CN103980194A - 6,8-disubstituted quinoline compound or pharmaceutically acceptable salt thereof, preparing method and application of same - Google Patents

6,8-disubstituted quinoline compound or pharmaceutically acceptable salt thereof, preparing method and application of same Download PDF

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CN103980194A
CN103980194A CN201410204002.2A CN201410204002A CN103980194A CN 103980194 A CN103980194 A CN 103980194A CN 201410204002 A CN201410204002 A CN 201410204002A CN 103980194 A CN103980194 A CN 103980194A
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ethyl
quinoline
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compound
suc
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CN103980194B (en
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黄文海
沈正荣
杨叶伟
马臻
王尊元
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Zhejiang Academy of Medical Sciences
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof
    • C07D215/32—Esters
    • C07D215/34—Carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/24—Oxygen atoms attached in position 8
    • C07D215/26—Alcohols; Ethers thereof

Abstract

The invention discloses a 6,8-disubstituted quinoline compound and a pharmaceutically acceptable salt thereof, wherein the 6,8-disubstituted quinoline compound is represented as formula I. The invention also discloses a preparation method of the 6,8-disubstituted quinoline compound. Anti-senile dementia drug Rivastigmine is employed as a lead compound and is fused with a metal ion chelating fragment 8-hydroxyquinoline to obtain a series of 6,8-disubstituted quinoline compounds. The method is wide in source of raw materials, easy to carry out, simple in operation, mild in reaction conditions, easy to control, low in cost and suitable for industrial production. The invention also discloses applications of the 6,8-disubstituted quinoline compounds and the pharmaceutically acceptable salts thereof in respect of treating senile dementia disease. The novel compounds have an acetylcholinesterase inhibitory activity and an A[beta] aggregation inhibitory capability. In addition, hydrolysis products of the novel compounds have a metal ion chelation effect. The novel compounds can treat the senile dementia disease from multiple targets and have a good application prospect of anti-senile dementia.

Description

The two substd quinolines compounds of 6,8-or its pharmacy acceptable salt and its preparation method and application
Technical field
The present invention relates to a kind of derivative of quinoline, be specifically related to the two substd quinolines compounds of a kind of 6,8-, pharmacy acceptable salt and preparation method and application.
Background technology
The Aging Problem of China's population is on the rise at present, and " 2011 annual Chinese programs for the elderly statistical communique of development " shows, ended for the year ends 2011, and 60 years old, the whole nation and the above size of population have reached 1.85 hundred million, have entered the society of the aged.Wherein, the degenerative diseases such as senile dementia are common complaint among the elderly and frequently-occurring disease, its sickness rate over-65s be 8%, 75 years old be 20% above, by 85 years old above up to 40% left and right.
The treatment of senile dementia at present there is no specific medicament, main marketed drug is five acetylcholinesterase (Acetylcholinesterase, AChE) inhibitor and a N-methyl-D-aspartate (N-methyl-D-aspartic acid, NMDA) receptor antagonist.But it only can delay gently, moderate AD patient's symptom, be difficult to the PD of containment or reverse AD.Research shows, the pathogenesis of AD is very complicated, so use single target drug effectively not control or to cure.In recent years, the treatment of two target drugs provides new thinking for the new drug development of AD.Because two target drugs play a role by the different pathological physiology link to disease, can heighten the effect of a treatment, reduce side effect.
In recent years, the research and development of the anti-AD medicine of many target spots have obtained certain achievement, have had many target drugs to enter clinical trial.Just there is AChE and MAO dual restraining activities such as entering the Ladostigil that the clinical II phase studies.Also has part of compounds also in the preclinical study stage.Carry out a pair of horses going side by side for total thyl methyl amine structure in bright and close as Kogen research group utilizes selective serotonin reuptake inhibitor (SSRI) fluoxetine (fluoxetine) and AChE inhibitor profit to cut down department, obtaining new compound 1 has higher inhibition activity to AChE and SERT; The people such as Elsinghorst are by containing the connection chain of hydrazides, flaxedil is connected, obtains compound 2 ability with antagonism M2 acceptor with tacrine, and to the inhibition activity of AChE in nmole level.(Chinese pharmaceutical chemistry magazine .2011,21:433-441.)
Therefore, the research of the two anti-AD medicines of target spot of exploitation is significant to China's medicinal industry and social development.
Research recently shows, the random development, particularly iron that can accelerate the AD state of an illness of the metabolism of metal ion wadding in brain, copper, zinc plasma.Find by the concentration of metal ions monitoring in patient's AD brain, the metal ion (iron, copper, zinc) in AD patient's brain is 3-7 times of normal people's concentration.Concentration of metal ions extremely not only can directly affect the development of the AD course of disease, can also accelerate the gathering of A β, promotes the formation of the senile plaque in AD patient's brain.Therefore, metal ion chelation agent is also one of hot research field of AD medicine.Deferoxamine (DFO) is the metal ion chelation agent of clinical life-time service, and two-year double blind experiment shows, intramuscular injection DFO can significantly improve AD patient's symptom.Iodochlorhydroxyquin (CQ) is originally used for the treatment of malaria, the chelation of metal ion that its tool of rear discovery is good, II phase clinical study also shows that Iodochlorhydroxyquin can obviously reduce the gathering of the amyloid in patient's brain, is a promising AD medicine.
It is the first-line drug of current clinical use for name that AChE inhibitor profit is cut down this, has hypotoxicity, and good pharmacokinetic property, without advantages such as the interactions between medicine.
Therefore, cut down this for primer by name with CQ and profit, exploitation has two target spots, and the compound of multiple anti-AD activity has good patent medicine prospect.
Summary of the invention
Be all single target treatment medicine for existing anti-AD medicine, only can delay AD advancing of disease, the invention provides a kind of novel, efficiently two anti-AD compound 6 of target spot, the two substd quinolines compounds of 8-and pharmacy acceptable salt thereof.
The two substd quinolines compounds of a kind of 6,8-or its pharmacy acceptable salt, described 6, the structure of the two substd quinolines compounds of 8-is suc as formula shown in I:
Wherein, R 1or R 2structural formula be independently-NR 4r 5;
R 4or R 5independently selected from H, C 1-C 4alkyl, C 1-C 4thiazolinyl, C 1-C 4haloalkyl, C 1-C 4oxa alkyl, C 1-C 4azepine alkyl, aryl, alkaryl, alkoxy aryl, halogenated aryl, or R 4, R 5form five yuan, hexa-atomic or seven-membered ring with N, described five yuan, hexa-atomic or seven-membered ring are oxazolyl, pyrryl, pyrrolidyl, imidazolyl, pyrazolyl, piperidyl, piperazinyl, methylpiperazine base, homopiperazine base, morpholinyl or homopiperidinyl or its substituent;
R 3independently selected from C 1-C 10alkyl, C 1-C 10thiazolinyl, C 1-C 10haloalkyl, C 1-C 10oxa alkyl, C 1-C 10azepine alkyl; X is oxygen or sulphur.
The compound with structure shown in formula I has good In-vitro Inhibitory Effect to acetylcholinesterase, and has significant chelation of metal ion and A beta peptide aggregation restraining effect.
As preferably, described R 1, R 2structural formula be independently-NR 4r 5, wherein R 4, R 5independently selected from H, methyl, ethyl, propyl group, sec.-propyl, or R 4, R 5form five yuan, hexa-atomic or seven-membered ring with N, described five yuan, hexa-atomic or seven-membered ring are pyrrolidyl, piperidyl, piperazinyl, methylpiperazine base, homopiperazine base, morpholinyl or homopiperidinyl; R 3independently selected from methyl, ethyl, propyl group, sec.-propyl, vinyl, allyl group; X is oxygen or sulphur.
As preferably, described R 4, R 5independently selected from H, methyl, ethyl, propyl group, sec.-propyl, or R 4, R 5form five yuan, hexa-atomic or seven-membered ring with N, described five yuan, hexa-atomic or seven-membered ring are pyrrolidyl, piperidyl, piperazinyl, methylpiperazine base, homopiperazine base, morpholinyl or homopiperidinyl; R 3independently selected from methyl, ethyl, propyl group, sec.-propyl, vinyl, allyl group.
Further preferably, described 6, the two substd quinolines compounds of 8-are selected from:
6-[(1-methylamino) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-methylamino) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-methylamino) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-methylamino) ethyl]-8-diethylin methanoyl quinoline
6-[(1-methylamino) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-dimethylamino) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-dimethylamino) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-dimethylamino) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-dimethylamino) ethyl]-8-diethylin methanoyl quinoline
6-[(1-dimethylamino) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-the first and second amino) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-the first and second amino) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-the first and second amino) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-the first and second amino) ethyl]-8-diethylin methanoyl quinoline
6-[(1-the first and second amino) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-diethylin) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-diethylin) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-diethylin) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-diethylin) ethyl]-8-diethylin methanoyl quinoline
6-[(1-diethylin) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(1 '-morpholine) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(1 '-morpholine) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(1 '-morpholine) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(1 '-morpholine) ethyl]-8-diethylin methanoyl quinoline
6-[1-(1 '-morpholine) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-diethylin methanoyl quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(1 '-piperidines) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(1 '-piperidines) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(1 '-piperidines) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(1 '-piperidines) ethyl]-8-diethylin methanoyl quinoline
6-[1-(1 '-piperidines) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-diethylin methanoyl quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-dimethylamino) ethyl]-8-{1-[(1 '-tetramethyleneimine) formyl radical] oxygen base } quinoline
6-[(1-dimethylamino) ethyl]-8-{1-[(1 '-piperidines) formyl radical] oxygen base } quinoline
6-[(1-the first and second amino) ethyl]-8-{1-[(1 '-tetramethyleneimine) formyl radical] oxygen base } quinoline
6-[(1-the first and second amino) ethyl]-8-{1-[(1 '-piperidines) formyl radical] oxygen base } quinoline
6-[(1-diethylin) ethyl]-8-{1-[(1 '-tetramethyleneimine) formyl radical] oxygen base } quinoline
6-[(1-diethylin) ethyl]-8-{1-[(1 '-piperidines) formyl radical] oxygen base } quinoline.
Further preferred, described 6, the two substd quinolines compounds of 8-are selected from:
Described pharmacy acceptable salt is described 6, the salt that the two substd quinolines compounds of 8-and mineral acid, organic acid reaction form.As preferably, described pharmacy acceptable salt is hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, oxalate, tartrate, mesylate, tosilate, fumarate, taurate, Citrate trianion or succinate.
It is a kind of described 6 that the present invention also provides, and the preparation method of the two substd quinolines compounds of 8-has starting material wide material sources, an advantage such as cost is low, method is simple to operate, mild condition.
The preparation method of the two substd quinolines compounds of a kind of 6,8-, for starting raw material, obtains VI by nucleophilic, reduction, halo with the two substd quinolines Compound I I of 6,8-, then with introduce R with the nucleophilic substitution reaction of halohydrocarbon 2group, then under HBr condition demethylation, further with acyl chloride reaction obtain a series of 6, the two substd quinolines Compound I of 8-.Specifically comprise the following steps:
(1) in the first organic solvent, react with the compound suc as formula III the compound obtaining suc as formula IV suc as formula the compound of II, temperature of reaction is that room temperature extremely refluxes, and the reaction times is 1～12 hour;
(2) in the second organic solvent, react suc as formula the compound of IV the compound obtaining suc as formula V with reductive agent, temperature of reaction is-20～40 DEG C, 12～72 hours reaction times;
(3) suc as formula the compound of V in the 3rd organic solvent, react the compound obtaining suc as formula VI with thionyl chloride, temperature of reaction is room temperature～150 DEG C, 1～24 hour reaction times;
(4) in the 4th organic solvent, react the compound obtaining suc as formula VIII with the compound suc as formula VII suc as formula the compound of VI, temperature of reaction is that room temperature is to backflow, 1～12 hour reaction times;
(5) react suc as formula the compound of VIII the compound obtaining suc as formula IX with Hydrogen bromide, temperature of reaction is room temperature to 200 DEG C, 12～72 hours reaction times;
(6) suc as formula the compound of IX in the 5th organic solvent, under the existence of acid binding agent, react with formula X compound the compound obtaining suc as formula I, temperature of reaction is-50～50 DEG C, 1～24 hour reaction times;
Reaction formula is as follows:
Wherein, R 1, R 2, R 3with the definition of X as mentioned before; R 6reaction by step (1) is converted into R 3.R 6concrete structure can according to those skilled in the art according to existing knowledge determine, work as R 3for alkyl time, R 6for corresponding alkylidene group, for example, work as R 3for CH 3cH 2-time, R 6for CH 3cH=; Work as R 3for thiazolinyl time, R 6for corresponding alkenylene, for example, work as R 3for CH 2when=CH-, R 6for CH 2=C=.
Compound III, VII, X are commercial goods, and compound ii can make according to the disclosed method of US Patent No. 20130116430.
In step (1), the first organic solvent used is selected in methyl alcohol, ethanol, ethylene glycol any or mixture.As preferably, the first organic solvent in described step (1) is ethanol.
In described step (2), the second organic solvent used is selected in tetrahydrofuran (THF), ether, acetone, butanone any or mixture; Reductive agent is sodium borohydride or lithium aluminium hydride.
As preferably, the second organic solvent in described step (2) is tetrahydrofuran (THF); Reductive agent is sodium borohydride.
In step (3), the 3rd organic solvent used is selected in acetonitrile, acetone, trichloromethane, methylene dichloride any or mixture.As preferably, the 3rd organic solvent in described step (3) is methylene dichloride.
In step (4), the 4th organic solvent used is selected in acetonitrile, acetone, butanone, methylene dichloride any or mixture.As preferably, the 4th organic solvent in described step (4) is acetonitrile.
Any concentration that Hydrogen bromide concentration in step (5) is 10%-48%.As preferably, the Hydrogen bromide concentration in described step (5) is 40%.
In step (6), the 5th organic solvent selects in tetrahydrofuran (THF), acetone, methylene dichloride any or mixture, acid binding agent to select in carbonic acid (hydrogen) potassium, sodium carbonate, butyllithium, sodium hydride any or mixture.As preferably, the 5th organic solvent in described step (6) is tetrahydrofuran (THF); Acid binding agent is sodium hydride.
The preparation method of described pharmacy acceptable salt is as follows, reaction is made various 6, the two substd quinolines compounds of 8-are dissolved in the one in ether, acetone, methyl alcohol, ethanol, ethyl acetate, drip mineral acid or organic acid solution, make pharmacy acceptable salt.
Specifically, by various 6, the two substd quinolines compounds of 8-are dissolved in the one in ether, acetone, methyl alcohol, ethanol or ethyl acetate, drip hydrochloric ethyl acetate solution under ice-water bath, make hydrochloride; Or various N-substituted aryl pyridinone compounds are dissolved in to the one in ether, acetone, methyl alcohol, ethanol or ethyl acetate, mole methylsulfonic acids such as dropping, obtain its mesylate; Or by various 6, the two substd quinolines compounds of 8-are dissolved in the one in ether, acetone, methyl alcohol, ethanol or ethyl acetate, drip concentrated sulfuric acid solution and make vitriol under ice-water bath, etc.
In addition, the present invention also provides the midbody compound shown in formula IV～IX:
R in formula IV～IX 1～R 3definition as mentioned before.
More preferably, the midbody compound shown in formula IV is:
1-(8-methoxy quinoline-6-yl) ethyl ketone (is R 3for methyl).
Midbody compound shown in formula V is:
1-(8-methoxy quinoline-6-yl) ethanol (is R 3for methyl).
Midbody compound shown in formula VI is:
6-(1-chloroethyl)-8-methoxy quinoline (is R 3for methyl).
Midbody compound shown in formula VIII is:
1-(8-methoxy quinoline-6-yl)-N-methyl ethyl-amine (is R 2for methylamino-, R 3for methyl);
1-(8-methoxy quinoline-6-yl)-N, N-dimethyl amine (is R 2for dimethylin, R 3for methyl);
N-ethyl-1-(8-methoxy quinoline-6-yl)-N-methyl ethyl-amine (is R 2be the first and second amidos, R 3for methyl);
N, N-diethyl-1-(8-methoxy quinoline-6-yl) ethamine (is R 2for diethylin, R 3for methyl);
8-methoxyl group-6-[1-(pyrrolidin-1-yl) ethyl] quinoline (is R 2for pyrrolidyl, R 3for methyl);
8-methoxyl group-6-[1-(piperidin-1-yl) ethyl] quinoline (is R 2for piperidyl, R 3for methyl);
4-[1-(8-methoxy quinoline-6-yl) ethyl] morpholine (is R 2for morpholinyl, R 3for methyl); Or
8-methoxyl group-6-[1-(4-methylpiperazine-1-yl) ethyl] quinoline (is R 2for N methyl piperazine base, R 3for methyl).
Midbody compound shown in formula IX is:
6-[1-(methylamine) ethyl] quinoline-8-alcohol (is R 2for methylamino-, R 3for methyl);
6-[1-(dimethyl amine) ethyl] quinoline-8-alcohol (is R 2for dimethylin, R 3for methyl);
6-{1-[ethyl (methyl) amine] ethyl } quinoline-8-alcohol (is R 2be the first and second amidos, R 3for methyl);
6-[1-(diethylamide) ethyl] quinoline-8-alcohol (is R 2for diethylin, R 3for methyl);
6-[1-(pyrrolidin-1-yl) ethyl] quinoline-8-alcohol (is R 2for pyrrolidyl, R 3for methyl);
6-[1-(piperidin-1-yl) ethyl] quinoline-8-alcohol (is R 2for piperidyl, R 3for methyl);
6-(1-morpholine ethyl) quinoline-8-alcohol (is R 2for morpholinyl, R 3for methyl); Or
6-[1-(4-methylpiperazine-1-yl) ethyl] quinoline-8-alcohol (is R 2for N methyl piperazine base, R 3for methyl).
Described in the present invention also provides 6, the application in preparation treatment senile dementia disease medicament of the two substd quinolines compounds of 8-and pharmacy acceptable salt thereof.Preliminary pharmacological testing finds that these compounds great majority have restraining effect to acetylcholinesterase, and its inhibition activity of part of compounds is better than lead compound Rivastigmine, and all compounds all have metal ion-chelant ability.
The present invention is taking AChE inhibitor rivastigmine as lead compound, is retaining on basic parent nucleus basis, introduce the oxine fragment with chelation of metal ion obtain a series of 6, the two substd quinolines compounds of 8-.Have starting material and be easy to preparation, method is simple to operate, mild condition, and cost is low, is suitable for the advantages such as suitability for industrialized production.
Brief description of the drawings
Fig. 1 is the ultraviolet spectrogram before and after hydrolysate and cupric ion effect in embodiment 38;
Fig. 2 is the ultraviolet spectrogram before and after hydrolysate and iron ion action in embodiment 38;
Fig. 3 is the A beta peptide aggregation state graph of the blank in embodiment 39;
Fig. 4 is the state of aggregation figure that adds A β after compound in embodiment 39.
Embodiment
Following examples are used for illustrating the present invention, but are not used for limiting the scope of the invention.
(IV a) for ethyl ketone for embodiment 1,1-(8-methoxy quinoline-6-yl)
By formula II compound 2.4g (10mmol), palladium 110mg (0.5mmol), 1; two (diphenylphosphine) propane 410mg (1mmol) of 3-are dissolved in ethanol 20ml; nitrogen protection; add triethylamine 25mmol and 1-(vinyl oxygen base) butane IIIa30mmol, be heated to 150 DEG C of reactions 24 hours.The 30ml that adds water, methylene dichloride 30ml*3 extracts, and merges organic layer, dry, concentrated.With silicagel column separation (sherwood oil: ethyl acetate: triethylamine=2:1:0.1), obtain faint yellow solid IV a, yield 52%.m.p.64-66℃。
1H-NMR(δ,CDCl 3):9.03(d,1H,J＝3.2Hz,ArH),8.26(d,1H,J＝8.0Hz,ArH),8.04(s,1H,ArH),7.64(s,1H,ArH),7.52(dd,1H,J 1＝8.0Hz,J 2＝3.2Hz,ArH),4.16(s,3H,-OCH 3),2.75(s,3H,-COCH 3).
(V a) for ethanol for embodiment 2,1-(8-methoxy quinoline-6-yl)
Compounds Ⅳ a1.02g (5mmol) is dissolved in to 50ml tetrahydrofuran (THF), and gradation adds sodium borohydride 0.23g (6mmol), room temperature reaction 3 hours.The 50ml that adds water, ethyl acetate 50ml*3 extracts, and merges organic layer, dry, concentrated, obtains faint yellow solid V a, yield 95%, m.p.51-53 DEG C.
1H-NMR(δ,CDCl 3):8.87(dd,1H,J 1＝4.4Hz,J 2＝2.0Hz,ArH),8.07(dd,1H,J 1＝8.0Hz,J 2＝2.0Hz,ArH),7.40(dd,1H,J 1＝8.0Hz,J 2＝4.4Hz,ArH),7.32(s,1H,ArH),7.09(s,1H,ArH),5.04(q,1H,J＝6.0Hz,-CHOHCH 3),4.84(s,1H,-CHOHCH 3),4.09(s,3H,-OCH 3),1.57(d,3H,J＝6.0Hz,-CHOHCH 3).
(1-chloroethyl)-(VI a) for 8-methoxy quinoline for embodiment 3,6-
Compound V a1.4g (5mmol) is dissolved in to 10ml methylene dichloride, adds thionyl chloride 1ml, room temperature reaction 12 hours.The 10ml that adds water, separates organic layer, dry, concentrated, obtains faint yellow oily matter VI a, yield 70%.
1H-NMR(δ,CDCl 3):9.03(dd,1H,J 1＝4.4Hz,J 2＝1.6Hz,ArH),8.12(dd,1H,J 1＝8.4Hz,J 2＝1.6Hz,ArH),7.49(dd,1H,J 1＝8.4Hz,J 2＝4.4Hz,ArH),7.38(s,1H,ArH),7.13(s,1H,ArH),4.89(q,1H,J＝6.0Hz,-CHClCH 3),3.98(s,3H,-OCH 3),1.64(d,3H,J＝6.0Hz,-CHClCH 3).
(VIII a) for morpholine for embodiment 4,4-(1-(8-methoxy quinoline-6-yl) ethyl)
Compound VI a0.22g (1mmol) is dissolved in 5ml acetonitrile, adds morpholine VII a0.5ml, back flow reaction 3 hours.The 10ml that adds water, separates organic layer, dry, concentrated, obtains yellow oil VIII a, yield 92%.
1H-NMR(δ,CDCl 3):8.83(dd,1H,J 1＝4.0Hz,J 2＝2.0Hz,ArH),8.00(dd,1H,J 1＝8.0Hz,J 2＝2.0Hz,ArH),7.34(dd,1H,J 1＝8.0Hz,J 2＝4.0Hz,ArH),7.23(s,1H,ArH),7.11(s,1H,ArH),4.04(s,3H,-OCH 3),3.61(m,5H,morpholine,-CHCH 3),2.32(m,4H,morpholine),1.57(d,3H,J＝6.4Hz,-CHCH 3).
(IX a) for-oxine for embodiment 5,6-(1-morpholinyl ethyl)
Compound VIII a0.26g (1mmol) is added in 5ml Hydrogen bromide, and 100 DEG C are reacted 24 hours.Use NaHCO 3regulate pH=8, ethyl acetate 10ml*3 extracts, and merges organic layer, dry, and concentrated, column chromatography for separation (sherwood oil: ethyl acetate: triethylamine=2:1:0.1), obtains brown color oily matter IX a, yield 45%.
1H-NMR(δ,CDCl 3):8.75(s,1H,ArH),8.12(d,1H,J＝8.4Hz,ArH),7.34(dd,1H,J 1＝8.4Hz,J 2＝5.2Hz,ArH),7.28(s,1H,ArH),7.26(d,1H,J＝5.2Hz,ArH),3.72(m,4H,morpholine),3.41(q,1H,J＝6.4Hz,-CHCH 3),2.36(m,4H,morpholine),1.41(d,3H,J＝6.4Hz,-CHCH 3).
(I a) for quinoline-8-yl-dimethyl formamide for embodiment 6,6-(1-morpholine ethyl)
Compound IX a0.11g (0.5mmol) is dissolved in to 10ml tetrahydrofuran (THF), add sodium hydride 14mg (0.6mmol), room temperature reaction 4 hours, drips N, N-dimethylcarbamyl chloride Xa0.73mg (0.6mmol), room temperature reaction 12 hours.Remove solvent under reduced pressure, add 20ml water, ethyl acetate 20ml*3 extracts, and merges organic layer, dry, and concentrated, column chromatography for separation (sherwood oil: ethyl acetate: triethylamine=2:1:0.1), obtains orange oily matter IX a, yield 42%.
1H-NMR(δ,CDCl 3):8.91(d,1H,J＝4.4Hz,ArH),8.13(d,1H,J＝8.0Hz,ArH),7.60(s,1H,ArH),7.55(s,1H,ArH),7.41(dd,1H,J 1＝8.0Hz,J 2＝4.4Hz,ArH),3.72(m,4H,morpholine),3.50(d,1H,J＝5.6Hz,-CHCH 3),3.30(s,3H,-NCH 3),3.09(s,3H,-NCH 3),2.50(m,4H,morpholine),1.44(d,4H,J＝5.6Hz,-CHCH 3)。
(I b) for embodiment 7,6-(1-morpholine ethyl) quinoline-8-yl-ethyl (methyl) methane amide
Operating process is referring to embodiment 6, by N-methyl-N-ethylamino formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain yellow oil I b, yield 51%.
1H-NMR(δ,CDCl 3):8.89(d,1H,J＝4.0Hz,ArH),8.12(d,1H,J＝8.0Hz,ArH),7.59(s,1H,ArH),7.54(d,1H,J＝8.0Hz,ArH),7.39(dd,1H,J 1＝8.0Hz,J 2＝4.0Hz,ArH),3.72(m,5H,morpholine，-NCH 2CH 3),3.47(m,2H,-NCH 2CH 3，-CHCH 3),3.27(s,1.5H,-NCH 3),3.07(s,1.5H,-NCH 3),2.49(m,4H,morpholine),1.42(m,4.5H,-CHCH 3,-NCH 2CH 3),1.25(m,1.5H,-NCH 2CH 3)。
(I c) for quinoline-8-yl-diethylformamide for embodiment 8,6-(1-morpholine ethyl)
Operating process is referring to embodiment 6, and with N, N-diethylamino formyl chloride replaces N, N-dimethylcarbamyl chloride.Obtain yellow oil I c, yield 59%.
1H-NMR(δ,CDCl 3):8.86(d,1H,J＝4.0Hz,ArH),8.10(d,1H,J＝8.4Hz,ArH),7.58(s,1H,ArH),7.53(s,1H,ArH),7.37(dd,1H,J 1＝8.4Hz,J 2＝4.0Hz,ArH),3.71(m,4H,morpholine),3.63(d,2H,J＝7.2Hz,-NCH 2CH 3),3.45(m,3H,-NCH 2CH 3，-CHCH 3),2.49(m,4H,morpholine),1.40(m,6H,-CHCH 3,-NCH 2CH 3),1.25(d,3H,J＝7.2Hz,-NCH 2CH 3).
(I d) for quinoline-8-yl-pyrrolidyl-1-methane amide for embodiment 9,6-(1-morpholine ethyl)
Operating process is referring to embodiment 6, by pyrrolidyl-1-formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain brown color oily matter I d, yield 43%.
1H-NMR(δ,CDCl 3):8.92(d,1H,J＝2.4Hz,ArH),8.14(d,1H,J＝8.4Hz,ArH),7.60(s,1H,ArH),7.43(dd,1H,J 1＝8.4Hz,J 2＝2.4Hz,ArH),7.30(s,1H,ArH),4.14(m,2H,pyrrolidine),3.82(m,1H,pyrrolidine),3.73(m,4H,morpholine),3.56(m,1H,pyrrolidine),3.49(m,1H,-CHCH 3),2.51(m,4H,morpholine),2.00(m,4H,pyrrolidine),1.45(m,3H,-CHCH 3).
(I e) for quinoline-8-yl-piperidyl-1-methane amide for embodiment 10,6-(1-morpholine ethyl)
Operating process is referring to embodiment 6, by piperidyl-1-formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain brown oil I e, yield 63%.
1H-NMR(δ,CDCl 3):8.89(d,1H,J＝4.0Hz,ArH),8.10(d,1H,J＝8.0Hz,ArH),7.42(dd,1H,J 1＝8.0Hz,J 2＝4.0Hz,ArH),7.29(s,1H,ArH),7.17(s,1H,ArH),4.13(m,2H,piperidine),3.74(m,6H,piperidine,morpholine),3.43(m,1H,-CHCH 3),2.49(m,4H,morpholine),1.68(m,3H,-CHCH 3),1.42(m,4H,piperidine),1.26(m,2H,piperidine).
(I f) for quinoline-8-yl-morpholinyl-1-methane amide for embodiment 11,6-(1-morpholine ethyl)
Operating process is referring to embodiment 6, by morpholinyl-1-formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain yellow oil I f, yield 61%.
1H-NMR(δ,CDCl 3):8.86(s,1H,ArH),8.11(d,1H,J＝8.4Hz,ArH),7.58(s,1H,ArH),7.55(s,1H,ArH),7.37(m,1H,ArH),4.13(m,2H,piperidine),3.74(m,12H,morpholine),3.46(q,1H,J＝6.4Hz,-CHCH 3),2.47(m,4H,morpholine),1.41(d,3H,J＝6.4Hz,-CHCH 3).
Embodiment 12,1-(8-methoxy quinoline-6-yl)-N, (VIII b) for N-dimethyl amine
Operating process is referring to embodiment 4, replaces morpholine with dimethylamine hydrochloride.Obtain yellow oil VIII b, yield 90%.
1H-NMR(δ,CDCl 3):8.93(dd,1H,J 1＝4.4Hz,J 2＝2.0Hz,ArH),8.07(dd,1H,J 1＝8.0Hz,J 2＝2.0Hz,ArH),7.40(dd,1H,J 1＝8.0Hz,J 2＝4.4Hz,ArH),7.29(s,1H,ArH),7.16(s,1H,ArH),4.03(s,3H,-OCH 3),3.67(q,1H,J＝6.0Hz,-CHCH 3),2.38(s,6H,-N(CH 3) 2),1.57(d,3H,J＝6.0Hz,-CHCH 3).
(IX b) for-oxine for embodiment 13,6-(1-(dimethylin) ethyl)
Operating process is referring to embodiment 5.Replace VIII a with VIII b, obtain yellow oil IX b, yield 46%.
1H-NMR(δ,CDCl 3):8.75(s,1H,ArH),8.13(d,1H,J＝8.4Hz,ArH),7.41(dd,1H,J 1＝8.4Hz,J 2＝4.0Hz,ArH),7.23(s,1H,ArH),7.13(d,1H,J＝4.0Hz,ArH),3.71(q,1H,J＝6.8Hz,-CHCH 3),2.28(s,6H,-N(CH 3) 2),1.46(d,3H,J＝6.8Hz,-CHCH 3).
(I g) for quinoline-8-yl-dimethyl formamide for embodiment 14,6-(1-(dimethylin) ethyl)
Operating process is referring to embodiment 6, with IX b replacement IX a.Obtain yellow oil I g, yield 48%.
1H-NMR(δ,CDCl 3):8.89(d,1H,J＝2.8Hz,ArH),8.12(d,1H,J＝8.0Hz,ArH),7.60(s,1H,ArH),7.51(s,1H,ArH),7.39(dd,1H,J 1＝8.0Hz,J 2＝2.8Hz,ArH),3.46(q,1H,J＝6.8Hz,-CHCH 3),3.28(s,3H,-CON(CH 3) 2),3.07(s,3H,-CON(CH 3) 2),2.28(s,6H,-CHN(CH 3) 2),1.46(d,3H,J＝6.8Hz,-CHCH 3).
(I h) for quinoline-8-yl-ethyl (methyl) methane amide for embodiment 15,6-(1-(dimethylin) ethyl)
Operating process is referring to embodiment 14, by N-methyl-N-ethylamino formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain brown color oily matter I h, yield 51%.
1H-NMR(δ,CDCl 3):8.89(d,1H,J＝4.0Hz,ArH),8.12(d,1H,J＝8.0Hz,ArH),7.59(s,1H,ArH),7.52(d,1H,J＝8.0Hz,ArH),7.38(dd,1H,J 1＝8.0Hz,J 2＝4.0Hz,ArH),3.67(m,1H,-NCH 2CH 3),3.45(m,2H,-NCH 2CH 3，-CHCH 3),3.26(s,1.5H,-NCH 3),3.06(s,1.5H,-NCH 3),2.27(s,6H,-NCH 3),1.45(m,3H,-CHCH 3),1.38(m,1.5H,-NCH 2CH 3),1.25(m,1.5H,-NCH 2CH 3).
(I i) for quinoline-8-yl-diethylformamide for embodiment 16,6-(1-(dimethylin) ethyl)
Operating process is referring to embodiment 14, and with N, N-diethylamino formyl chloride replaces N, N-dimethylcarbamyl chloride.Obtain yellow oil I i, yield 58%.
1H-NMR(δ,DMSO-d 6):8.78(dd,1H,J 1＝4.0Hz,J 2＝1.6Hz,ArH),8.25(dd,1H,J 1＝8.4Hz,J 2＝1.6Hz,ArH),7.49(dd,1H,J 1＝8.4Hz,J 2＝4.0Hz,ArH),7.37(s,ArH),6.96(s,1H,ArH),4.01(q,4H,J＝7.2Hz,-NCH 2CH 3),3.99(m,1H,-CHN(CH 3) 2),2.16(s,6H,-CHN(CH 3) 2),1.35(d,3H,J＝6.4Hz,-CHCH 3),1.16(t,6H,J＝7.2Hz,-CHCH 3).
(I j) for quinoline-8-yl-pyrrolidyl-1-methane amide for embodiment 17,6-(1-(dimethylin) ethyl)
Operating process is referring to embodiment 14, by pyrrolidyl-1-formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain brown color oily matter I j, yield 41%.
1H-NMR(δ,CDCl 3):8.88(dd,1H,J 1＝4.0Hz,J 2＝1.6Hz,ArH),8.07(dd,1H,J 1＝8.0Hz,J 2＝1.6Hz,ArH),7.39(dd,1H,J 1＝8.0Hz,J 2＝4.0Hz,ArH),7.21(s,ArH),7.13(s,1H,ArH),4.12(t,4H,J＝6.0Hz,-CHN(CH 3) 2),3.34(m,4H,pyrrolidine),2.27(s,6H,-CHN(CH 3) 2),1.42(t,3H,J＝6.0Hz,-CHCH 3),1.23(m,4H,pyrrolidine).
(I k) for quinoline-8-yl-piperidyl-1-methane amide for embodiment 18,6-(1-(dimethylin) ethyl)
Operating process is referring to embodiment 14, by piperidyl-1-formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain brown oil I k, yield 46%.
1H-NMR(δ,CDCl 3):8.87(d,1H,J＝6.8Hz,ArH),8.06(d,1H,J＝8.4Hz,ArH),7.38(dd,1H,J 1＝8.4Hz,J 2＝6.8Hz,ArH),7.26(d,1H,J＝1.6Hz,ArH),7.14(d,1H,J＝1.6Hz,ArH),4.10(m,5H,-CHCH 3,piperidine),2.25(m,10H,piperidine,-CHN(CH 3) 2),1.44(d,3H,J＝6.8Hz,-CHCH 3).
(I l) for quinoline-8-yl-morpholinyl-1-methane amide for embodiment 19,6-(1-(dimethylin) ethyl)
Operating process is referring to embodiment 14, by morpholinyl-1-formyl chloride replacement N, N-dimethylcarbamyl chloride.Obtain yellow oil I l, yield 59%.
1H-NMR(δ,CDCl 3):8.77(d,1H,J＝4.4Hz,ArH),7.96(d,1H,J＝8.4Hz,ArH),7.27(dd,1H,J 1＝8.4Hz,J 2＝4.4Hz,ArH),7.16(d,1H,J＝1.6Hz,ArH),7.05(d,1H,J＝1.6Hz,ArH),4.00(q,1H,J＝6.4Hz,-CHCH 3,),3.57(t,4H,J＝4.8Hz,morphine),3.16(t,4H,J＝4.8Hz,morphine),2.14(s,6H,-CHN(CH 3) 2),1.32(d,3H,J＝6.4Hz,-CHCH 3).
Embodiment 20, N, (VIII c) for ethamine for N-diethyl-1-(8-methoxy quinoline-6-yl)
Operating process is referring to embodiment 4, replaces morpholine with diethylamine.Obtain yellow oil VIII c, yield 88%.
1H-NMR(δ,CDCl 3):8.98(s,1H,ArH),8.18(d,1H,J＝8.4Hz,ArH),7.52(dd,1H,J 1＝8.4Hz,J 2＝5.6Hz,ArH),7.40(s,1H,ArH),7.22(s,1H,J＝5.6Hz,ArH),4.22(s,3H,-OCH 3),4.03(q,1H,J＝6.0Hz,-CHCH 3),2.72(m,4H,-N(CH 2CH 3) 2),1.53(d,3H,J＝6.0Hz,-CHCH 3),1.08(m,6H,-N(CH 2CH 3) 2).
(IX c) for-oxine for embodiment 21,6-(1-(diethylin) ethyl)
Operating process is referring to embodiment 5.Obtain yellow solid IX c, yield 46%.m.p.65-67℃。
1H-NMR(δ,CDCl 3):8.72(s,1H,ArH),8.11(d,1H,J＝8.4Hz,ArH),7.39(dd,1H,J 1＝8.4Hz,J 2＝5.2Hz,ArH),7.32(s,1H,ArH),7.20(d,1H,J＝5.2Hz,ArH),3.91(q,1H,J＝6.0Hz,-CHCH 3),2.57(m,4H,-N(CH 2CH 3) 2),1.42(d,3H,J＝6.0Hz,-CHCH 3),1.01(m,6H,-N(CH 2CH 3) 2).
(I m) for quinoline-8-yl-methylformamide for embodiment 22,6-(1-(diethylamino) ethyl)
Operating process, referring to embodiment 14, uses N-ethylamino formyl chloride to replace N, N-dimethylcarbamyl chloride, and IX c replaces IX b.Obtain yellow oil I m, yield 32%.
1H-NMR(δ,CDCl 3):8.89(d,1H,J＝2.4Hz,ArH),8.09(d,1H,J＝8.0Hz,ArH),7.41(dd,1H,J 1＝8.0Hz,J 2＝2.4Hz,ArH),7.36(s,1H,ArH),7.31(s,1H,ArH),4.12(d,3H,J＝5.6Hz,-NCH 3),3.96(d,1H,J＝6.4Hz,-CHCH 3),2.72(s,4H,-N(CH 2CH 3) 2),1.48(s,3H,-CHCH 3),1.06(d,6H,J＝6.4Hz,-N(CH 2CH 3) 2).
(I n) for quinoline-8-yl-ethyl (methyl) methane amide for embodiment 23,6-(1-(diethylamino) ethyl)
Operating process is referring to embodiment 14, and IX c replaces IX b.Obtain yellow oil I n, yield 54%.
1H-NMR(δ,CDCl 3):8.89(d,1H,J＝4.0Hz,ArH),8.12(d,1H,J＝8.0Hz,ArH),7.62(s,1H,ArH),7.60(d,1H,J＝6.8Hz,ArH),7.38(dd,1H,J 1＝8.0Hz,J 1＝6.8Hz,ArH),3.99(d,1H,J＝6.0Hz,-CHCH 3),3.68(m,1H,-CONCH 2CH 3),3.48(m,1H,-CONCH 2CH 3),3.27(s,1.5H,-NCH 3),3.06(s,1.5H,-NCH 3),2.61(q,4H,J＝6.8Hz,-CHN(CH 2CH 3) 2),1.44(d,3H,J＝6.0Hz,-CHCH 3),1.37(m,1.5H,-CONCH 2CH 3),1.26(m,1.5H,-CONCH 2CH 3),1.03(t,6H,J＝6.8Hz,-CHN(CH 2CH 3) 2).
(VIII d) for ethamine for embodiment 24, N-methyl-N-ethyl-1-(8-methoxy quinoline-6-yl)
Operating process is referring to embodiment 4, replaces morpholine with thyl methyl amine.Obtain yellow oil VIII d, yield 82%.
(IX d) for-oxine for embodiment 25,6-(1-(ethyl (methyl) amido) ethyl)
Operating process is referring to embodiment 5.Obtain brown color oily matter IX d, yield 44%.
1H-NMR(δ,CDCl 3):8.73(d,1H,J＝2.8,ArH),8.10(d,1H,J＝8.4Hz,ArH),7.40(dd,1H,J 1＝8.4Hz,J 2＝2.8Hz,ArH),7.27(s,1H,ArH),7.25(s,1H,ArH),3.68(q,1H,J＝6.4Hz,-CHCH 3),2.42(q,2H,J＝2.8,-N(CH 3)CH 2CH 3),2.16(s,3H,-N(CH 3)CH 2CH 3),1.43(d,3H,J＝6.4Hz,-CHCH 3),1.04(q,3H,J＝2.8,-N(CH 3)CH 2CH 3).
(I o) for quinoline-8-yl-ethyl (methyl) methane amide for embodiment 26,6-(1-(ethyl (methyl) amino) ethyl)
Operating process is referring to embodiment 14, and IX d replaces IX b.Obtain yellow oil I o, yield 55%.
1H-NMR(δ,CDCl 3):8.91(d,1H,J＝3.6Hz,ArH),8.10(d,1H,J＝8.4Hz,ArH),7.43(dd,1H,J 1＝8.4Hz,J 2＝3.6Hz,ArH),7.30(s,1H,ArH),7.24(s,1H,ArH),4.14(m,3.5H,-CONCH 3,-CONCH 2CH 3,-CHCH 3),3.71(m,1.5H,-CONCH 3),3.50(m,1H,-CONCH 2CH 3),2.58(m,2H,-NCH 2CH 3),2.33(s,3H,-NCH 3),1.50(d,3H,J＝6Hz,-CHCH 3),1.26(m,3H,-CONCH 2CH 3),1.10(m,3H,-NCH 2CH 3).
(VIII e) for quinoline for embodiment 27,8-methoxyl group-6-(1-(pyrrolidin-1-yl) ethyl)
Operating process is referring to embodiment 4, replaces morpholine with tetramethyleneimine.Obtain yellow oil VIII e, yield 85%.
(IX e) for-oxine for embodiment 28,6-(1-(pyrrolidin-1-yl) ethyl)
Operating process is referring to embodiment 5.Obtain yellow oil IX e, yield 45%.
1H-NMR(δ,CDCl 3):8.73(d,1H,J＝4.0,ArH),8.08(d,1H,J＝8.0Hz,ArH),7.39(dd,1H,J 1＝8.0Hz,J 2＝4.0Hz,ArH),7.30(s,1H,ArH),7.17(s,1H,ArH),3.30(q,1H,J＝6.0Hz,-CHCH 3),2.42(m,4H,pyrrolidine),1.77(m,4H,pyrrolidine),1.46(d,3H,J＝6.0Hz,-CHCH 3).
(I p) for quinoline-8-yl-ethyl (methyl) methane amide for embodiment 29,6-(1-(pyrrolidin-1-yl) ethyl)
Operating process is referring to embodiment 14, and IX e replaces IX b.Obtain yellow oil I p, yield 52%.
1H-NMR(δ,CDCl 3):8.89(d,1H,J＝4.0Hz,ArH),8.09(d,1H,J＝8.8Hz,ArH),7.41(dd,1H,J 1＝8.8Hz,J 2＝4.0Hz,ArH),7.30(s,1H,ArH),7.20(s,1H,ArH),4.12(m,5H,-NCH 3,-NCH 2CH 3),3.37(q,1H,J＝5.6Hz,-CHCH 3),2.56(m,4H,pyrrolidine),1.82(m,4H,pyrrolidine),1.51(d,3H,J＝5.6Hz,-CHCH 3),1.26(t,3H,J＝6.8Hz,-NCH 3).
(VIII f) for quinoline for embodiment 30,8-methoxyl group-6-(1-(piperidin-1-yl) ethyl)
Operating process is referring to embodiment 4, replaces morpholine with piperidines.Obtain yellow oil VIII f, yield 90%.
(IX f) for-oxine for embodiment 31,6-(1-(piperidin-1-yl) ethyl)
Operating process is referring to embodiment 5.Obtain faint yellow solid IX f, yield 52%.m.p.104-106℃。
1H-NMR(δ,CDCl 3):8.74(d,1H,J＝4.4,ArH),8.12(d,1H,J＝8.4Hz,ArH),7.41(dd,1H,J 1＝8.4Hz,J 2＝4.4Hz,ArH),7.28(s,1H,ArH),7.25(s,1H,ArH),3.49(q,1H,J＝3.6Hz,-CHCH 3),2.39(m,4H,piperidine),1.55(m,4H,piperidine),1.41(m,5H,-CHCH 3,piperidine).
(I q) for quinoline-8-yl-ethyl (methyl) methane amide for embodiment 32,6-(1-(piperidin-1-yl) ethyl)
Operating process is referring to embodiment 14, and IX f replaces IX b.Obtain yellow oil I q, yield 57%.
1H-NMR(δ,CDCl 3):8.87(d,1H,J＝2.8Hz,ArH),8.11(d,1H,J＝8.4Hz,ArH),7.57(s,1H,ArH),7.53(d,1H,J＝6.8Hz,ArH),7.37(dd,1H,J 1＝8.4Hz,J 2＝6.8Hz,ArH),3.68(q,1H,J＝6.8Hz,-CHCH 3),3.56(q,1H,J＝6.8Hz,-CH 2CH 3),3.48(q,1H,J＝6.8Hz,-CH 2CH 3),3.26(s,1.5H,-NCH 3),3.06(s,1.5H,-NCH 3),2.42(m,4H,piperidine),1.57(m,4H,piperidine),1.44(d,3H,J＝6.8Hz,-CHCH 3),1.39(m,2H,piperidine),1.25(t,1.5H,J＝6.8Hz,-CH 2CH 3),1.25(t,1.5H,J＝6.8Hz,-CH 2CH 3).
(VIII g) for quinoline for embodiment 33,8-methoxyl group-6-(1-(4-methylpiperazine-1-yl) ethyl)
Operating process is referring to embodiment 4, replaces morpholine with N methyl piperazine.Obtain yellow oil VIII g, yield 90%.
(IX g) for-oxine for embodiment 34,6-(1-(4-methylpiperazine-1-yl) ethyl)
Operating process is referring to embodiment 5.Obtain yellow solid IX g, yield 45%.m.p.117-119℃。
1H-NMR(δ,CDCl 3):8.72(d,1H,J＝4.0,ArH),8.09(d,1H,J＝8.0Hz,ArH),7.40(dd,1H,J 1＝8.0Hz,J 2＝4.0Hz,ArH),7.27(s,1H,ArH),7.24(s,1H,ArH),3.44(q,1H,J＝6.4Hz,-CHCH 3),2.47(m,8H,1-methylpiperazine),2.29(s,3H,-NCH 3),1.40(d,3H,J＝6.4Hz,-CHCH 3).
(I r) for quinoline-8-yl-ethyl (methyl) methane amide for embodiment 35,6-(1-(4-methylpiperazine-1-yl) ethyl)
Operating process is referring to embodiment 14, and IX g replaces IX b.Obtain yellow oil I r, yield 40%.
1H-NMR(δ,CDCl 3):8.88(d,1H,J＝3.2Hz,ArH),8.12(d,1H,J＝8Hz,ArH),7.58(s,1H,ArH),7.53(d,1H,J＝8Hz,ArH),7.39(dd,1H,J 1＝8.0Hz,J 2＝3.2Hz,ArH),4.13(q,1H,J＝6.8Hz,-CHCH3),3.67(q,1H,J＝7.2Hz,-NCH 2CH 3),3.27(m,2.5H,-CONCH 3,-NCH 2CH 3),3.06(s,1.5H,-CONCH 3),2.67(m,8H,1-Methyl-piperazine),2.32(s,3H,-NCH 3),1.43(d,3H,J＝6.8Hz,-CHCH 3),1.41(t,1.5H,J＝7.2Hz,-NCH 2CH 3),1.12(t,1.5H,J＝7.2Hz,-NCH 2CH 3).
The hydrochloride of embodiment 36, chemical compounds I o
Get chemical compounds I o1.0g, be dissolved in 10mL ethyl acetate, in ice-water bath, be cooled to 0 DEG C, drip saturated HCl ethyl acetate solution, centrifugal, obtain white solid, yield 70%.
Embodiment 37, inhibiting activity of acetylcholinesterase, testing method
PCMV-AChE transfected HEK 293: pCMV-AChE plasmid is added to serum free medium, add lipofectamineTM2000 transfection reagent, mix, preparation transfection liquid, leaves standstill 20min.Take out the HEK293 cell after cultivating, add serum free medium, slowly drip transfection liquid, place 37 DEG C, 1h in 5%CO2 incubator, discards nutrient solution, adds perfect medium, puts in incubator and cultivates.After 72h, collect nutrient solution, the centrifugal 5min of 12000rcf, getting supernatant liquor is enzyme liquid, enzyme analysis activity is immediately frozen in-80 DEG C of refrigerators after the packing of unnecessary enzyme liquid.
Inhibiting activity of acetylcholinesterase, test: add 4 μ L enzyme liquid in reaction system, 20 μ L inhibitor (being Ia～Ir), 50 μ L DTNB (0.1%), add water and supply 150 μ L, hatch 5min for 37 DEG C, add 37 DEG C of 50 μ LATCh (0.5mmol/L) to hatch 15min, add 50 μ L SDS (3%) termination reactions, measure OD value, parallel three parts at 412nm place.Select seven to nine its enzyme inhibition rates of concentration determination of compound according to primary dcreening operation result, carry out linear regression (computed in software) with the negative logarithm of compound volumetric molar concentration and enzyme inhibition rate and ask for IC50 value.
Acquired results is in table 1:
Table 1 compound is to inhibiting activity of acetylcholinesterase, result
a.***：0.1～10μmol/L；**：10～50μmol/L；*：50～100μmol/L。
As can be seen from Table 1: (1) all compounds are inhibited to acetylcholinesterase.(2) most compound suppresses active between 10～50 μ mol/L.The inhibition activity of (3) 3 compounds is at 0.1～10 μ mol/L, active better or suitable than marketed drug rivastigmine.
Embodiment 38, metal ion-chelant aptitude tests method
The acetylcholinesterase hydrolysis experiment of compound: (be that IX a～IX PBS solution r) joins in 160 μ L PBS damping fluids (pH=7.4) by 20 μ L compounds, add again the Triton X-100 of 0.05% (v/v) and the acetylcholinesterase homogenate of 20 μ L of 10 μ L, at 37 DEG C, hatch 48 hours.Ethyl acetate is extracted, and merges organic layer, anhydrous sodium sulfate drying.Pressure reducing and steaming solvent, obtains the acetylcholinesterase hydrolysate of compound
The metal ion-chelant aptitude tests of hydrolysate: hydrolysate is dissolved in 1mL methyl alcohol, adds copper or the iron ion of different concns, add water and be settled to 100mL, detect it after 0.5h in 200-600nm uv-absorbing.Detect the UV spectrum of hydrolysate simultaneously.Ultraviolet figure by hydrolysate under different concns Metal Ions Conditions and the uv-spectrogram of compound compare, and judge whether it has metal ion-chelant ability.Wherein the result of Compound I l is as follows:
In Fig. 1, the UV spectrum that curve a is hydrolysate, curve b is that hydrolysate adds the UV spectrum after cupric ion, obviously can find: 1) displacement has occurred maximum absorption wavelength in figure; 2) change obviously in the absorption intensity of the maximum absorption wavelength 240nm of hydrolysate.Hydrolysate chelating has been described cupric ion, has formed with it mixture.The UV spectrum that in Fig. 2, curve a is hydrolysate, curve b is that hydrolysate adds the UV spectrum after iron ion, has illustrated that equally hydrolysate can chelated iron ion.
Embodiment 39, A beta peptide aggregation suppress aptitude tests
A β peptide is made into the solution of 0.1mM with 1% ammoniacal liquor, gets 50 μ L and be added to the metal ion aqueous solution (0.1mM) of 50 μ L, room temperature shaking table, after 2 minutes, adds the Compound I l aqueous solution (0.1mM) of 100 μ L, 37 DEG C of shaking tables 48 hours.Use the state of aggregation of tem study A β.
Fig. 3 is the A beta peptide aggregation state of blank, and Fig. 4 is the state of aggregation that adds A β after compound, from figure, can obviously find out and add after compound, and black patch reduces, and illustrates that compound can suppress the gathering of A β.
Generally speaking, such new compound not only has inhibiting activity of acetylcholinesterase, and A beta peptide aggregation suppresses ability, its hydrolysate also has chelation of metal ion, can treat senile dementia from multiple target spots, there is good anti-senile dementia application prospect, thereby there is good commercial value.
Without further elaborating, believe employing disclosed content above, those skilled in the art can apply the present invention to greatest extent.Therefore, embodiment is above interpreted as only illustrating, but not limits the scope of the invention by any way.

Claims (13)

1. one kind 6, the two substd quinolines compounds of 8-, is characterized in that, structure is suc as formula shown in I:
Wherein, R 1or R 2structural formula be independently-NR 4r 5;
R 4or R 5independently selected from H, C 1-C 4alkyl, C 1-C 4thiazolinyl, C 1-C 4haloalkyl, C 1-C 4oxa alkyl, C 1-C 4azepine alkyl, aryl, alkaryl, alkoxy aryl, halogenated aryl, or R 4, R 5form five yuan, hexa-atomic or seven-membered ring with N, described five yuan, hexa-atomic or seven-membered ring are oxazolyl, pyrryl, pyrrolidyl, imidazolyl, pyrazolyl, piperidyl, piperazinyl, methylpiperazine base, homopiperazine base, morpholinyl or homopiperidinyl or its substituent;
R 3independently selected from C 1-C 10alkyl, C 1-C 10thiazolinyl, C 1-C 10haloalkyl, C 1-C 10oxa alkyl, C 1-C 10azepine alkyl; X is oxygen or sulphur.
2. as claimed in claim 16, the two substd quinolines compounds of 8-, is characterized in that described R 4, R 5independently selected from H, methyl, ethyl, propyl group, sec.-propyl, or R 4, R 5form five yuan, hexa-atomic or seven-membered ring with N, described five yuan, hexa-atomic or seven-membered ring are pyrrolidyl, piperidyl, piperazinyl, methylpiperazine base, homopiperazine base, morpholinyl or homopiperidinyl; R 3independently selected from methyl, ethyl, propyl group, sec.-propyl, vinyl, allyl group.
3. as claimed in claim 16, the two substd quinolines compounds of 8-or its pharmacy acceptable salt, is characterized in that, described 6, and the two substd quinolines compounds of 8-are selected from:
6-[(1-methylamino) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-methylamino) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-methylamino) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-methylamino) ethyl]-8-diethylin methanoyl quinoline
6-[(1-methylamino) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-dimethylamino) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-dimethylamino) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-dimethylamino) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-dimethylamino) ethyl]-8-diethylin methanoyl quinoline
6-[(1-dimethylamino) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-the first and second amino) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-the first and second amino) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-the first and second amino) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-the first and second amino) ethyl]-8-diethylin methanoyl quinoline
6-[(1-the first and second amino) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-diethylin) ethyl]-8-methylamino-methanoyl quinoline
6-[(1-diethylin) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[(1-diethylin) ethyl]-8-the first and second carbamoyloxy quinoline
6-[(1-diethylin) ethyl]-8-diethylin methanoyl quinoline
6-[(1-diethylin) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(1 '-morpholine) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(1 '-morpholine) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(1 '-morpholine) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(1 '-morpholine) ethyl]-8-diethylin methanoyl quinoline
6-[1-(1 '-morpholine) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-diethylin methanoyl quinoline
6-[1-(1 '-tetramethyleneimine) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(1 '-piperidines) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(1 '-piperidines) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(1 '-piperidines) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(1 '-piperidines) ethyl]-8-diethylin methanoyl quinoline
6-[1-(1 '-piperidines) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-methylamino-methanoyl quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-formyl oxygen dimethylamino quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-the first and second carbamoyloxy quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-diethylin methanoyl quinoline
6-[1-(4 '-methylpiperazine) ethyl]-8-{1-[(1 '-morpholine) formyl radical] oxygen base } quinoline
6-[(1-dimethylamino) ethyl]-8-{1-[(1 '-tetramethyleneimine) formyl radical] oxygen base } quinoline
6-[(1-dimethylamino) ethyl]-8-{1-[(1 '-piperidines) formyl radical] oxygen base } quinoline
6-[(1-the first and second amino) ethyl]-8-{1-[(1 '-tetramethyleneimine) formyl radical] oxygen base } quinoline
6-[(1-the first and second amino) ethyl]-8-{1-[(1 '-piperidines) formyl radical] oxygen base } quinoline
6-[(1-diethylin) ethyl]-8-{1-[(1 '-tetramethyleneimine) formyl radical] oxygen base } quinoline, or
6-[(1-diethylin) ethyl]-8-{1-[(1 '-piperidines) formyl radical] oxygen base } quinoline.
As described in claim 1～3 any one 6, the two pharmaceutically acceptable salt of substd quinolines compound of 8-, is characterized in that: described pharmacy acceptable salt is described 6, the two substd quinolines compounds of 8-and mineral acid, organic acid reaction salify.
5. as claimed in claim 46; the two pharmaceutically acceptable salt of substd quinolines compound of 8-, is characterized in that: described pharmacy acceptable salt is hydrochloride, hydrobromate, hydriodate, vitriol, hydrosulfate, phosphoric acid salt, acetate, propionic salt, butyrates, oxalate, tartrate, mesylate, tosilate, fumarate, taurate, Citrate trianion or succinate.
One kind as described in claim 1～3 any one 6, the preparation method of the two substd quinolines compounds of 8-, is characterized in that, comprises the following steps:
(1) in the first organic solvent, react with the compound suc as formula III the compound obtaining suc as formula IV suc as formula the compound of II, temperature of reaction is that room temperature extremely refluxes, and the reaction times is 1～12 hour;
(2) in the second organic solvent, react suc as formula the compound of IV the compound obtaining suc as formula V with reductive agent, temperature of reaction is-20～40 DEG C, 12～72 hours reaction times;
(3) suc as formula the compound of V in the 3rd organic solvent, react the compound obtaining suc as formula VI with thionyl chloride, temperature of reaction is room temperature to 150 DEG C, 1～24 hour reaction times;
(4) in the 4th organic solvent, react the compound obtaining suc as formula VIII with the compound suc as formula VII suc as formula the compound of VI, temperature of reaction is that room temperature is to backflow, 1～12 hour reaction times;
(5) react suc as formula the compound of VIII the compound obtaining suc as formula IX with Hydrogen bromide, temperature of reaction is room temperature to 200 DEG C, 12～72 hours reaction times;
(6) suc as formula the compound of IX in the 5th organic solvent, under the existence of acid binding agent, react with the compound of formula X the compound obtaining suc as formula I, temperature of reaction is-50～50 DEG C, 1～24 hour reaction times;
Reaction formula is as follows:
Wherein, R 1, R 2, R 3with the definition of X as described in claim 1～3 any one; R 6reaction by step (1) is converted into R 3.
7. as claimed in claim 66, the preparation method of the two substd quinolines compounds of 8-, is characterized in that, in step (1), the first organic solvent used is selected in methyl alcohol, ethanol, ethylene glycol any or mixture;
In step (2), the second organic solvent used is selected in tetrahydrofuran (THF), ether, acetone, butanone any or mixture; Reductive agent is sodium borohydride or lithium aluminium hydride;
In step (3), the 3rd organic solvent used is selected in acetonitrile, acetone, trichloromethane, methylene dichloride any or mixture;
In step (4), the 4th organic solvent used is selected in acetonitrile, acetone, butanone, methylene dichloride any or mixture;
In step (5), Hydrogen bromide mass percent concentration is any concentration between 10%-48%;
In step (6), the 5th organic solvent selects in tetrahydrofuran (THF), acetone, methylene dichloride any or mixture, acid binding agent to select in salt of wormwood, saleratus, sodium carbonate, butyllithium, sodium hydride any or mixture.
One kind as described in claim 1～3 any one 6, the two substd quinolines compounds of 8-or as described in claim 4 or 56, the pharmaceutically application of acceptable salt in the degenerative disease medicines such as preparation treatment senile dementia of the two substd quinolines compounds of 8-.
9. one kind 6, the two substd quinolines compounds of 8-, is characterized in that, structure is suc as formula shown in IV:
Wherein, R 3definition as claimed in claim 1 or 2.
10. one kind 6, the two substd quinolines compounds of 8-, is characterized in that, structure is suc as formula shown in V:
Wherein, R 3definition as claimed in claim 1 or 2.
11. a kind 6, the two substd quinolines compounds of 8-, is characterized in that, structure is suc as formula shown in VI:
Wherein, R 3definition as claimed in claim 1 or 2.
12. a kind 6, the two substd quinolines compounds of 8-, is characterized in that, structure is suc as formula shown in VIII:
Wherein, R 2or R 3definition as claimed in claim 1 or 2.
13. a kind 6, the two substd quinolines compounds of 8-, is characterized in that, structure is suc as formula shown in IX:
Wherein, R 2or R 3definition as claimed in claim 1 or 2.
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