hr, taking 20 μ L sample solution, diluting with 50mM glycine-NaOH buffer solution to 200 μ L, mixing, and scanning with fluorescence intensity of 300 s ((λ -NaOH buffer solution)exc＝450nm；λem485 nm). Percent inhibition rate (1-IF)i/IFc)×100，IFiAnd IFcFluorescence intensity with and without inhibitor after background subtraction is represented, respectively.
TABLE 1 inhibition of A β aggregation induced by copper ions of compounds determined by Th-T fluorimetry
Claims (4)
1.8-aminoquinoline-hydroxycarbazole heterozygote having the structural formula shown in formula (I):
wherein R is1＝H，F，Cl，Br；R2＝H，OH，OCH3；R1At the 5-, 6-, 7-or 8-position of the carbazole; r2At the 5 ' -position, 6 ' -position or 7 ' -position of quinoline; the oxygen end of-O-CH 2-is at the 1-, 2-, 3-or 4-position of the carbazole.
2. The method of preparing the 8-aminoquinoline-hydroxycarbazole hybrid of claim 1, comprising the steps of:
(1) will be provided with
Dissolving in acetonitrile, adding catalyst potassium carbonate and epoxy chloropropane, heating and refluxing until the raw materials react completely, spin-drying solvent, extracting, and purifying by column chromatography to obtain intermediate product
(2) Will be provided with
Dissolving in methanol, adding
Heating to 50 deg.C until the raw materials react completely, evaporating solvent, and purifying the crude product by column chromatography to obtain final product
3. The use of the heterobody of claim 1 for the preparation of a medicament for the treatment of alzheimer's disease.
4. The hybrid body of claim 1, wherein the dosage form of the hybrid body for preparing the medicament for treating the Alzheimer disease is tablets, pills, capsules, injections, suspensions or emulsions.
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| CN105906608A (en) * | 2016-05-03 | 2016-08-31 | 中山大学 | 8-aminoquinoline-melatonin complex and pharmaceutical composition thereof |
| CN106045972A (en) * | 2016-06-03 | 2016-10-26 | 中山大学 | Carbazole-rivastigmine diad and pharmaceutical composition and application thereof |
| CN108137540A (en) * | 2015-03-09 | 2018-06-08 | 艾维丁股份有限公司 | Enantiomers of 8-hydroxyquinoline derivatives and synthesis thereof |
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| CN108137540A (en) * | 2015-03-09 | 2018-06-08 | 艾维丁股份有限公司 | Enantiomers of 8-hydroxyquinoline derivatives and synthesis thereof |
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