CN108484591A - Compound for treating Alzheimer's disease and its application - Google Patents
Compound for treating Alzheimer's disease and its application Download PDFInfo
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- CN108484591A CN108484591A CN201810518770.3A CN201810518770A CN108484591A CN 108484591 A CN108484591 A CN 108484591A CN 201810518770 A CN201810518770 A CN 201810518770A CN 108484591 A CN108484591 A CN 108484591A
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Abstract
The present invention relates to a kind of compound of isobioquin group of formula (I) and its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate, nitrogen oxides or prodrugs, and the invention further relates to the preparation method and its usages of the compound.Test result shows that the compounds of this invention has very excellent inhibitory activity to acetylcholinesterase (AChE), and has enhancing memory effect to SAM P/8 dementia mices.In addition, compared with existing drug galanthamine, inhibitory activity of the compounds of this invention for acetylcholinesterase and the memory-enhancing effect effect to dementia mice are significantly more excellent.Therefore, the compounds of this invention is suitable for treatment Alzheimer's disease.
Description
Technical field
The present invention relates to field of medicaments, in particular to a kind of compound for treating Alzheimer's disease.This hair
The bright preparation and its application for further relating to the compound.
Background technology
Alzheimer's disease (Alzheimer ' s disease, AD) is referred to as senile dementia or degenerative brain disorder,
It is a kind of chronic, the progressive nerve cell retrogression pathological changes for being common in the elderly.With the aging of population, AD has become only
The 4th cause of the death is occupied inferior to cardiovascular disease, tumour and apoplexy, it is contemplated that right to the year two thousand forty whole world by shared AD patient 81,000,000
The research of AD pathogenesis and the efficient AD medicines of searching have become the international hot spot and Disciplinary Frontiers attracted attention.
The intracerebral pathological characters of patient AD are mainly that beta-amyloid protein deposits the senile plaque to be formed, microtubule associated protein mistake
Spend the neurofibrillary tangles and neuron loss caused by phosphorylation.So far the mankind still lack its pathogenesis comprehensively and substantive
Property understanding, numerous mechanism explanation in, " cholinergic hypothesis " and " β starch peptides hypothesis " is that generally accepted two kinds of people are important
Illustrate (Coyle J.T., Science, 1983,219：1184；Hardy J., Curr.Alzheimer Res., 2006,3：
71)。
The AD medicines of Clinical practice are mainly based upon the acetylcholinesterase (AChE) of cholinergic hypothesis design at present
Inhibitor improves the ACh concentration between cynapse, so as to improve learning and memory work(by inhibiting the hydrolysis of acetylcholine (Ach)
Energy and human-subject test.Now U.S. FDA approval listing five AD medicines in there are four be AChE inhibitor, including he gram
Woods, donepezil, Rivastigmine and galanthamine.Tacrine is seldom used because it is with hepatotoxicity wind agitation and serious adverse reaction
In clinic；Donepezil, Rivastigmine and galanthamine are the 2nd generation AChE inhibitor of three kinds of widely used treatment AD,
Higher inhibiting activity of acetylcholinesterase is shown, but still there is certain toxicity, and these AChE inhibitor can only mitigate
AD symptoms and its pathologic process cannot be reversed.Therefore, it is necessary to develop more drugs that can be used for treating Alzheimer's disease.
Invention content
The present invention provides a kind of compound of isobioquin group can be used for treating Alzheimer's disease, the compounds pair
There is very excellent inhibiting effect in acetylcholinesterase (AChE), can be used for effectively treating Alzheimer's disease.
On the one hand, the present invention provides a kind of formula (I) compound or its pharmaceutically acceptable salt, stereoisomer,
Tautomer, hydrate, solvate, nitrogen oxides or prodrug：
Wherein：
R1、R2、R3、R4It is identical or different, it is each independently selected from H, halogen, hydroxyl, nitro, cyano, amino, C1-6 alkane
Base, C1-6 alkoxies or C1-6 alkoxy carbonyl groups；
R5Selected from H, halogen or C1-6 alkyl；
R6Selected from H or C1-6 alkyl；
R7、R8、R9It is identical or different, be each independently selected from H, nitro, cyano, amino, C1-6 alkyl, C3-8 naphthenic base,
C1-6 alkylaminos, C1-6 alkoxies or 5-10 membered heterocycloalkyls；
Wherein, the C1-6 alkyl, C3-8 naphthenic base, C1-6 alkylaminos, C1-6 alkoxies, C1-6 alkoxy carbonyl groups or 5-10
First heteroarylalkyl is optionally replaced by 1 or more group selected from the following：Halogen, C1-4 alkyl, C1-4 alkoxies or C1-4
Alkylamino.
In the certain preferred embodiments of the present invention, the R1For H or methoxyl group；The R2For H, methoxyl group, fluorine, first
Base, trifluoromethyl or ethoxy ethoxy；The R3For hydrogen, methoxyl group or methyl；The R4For hydrogen or methoxycarbonyl.
In the certain preferred embodiments of the present invention, the R5For H or tertiary butyl.
In the certain preferred embodiments of the present invention, the R6For H, methyl or ethyl.
In the certain preferred embodiments of the present invention, the R7、R9For H, methoxyl group, ethyoxyl, nitro, cyano, isopropyl
Base, cyclohexyl or methyl；The R8For H, methoxyl group, ethyoxyl, amino, methylamino, pyrrolidin-1-yl or methyl.
In the certain preferred embodiments of the present invention, the compound is selected from：
On the other hand, the present invention provides a kind of pharmaceutical composition, described pharmaceutical composition includes at least one formula
(I) compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvate or prodrug, with
And pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or combinations thereof.
In another aspect, a kind of compound of present invention offer or described pharmaceutical composition are preparing acetylcholinesterase
(AChE) application in inhibitor.
Another aspect, a kind of compound of present invention offer or described pharmaceutical composition are being prepared for treating A Erci
Application in the drug of the silent disease in sea.
Detailed description of the invention
Definition and general terms
It will now be described in more detail certain embodiments of the present invention, the example is by the structural formula and chemical formula explanation that are appended.This
Invention is intended to cover all replacement, modification and equivalent technical solutions, they are included in the present invention defined such as claim
In range.Those skilled in the art will appreciate that many can be used in reality with similar or equivalent method and material described herein
Trample the present invention.
In the present invention, term " halogen " refers to fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
In the present invention, term " alkyl " indicates saturated straight chain or branch univalent hydrocarbyl group containing 1-20 carbon atom.
In some embodiments, alkyl contains 1-12 carbon atom；In other embodiments, alkyl group contains 1-6 carbon
Atom；In other embodiment, alkyl group contains 1-4 carbon atom.Alkyl is, for example, methyl, ethyl, n-propyl, different
Propyl, normal-butyl, isobutyl group, sec-butyl, tertiary butyl, n-pentyl, n-hexyl etc..
In the present invention, term " naphthenic base " indicates the saturated cyclic group containing 3-12 carbon atom.In some embodiment party
In case, naphthenic base contains 3-8 carbon atom.Alkyl is, for example, that cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl and ring are pungent
Base.
In the present invention, term " Heterocyclylalkyl " indicate containing 1-4 (preferably 1,2,3 or 4) be selected from nitrogen-atoms,
The hetero atom of oxygen atom and sulphur atom and the 5-10 members saturation ring group for containing 1-9 (preferably 2-5) carbon atoms, it is described
When ring member nitrogen atoms are nitrogen-atoms or sulphur atom, the nitrogen-atoms, sulphur atom can form oxide.In some embodiments
In, Heterocyclylalkyl is, for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, tetrahydrofuran base, piperidyl, morpholinyl, dithiane
Base, thiomorpholine base, piperazinyl, trithiane base.
In the present invention, term " pharmaceutically acceptable salt " refers to the organic salt and inorganic salts of the compounds of this invention.Pharmacy
Upper acceptable salt includes, but is not limited to, and inorganic acid salt formed by reacting with amino groups to form has hydrochloride, hydrobromate, phosphorus
Hydrochlorate, sulfate, perchlorate and acylate such as acetate, oxalates, maleate, tartrate, citrate, amber
Amber hydrochlorate, malonate, adipate, alginates, ascorbate, aspartate, benzene sulfonate, benzoate, weight sulphur
Hydrochlorate, borate, butyrate, camphor hydrochlorate, camsilate, cyclopentyl propionate, esilate, formates, anti-butylene two
Hydrochlorate, gluceptate, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, lactose aldehyde
Hydrochlorate, lactate, laruate, malate etc..
In the present invention, the compounds of this invention includes that all stereoisomers, enantiomter and diastereomeric are different in structure
Structure body.Absolute configuration on asymmetric atom is indicated by R or S.The unknown parsing compound of its absolute configuration can be with
It is indicated by (+) or (-).When confirming particular stereoisomer, this indicates the stereoisomer substantially free of other isomeries
Body is less than 50%, is preferably smaller than 20%, more preferably less than 5%, particularly other isomers less than 2% or 1%.
The compounds of this invention can with one or their mixture in isomers, such as racemic modification and non-corresponding it is different
The form of structure body mixture exists.Chiral synthon or chiral reagent system can be used in optically active (R)-or (S)-isomers
It is standby, or split using routine techniques.
In the present invention, term " tautomer " refers to that with different energy can be by the structure of the mutual inversion of phases of low energy barrier
Isomers.If tautomerism is possible, the chemical balance of tautomer can be reached.For example, proton tautomer
Also referred to as Prototropic tautomers include the mutual inversion of phases carried out by proton transfer, such as keto-enol isomerization and Asia
Amine-ene amine isomerization.Valence tautomerism body includes the mutual inversion of phases carried out by the recombination of some bonding electrons.
In the present invention, term " solvate " refers to that one or more solvent molecules are formed by with the compound of the present invention
Associated matter.The solvent for forming solvate includes, but is not limited to, water, isopropanol, ethyl alcohol, methanol, dimethyl sulfoxide, acetic acid second
Ester, acetic acid and ethylaminoethanol.Term " hydrate " refers to that solvent molecule is that water is formed by associated matter.
In the present invention, term " nitrogen oxides " refers to the nitrogen that can be by 1 or more than 1 when compound when containing amine functional group
Atoms form N- oxides.The particular example of N- oxides is the N- oxides of tertiary amine or the N- oxygen of nitrogen heterocyclic ring nitrogen-atoms
Compound.Available oxidant such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) handle corresponding amine and form N- oxides.
In the present invention, term " prodrug " indicates the compound that can be converted into formula (I) compound in vivo.Such conversion
It is hydrolyzed by pro-drug or is influenced for precursor structure through enzymatic conversion in blood or tissue in blood.Pro-drug of the present invention
Class compound can be ester, and ester can have phenyl ester class, aliphatic ester, acyloxy as pro-drug in existing invention
Methyl esters, carbonic ester, carbamates and amino acid esters.
Pharmaceutical composition
The present invention provides suitable for pharmaceutical composition that is medicinal, including at least one reactive compound of the present invention
Object.The pharmaceutical composition can also further include pharmaceutically acceptable carrier, excipient, diluent, adjuvant, medium or
A combination thereof.Described pharmaceutical composition is inhibited for acetylcholinesterase (AChE), can be used for treating alzheimer '
Silent disease.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, representative method of application include but
It is not limited to：Oral, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral medication includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), or is mixed with following compositions：(a) filler
Or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) adhesive, for example, hydroxymethyl cellulose,
Alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) disintegrant, for example, agar, calcium carbonate, potato
Starch or tapioca, alginic acid, certain composition silicates and sodium carbonate；(d) wetting agent, for example, cetanol and monostearate it is sweet
Grease；(f) lubricant, for example, talcum, calcium stearate, magnesium stearate, solid polyethylene glycol, lauryl sodium sulfate or its
Mixture.In capsule, tablet and pill, dosage form also may include buffer.
Other than these inert diluents, preparation also may include auxiliary agent, such as emulsifier and suspending agent, sweetener, corrigent
And fragrance.
Preparation for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid, hang
Supernatant liquid or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.Suitable is aqueous and non-
Water carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, propellant and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
For the present invention, suitable dosage level is typically about 0.001 to 100mg daily per kg patient's weight,
It can be applied with single dose or multi-dose.Preferably, dosage level is about 0.01 daily to about 25mg/kg；It is highly preferred that about 0.05
It is daily to about 10mg/kg.Suitable dosage level can be about 0.01 to 25mg/kg daily, about 0.05 to 10mg/kg daily or
About 0.1 to 5mg/kg is daily.In the range, dosage can be that 0.005 to 0.05,0.05 to 0.5 or 0.5 to 5.0mg/kg are every
It.For being administered orally, preparation preferably provides in form of tablets, and the tablet includes 1.0 to 1000 milligrams of active constituents, special
Be not 1.0,3.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,
400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams of active constituents, for the agent to patient to be treated
The symptom of amount adjusts.Compound can be daily 1 to 4 time therapeutic scheme application, preferably once a day or twice daily.
However, the specific dosage level and administration frequency for any particular patient can change, and will depend on a variety of
Factor, including the activity of particular compound, the metabolic stability of the compound and the effect duration, the age, weight, general that use
Health, gender, diet, administration mode and time, rate of discharge, pharmaceutical composition, the seriousness of particular condition and decent treated
Host.
The compounds of this invention can with other pharmaceutical agent combinations or be applied in combination, other described medicaments can be used for treating, prevent, press down
System improves the compounds of this invention disease or situation useful to its, including Alzheimer's disease.Other described medicaments can be selected from：
Acetylcholinesterase (AChE) inhibitor, non-steroidal anti-inflammatory drugs.
Universal synthesis method
Usually, the compound of the present invention described method can be prepared through the invention, unless there are further
Explanation, wherein the definition of substituent group is as shown in formula (I) compound.Following reaction scheme and embodiment is for further lifting
Example illustrates present disclosure.
The present invention's provides the method for preparing formula (I) compound, the described method comprises the following steps：
Isoquinolines shown in formula (II) are made to be reacted in the presence of base with production with halides shown in formula (III)
(I) compound：
Wherein, R1-R9Definition it is as described herein, X indicates halogen, preferably chlorine or bromine；
The alkali includes inorganic base, such as hydride, such as sodium hydride or hydrofining；Hydroxide, for example, sodium hydroxide or
Potassium hydroxide；Carbonate, such as sodium carbonate or potassium carbonate；Bicarbonate, such as sodium bicarbonate or saleratus；Acetate, example
Such as sodium acetate or potassium acetate and organic base, such as pyridine or triethylamine.
Advantageous effect
The compounds of this invention has very excellent inhibitory activity to acetylcholinesterase (AChE), and to SAM-P/8
Dementia mice has enhancing memory effect.In addition, compared with existing drug galanthamine, the compounds of this invention is for acetylcholine
The inhibitory activity of esterase and significantly more excellent to the effect of the memory-enhancing effect of dementia mice.Therefore, the compounds of this invention is suitable for
Treat Alzheimer's disease.
Specific implementation mode
The present invention is described below in more detail to contribute to the understanding of the present invention.
Those skilled in the art will realize that：Chemical reaction described in the invention can be used for suitably preparing perhaps
Other compounds of more present invention, and other methods for the preparation of the compounds of the present invention are considered as the model in the present invention
Within enclosing.For example, can be successfully by those skilled in the art according to the synthesis of the compound of those non-illustrations of the invention
It is completed by method of modifying, such as protection interference group appropriate, by using other known reagent in addition to described in the invention
, or reaction condition is made into some conventional modifications.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged
Ground is suitable for the preparation of other compounds of the invention.
Embodiment 1：2- ((5- p-methylphenyl -1,3,4- thiadiazoles -2- bases) methyl) isoquinolin -1 (2H) -one (compound
TDIQ-1)
Isoquinolin -1 (2H) -one (5.0mmol) is dissolved in dry DMF (40mL), sodium hydride is added portionwise
After stirring 0.5h at room temperature, 2- bromomethyl -5- p-methylphenyls -1,3,4- thiadiazoles (5.5mmol) is added in (10.0mmol).
Obtained mixture continues to stir 5h at ambient temperature, and TLC monitoring reactions carry out.After reaction, reaction product is fallen
Enter in 100mL water, has white precipitate precipitation, stand overnight.It filters, solid is washed three times with 1M HCl/water solution, dry, it is thick to produce
Object (petroleum ether: ethyl acetate=10: 1), obtains white solid 1.38g, yield through silica gel chromatography：83.2%.
Mass spectrum (ESI)：334.09[M+H]+
Elemental analysis：Theoretical value C, 68.45；H,4.53；N,12.60；O,4.80；S,9.62
Measured value C, 68.23；H,4.68；N,12.71；O,4.95；S,9.43
Hydrogen spectrum (400MHz, DMSO) δ 7.40-7.71 (m, 7H), 7.15 (d, 2H), 6.15 (d, 1H), 4.54 (s, 2H),
2.32(s,3H)。
Embodiment 2：2- (1- (5- (3,4- diethoxies phenyl) -1,3,4- thiadiazoles -2- bases) ethyl) -6- methoxyl groups are different
Quinoline -1 (2H) -one (compound TDIQ-2)
6- methoxyisoquinoliaes -1 (2H) -one (5.0mmol) is dissolved in dry DMF (30mL), hydrogen is added portionwise
Change sodium (10.0mmol), after stirring 0.5h at room temperature, 2- (1- chloroethyls) -5- (3,4- diethoxy phenyl) -1,3 be added,
4- thiadiazoles (5.5mmol).Obtained mixture continues to stir 8h at ambient temperature, and TLC monitoring reactions carry out.Reaction knot
Shu Hou pours into reaction product in 100mL water, has pale precipitation precipitation, stands overnight.It filters, is washed with 1MHCl aqueous solutions
Three times, drying, crude on silica gel column chromatography purifying (hexamethylene: ethyl acetate=20: 1), obtains white solid to solid
1.82g yield：81.0%.
Mass spectrum (ESI)：452.16[M+H]+
Elemental analysis：Theoretical value C, 63.84；H,5.58；N,9.31；O,14.17；S,7.10
Measured value C, 63.97；H,5.42；N,9.20；O,14.36；S,7.05
Hydrogen spectrum (400MHz, DMSO) δ 7.65 (d, 1H), 7.43 (d, 1H), 7.28 (d, 1H), 7.20 (s, 1H), 7.13 (s,
1H),7.02(d,1H),6.91(d,1H),6.12(d,1H),5.14(q,1H),4.10(q,4H),3.84(s,3H),1.43(d,
3H),1.30(t,6H)。
Embodiment 3：8- methoxyl groups -2- (1- (5- (4- methoxyl group -3- nitrobenzophenones) -1,3,4- thiadiazoles -2- bases) second
Base)-isoquinolin -1 (2H) -one (compound TDIQ-3)
8- methoxyisoquinoliaes -1 (2H) -one (5.0mmol) is dissolved in dry DMF (30mL), hydrogen is added portionwise
Change potassium (10.0mmol), after stirring 0.5h at room temperature, 2- (1- chloroethyls) -5- (4- methoxyl group -3- nitrobenzophenones) -1 be added,
3,4- thiadiazoles (5.5mmol).Obtained mixture continues to stir 6h at ambient temperature, and TLC monitoring reactions carry out.Reaction
After, reaction product is poured into 100mL water, has light-yellow precipitate precipitation, stands overnight.It filters, with 1M HCl/water solution
Wash solid three times, drying, crude on silica gel column chromatography purifying (hexamethylene: methanol=60: 1), obtains light yellow solid
1.74g yield：79.6%.
Mass spectrum (ESI)：439.10[M+H]+
Elemental analysis：Theoretical value C, 57.53；H,4.14；N,12.78；O,18.25；S,7.31
Measured value C, 57.71；H,4.04；N,12.89；O,18.11；S,7.24
Hydrogen spectrum (400MHz, DMSO) δ 8.61 (s, 1H), 8.10 (d, 1H), 7.88 (t, 1H), 7.50 (d, 1H), 7.43 (d,
1H),7.12(d,1H),7.06(d,1H),6.13(d,1H),5.10(q,1H),3.85(s,3H),3.80(s,3H),1.42(d,
3H)。
In a similar way, corresponding raw material is used to synthesize following compound：
Effect example 1：External acetylcholine enzyme inhibition activity
Inhibiting activity of acetylcholinesterase uses Ellman colorimetric methods：It is raw according to acetylcholinesterase hydrolyse acetylcholine
At choline and acetic acid, choline is reacted with sulfydryl color developing agent generates yellow compound, colorimetric determination choline quantity, to hydrolysis
The quantity of product choline reflects Acetylcholinesterasein.Drug situation is：Acetylcholinesterase (AChE, electric eel,
Sigma companies), 5,5 '-two thiobis (2- nitrobenzoic acids) (Dithiobisnitrobenzoic acid, DTNB,
Sigma), acetylthiocholine iodide (Acetylthiocholine, ATCI, Sigma).Positive control be galantamine hydrobromide he
It is quick.
Determination step：0.05mL enzyme solutions and 0.05mL testing compound solutions are mixed, 20 points of kinds are kept the temperature at 37 DEG C；Then
0.5mL Ellman color developing agent DTNB and 0.5mL acetylthiocholine iodide solution is added, is reacted 6 minutes at 37 DEG C；Exist again
Its optical density is measured at 412nm wavelength with ultraviolet specrophotometer at room temperature, compared with the blank tube for being not added with untested compound
The reduction percentage being calculated is enzyme inhibition rate.Its enzyme inhibition rate of six to seven concentration mensurations of selection compound, and with
The negative logarithm of the compound molar concentration carries out linear regression with enzyme inhibition rate, and it is to be somebody's turn to do to acquire molar concentration when 50% inhibition
The IC of compound50Value measures be averaged three times.As a result it is shown in following table 1：
Table 1：External acetylcholine enzyme inhibition activity
The result shows that the compounds of this invention has enzyme acetylcholine very excellent inhibitory activity, which is better than
Known drug galanthamine, therefore, the compounds of this invention can be used for treating Alzheimer's disease.
Effect example 2：The Behaviors survey (Morris water mazes) of dementia mice (SAM-P/8)
SAM-P/8 dementia mices are randomly divided into 15 groups, every group 10, be respectively model group, experimental group i.e. TDIQ-1 extremely
TDIQ-13 groups, control group.Control group galanthamine hydrobromide suspension 400mg/kg gavages, once a day, experimental group is used etc.
Compound TDIQ-1 is measured to TDIQ-13 dirty solution gavages, model group normal saline gavage carried out 3 weeks, altogether every 3 days
Rest 1 day.Each group animal is after administration 3 weeks, according to literature method (Morris R., Developments of Water-Maze
procedure for studying spatial learning inthe rat,Journal of Neuroscience
Methods,1984,11:471) Morris water maze trainings are carried out 7 days, during which continues to be administered, after the completion of training 7 days, test is small
Mouse finds the incubation period of platform, across platform number and original platform quadrant swim distance and total swimming distance ratio t4/
tAlways.As a result it is shown in following table 2：
Table 2：Mouse Morris water mazes test (n=10)
Note：Compared with model group,#P<0.05；Compared with the control group,*P<0.05
The result shows that compared with model group, mouse incubation period of experimental group, that is, TDIQ-1 to TDIQ-13 groups is obviously shortened,
Cross platform number increase, where original platform quadrant swim distance and total swimming distance ratio bigger, and there is significant difference
(P ＜ 0.05) shows that each group mouse is good compared with model group to the memory of original platform quadrant, this shows the compounds of this invention to SAM-P/
8 dementia mices have enhancing memory effect.In addition, compared with the control group, the every of experimental mice shows more excellent (P ＜
0.05), it was demonstrated that the enhancing memory effect of the compounds of this invention is even also advantageous over galanthamine.Thus, the compounds of this invention is suitable
It shares in treatment Alzheimer's disease.
The foregoing describe the preferred embodiment for the present invention, and however, it is not to limit the invention.Those skilled in the art couple
Embodiment disclosed herein can carry out improvement and the variation without departing from scope and spirit.
Claims (10)
1. a kind of formula (I) compound or its pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, solvation
Object, nitrogen oxides or prodrug：
Wherein：
R1、R2、R3、R4It is identical or different, it is each independently selected from H, halogen, hydroxyl, nitro, cyano, amino, C1-6 alkyl, C1-
6 alkoxies or C1-6 alkoxy carbonyl groups；
R5Selected from H, halogen or C1-6 alkyl；
R6Selected from H or C1-6 alkyl；
R7、R8、R9It is identical or different, it is each independently selected from H, nitro, cyano, amino, C1-6 alkyl, C3-8 naphthenic base, C1-6
Alkylamino, C1-6 alkoxies or 5-10 membered heterocycloalkyls；
Wherein, the C1-6 alkyl, C3-8 naphthenic base, C1-6 alkylaminos, C1-6 alkoxies, C1-6 alkoxy carbonyl groups or 5-10 members are miscellaneous
Aralkyl is optionally replaced by 1 or more group selected from the following：Halogen, C1-4 alkyl, C1-4 alkoxies or C1-4 alkane ammonia
Base.
2. compound according to claim 1, which is characterized in that the R1For H or methoxyl group；The R2For H, methoxyl group,
Fluorine, methyl, trifluoromethyl or ethoxy ethoxy；The R3For hydrogen, methoxyl group or methyl；The R4For hydrogen or methoxycarbonyl.
3. compound according to claim 1, which is characterized in that the R5For H or tertiary butyl.
4. compound according to claim 1, which is characterized in that the R6For H, methyl or ethyl.
5. compound according to claim 1, which is characterized in that the R7、R9For H, methoxyl group, ethyoxyl, nitro, cyanogen
Base, isopropyl, cyclohexyl or methyl；The R8For H, methoxyl group, ethyoxyl, amino, methylamino, pyrrolidin-1-yl or methyl.
6. compound according to claim 1, which is characterized in that the compound is selected from：
7. a kind of pharmaceutical composition, including at least one formula (I) compound according to claim 1 or its can pharmaceutically connect
Salt, stereoisomer, tautomer, hydrate, solvate, nitrogen oxides or the prodrug received and pharmaceutically acceptable
Carrier, excipient, diluent, adjuvant, medium or combinations thereof.
8. formula (I) compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomerism
Body, hydrate, solvate, nitrogen oxides or prodrug or pharmaceutical composition according to claim 7 are preparing acetyl
Application in cholinesterase (AChE) inhibitor.
9. formula (I) compound according to claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomerism
Body, hydrate, solvate, nitrogen oxides or prodrug or pharmaceutical composition according to claim 7 are used in preparation
Treat the application in the drug of Alzheimer's disease.
10. a kind of method preparing formula according to claim 1 (I) compound, the described method comprises the following steps：
Isoquinolines shown in formula (II) are made to be reacted in the presence of base with halides shown in formula (III) to generate formula (I)
Close object：
Wherein, R1-R9Definition as described in the appended claim 1, X indicates halogen, preferably chlorine or bromine；
The alkali includes inorganic base, such as hydride, such as sodium hydride or hydrofining；Hydroxide, such as sodium hydroxide or hydrogen-oxygen
Change potassium；Carbonate, such as sodium carbonate or potassium carbonate；Bicarbonate, such as sodium bicarbonate or saleratus；Acetate, such as vinegar
Sour sodium or potassium acetate and organic base, such as pyridine or triethylamine.
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| CN201810518770.3A CN108484591B (en) | 2018-05-28 | 2018-05-28 | For treating compound and its application of Alzheimer's disease |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001247569A (en) * | 1999-08-12 | 2001-09-11 | Japan Tobacco Inc | Pyrrolidine derivative or piperidine derivative and its medicinal use |
| CN102123998A (en) * | 2008-06-23 | 2011-07-13 | H.隆德贝克有限公司 | Isoquinolinone derivatives as nk3 antagonists |
| CN103992313A (en) * | 2013-02-18 | 2014-08-20 | 江苏欧威医药有限公司 | 1,2,4-thiadiazole-3,5-dione derivatives, and pharmaceutical composition and application thereof |
| CN104203919A (en) * | 2011-11-09 | 2014-12-10 | 艾伯维德国有限责任两合公司 | eterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10A |
-
2018
- 2018-05-28 CN CN201810518770.3A patent/CN108484591B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2001247569A (en) * | 1999-08-12 | 2001-09-11 | Japan Tobacco Inc | Pyrrolidine derivative or piperidine derivative and its medicinal use |
| CN102123998A (en) * | 2008-06-23 | 2011-07-13 | H.隆德贝克有限公司 | Isoquinolinone derivatives as nk3 antagonists |
| CN104203919A (en) * | 2011-11-09 | 2014-12-10 | 艾伯维德国有限责任两合公司 | eterocyclic carboxamides useful as inhibitors of phosphodiesterase type 10A |
| CN103992313A (en) * | 2013-02-18 | 2014-08-20 | 江苏欧威医药有限公司 | 1,2,4-thiadiazole-3,5-dione derivatives, and pharmaceutical composition and application thereof |
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