CN103923009B - 8-replaces the different aporphine derivative of oxidation and synthetic method and application - Google Patents

8-replaces the different aporphine derivative of oxidation and synthetic method and application Download PDF

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CN103923009B
CN103923009B CN201410150074.3A CN201410150074A CN103923009B CN 103923009 B CN103923009 B CN 103923009B CN 201410150074 A CN201410150074 A CN 201410150074A CN 103923009 B CN103923009 B CN 103923009B
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oxidation
synthetic method
replaces
different aporphine
chloride
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CN103923009A (en
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唐煌
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Guangxi Normal University
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    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
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Abstract

The invention discloses a series of 8-and replace the different aporphine derivative of oxidation and synthetic method and application.The synthetic method that described 8-replaces the different aporphine derivative of oxidation comprises the following steps: 1) with 3-chloro-phthalic anhydride and phenylethylamine for raw material, build 8-Cl-1-azepine benzanthrone parent through twice ring closure reaction; 2) 8-Cl-1-azepine benzanthrone parent obtains 8-amino-7H-dibenzoquinoline-7-ketone through ammonification; 3) 8-amino-7H-dibenzoquinoline-7-ketone reacts with the chloride compounds being connected to piperidines, obtains corresponding target product.Applicant finds by investigating, derivative of the present invention has very strong inhibit activities to acetylcholinesterase, there is good potential pharmaceutical use, be expected to be used for the treatment of alzheimer's disease, cerebrovascular dementia and reduce with the neurotransmitter of cholinomimetic energy the relative disease caused.The structure that above-mentioned 8-replaces the different aporphine derivative of oxidation is shown below.

Description

8-replaces the different aporphine derivative of oxidation and synthetic method and application
Technical field
The present invention relates to field of pharmaceutical chemistry technology, be specifically related to 8-and replace the different aporphine derivative of oxidation and synthetic method and application.
Background technology
Acetylcholinesterase (acetylcholinesterase, AChE, EC3.1.1.7.), also known as choline lytic enzyme (acetylcholinehydrolase), its main biological function is in cholinergic synapses by fast hydrolyzing neurotransmitter acetylcholine (ACh), thus reaches the transmission stopping nerve impulse.Its reaction formula is as follows:
Butyrylcholine esterase (butyrylcholinesterase, BChE, EC3.1.1.8), is also called false or unspecific cholinesterase, is the enzyme of hydrolysis BuCh.It belongs to serine ester enzyme family, is mainly distributed in serum and liver, also has a small amount of existence in muscle and cerebral tissue.BChE can be hydrolyzed many ester classes, peptide class and amides in vital movement, and participate in the metabolic process of some drugs, it also has the effect of Promote cell's growth.Above two fermentoids constitute the Major Members of Pseudocholinesterase family, they optionally inhibitor be applied to the treatment of alzheimer's disease.
Alzheimer's disease (AlzheimerDisease, AD), also known as presenile dementia, is a kind of gradual neurodegenerative disease, shows as comprehensive cognitive disorder, comprises the aspects such as memory, location, judgement and reasoning.Patient behavior is abnormal, social activity is subject to obstacle, along with increasing the weight of of the state of an illness, even loses the ability of living on one's own life.AD patient has multiple pathological characters, comprise that the formation of senile plaque, neuron loss, pallium are petty, inflammatory reaction, oxidative stress enhancing etc., have three large features the most obvious in the middle of this, that is: the amyloid beta of pallium and hippocampus accumulates outward born of the same parents and forms Tau abnormal protein in senile plaque, cranial nerve cell and assembles neurofibrillary tangles, synapse dysfunction and the cone neurocyte loss formed.Because AD disease relates to multiple pathologic process, make its cause of disease not yet have very specifically method up till now, its pathogenesis is very complicated, multimachine system, a multifactorial process for this reason.
According to clinical result of study, form various theory to explain the mechanism of AD disease and to set up corresponding therapeutic strategy, such as Tau protein hyperphosphorylation theory, inflammation reaction theory, apoptosis theory etc. are wherein the amyloid cascade hypothesis of the people such as cholinergic theory and Hardy of the people such as Bartus for Most scholars accepted and was most widely used.According to cholinergic theory, the cholinergic neuron of AD patient is damaged, the level of vagusstoff in brain (ACh) is reduced, and the decline of the degree reduced and Patients ' Cognitive ability is remarkable dependency, the level of vagusstoff is improved by acetylcholine esterase inhibition (AChE), the memory of patient, cognitive power just can improve.Amyloid cascade hypothesis is thought: amyloid beta is one of important risk factor of AD disease, AchE secretes also and amyloid beta (A β) codeposition with soluble form outside neuronal cell, finally causes the formation of senile plaque (SP); In other words, AChE plays the effect of an effective startup factor for the deposition of amyloid beta thus brings out AD disease.Therefore, AChE becomes the key link connecting cholinergic theory and amyloid cascade hypothesis, the level optionally suppressing AChE can not only promote ACh reaches the effect improving cholinergic nerve function, and the deposition of amyloid-beta can be suppressed, greatly improve the cognitive ability of AD patient, therefore in current existing therapeutic strategy, AChE inhibitor medicaments is the most conventional.Simultaneously, research shows that the activity of BuChE in AD patient cynapse there is no and obviously increases, therefore the exploitation for anticholinesterase medicine, the effect of suppression and selectivity will be the Important Problems that developer is concerned about, this reduces side effect play an important role to enhancing drug effect.
So far the AChE inhibitor for clinical treatment AD has tacrine, lycoremine, selagine, be piperazine is neat more, Li Fansi bright and their analogue etc.But these anticholinesterase medicines can only relief of symptoms be attended by the defects such as larger side effect in short-term, seek novel, low, the eutherapeutic anticholinesterase of side effect is the direction that investigator makes great efforts always.
The drug target of alzheimer's disease still do not treated by Pseudocholinesterase, and is the drug target of cerebrovascular dementia, glaucoma or myasthenia gravis disease, and its inhibitor becomes these disease primary treatment medicines at present.Vascular dementia (vasculardementia, VaD) is the chronic syndromes of the intelligent infringement of acquisition that various cerebrovascular disease causes and cognitive disorder, is the common dementia of second being only second to AD disease.The degree of awareness of VaD patient also reduces with the level of vagusstoff (ACh) and relatively with the activity of acetylcholinesterase (AChE) increases relevant, and in VaD patient's brain, the degree of the level reduction of vagusstoff (Ach) is consistent with dementia degree.Glaucoma causes intraocular pressure to raise and the disease that causes because intraocular aqueous humor flows into flowing out lack of proper care, therefore to reduce intraocular pressure be treat glaucomatous Main Means at present.Reversible anticholinesterase has miosis, about flesh and the effect such as ciliary muscle, the spasm of accommodation are expanded in excited hole, thus reduction intraocular pressure reaches the glaucomatous object for the treatment of.Myasthenia gravis disease is a kind of autoimmune disorder damaging whole body neuromuscular junction, and clinical manifestation is neuromuscular transmission retardance, causes eye muscle, swallows flesh, respiratory muscle and appendicular skeleton myasthenia.Generally believe that acetylcholine receptor antibodies (AchRab) is one of principal element of myasthenia gravis disease incidence at present, the acetylcholine receptor of myasthenia gravis disease people and acetylcholine receptor antibodies (AchRab) combine, acetylcholine receptor is degenerated and hinders acceptor to regenerate, acetylcholine receptor quantity is reduced, the end plate potential formed can not be brought out myocyte and be produced action potential, so that muscle can not shrink, thus cause myasthenia gravis disease.As can be seen here, acetylcholinesterase depressant can pass through the level that acetylcholine esterase inhibition (AChE) improves vagusstoff (Ach), thus improving VaD patient's dementia degree, reduce intraocular pressure and be used for the treatment of glaucoma, and by extending and enhance the interactional ability of vagusstoff and acetylcholine receptor, reach rising miniature plate potential, the safety coefficient increasing Neuromuscular Conduction reaches treatment and alleviates the effect of myasthenia gravis disease.Therefore the potentiality candidate that acetylcholinesterase depressant is also expected to develop into cerebrovascular dementia, glaucoma or myasthenia gravis disease selects medicine.
Yellow parilla (MenispermumdauricumDC.), another name Rhizoma Menispermi, Radix Stephaniae Tetrandrae are Menispermaceae moon-seeds.Yellow parilla contains multiple alkaloid, and these alkaloids not only have inhibiting bacteria and diminishing inflammation effect, but also has and improve cardio and vascular function, immunomodulatory and antitumor action etc.Yellow parilla has good anti-heart disorder, antithrombotic function.Beidougen Capsule, Beidougen Tablets have been listed in national protection new drug.Yellow parilla is the luxuriant and rich with fragrance alkaloidal exclusive source of the different A Piao of Native Oxide.A common trait of the different aporphine alkaloid of all oxidations is exactly 1-azepine benzanthrone (1-azabenzanthrone) structure having an aromaticity.But be all be limited to Extraction and separation to its report in recent years, to its transformation and the rarely found report of activity research, there is not yet to be oxidized different A Piao so far luxuriant and rich with fragrance is parent and the relevant report of chloride compounds Reactive Synthesis medicine being connected to piperidines.
Summary of the invention
The technical problem to be solved in the present invention is to provide the new 8-of a class and replaces the different aporphine derivative of oxidation and synthetic method thereof, and above-mentioned 8-replaces the application of the different aporphine derivative of oxidation in pharmacy field.
8-of the present invention replaces the different aporphine derivative of oxidation or pharmacy acceptable salt, has the structure shown in following formula (I):
Wherein, n=1 ~ 5.
It can be that the 8-shown in through type (I) replaces the different aporphine derivative of oxidation and protonic acid reacts the salt generated that described 8-replaces the different aporphine derivative pharmacy acceptable salt of oxidation, or itself and methyl halide, ethyl halide, benzyl halide react the quaternary ammonium salt formed.
The synthetic route of the different aporphine derivative of oxidation that 8-of the present invention replaces is as follows:
Above-mentioned 8-replaces the synthetic method of the different aporphine derivative of oxidation, comprises the following steps:
1) with 3-chloro-phthalic anhydride and phenylethylamine for raw material, build 8-Cl-1-azepine benzanthrone parent compound through twice ring closure reaction;
2) 8-Cl-1-azepine benzanthrone parent compound obtains 8-amino-7H-dibenzoquinoline-7-ketone through ammonification;
3) 8-amino-7H-dibenzoquinoline-7-ketone reacts with the chloride compounds being connected to piperidines, obtains corresponding target product.
In order to improve the purity of target product, usually the target product of gained is carried out purifying through recrystallization or silica gel column chromatography.In this application, silica gel column chromatography is preferably adopted to carry out purifying, preferably being that the mixed solvent that forms of the sherwood oil of 5 ~ 100:1 and chloroform is for eluent by volume ratio during chromatography.
The step 1 of above-mentioned synthetic method) in, with 3-chloro-phthalic anhydride and phenylethylamine for raw material, carry out according to similar Bradsher reaction mechanism, recycling dehydrating agent sulfuric acid closes ring and obtains 8-Cl-1-azepine benzanthrone parent compound.Specifically comprise:
1.1) with 3-chloro-phthalic anhydride and phenylethylamine for raw material, take toluene as solvent, back flow reaction is to completely, and reactant cools, and crystallization, isolates crystal, dry, obtains 4-chloro-2-phenyl isoindoline-1,3-diketone;
1.2) get aluminum trichloride (anhydrous) and sodium-chlor is heated to melting, then add 4-chloro-2-phenyl isoindoline-1,3-diketone wherein, be warming up to 180 ~ 200 DEG C, stirring reaction, after reacting completely, cooling, smashs to pieces, obtains red brown solid product; Get the vitriol oil and be placed in container, add red brown solid product wherein, be warming up to 170 ~ 190 DEG C, stirring reaction, after reacting completely, cooling, reactant is poured in frozen water, the pH value of regulation system is 2 ~ 3, separate out a large amount of solid, suction filtration, washing, drying, obtains the thick product containing 8-Cl-1-azepine benzanthrone and 10-Cl-1-azepine benzanthrone mixture.The thick product of gained by purification by silica gel column chromatography, obtains 8-Cl-1-azepine benzanthrone to be separated, when chromatography, usually being that the mixed solvent that forms of the sherwood oil of 10 ~ 40:1 and ethyl acetate is for eluent by volume ratio.
Above-mentioned steps 1.1) in, solvent toluene can substitute with methyl alcohol or acetonitrile, and the mol ratio of raw material 3-chloro-phthalic anhydride and phenylethylamine is stoichiometric ratio, is preferably 1 ~ 1.1:1.Above-mentioned steps 1.2) in, 4-chloro-2-phenyl isoindoline-1, the mol ratio of 3-diketone and aluminum trichloride (anhydrous) is preferably 1:2.8 ~ 3, the mol ratio of aluminum trichloride (anhydrous) and sodium-chlor is preferably 2.1 ~ 2.3:1, the consumption of the vitriol oil is preferably 4 ~ 6 times of 4-chloro-2-phenyl isoindoline-1,3-diketone quality.
The step 2 of above-mentioned synthetic method) in, the ammonification of 8-Cl-1-azepine benzanthrone is carried out in ammoniacal liquor, and ammonification is preferably carried out under 140 ~ 160 DEG C of conditions, and the mol ratio of 8-Cl-1-azepine benzanthrone and ammoniacal liquor is stoichiometric ratio, is preferably 1:4.5 ~ 5.
The step 3 of above-mentioned synthetic method) in, the described chloride compounds being connected to piperidines can be specifically 2-(piperidino) Acetyl Chloride 98Min., 3-(piperidino) propionyl chloride, 4-(piperidino) butyryl chloride, 5-(piperidino) valeryl chloride or 6-(piperidino) caproyl chloride.Described 8-amino-7H-dibenzoquinoline-7-ketone carries out stirring and refluxing reaction in the presence of a solvent with the reaction of the chloride compounds being connected to piperidines, and solvent can be methylene dichloride, ethanol or acetonitrile; After reacting completely, the pH value regulating gained reactant is 2 ~ 3, and washing, solvent layer anhydrous sodium sulfate drying, namely obtains corresponding target product crude product.In this step, 8-amino-7H-dibenzoquinoline-7-ketone is stoichiometric ratio with the mol ratio of the chloride compounds being connected to piperidines, is preferably 1:5 ~ 10.
In synthetic method of the present invention, judge that whether reaction is complete, adopt thin-layer chromatography tracing detection.When regulating the pH value of reactant or system, usually regulate with the alkaline matter such as sodium bicarbonate or sodium carbonate.
The present invention also comprises the above-mentioned 8-replacement different aporphine derivative of oxidation or its pharmacy acceptable salt is preparing the application in acetylcholine esterase inhibitor medication.It can be specifically the application in preparation treatment alzheimer's disease, cerebrovascular dementia, glaucoma or myasthenia gravis medicine.
The present invention also comprises and replaces with 8-the acetylcholine esterase inhibitor medication being oxidized different aporphine derivative and preparing for effective ingredient.This medicine can make regular dosage form pharmaceutically, specifically can make the formulations such as injection, tablet, pill, capsule, suspension agent or emulsion.
Compared with prior art, the invention provides the new 8-of a class and replace the different aporphine derivative of oxidation and synthetic method thereof, applicant is by investigating the restraining effect of its external acetylcholinesterase and butyrylcholine esterase, result shows that 8-replaces the different aporphine derivative of oxidation and has very strong inhibit activities to acetylcholinesterase, to the IC that AChE suppresses 50the IC that value and BChE suppress 50value all reaches micromolar levels, has good potential pharmaceutical use, is expected to be used for the treatment of alzheimer's disease, cerebrovascular dementia and reduce with the neurotransmitter of cholinomimetic energy the relative disease caused.
Embodiment
With specific embodiment, the invention will be further described below, but the present invention is not limited to these embodiments.
The synthesis of embodiment 1:4-chloro-2-phenyl isoindoline-1,3-diketone (compound 1)
57g (0.1mol) 3-chloro-phthalic anhydride and 45g (0.1mol) phenylethylamine are joined in the three hole round-bottomed flasks of 1L, add 500ml toluene again, reflux 6 hours, pour out while hot, cooling, crystallization, suction filtration, obtain compound 1 (white flaky crystals), productive rate about 98%.
Analyze compound 1, its spectral characteristic is as follows:
1HNMR(CDCl 3,500MHz):δ3.00～3.04(m,2H),3.94～3.97(m,2H),7.23～7.34(m,5H),7.65(d,J=1.7,1H),7.66(s,1H),7.78(dd,J 1=5.0andJ 2=3.2,1H);ESI-MS(m/z):287[M+H] +.
Therefore, can determine that above-claimed cpd 1 is for 4-chloro-2-phenyl isoindoline-1,3-diketone, its structural formula is shown below:
The synthesis of embodiment 2:8-Cl-1-azepine benzanthrone (compound 2)
The aluminum trichloride (anhydrous) of 75g (0.56mol) and 15g sodium-chlor are added in the three hole round-bottomed flasks of 1L, be mixed and heated to 140 DEG C of meltings, slowly add the compound 1 of 53g (0.2mol) again to it in batches, add complete, be warming up to 220 DEG C, stirring reaction 3 hours, take advantage of heat to pour in mortar, cooling, smashs to pieces, obtain red brown solid, be positioned in dry vessel.
Getting the 600ml vitriol oil joins in the three hole round-bottomed flasks of 2L, when being warmed up to 80 DEG C, starting to add red brown solid obtained above in batches, after adding, be warming up to 230 DEG C, stirring reaction 2.5 hours, cooling, is poured in the frozen water of about 600g, is about 2-3 by NaOH adjust ph, separate out a large amount of solid, suction filtration, washing, obtains thick product.Thick product, through silica gel column chromatography (petrol ether/ethyl acetate=20:1) purifying, obtains compound 2 (yellow powder), productive rate about 35%.
Analyze compound 2, its spectral characteristic is as follows:
1HNMR(CDCl 3,500MHz):δ7.72(d,J=5.6Hz1H),7.76(t,J=8.2Hz,1H),7.89(t,J=7.3Hz,1H),8.12(d,J=8.2Hz,1H),8.64(d,J=7.3Hz,1H),8.71(d,J=7.9Hz,1H),8.76(d,J=5.6Hz,1H),9.07(d,J=7.3Hz,1H);ESI-MS(m/z):266[M+H] +.
Therefore, can determine that above-claimed cpd 2 is for 8-Cl-1-azepine benzanthrone, its structural formula is shown below:
The synthesis of embodiment 3:8-amino-7H-dibenzoquinoline-7-ketone (compound 3)
Get 1.5g compound 2 in autoclave inner bag, then add the ammoniacal liquor of 100ml, react 12h at 180 DEG C after, stopped reaction.Adjust pH to 7-8, suction filtration with the HCl of 3mol/L after cooling, dry.Thick product, through silica gel column chromatography (sherwood oil/chloroform=7:1) purifying, obtains compound 3 (red solid), productive rate 40%.
Analyze compound 3, its spectral characteristic is as follows:
1HNMR(500MHz,DMSO):δ8.73(d,J=5.5Hz,1H),8.45(d,J=7.2Hz,1H),8.29(d,J=8.2Hz,1H),8.06(d,J=8.4Hz,1H),8.02–7.97(m,1H),7.94(d,J=5.6Hz,1H),7.55–7.48(m,1H),7.00(d,J=7.3Hz,1H),2.51(t,J=2.8Hz,2H);ESI-MS(m/z):247[M+H] +.
Therefore, can determine that above-claimed cpd 3 is for 8-amino-7H-dibenzoquinoline-7-ketone, its structural formula is shown below:
The synthesis of embodiment 4:8-(2-piperidines kharophen)-7H-dibenzoquinoline-7-ketone (compound 4)
Get 0.3g (0.0012mol) compound 3 in 25mL round-bottomed flask, add 15mLCH 2cl 2after making it all dissolve, slowly drip in the reaction flask that 2.95g (0.0183mol) 2-(piperidino) Acetyl Chloride 98Min. is housed, dropwise rear TLC following response 2.5h, use NaHCO 3adjust pH to 2-3, and with distilled water wash 3-4 time, CH 2cl 2layer anhydrous Na 2sO 4drying, thick product silica gel column chromatography (sherwood oil/chloroform=5:1) purifying, obtains compound 4 (orange-yellow powder), productive rate 89.0%.
Analyze compound 4, its spectral characteristic is as follows:
1HNMR(500MHz,CDCl 3)δ13.45(s,1H),9.10(d,J=7.3Hz,1H),8.78(d,J=5.5Hz,1H),8.73(d,J=6.7Hz,1H),8.66(d,J=7.2Hz,1H),8.14(d,J=7.2Hz,1H),7.95–7.88(m,1H),7.79(t,J=8.1Hz,1H),7.74(d,J=5.6Hz,1H),3.27(s,2H),2.67(s,4H),1.97–1.82(m,4H),1.28(s,2H).ESI-MS(m/z):372[M+H] +.
Therefore, can determine that above-claimed cpd 4 is for 8-(2-piperidines kharophen)-7H-dibenzoquinoline-7-ketone, its structural formula is shown below:
The synthesis of embodiment 5:8-(3-piperidines propionamido)-7H-dibenzoquinoline-7-ketone (compound 5)
Get 0.3g (0.0012mol) compound 3 in 25mL round-bottomed flask, add 15mLCH 2cl 2after making it all dissolve, slowly drip in the reaction flask that 3.2g (0.018mol) 3-(piperidino) propionyl chloride is housed, dropwise rear TLC following response 3h, use NaHCO 3adjust pH to 2 ~ 3, and with distilled water wash 3 ~ 4 times, CH 2cl 2layer anhydrous Na 2sO 4drying, thick product silica gel column chromatography (sherwood oil/chloroform=5:1) purifying, obtains compound 5 (orange-yellow powder), productive rate 90%.
Analyze compound 5, its spectral characteristic is as follows:
1HNMR(500MHz,CDCl 3)δ12.81(s,1H),8.97(d,J=8.4Hz,1H),8.79(d,J=5.5Hz,1H),8.70(d,J=7.9Hz,1H),8.61(d,J=7.3Hz,1H),8.16(d,J=8.2Hz,1H),7.92(t,J=7.7Hz,1H),7.78(t,J=8.1Hz,1H),7.75(d,J=5.7Hz,1H),2.92(t,J=7.2Hz,2H),2.82(t,J=7.3Hz,2H),2.58(s,4H),1.79–1.60(m,4H),1.28(s,2H).ESI-MS(m/z):386[M+H] +.
Therefore, can determine that above-claimed cpd 5 is for 8-(3-piperidines propionamido)-7H-dibenzoquinoline-7-ketone, its structural formula is shown below:
The synthesis of embodiment 6:8-(4-piperidines butyrylamino)-7H-dibenzoquinoline-7-ketone (compound 6)
Get 0.2g (0.0008mol) compound 3 in 25mL round-bottomed flask, add 15mLCH 2cl 2after making it all dissolve, slowly drip in the reaction flask that 2.3g (0.012mol) 4-(piperidino) butyryl chloride is housed, dropwise rear TLC following response 2.5h, use NaHCO 3adjust pH to 2 ~ 3, and with distilled water wash 3 ~ 4 times, CH 2cl 2layer anhydrous Na 2sO 4drying, thick product silica gel column chromatography (sherwood oil/chloroform=20:1) purifying, obtains compound 6 (orange-yellow powder), productive rate 85%.
Analyze compound 6, its spectral characteristic is as follows:
1HNMR(500MHz,CDCl 3)δ12.83(s,1H),8.95(d,J=8.4Hz,1H),8.79(d,J=5.5Hz,1H),8.71(d,J=7.9Hz,1H),8.62(d,J=7.2Hz,1H),8.17(d,J=8.2Hz,1H),7.97–7.89(m,1H),7.79(d,J=8.1Hz,1H),7.76(d,J=5.5Hz,1H),3.85–3.71(m,2H),3.29(t,J=12.6Hz,2H),2.91–2.76(m,4H),2.69(t,J=7.0Hz,2H),1.92–1.77(m,4H),1.28(s,2H).ESI-MS(m/z):400[M+H] +.
Therefore, can determine that above-claimed cpd 6 is for 8-(4-piperidines butyrylamino)-7H-dibenzoquinoline-7-ketone, its structural formula is shown below:
The synthesis of embodiment 7:8-(5-piperidines valeryl is amino)-7H-dibenzoquinoline-7-ketone (compound 7)
Get 0.3g (0.0012mol) compound 3 in 25mL round-bottomed flask, add 15mLCH 2cl 2after making it all dissolve, slowly drip in the reaction flask that 3.7g (0.018mol) 5-(piperidino) valeryl chloride is housed, dropwise rear TLC following response 2.5h, use NaHCO 3adjust pH to 2-3, and with distilled water wash 3-4 time, CH 2cl 2layer anhydrous Na 2sO 4drying, thick product silica gel column chromatography (sherwood oil/chloroform=20:1) purifying, obtains compound 7 (orange-yellow powder), productive rate 75%.
Analyze compound 7, its spectral characteristic is as follows:
1HNMR(500MHz,CDCl 3)δ12.84(s,1H),8.94(d,J=8.4Hz,1H),8.80(d,J=5.5Hz,1H),8.73(d,J=7.9Hz,1H),8.64(d,J=7.3Hz,1H),8.18(d,J=8.2Hz,1H),7.99–7.91(m,1H),7.80(d,J=8.2Hz,1H),7.78–7.76(m,1H),4.15(q,J=7.2Hz,2H),3.12–3.00(m,2H),2.68(t,J=7.1Hz,4H),2.39(t,J=7.1Hz,2H),1.92(dd,J=15.2,7.5Hz,4H),1.76–1.63(m,2H),1.28(t,J=7.1Hz,2H).ESI-MS(m/z):414[M+H] +.
Therefore, can determine that above-claimed cpd 7 is for 8-(5-piperidines valeryl is amino)-7H-dibenzoquinoline-7-ketone, its structural formula is shown below:
The synthesis of embodiment 8:8-(6-piperidines hexanamido)-7H-dibenzoquinoline-7-ketone (compound 8)
Get 0.3g (0.0012mol) compound 3 in 25mL round-bottomed flask, add 15mLCH 2cl 2after making it all dissolve, slowly drip in the reaction flask that 3.9g (0.018mol) 6-(piperidino) caproyl chloride is housed, dropwise rear TLC following response 2.5h, use NaHCO 3adjust pH to 2 ~ 3, and with distilled water wash 3 ~ 4 times, CH 2cl 2layer anhydrous Na 2sO 4drying, thick product silica gel column chromatography (sherwood oil/chloroform=20:1) purifying, obtains compound 8 (orange-yellow powder), productive rate 66%.
Analyze compound 8, its spectral characteristic is as follows:
1HNMR(500MHz,CDCl 3)δ12.80(s,1H),8.97(dd,J=8.4,1.1Hz,1H),8.79(d,J=5.5Hz,1H),8.70(dd,J=7.9,1.1Hz,1H),8.62(dd,J=7.3,1.0Hz,1H),8.17(dd,J=8.2,0.9Hz,1H),7.93(dd,J=8.1,7.4Hz,1H),7.78(d,J=8.1Hz,1H),7.77–7.73(m,1H),2.99(s,2H),2.93–2.84(m,2H),2.61(t,J=7.3Hz,2H),1.97(m,6H),1.89(m,2H),1.63(s,2H),1.54(m,2H),1.27(s,2H).ESI-MS(m/z):428[M+H] +.
Therefore, can determine that above-claimed cpd 8 is for 8-(6-piperidines hexanamido)-7H-dibenzoquinoline-7-ketone, its structural formula is shown below:
Experimental example: 8-replaces the mensuration of the oxidation external acetylcholinesterase of different aporphine derivative and butyrylcholine esterase inhibit activities
Application Ellman (Ellman, G.L.; Courtney, K.D.; Andres, V.; Etal.Biochem.Pharmacol.1961,7,88.) IC that method test compounds suppresses acetylcholinesterase and butyrylcholine esterase 50value.All tests are all use MicroplatereaderELX808 tMtype microplate reader (BioTek company of the U.S.), measures under 37 DEG C of conditions.Data analysis software uses Origin software to carry out data processing, uses Tacrine product in contrast.
1, the preparation of inhibitor storing solution: the inhibitor tested is made into the DMSO solution of 10mM.
2, the preparation of enzyme storing solution: acetylcholinesterase (extracting from electric eel) and butyrylcholine esterase (extracting from the blood plasma of horse) available from Sigma; 0.1mg/mL is made into respectively, 0.5mg/mL with the phosphate buffered saline buffer of pH=8.0.
3, the preparation of Substrate stock liquid: acetyl mercapto choline (acetylcholine ester enzyme substrates) and butyryl sulfydryl choline (butyrylcholine esterase substrate) available from Sigma; 2mg/mL is made into respectively, 2mg/mL with the phosphate buffered saline buffer of pH=8.0.
4, the preparation of developer storing solution: developer DTNB available from Sigma; 4mg/mL and 2mg/mL is made into respectively with the phosphate buffered saline buffer of pH=8.0.
5, test: the volume of each test is all the phosphate buffered saline buffer of the pH=8.0 of 150 μ L.
PH=8.0 phosphate buffer soln 150 μ L is added in 96 hole enzyme plates, 10 μ L developer storing solutions, 10 μ L enzyme storing solutions, add 20 μ L different concns inhibitor solutions (with pH=8.0 phosphate buffer soln dilution inhibitor storing solution) more respectively, 15min is incubated in the microplate reader of 37 DEG C, add 20 μ L Substrate stock liquid immediately, one minute absorbancy changes (slope) at λ=420nm place to survey it after mixing immediately.Reference liquid is pH=8.0 phosphate buffer soln.
6, result judges: change (slope) as 100 unit of activity using the absorbancy do not added measured by sample; Enzyme activity=(adding absorbancy change (slope) of absorbancy change (slope)/the do not add inhibitor of inhibitor) × 100, the concentration of the inhibitor when the relative activity of enzyme is 50 is the IC of inhibitor 50value, result as described in Table 1.
Table 1: compound 4-8 is to the IC of acetylcholinesterase and butyrylcholine esterase inhibit activities 50value and the selectivity suppressed
ato the selectivity=IC of acetylcholinesterase 50(butyrylcholine esterase)/IC 50(acetylcholinesterase).
7. conclusion: as shown in Table 1, synthesized 8-replaces the different aporphine derivative of oxidation (4 ~ 8) to the suppression IC of acetylcholinesterase 50value is all at micromolar levels.And the suppression to butyrylcholine esterase, also reach micromolar level.Compound 5 has the highest inhibit activities (IC to acetylcholinesterase in the compound of all tests 50=0.081 μM), and it is approximately 56 times of reference substance tacrine to the selectivity of acetylcholinesterase.

Claims (10)

1. the 8-with structure shown in following formula (I) replaces the different aporphine derivative of oxidation or its pharmacy acceptable salt:
Wherein, n=1 ~ 5.
2. 8-according to claim 1 replaces the synthetic method of the different aporphine derivative of oxidation, comprises the following steps:
1) with 3-chloro-phthalic anhydride and phenylethylamine for raw material, build 8-Cl-1-azepine benzanthrone parent compound through twice ring closure reaction;
2) 8-Cl-1-azepine benzanthrone parent compound obtains 8-amino-7H-dibenzoquinoline-7-ketone through ammonification;
3) 8-amino-7H-dibenzoquinoline-7-ketone reacts with the chloride compounds being connected to piperidines, obtains corresponding target product.
3. synthetic method according to claim 2, is characterized in that: the target product of gained carries out purifying through recrystallization or silica gel column chromatography.
4. the synthetic method according to Claims 2 or 3, it is characterized in that: step 1) in, with 3-chloro-phthalic anhydride and phenylethylamine for raw material, carry out according to similar Bradsher reaction mechanism, recycling dehydrating agent sulfuric acid closes ring and obtains 8-Cl-1-azepine benzanthrone parent compound.
5. the synthetic method according to Claims 2 or 3, is characterized in that: step 2) in, ammonification is carried out under 140 ~ 160 DEG C of conditions.
6. the synthetic method according to Claims 2 or 3, it is characterized in that: step 3) in, the described chloride compounds being connected to piperidines is 2-(piperidino) Acetyl Chloride 98Min., 3-(piperidino) propionyl chloride, 4-(piperidino) butyryl chloride, 5-(piperidino) valeryl chloride or 6-(piperidino) caproyl chloride.
7. the 8-replacement different aporphine derivative of oxidation according to claim 1 or its pharmacy acceptable salt are preparing the application in acetylcholine esterase inhibitor medication.
8. application according to claim 7, is characterized in that: described 8-replaces the application of the different aporphine derivative of oxidation in preparation treatment alzheimer's disease, cerebrovascular dementia, glaucoma or myasthenia gravis medicine.
9. the acetylcholine esterase inhibitor medication being oxidized different aporphine derivative and preparing for effective ingredient is replaced with 8-according to claim 1.
10. medicine according to claim 9, is characterized in that: the formulation of described medicine is injection, tablet, pill, capsule, suspension agent or emulsion.
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