CN102516200A - Hybrid compound with indanone and phenothiazine as skeletal structures and application thereof - Google Patents
Hybrid compound with indanone and phenothiazine as skeletal structures and application thereof Download PDFInfo
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- 0 C*[C@@](C)C(C(CC1)=CCC1*=*)=O Chemical compound C*[C@@](C)C(C(CC1)=CCC1*=*)=O 0.000 description 5
- YWSUKAVVJWNXMP-UHFFFAOYSA-N C(CN1CCNCC1)CN1c(cccc2)c2Sc2c1cccc2 Chemical compound C(CN1CCNCC1)CN1c(cccc2)c2Sc2c1cccc2 YWSUKAVVJWNXMP-UHFFFAOYSA-N 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N C1NCCNC1 Chemical compound C1NCCNC1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- MNDRUZXSFMZNER-UHFFFAOYSA-N N#CCN1CCN(CCCN2c(cccc3)c3Sc3c2cccc3)CC1 Chemical compound N#CCN1CCN(CCCN2c(cccc3)c3Sc3c2cccc3)CC1 MNDRUZXSFMZNER-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention discloses a hybrid compound with indanone and phenothiazine as skeletal structures as shown in the general formulas (I) and (II). The compound has a biological activity for inhibiting cholinesterase and can be used to prepare drugs for preventing and treating neurological diseases containing Alzheimer disease.
Description
One, technical field
The present invention relates to one type is the assorted diad compounds and the compound method thereof of parent nucleus with indone and thiodiphenylamine, and this compounds has cholinesterase inhibition, is used for the prevention and the treatment of nervous system disorderss such as alzheimer's disease.
Two, background technology
Alzheimer's disease (Alzheimer ' s Disease; AD) be a kind of common nerve degenerative diseases; Main clinical manifestation be cognition dysfunction be losing one's memory, personality and behavior change, judgment declines, self care ability forfeiture etc., having a strong impact on the mankind's healthy and quality of life.In developed country, AD has become the 4th big killer after heart trouble, tumour and apoplexy at present.
Cholinergic nerve damage hypothesis is widely accepted at present, obviously occurs cholinergic neuron in AD patient's brain and loses, and causes the choline level at cynapse position to descend, and influences people's short-term attention and memory, in the AD morbidity, plays an important role.And acetylcholinesterase depressant (acetylcholinesterase inhibitor; AChEI) through acetylcholine esterase inhibition (acetylcholinesterase; AChE) activity, the normal level of recovery vagusstoff, the irritability of raising cholinergic neuron.Drugmaker carries out the exploitation of AD medicine one after another according to this hypothesis; Over nearly 10 years; The most active in the research of anti senile dementia drug, the most effective field is an acetylcholinesterase depressant; In the control experiment of extensive, multicenter, double blinding and placebo, this compounds all has statistics significantly to improve to patient's AD cognitive ability and quality of life, and the mechanism of action of AChE suppressor factor is clearer and more definite; Therefore, remain the target compound that many researchists seek treatment senile dementia new drug at present.
It is existing that (food and drug administration, FDA) AChEI of approval use has tacrine, E2020, rivastigmine and lycoremine etc. with drug administration by U.S. food.
Tacrine (tacrine): first obtained the medicine that drugs approved by FDA is used to treat mild to moderate AD in 1993, and its shortcoming is that the transformation period is too short, and has liver toxicity.
E2020 (donepezil): second reversibility AChEI that obtains drugs approved by FDA in 1997, its advantage is easy administration, long action time, strong drug action, safe, untoward reaction is little, and aspect pharmacology, is superior to tacrine.
Physostigmine (physostigmine): Physostigmine belongs to the reversibility AChEI of tertiary amines, can significantly improve patient's AD cognitive ability in a short time, and its shortcoming is exactly that untoward reaction is obvious, withdraws from the treatment rate height.
Lycoremine (galantamine): calendar year 2001 the 3rd reversibility AChEI that obtains drugs approved by FDA, its inhibition is weaker than Physostigmine slightly, but it is prone to patient's tolerance and untoward reaction are few, and its curative effect of preliminary study demonstration is suitable with tacrine, but does not have liver toxicity.
Selagine (huperzine A): selagine is that Shanghai Pharmaceutical Inst., Chinese Academy of Sciences separates a kind of new alkaloids that obtains from the plants of Huperzia Herba Lycopodii serrati, is the strong effect reversibility AChEI of China's initiative.Its restraining effect is better than tacrine, approval listing at home.
Rivastigmine (rivastigmine): rivastigmine also is a kind of reversibility AChEI; The AChE in brain districts such as its alternative combination cortex and hippocampus; And the inhibition time to AChE is long; Have safety, better tolerance, advantage such as nontoxic, and untoward reaction is lighter, can disappear after the for some time of taking medicine.Gone on the market by drugs approved by FDA in 2000.
Metrifonate (metrifonate): itself is not AChEI, but can be converted into the activity that dimethyl-divinyl phosphoric acid vinegar (DDVP) suppresses AChE in vivo.
AChEI generally is applicable to mild to moderate AD patient, can improve patient symptom and can not radical curing of disease, AChEI is for the AD patients with terminal, curative effect is very little.But the expense of using AChEI treatment AD is relatively low, therefore uses very wide.
E2020 is a line medicine of treating alzheimer's disease at present as a kind of acetylcholinesterase depressant, and its characteristic pharmacophore has indone, piperidines and benzyl etc.At present mainly concentrate on synthetic to the E2020 analogue for the report of indone class, and E2020 and the tacrine molecular structure link coupled diad of mixing.
Sheng Rong etc. are the analogue that skeleton has synthesized some E2020s with the indone; As 5; 2 connections of 6-dimethoxy-1-indone gone up the band substituted-amino phenoxy (Bioorganic&Medicinal Chemistry 2008,16,7646-7653) or band replace aminomethyl benzyl (European Journal of Medicinal Chemistry 2009; 44,7-17).Be shown below:
Pelayo Camps etc. combine the structure of E2020 and tacrine, transform and have synthesized one type of novel compound (J.Med.Chem.2008,51; 3588-3598); The inhibition that has significantly improved E.C. 3.1.1.7 is active, and wherein X=O, n=3 are for the IC of E.C. 3.1.1.7
50Value can reach 90pM (bAChE) and 0.27nM (hAChE).
The phenothiazines medicine is one type of psychotroptic drug using always, has sulphur naphthazin(e) parent nucleus on the structure.Include CHLORPROMAZINE HCL, Prophenamine, Fluphenazine, Acetophenazine, Levopromazine, trilafon, Pipothiazine, prochlorperazine, promazine, promethazine, propiomazine, Tietylperazine, TP 21, trifluoperazine, Triflupromazine etc.
Silke Dollinger etc. utilizes the pharmacophore of acrinamin and imipramine, has synthesized the heterozygote of serial thiodiphenylamine and acridine, is shown below.(Journal?of?Medicinal?Chemistry，2006，49(22)，6591-6595)
Socryl Blue BRL (Methylene blue MB) as a kind of phenothiazines medicine, has experienced one-hundred-year history, since cheap, all have a wide range of applications at aspects such as dyestuff, chemical industry, medicines.。Wiskchik, in vitro testss such as C M show, can make neurofibrillary tangles (Neurofibrillary tangles under the Socryl Blue BRL lower concentration; NFTs) dissolving (Wiskchik; C M etc., ProcNatl Acad Sci.1996,93:11213); Thereby Socryl Blue BRL can splicing thread under extremely low concentration plastochondria complex body VI function delay HELF (IMR90) old and feeble (Atamna H etc., FASEB J.2008; 22 (3): 703).Rember is a kind of medicine of treatment alzheimer's disease newly developed; Its staple is a Socryl Blue BRL, in phase ii clinical trial, shows good curative effect (Gum T.Hope in Alzheimer ' s fight emerges from unexpected places.Nat Med.2008; 14:894).Li Zhaosheng etc. avoid experimental study through diving tower and show that the result shows that MB can improve the learning memory disorder of APP/PS1 mouse (Li Zhaosheng, Chinese Medical Sciences University's 2010 Master's thesis).
Three, summary of the invention
It is the assorted diad compound of parent nucleus with indone and thiodiphenylamine that the present invention aims to provide one type, has acetylcholine esterase inhibition activity, with prevention and the treatment that is used for Alzheimer's disease and other nervous system disorderss.
One type is compound or its acceptable for pharmaceutical salt of the assorted diad of skeleton structure with indone and thiodiphenylamine, it is characterized in that: be the structure shown in the following structural formula (I),
In the formula: n1 is 0-8, and n2 is 1-6;
R
1-R
6Represent independently hydrogen, halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b,-COOH ,-COOR
a,-NO
2,-C
1-C
12Alkyl ,-CF
3,-CN ,-OCH
2-phenyl ,-OCH
2Substituted-phenyl ,-the O-phenyl ,-the O-substituted-phenyl ,-the CH=CH-phenyl ,-the CH=CH-substituted-phenyl ,-O (CH
2)
nNR
aR
b,-O (CH
2)
nOR
a,-(OCH
2)
nOR
a,-(OCH
2CH
2)
nOR
a,-(OCH
2CH
2)
nNR
aR
b,-CO-NR
aR
b, wherein n is 1-6, R
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl or-(CH
2)
m-phenyl, m are 0-7.
R
1, R
2Preferably-OH ,-OCH
3,-NH
2,-NHR
a,-NR
aR
b
Work as R
3=R
5=H, R
4, R
6Preferred halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b
Work as R
4=R
6=H, R
3, R
5Preferably-H, halogen ,-OH ,-OR
a,-COOH ,-NH
2,-NHR
a,-NR
aR
b,-CF
3,-CN;
R wherein
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl, m are 1-7.
One type is compound or its acceptable for pharmaceutical salt of the assorted diad of skeleton structure with indone and thiodiphenylamine, it is characterized in that: be the structure shown in the following structural formula (II),
In the formula: n1 is 1-8, and n2 is 1-6;
R
1-R
6Represent independently hydrogen, halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b,-COOH ,-COOR
a,-NO
2,-C
1-C
12Alkyl ,-CF
3,-CN ,-OCH
2-phenyl ,-OCH
2Substituted-phenyl ,-the O-phenyl ,-the O-substituted-phenyl ,-the CH=CH-phenyl ,-the CH=CH-substituted-phenyl ,-O (CH
2)
nNR
aR
b,-O (CH
2)
nOR
a,-(OCH
2)
nOR
a,-(OCH
2CH
2)
nOR
a,-(OCH
2CH
2)
nNR
aR
b,-CO-NR
aR
b, wherein n is 1-6, R
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl or-(CH
2)
m-phenyl, m are 0-7.
R
1, R
2Preferably-OH ,-OCH
3,-NH
2,-NHR
a,-NR
aR
b
Work as R
3=R
5=H, R
4, R
6Preferred halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b
Work as R
4=R
6=H, R
3, R
5Preferably-H, halogen ,-OH ,-OR
a,-COOH ,-NH
2,-NHR
a,-NR
aR
b,-CF
3,-CN;
R wherein
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl, m are 1-7.
Compound shown in general formula (I) or its acceptable for pharmaceutical salt, ester, acid amides, prodrug, vehicle or thinner have cholinesterase inhibition.Its purposes is in the preparation prevention and treats the application in the nervous system disorders medicine that comprises Alzheimer's disease.
Compound shown in general formula (II) or its acceptable for pharmaceutical salt, ester, acid amides, prodrug, vehicle or thinner have cholinesterase inhibition.Its purposes is in the preparation prevention and treats the application in the nervous system disorders medicine that comprises Alzheimer's disease.
Synthetic route:
Synthesizing shown in route 1 shown in the general formula (I):
Route 1:
Synthesizing shown in route 2 shown in the general formula (II):
Route 2:
The compounds of this invention has the effect of good acetylcholine esterase inhibition activity, and the warp study of behaviour experimental study of mouse aging (SAM-P/8) fast shows, can effectively improve the memory function of SAM-P/8 mouse.
The application of The compounds of this invention in the preparation medicine; Said medicine is used to treat cognitive disorder such as senile dementia, vascular dementia, mild cognitive damage, ADD; And/or have a paraprotein accumulative neurodegeneration dementia, like alzheimer's disease particularly.
The compounds of this invention can pass through the diverse ways administration, and is for example oral with capsule or tablet, non-through gastrointestinal administration with sterile solution agent or suspensoid, and can be in some cases, can be with the intravenous injection of solution form.Can free basic cpd of the present invention be prepared and take with the acid salt form that it pharmaceutically is suitable for.The acid that pharmaceutically is suitable for comprises mineral acid (example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid and similar) or organic acid (like acetate, oxalic acid, toxilic acid, methylsulfonic acid, Whitfield's ointment, succsinic acid, Hydrocerol A, tartrate and similar) etc.
Four, embodiment
Embodiment 1:
Take by weighing 199mg (1mmol) thiodiphenylamine, be dissolved in 15mLDMF, add 30mgNaH, ice bath drips the solution that 173mg (1.1mmol) 1-chloro-3-N-PROPYLE BROMIDE is dissolved in 5mLDMF, after dripping off, keeps thermotonus one hour, rises to room temperature reaction again three hours.Add the 20mL washing, extracted with diethyl ether (20mL * 2) merges organic phase, and anhydrous sodium sulfate drying filters removal of solvent under reduced pressure.Cross silicagel column, with sherwood oil: ETHYLE ACETATE 6/1 wash-out, collect respective components, product, productive rate 55%.
1H?NMR(300MHz)δ2.24(quint，J＝6.2Hz，2H)，3.66(t，J＝6.2Hz，2H)，3.98-4.18(m，2H)，6.81-7.01(m，4H)，7.09-7.21(m，4H).
Embodiment 2:
In round-bottomed flask, add 10-N-chloropropyl thiodiphenylamine 262mg (1mmol), Piperazine anhydrous 430mg (5mmol), potassiumiodide 166mg (1mmol) and 30mLN; Dinethylformamide; Stir and slowly add salt of wormwood 152mg (1.1mmol) down, stirring at room reaction 12h.Most of N is removed in underpressure distillation, dinethylformamide and piperazine.Add ETHYLE ACETATE and water, behind the separatory, water again with ethyl acetate extraction once merges organic phase, after washing of 20mL salt and 20mL washing, and anhydrous sodium sulfate drying.Filter, removal of solvent under reduced pressure gets white solid.Productive rate 86%.
1HNMR(300MHz)δ2.01(br，1H)，2.24-2.27(m，2H)，2.44-2.50(m，4H)，2.73-2.78(m，4H)，3.24-3.26(m，2H)，3.65-3.67(m，2H)，6.88-6.97(m，4H)，7.09-7.18(m，4H).
Embodiment 3:
In round-bottomed flask, add 163mg (0.5mmol) 10-N-(3-piperazinyl) propyl group-thiodiphenylamine, 135mg (0.5mmol) 2-bromo-5 successively, 6-dimethoxy-1-indone, 15mL acetonitrile and 83mg (0.6mmol) salt of wormwood, stirring at room reaction 8h.Removal of solvent under reduced pressure adds entry, with 10mL dichloromethane extraction three times, merges organic phase, anhydrous sodium sulfate drying.Filtration, removal of solvent under reduced pressure is crossed silicagel column, crosses post at 50: 1 with chloroform/methanol, collects respective components, concentrates, and gets product.Productive rate 76%.
1H?NMR(300MHz)δ7.33(s，1H)，7.23-7.15(m，4H)，7.08(s，1H)，7.02-6.94(m，4H)，3.69-3.66(m，1H)，3.19-3.14(m，2H)，2.79-2.74(m，4H)，2.71-2.68(m，2H)，2.52-2.42(m，6H)2.02-1.99(m，2H)。
Embodiment 4:
Take by weighing 325mg (1mmol) 10-N-(3-piperazinyl) propyl group-thiodiphenylamine and be dissolved in the 10mL acetonitrile, add 240mg (2mmol) bromoacetonitrile, 138mg salt of wormwood (1mmol), room temperature reaction 16h.Add salt solution, the 30mL extracted with diethyl ether, dried over sodium sulfate is filtered, and removal of solvent under reduced pressure is crossed silicagel column, sherwood oil: ETHYLE ACETATE 4/1 wash-out gets yellow solid (productive rate 56%).
1HNMR(300MHz)δ1.93(quint，J＝6.8Hz，2H)，2.39-2.59(m，10H)，3.47(s，2H)，3.94(t，J＝6.8Hz，2H)，6.86-6.94(m，4H)，7.09-7.17(m，4H).
Embodiment 5:
Press embodiment 4 similar methods synthetic (productive rate 64%) with bromopropionitrile.
1H?NMR(300MHz)δ1.94(quint，J＝6.9Hz，2H)，2.33-2.58(m，12H)，2.67(t，J＝6.8Hz，2H)，3.92(t，J＝6.9Hz，2H)，6.85-6.94(m，4H)，?7.10-7.16(m，4H).
Embodiment 6:
Synthetic with bromine butyronitrile embodiment 4 similar methods.(72％)
1HNMR(300MHz)δ1.79(quint，J＝6.7Hz，2H)，1.95(quint，J＝7.0Hz，2H)，2.35-2.49(m，14H)，3.91(t，J＝7.0Hz，2H)，6.87-6.92(m，4H)，7.11-7.15(m，4H)。EI-MS?m/z?392(M
+).
Embodiment 7:
364mg (1mmol) 10-N-(3-(4-acetonitrile-base) piperazinyl) propyl group-thiodiphenylamine is dissolved in the ether of 10mL through no water treatment, is chilled to 0 ℃, 42mg (1.1mmol) LiAlH
4Be dissolved in the 2.5mL anhydrous diethyl ether and be added dropwise to reaction system, drip and finish, at room temperature react 1h.Reaction mixture with the sodium carbonate solution cancellation, adds the 30mL ethyl acetate extraction under cooling, anhydrous sodium sulfate drying revolves dried solvent, gets product (productive rate 46%).
1H?NMR(500MHz)δ1.89-1.98(m，2H)，1.71(br，2H)，2.76(t，J＝6.2Hz，2H)，2.34-2.56(m，12H)，3.91(t，J＝7.2Hz，2H)，6.84-6.93(m，4H)，7.09-7.16(m，4H)。EI-MS?m/z?368(M
+)。
Embodiment 8:
With synthetic with embodiment 7 similar methods, productive rate 62%.
1H?NMR(300MHz)δ1.63(quint，J＝6.9Hz，2H)，?1.80(br，2H)，1.95(quint，J＝7.0Hz，2H)，2.33-2.53(m，10H)，2.74(t，J＝6.9Hz，2H)，3.91(t，J＝7.0Hz，2H)，6.85-6.93(m，4H)，7.09-7.16(m，4H).
Embodiment 9:
With synthetic with embodiment 7 similar methods, productive rate 63%.
1H?NMR(300MHz)δ1.44-1.55(m，4H)，1.74(br，2H)，1.95(quint，J＝7.0Hz，2H)，2.26-2.55(m，12H)，2.70(t，J＝6.9Hz，2H)，3.91(t，J＝7.0Hz，2H)，6.85-6.94(m，4H)，7.09-7.16(m，4H)。EI-MS?m/z?396(M
+)。
Embodiment 10:
In round-bottomed flask, add 368mg (1mmol) 10-N-(3-(4-ethylamino) piperazinyl) propyl group-thiodiphenylamine, 277mg (1mmol) 2-bromo-5 successively, 6-dimethoxy indone, 166mg (1.2mmol) salt of wormwood and 20mL acetonitrile, back flow reaction 4h.Removal of solvent under reduced pressure adds entry, with ethyl acetate extraction twice, merges organic phase, anhydrous sodium sulfate drying.Filter, revolve driedly, cross silicagel column, with sherwood oil: ETHYLE ACETATE 3/1 wash-out, collect respective components, product, productive rate 75%.
1H?NMR(300MHz)δ1.89-1.98(m，2H)，2.34-2.56(m，12H)，2.76(t，J＝6.2Hz，2H)，3.26(m，2H)，3.91(m，2H)，3.95(s，3H)，3.99(s，3H)，4.54(m，1H)，6.84-6.93(m，4H)，7.06(s，1H)，7.09-7.16(m，4H)，7.28(s，1H)。
Embodiment 11:
With synthetic with embodiment 10 similar methods, productive rate 68%.
1H?NMR(300MHz)δ1.72-1.78(m，2H)，1.89-1.98(m，2H)，2.36-2.57(m，12H)，2.81(m，2H)，3.26(m，2H)，3.88(t，J＝7.2Hz，2H)，3.92(s，3H)，3.96(s，3H)，4.53(m，1H)，6.84-6.93(m，4H)，7.06(s，1H)，7.09-7.16(m，4H)，7.28(s，1H)。
It is active that embodiment 12 E.C. 3.1.1.7s (AChE) suppress
Method (Ellman, G L according to Ellman etc.; Courtney, K D; Andres, B; Featherstone R M.Biochem.Pharmacol.1961,7,88-95).Measuring solution is made up of and the following: 0.1M pH8.0 phosphate buffered saline buffer; 200 μ M5; Two (2-nitrobenzoic acid) (DTNB, Ellman ' the s reagent) of 5 '-dithio, 0.02 unit/mL people E.C. 3.1.1.7 (E.C.3.1.1.7 that recombinates; Sigma Chemical Co.) and 400 μ M acetyl thio choline iodide as the substrate of enzymatic reaction.The compound that detects is added in the mensuration solution, and bathe 10min 30 ℃ of preparatory down temperature with enzyme.After this time, add substrate.The absorbancy that is recorded in the 412nm place with Perkin-Elmer 550 SE UV/Vis spectrophotometers changed 5 minutes, and relatively speed of reaction is calculated because the per-cent that the existence of test compounds causes suppresses.IC
50For not having relatively under the suppressor factor condition, the activity of enzyme is reduced by 50% compound concentrations.Show in result such as the table 1.
Table 1 is active for the recombinate inhibition of E.C. 3.1.1.7 (AChE) of people
Embodiment 13, butyrylcholine esterase (BChE) suppress active
Through (Ellman, G L such as Ellman; Courtney, K D; Andres, B; Featherstone R M.Biochem.Pharmacol.1961,7,88-95) reported method assessment butyrylcholine esterase suppresses active.Measuring solution is made up of and the following: 0.01 unit derives from the butyrylcholine esterase (E.C.3.1.1.8 of human serum; Lee Biosolutions); 0.1M the pH8.0 phosphate buffered saline buffer, 300 μ M5, two (2-the nitrobenzoic acid) (DTNB of 5 '-dithio; Ellman ' s reagent) and 500 μ M Butyryl thiocholine iodide as the substrate of enzymatic reaction.With the absorbancy under 405nm during the microplate Digiscan 340T measurement 5min, measure enzymic activity.Test compounds and enzyme are bathed 10min 30 ℃ of preparatory down temperature.Calculate speed of reaction with triplicate at least observed value.IC
50For not having relatively under the suppressor factor condition, the activity of enzyme is reduced by 50% compound concentrations.Show in result such as the table 1.
Table 2 is active for the inhibition from the butyrylcholine esterase (BChE) of human serum
Embodiment 14, the study of behaviour experiment (Morris water maze) of mouse aging (SAM-P/8) fast
The SAM-P/8 mouse is divided into three groups at random, and 15 every group is respectively model group, experimental group, treatment group.The treatment group is irritated stomach with aricept suspension 400mg/kgd, and experimental group is irritated stomach with the muddy liquid of equivalent compound, and model group is irritated 3 weeks of stomach with equivalent saline water, whenever has a rest 1 day at a distance from 3 days.Each treated animal is after 3 weeks of administration; According to document (Morris R.Developments of Water-Maze procedure for studying spatial learning in the rat.Neurosci Methods.1984; 11:471) method is carried out Morris water maze training 7 days; Continue administration during this time, train accomplished in 7 days after, the test mouse seek platform latent period, cross over the platform number of times and in the ratio of original platform quadrant swimming distance with total swimming distance.Test-results is seen table 2, and experimental group and treatment group obviously shorten, cross the platform number of times latent period and increase, and compares with model group to have difference (P＜0.05).Each administration group and model group compare, and bigger with the ratio of total swimming distance in original platform place quadrant swimming distance, significant difference (P＜0.05) shows that each administration group is good than model group to the memory of original platform quadrant, promptly has the hypermnesis effect to the SAM-P/8 mouse.
Table 3 mouse Morris water maze test
Claims (6)
1. one kind is assorted diad compound or its acceptable for pharmaceutical salt of skeleton structure with indone and thiodiphenylamine, it is characterized in that: be the compound or pharmaceutically acceptable salt thereof shown in the following structural formula (I)
In the formula: n1 is 0-8, and n2 is 1-6;
R
1-R
6Represent independently hydrogen, halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b,-COOH ,-COOR
a,-NO
2,-C
1-C
12Alkyl ,-CF
3,-CN ,-OCH
2-phenyl ,-OCH
2Substituted-phenyl ,-the O-phenyl ,-the O-substituted-phenyl ,-the CH=CH-phenyl ,-the CH=CH-substituted-phenyl ,-O (CH
2)
nNR
aR
b,-O (CH
2)
nOR
a,-(OCH
2)
nOR
a,-(OCH
2CH
2)
nOR
a,-(OCH
2CH
2)
nNR
aR
b,-CO-NR
aR
b, wherein n is 1-6, R
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl or-(CH
2)
m-phenyl, m are 0-7.
2. compound according to claim 1, R
1, R
2Be selected from-OH ,-OCH
3,-NH
2,-NHR
a,-NR
aR
b
Work as R
3=R
5=H, R
4, R
6Preferred halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b
Work as R
4=R
6=H, R
3, R
5Preferably-H, halogen ,-OH ,-OR
a,-COOH ,-NH
2,-NHR
a,-NR
aR
b,-CF
3,-CN;
R wherein
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl or-(CH
2)
m-phenyl, m are 1-7.
3. the purposes of the compound shown in general formula (I) or its acceptable for pharmaceutical salt, ester, acid amides, prodrug is characterized in that: prevent and treat the application in the nervous system disorders medicine that comprises Alzheimer's disease in preparation.
4. one kind is assorted diad compound or its acceptable for pharmaceutical salt of skeleton structure with indone and thiodiphenylamine, it is characterized in that: be the compound or pharmaceutically acceptable salt thereof shown in the following structural formula (II):
In the formula: n1 is 1-8, and n2 is 1-6;
R
1-R
6Represent independently hydrogen, halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b,-COOH ,-COOR
a,-NO
2,-C
1-C
12Alkyl ,-CF
3,-CN ,-OCH
2-phenyl ,-OCH
2Substituted-phenyl ,-the O-phenyl ,-the O-substituted-phenyl ,-the CH=CH-phenyl ,-the CH=CH-substituted-phenyl ,-O (CH
2)
nNR
aR
b,-O (CH
2)
nOR
a,-(OCH
2)
nOR
a,-(OCH
2CH
2)
nOR
a,-(OCH
2CH
2)
nNR
aR
b,-CO-NR
aR
b, wherein n is 1-6, R
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl or-(CH
2)
m-phenyl, m are 0-7.
5. compound as claimed in claim 3, R
1, R
2Be selected from-OH ,-OCH
3,-NH
2,-NHR
a,-NR
aR
b
Work as R
3=R
5=H, R
4, R
6Preferred halogen ,-OH ,-OR
a,-NH
2,-NHR
a,-NR
aR
b
Work as R
4=R
6=H, R
3, R
5Preferably-H, halogen ,-OH ,-OR
a,-COOH ,-NH
2,-NHR
a,-NR
aR
b,-CF
3,-CN;
R wherein
aAnd R
bRepresent hydrogen, C independently
1-C
6Alkyl or-(CH
2)
m-phenyl, m are 1-7.
6. the purposes of the compound shown in general formula (II) or its acceptable for pharmaceutical salt, ester, acid amides, prodrug is characterized in that: prevent and treat the application in the nervous system disorders medicine that comprises Alzheimer's disease in preparation.
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Cited By (4)
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| CN102936244A (en) * | 2012-12-04 | 2013-02-20 | 合肥工业大学 | Tacrine-phenothiazine isodiad compound and preparation method thereof |
| CN104829554A (en) * | 2015-05-25 | 2015-08-12 | 大连理工大学 | Phenothiazine compound and preparation method and application thereof |
| CN108530384A (en) * | 2018-03-26 | 2018-09-14 | 南京泽恒医药技术开发有限公司 | A kind of preparation method of prochlorperazine |
| CN114671829A (en) * | 2022-04-22 | 2022-06-28 | 合肥工业大学 | Heterodiad with indanone and dibenzoazepine as parent nucleus, hydrochloride thereof, preparation method and application thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102936244A (en) * | 2012-12-04 | 2013-02-20 | 合肥工业大学 | Tacrine-phenothiazine isodiad compound and preparation method thereof |
| CN102936244B (en) * | 2012-12-04 | 2015-02-04 | 合肥工业大学 | Tacrine-phenothiazine isodiad compound and preparation method thereof |
| CN104829554A (en) * | 2015-05-25 | 2015-08-12 | 大连理工大学 | Phenothiazine compound and preparation method and application thereof |
| CN108530384A (en) * | 2018-03-26 | 2018-09-14 | 南京泽恒医药技术开发有限公司 | A kind of preparation method of prochlorperazine |
| CN108530384B (en) * | 2018-03-26 | 2021-12-28 | 南京泽恒医药技术开发有限公司 | Preparation method of prochlorperazine |
| CN114671829A (en) * | 2022-04-22 | 2022-06-28 | 合肥工业大学 | Heterodiad with indanone and dibenzoazepine as parent nucleus, hydrochloride thereof, preparation method and application thereof |
| CN114671829B (en) * | 2022-04-22 | 2023-07-25 | 合肥工业大学 | Heterodiad taking indenone and dibenzoazepine as parent nucleus and hydrochloride thereof, preparation method and application thereof |
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| Publication number | Publication date |
|---|---|
| CN102516200B (en) | 2014-03-12 |
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