CN101302214A - Aralkyl piperidine (piperazidine) derivate and use thereof in mental disease treatment - Google Patents

Aralkyl piperidine (piperazidine) derivate and use thereof in mental disease treatment Download PDF

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CN101302214A
CN101302214A CNA2007100405455A CN200710040545A CN101302214A CN 101302214 A CN101302214 A CN 101302214A CN A2007100405455 A CNA2007100405455 A CN A2007100405455A CN 200710040545 A CN200710040545 A CN 200710040545A CN 101302214 A CN101302214 A CN 101302214A
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dihydro
quinolinone
butoxy
piperazinyl
piperazine
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CN101302214B (en
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李建其
彭少平
蔡王平
高凯
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Shanghai Institute of Pharmaceutical Industry
Jiangsu Hengyi Pharmaceutical Co Ltd
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JIANGSU GUOHUA INVESTMENT CO Ltd
Shanghai Institute of Pharmaceutical Industry
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Abstract

The invention discloses an aralkyl piperidine (oxazine) derivative and an application of the derivative in treating neurological and mental diseases. Pharmacological tests show that the derivative has a good effect of resisting schizophrenia and little toxicity. The derivative is free alkali or salt of a compound having the following structure general formula.

Description

Aralkyl piperidines (piperazine) derivative and the application in the spiritual sacred disease of treatment
Technical field
The present invention relates to aralkyl piperidines (piperazine) derivative and the application in the spiritual neurological disease drug of preparation treatment thereof.
Background of invention
Schizophrenia is that a kind of common mental disease is suffered from, be the most serious in all mental disorderes, that harm is maximum is a kind of, sickness rate in the global range is about 1%, and along with the deterioration of social environment and growing with each passing day of life stress, sickness rate is obvious ascendant trend.Abandoning cure tends to cause more serious societal consequence to most schizophrenia patients because treatment cycle is long, expense is high, side effect is big.Schizophrenia is except being the Mental health problems of being badly in need of capturing, the social responsibility of the arduousness that medical especially worker must bear.
The medicine that uses clinically is mainly traditional antipsychotic drug (as dopamine D 2 receptor antagonists) and atypical antipsychotic agents (as the D2/5-HT dual antagonist) at present, wherein, the tradition antipsychotic drug is eliminated gradually owing to cause extrapyramidal symptoms (EPS) easily, atypical antipsychotic agents is of a great variety, but which medicine does not have absolute advantage for the improvement of the whole pedigree of schizophrenia, majority is that a certain symptom in the positive or negative symptom is made moderate progress, or side effect reduces.Therefore it is low, rapid-action to seek toxic side effect, and the novel anti schizophrenia medicine of treatment spectrum width is the research focus of world's pharmacy industry always.
In recent years, scientist finds that Usage of Partial Dopamine Receptor Agonist can reduce the transmission of Dopamine HCL when the Dopamine HCL hyperactivity hyperkinesia, but not all blocking-up; Otherwise, when dopaminergic activity is low, then cause hormesis, psychosis positive and negative symptoms all there are significant curative effect, prolonged application also can reduce schizoid recurrence rate, improves mood and cognition dysfunction.The effect of its EPS side effect and rising serum prolactin level is all littler than traditional antipsychotics or atypical antipsychotic, therefore, have emphasis and the important development direction that d2 dopamine receptor part agonism novel anti schizophrenia medicine is research and development at present.In addition, because this compounds to dopaminergic stabilization in the brain, can also be used for other as spiritual class treatment of diseases such as Parkinson, bipolar affective disorders.
Summary of the invention
One of technical issues that need to address of the present invention are to disclose a kind of aralkyl piperidines (piperazine) derivative, and the defective of side effects such as existing medicine extrapyramidal symptoms is obvious to overcome, prolactin rising is to solve a clinical difficult problem and to satisfy the clinical application demand;
Two of the technical issues that need to address of the present invention are the application in the spiritual neurological disease drug of preparation treatment of open above-claimed cpd;
Aralkyl piperidines of the present invention (piperazine) derivative is for having the free alkali or the salt of compound shown in general structure (1) and this compound:
Figure A20071004054500081
Compound at general formula 1 is under the situation of free alkali, and they all can form various salt with various mineral acids and organic acid.
Described salt is for containing pharmaceutically acceptable anionic salt, such as hydrochloride, hydrobromate, hydriodate, nitrate, vitriol or hydrosulfate, phosphoric acid salt or acid phosphate, acetate, lactic acid salt, Citrate trianion, tartrate, maleate, fumarate, gluconate, saccharate, benzoate, mesylate, esilate, benzene sulfonate, tosilate, said salt preferably contains the crystal water of 0.5-3 molecule, is preferably hydrochloride or hydrobromate;
In general formula (1):
A is-(CH 2) n-,-(CH 2) nO-or-(CH 2) nNH-, n are the integer of 2--5, wherein-and (CH 2) n-,-(CH 2) nO-and-(CH 2) nTwo substituting groups replacements that one of the carbon of NH-or nitrogen-atoms or two can choose wantonly and be replaced or is connected with same carbon atom by one or two substituting group that is independently selected from fluorine and methyl independently, these two substituting groups can also form Spirocyclopropyl or volution butyl ring with the carbon that they connected;
Z is N, CH or C; Condition is when Z is N, and each is connected by singly-bound with the covalently bound carbon atom of Z;
P is O, S, SO or SO 2
Q is N, C or CH;
Figure A20071004054500082
Be--CH=CH--,--CH 2-CH 2-,--CH 2-NH--,--NH CH 2--,--N=CH--,--CH=N--,--O-CH 2--or--CH 2-O--, wherein
Figure A20071004054500083
Can on any available binding site, choose wantonly by 1--4 substituent R 2, R 2', R 3And R 3' replace;
R 1Be H or OH;
R 2, R 2',, R 3And R 3' be independently selected from hydrogen, halogen, cyano group, oxo, hydroxyl,--C (=O) CH 3, (C 1--C 4) alkyl and (C 1--C 4) alkoxyl group, wherein (C 1--C 4) alkyl, (C 1--C 4) alkoxyl group and-C (=O) CH 3The moieties of group can be chosen wantonly by 1--3 fluorine atom replacement and can also choose wantonly by amino or hydroxyl substituent and replace;
R 4, R 5Be independently selected from hydrogen, halogen, cyano group, oxo, hydroxyl,--C (=O) CH 3, (C 1--C 4) alkyl and (C 1--C 4) alkoxyl group, wherein (C 1--C 4) alkyl, (C 1--C 4) alkoxyl group and-C (=O) CH 3The moieties of group can be chosen wantonly by 1--3 fluorine atom replacement and can also choose wantonly by amino or hydroxyl substituent and replace;
R 6, R 7Select hydrogen and methyl independently;
R 8, R 9Be independently selected from hydrogen, halogen, cyano group, oxo, hydroxyl ,-C (=O) CH 3, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group, wherein (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and-C (=O) CH 3The moieties of group can be chosen wantonly by 1--3 fluorine atom replacement and can also choose wantonly by amino or hydroxyl substituent and replace;
Other preferred embodiment of the present invention relates to the compound and the pharmaceutically acceptable salt thereof of general formula 1, and wherein Z is that CH, Q are C, and P is O.
Other preferred embodiment of the present invention relates to the compound and the pharmaceutically acceptable salt thereof of general formula 1, and wherein Z is that N, Q are C, and P is S or SO 2
Other preferred embodiment of the present invention relates to the compound and the pharmaceutically acceptable salt thereof of general formula 1, and wherein Z is C, and Q is C, and P is O, and adjacent carbons links to each other with two keys on Z and the b ring.
Other preferred embodiment of the present invention relates to the compound and the pharmaceutically acceptable salt thereof of general formula 1, and wherein Z is N, R 6Or R 7Be methyl,
Other preferred embodiment of the present invention relates to the compound and the pharmaceutically acceptable salt thereof of general formula 1, and wherein Z is N, R 6And R 7Be methyl.
Other preferred embodiment of the present invention relates to the compound and the pharmaceutically acceptable salt thereof of general formula 1, and wherein Z is N, and Q is N, For-CH 2-CH 2-or-CH=CH-, and R1, R4 and R5 are hydrogen.
Other preferred embodiment of the present invention relates to the compound and the pharmaceutically acceptable salt thereof of general formula 1, and wherein Z is N, and Q is N,
Figure A20071004054500092
For-C (CH 3)=CH-, R 6, R 7Be hydrogen.
The preferred compound of the present invention is:
I-17-[4-(4-(6-chloro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-27-[4-(4-(5-chloro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-37-[4-(4-(benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-47-[4-(4-(6-fluoro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-57-[4-(4-(6-trifluoromethyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-67-[4-(4-(6-methyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-77-[4-(4-(5-methyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-87-[4-(4-(6-hydroxyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-97-[4-(4-(5-methoxyl group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-107-[4-(4-(5-cyano group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-117-[4-(4-(5-bromo-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-127-[4-(4-(7-bromo-6-methoxyl group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-17-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-27-[3-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-positive propoxy]-3,4-dihydro-2 (1H)-quinolinone
II-37-[2-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone
II-47-[2-(4-benzisoxa oxazole-piperidino)-oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone
II-57-[4-(4-(6-chloro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-67-[4-(4-(5-methoxyl group-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-77-[4-(4-(5-fluoro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-87-[4-(4-(5,6-dimethoxy-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-97-[4-(5-hydroxyl-benzisoxa oxazole)-piperidino)-and n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-107-[4-(5,6-dihydroxyl-benzisoxa oxazole)-piperidino)-and n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-117-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-n-butylamine-based]-3,4-dihydro-2 (1H)-quinolinone
III-17-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-27-[3-(1, the 2-benzisothiazole)-1-piperazinyl)--positive propoxy]-3,4-dihydro-2 (1H)-quinolinone
III-37-[2-(1, the 2-benzisothiazole)-1-piperazinyl)--oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone
III-47-[4-(6-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-57-[4-(7-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-67-[4-(5-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-77-[4-(4-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
IV-17-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
IV-27-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-2 (1H)-quinolinones
IV-37-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-2 (1H)-3-toluquinoline ketone
IV-47-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-2 (1H)-4-toluquinoline ketone
V-17-[4-(4 (6-fluoro-benzisothiazoles)-5,6-dihydro piperazinyl)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone
V-27-[4-(4 (6-fluoro-benzisothiazoles)-5,6-dihydro piperazinyl)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone
VI-17-[4-(4-(s, s-dioxy-1,2 benzisothiazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
VI-27-[3-(4-(s, s-dioxy-1,2 benzisothiazole)-1-piperazinyl)-positive propoxy]-3,4-dihydro-2 (1H)-quinolinone
VII-17-[4-(4-(6-fluoro-benzisoxa oxazole)-2,5-lupetazin base)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone
VII-27-[4-(4-benzisothiazole)-2,5-lupetazin base)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone
The concrete structure formula is as shown in table 1:
Figure A20071004054500121
Table 1 related compound structural formula
Figure A20071004054500122
Figure A20071004054500131
Figure A20071004054500141
Figure A20071004054500151
Figure A20071004054500161
Wherein, further, preferred compound comprises:
II-17-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-17-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
The compound of general formula 1 can contain chiral centre, and can exist with different enantiomorphs and diastereomer form thus.The present invention relates to all optically active isomers and all steric isomers of general formula 1 compound, as the form of the racemic mixture of this compounds and each enantiomorph and diastereomer, and the present invention relates separately to as above-mentioned defined all pharmaceutical compositions and the methods of treatment that contains or use them.Can obtain each isomer by known method, such as optical resolution, fractional crystallization, optics selective reaction or the chromatographic separation in preparation end product or its intermediate. each enantiomorph of general formula 1 compound may have advantage than the racemic mixture of these compounds in the process of various obstacles of treatment or illness.
Explained the synthesis step of each in the above-claimed cpd in the embodiment part hereinafter.
Compound of the present invention can adopt following method to synthesize:
Synthetic route one
Figure A20071004054500162
Compound 2 under alkaline environment with 3 condensations, the reaction finish the back removes excess reactant 3 with normal hexane or sherwood oil, promptly get compound 4,4 and 5 back flow reaction under alkaline environment, promptly get product.With this path of preparing series compound I, II, III, wherein compound 2 can be bought by commercial sources, and compound 5 can be used document J.Med.Chem.1991, and the 34.3316-3328 disclosed method makes.
Synthetic route two
Compound 6 under alkaline environment with the condensation of 1-bromo-4-chlorobutane, the reaction finish the back removes excessive 1-bromo-4-chlorobutane with normal hexane or sherwood oil, promptly get compound 7; 7 and 8 under alkaline environment back flow reaction; through deprotection, under molten state, react again, promptly get product with compound 10.With this path of preparing series series compound series IV, wherein compound 6 can be bought by commercial sources, or referenced patent method that WO2005019215 chats makes.
Synthetic route three
Figure A20071004054500172
By synthetic route three preparation compound V-1 and V-2, see example for details.
Synthetic route four
By synthetic route four preparation series of compounds VI, wherein 1 can make by scheme 1, get product through the metachloroperbenzoic acid oxidation again
Synthetic route five
Synthetic route five is used for synthetic compound series VII, sees example for details.
Extracorporeal receptor shows in conjunction with test, aralkyl piperidines (piperazine) derivative involved in the present invention has higher avidity to d2 dopamine receptor, most compounds in them shows the antagonistic activity to acceptor, and some compound embodies the part agonism to the D2 acceptor.
Animal test results shows that this compounds can improve the related symptoms of apomorphine model mice.Because the nervous system disorders that pharmacological model and Dopamine HCL dysfunction cause in these interaction in vitro target spots and the body, particularly schizophrenia is closely related, therefore point out the compound that the present invention relates to have the effect of the neural spiritual class disease of treatment, especially schizophrenia is had therapeutic action.
The present invention relates to the medicine that described aralkyl piperidines (piperazine) derivative also may be used to prepare other central nervous system disorder disease.For example: be used for the treatment of neuropathic pain, mania, anxiety disorder, various dysthymia disorders, schizophrenia, Parkinson's disease (PD), Huntington Chorea (HD), Alzheimer, senile dementia, Alzheimers type dementia, dysmnesia, execution afunction, vascular dementia and other dementia, and with intelligence, study or the relevant medicines such as functional disorder disease of memory.
Research of Animal Model for Study result shows that preferred compound II-1 has obvious antischizophrenic effect, and oral absorption is better, acute toxicity (LD 50＞2000mg/Kg, the mouse single gavages) suitable with Ziprasidone with Aripiprazole, well below risperidone, the Salmonella reversion test feminine gender, therapeutic index is bigger, possesses the potential value as the exploitation of novel anti schizophrenia.
Derivative of the present invention can composition form be applied to the patient who needs this treatment by modes such as oral, injections, its per daily dose is 5-30mg/kg body weight (oral) or 1-10mg/kg body weight (injection), specifically can be determined by the doctor according to patient's the state of an illness, age and sex;
Said composition contains said aralkyl piperidines (piperazine) derivative and the medically acceptable carrier for the treatment of significant quantity.
Said carrier is meant the carrier of pharmaceutical field routine, for example: thinner, vehicle such as water etc.; Tackiness agent such as derivatived cellulose, gelatin, polyvinylpyrrolidone etc.; Weighting agent such as starch etc.; Agent such as lime carbonate, sodium bicarbonate burst apart; Lubricant such as calcium stearate or Magnesium Stearate etc.In addition, can also in composition, add other auxiliarys such as flavouring agent and sweeting agent.Be used for when oral, it can be prepared into conventional solid preparation such as tablet, pulvis or capsule etc.; When being used to inject, it can be prepared into injection liquid.
The various formulations of composition of the present invention can adopt the method for medical field routine to be prepared, and wherein the content of activeconstituents is 0.1%～99.5% (weight ratio).
Aralkyl piperidines of the present invention (piperazine) derivative has higher avidity to d2 dopamine receptor, not only has stronger Hangzhoupro short of money activity, and embodies the part agonism to the D2 acceptor.In vivo test shows that this compounds can improve the related symptoms of apomorphine model mice.Because pharmacological model and schizophrenia are closely related in these interaction in vitro target spots and the body, therefore point out the compound that the present invention relates to have to schizoid therapeutic action.(LD50＞2000mg/Kg, the mouse single gavages) is suitable with Ziprasidone with Aripiprazole for the acute toxicity of Compound I I-1, and well below risperidone, the Salmonella reversion test feminine gender has the value as the exploitation of novel anti schizophrenia drug.
Description of drawings:
The positive medicine haloperidol of Fig. 1 is to D2 receptor antagonism result.
Fig. 2 is that Compound I I-1 is to D2 receptor antagonism result.
Fig. 3 is compound III-1 couple D2 receptor antagonism result.
Fig. 4 is compound IV-1 couple D2 receptor antagonism result.
Fig. 5 is that Compound I I-1 is to D2 acceptor portion agonism result.
Fig. 6 is that Compound I I-1 is to each time point stereotypic behavior exercising result of model mice.
Fig. 7 is that Compound I I-1 is to model mice accumulative total stereotypic behavior exercising result.
Embodiment
Embodiment 1
I-17-[4-(4-(6-chloro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 4-chloro-wintergreen oil
The 5ml vitriol oil is slowly splashed in the 100ml methyl alcohol, treat solution cooling back add 4-chloro-Whitfield's ointment powder (17.20g, 0.1mol), back flow reaction 24h, a large amount of precipitations are separated out in cooling, leach the small amount of methanol washing, with the dehydrated alcohol recrystallization, get 4-chloro-wintergreen oil 15.60g, yield 83%.
B) preparation 4-chloro-N, 2-dihydroxyl-benzamide
With (5.25g; 75mmol) the hydroxylamine chloride solid is put in the eggplant-shape bottle, and ice bath drips less water down and makes its dissolving, then Dropwise 5 0%NaOH solution 15ml; stirred 5 minutes; the N2 protection drips 4-chloro-wintergreen oil down in solution (9.3g, dioxane solution 50ml 50mmol) dropwise back room temperature reaction 24h; separate out red-brown precipitation; leach, put in the eggplant-shape bottle, add 10% hydrochloric acid 50ml; refluxed 0.5 hour; be cooled to room temperature, separate out yellow mercury oxide, leach; with the dehydrated alcohol recrystallization; get 4-chloro-N, 2-dihydroxyl-benzamide 8.25g, yield 88%.
C) preparation 3-hydroxyl-6-chloro-benzisoxa oxazole
N 2Protection is down with 4-chloro-N, and (8g 42.7mmol) adds in the 10ml tetrahydrofuran (THF) 2-dihydroxyl-benzamide, and temperature is lower than 30 ℃ in keeping, and slowly drips 10ml SOCl 2, dripping off the back and stir 30min, evaporate to dryness is with the most remaining SOCl of dry-out benzene band 2, evaporate to dryness gets yellow powder, and after powder was dissolved with the 10ml dioxane, temperature was lower than 30 ℃ in keeping, slowly Dropwise 5 ml Et 3N stirred 30 minutes, dripped 10% hydrochloric acid then to PH=2, stirred, and separated out a large amount of light-yellow precipitate, leach, recrystallizing methanol, 3-hydroxyl-6-chloro-benzisoxa oxazole 6.50g, yield 89%
D) preparation 3,6-dichloro benzo isoxzzole
With 3-hydroxyl-6-chloro-benzisoxa oxazole (6g, 35mmol), 20ml Phosphorus Oxychloride, 1mlEt 3N is as in the microwave reactor, 150 ℃ were reacted 0.5 hour down, boil off Phosphorus Oxychloride, residue adds mixture of ice and water 20g with methylene dichloride 20ml dilution, stir, tell organic phase, water continues the extraction with methylene dichloride 20ml*2, combined dichloromethane layer, saturated aqueous common salt 20ml washing, anhydrous MgSO 4Dehydration, evaporate to dryness is gone up in 30g aluminum oxide (200-300 order) capital end, with methylene dichloride: methyl alcohol=200: 1 wash-outs, 3,6-dichloro benzo isoxzzole 5.2g, yield 79%
E) preparation 6-chloro-3-piperazinyl-benzisoxa oxazole
With 3, and 6-dichloro benzo isoxzzole (5.2g, 27.8mmol), Piperazine anhydrous (24g, 278mmol) put in the eggplant-shape bottle, 120 ℃ were reacted 24 hours down, added the cancellation of 52ml frozen water after reaction finishes, in solution, add 50%NaOH solution 15ml again, stirred methylene dichloride 30ml*3 extraction, combined dichloromethane layer 5 minutes, saturated aqueous common salt 20ml washing, anhydrous MgSO 4Dehydration, evaporate to dryness is gone up in 40g aluminum oxide (200-300 order) capital end, with methylene dichloride: methyl alcohol=100: 1 wash-outs, 6-chloro-3-piperazinyl-benzisoxa oxazole 4.7g, yield 71%.
F) preparation 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone
With 1-bromo-4-chloro-butane (3.4g, 20mmol), the Anhydrous potassium carbonate powder (4.14g, 30mmol) with 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (1.63g, 10mmol) join in the 10ml acetone, backflow 24h, the reaction solution evaporate to dryness distributes with methylene dichloride and each 20ml of water, organic layer extracts with water 20ml*2, saturated aqueous common salt 20ml successively, anhydrous magnesium sulfate drying, evaporate to dryness gets buff powder, the gained powder is washed with normal hexane 20ml*3 making beating, filter, drying gets 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone 1.98g, yield 78%.
G) preparation 7-[4-(4-(6-chloro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone (278mg, 1.1mmol), 6-chloro-3-piperazinyl-benzisoxa oxazole (237mg, 1mmol), (414mg 3.3mmol) joins among the 10mlDMF back flow reaction 24h to the Anhydrous potassium carbonate powder, the evaporate to dryness reaction solution, distribute with methylene dichloride and each 20ml of water, organic layer is successively with water 20ml*2, saturated aqueous common salt 20ml extraction, anhydrous magnesium sulfate drying, evaporate to dryness, get buff powder,, put in the ice bath and stir with acetone 5ml dissolving, separate out white solid, filter small amount of acetone washing, drying, get 7-[4-(4-(6-chloro-benzisoxa oxazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone 260mg is dissolved in it in 5ml dehydrated alcohol, uses HCl/C 2H 5OH transfers pH=2, separates out white solid, leaches, and the dehydrated alcohol recrystallization gets product 200mg, yield 38%.
Ultimate analysis: C 24H 27ClN 4O 3(theoretical value %:C 63.36, and H 5.98, and N 12.31 for 2HCl; Experimental value %C 62.04, H 5.89, N 12.01).
1HNMR (DMSO-d 6): δ 9.82 (s, 1H, CONH), 7.94-6.48, (6H, aromatic ring-H), 4.09-4.10 (2H, piperazine-H), 3.83 (t, J=6.4HZ, 2H, O-CH2,) 3.56-3.60 (2H, piperazine-H), 3.21-3.48 (m, 6H), 2.76 (t, J=8HZ, 2H) 2.55 (t, J=8HZ, 2H) 1.60-1.93 (m, 4H)
MS：m/z 454
Embodiment 2
I-27-[4-(4-(5-chloro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 5-chloro-Whitfield's ointment Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 24H 27ClN 4O 32HCl (theoretical value %:C63.36, H 5.98, and N 12.31; Experimental value %C 62.72, H 5.92, N 12.24).
1HNMR (DMSO-d 6): δ 10.03 (s, 1H, CONH), 7.99-6.46, (6H, aromatic ring-H), 4.10-4.15 (2H, piperazine-H), 3.99 (t, J=6.4HZ, 2H, O-CH2,) 3.50-3.70 (2H, piperazine-H), 3.22-3.57 (m, 6H), 2.75 (t, J=8HZ, 2H), 2.45 (t, J=8HZ, 2H) 1.71-1.98 (m, 4H)
MS：m/z 454
Embodiment 3
I-37-[4-(4-(benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With the Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1.
Ultimate analysis: C 24H 28N 4O 3(theoretical value %:C 68.55, and H 6.71, and N 13.32 for 2HCl; Experimental value %C 68.00, H 6.65, N 13.21).
1HNMR (DMSO-d 6): δ 10.00 (s, 1H, CONH), 7.96-6.48, (7H, aromatic ring-H), 4.05-4.10 (2H, piperazine-H), 3.93 (t, J=6.4HZ, 2H, O-CH2,) 3.59-3.62 (2H, piperazine-H), 3.20-3.50 (m, 6H), 2.78 (t, J=8HZ, 2H) 2.41 (t, J=8HZ, 2H) 1.73-1.93 (m, 4H)
MS：m/z 420
Embodiment 4
I-47-[4-(4-(6-fluoro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 4-fluoro-Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 24H 27FN 4O 3(theoretical value %:C 56.36, and H 5.72, and N 10.96 for 2HCl; Experimental value %C 55.96, H 5.55, N 10.88).
1HNMR (DMSO-d 6): δ 10.08 (s, 1H, CONH), 8.02-6.48, (6H, aromatic ring-H), 4.01-4.11 (2H, piperazine-H), 3.97 (t, J=6.4HZ, 2H, O-CH2,) 3.57-3.64 (2H, piperazine-H), 3.22-3.48 (m, 6H), 2.79 (t, J=8HZ, 2H), 2.40 (t, J=8HZ, 2H) 1.80-1.93 (m, 4H)
MS：m/z 438
Embodiment 5
I-57-[4-(4-(6-trifluoromethyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 4-trifluoromethyl-Whitfield's ointment is raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 25H 27F 3N 4O 3(theoretical value %:C 53.48, and H 5.21, and N 9.98 for 2HCl; Experimental value %C 53.26, H 5.18, N 9.94).
1HNMR (DMSO-d 6): 89.93 (s, 1H, CONH), 8.04-6.48, (6H, aromatic ring-H), 4.03-4.09 (2H, piperazine-H), 3.98 (t, J=6.4HZ, 2H, O-CH2,) 3.55-3.60 (2H, piperazine-H), 3.21-3.49 (m, 6H), 2.80 (t, J=8HZ, 2H), 2.39 (t, J=8HZ, 2H) 1.80-1.93 (m, 4H)
MS：m/z 488
Embodiment 6
I-67-[4-(4-(6-methyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 4-methyl-Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 25H 30N 4O 3(theoretical value %:C 59.17, and H 6.36, and N 11.04 for 2HCl; Experimental value %C 59.05, H6.34, N 11.01).
1HNMR (DMSO-d 6): δ 9.89 (s, 1H, CONH), 7.94-6.48, (6H, aromatic ring-H), 4.03-4.09 (2H, piperazine-H), 3.87 (t, J=6.4HZ, 2H, O-CH2,) 3.57-3.60 (2H, piperazine-H), 3.21-3.51 (m, 6H), 2.80 (t, J=8HZ, 2H), 2.44 (t, J=8HZ, 2H), 1.79-1.93 (m, 7H)
MS：m/z 434
Embodiment 7
I-77-[4-(4-(5-methyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 5-methyl-Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 25H 30N 4O 3(theoretical value %:C 59.17, and H 6.36, and N 11.04 for 2HCl; Experimental value %C 58.93, H6.32, N 10.97).
1HNMR (DMSO-d 6): δ 9.90 (s, 1H, CONH), 7.74-6.48, (6H, aromatic ring-H), 4.09-4.18 (2H, piperazine-H), 3.88 (t, J=6.4HZ, 2H, O-CH2,) 3.57-3.63 (2H, piperazine-H), 3.20-3.57 (m, 6H), 2.78 (t, J=8HZ, 2H), 2.43 (t, J=8HZ, 2H) 1.80-2.01 (m, 7H)
MS：m/z 434
Embodiment 8
I-87-[4-(4-(6-hydroxyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 4-trifluoromethyl-Whitfield's ointment is raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 25H 28F3N 4O 3(theoretical value %:C 53.48, and H 5.21, and N 9.98 for 2HCl; Experimental value %C 53.26, H 5.18, N 9.94).
1HNMR (DMSO-d 6): δ 9.87 (s, 1H, CONH), 8.04-6.48, (6H, aromatic ring-H), 5.12 (b, 1H, hydroxyl-H), 4.10-4.15 (2H, piperazine-H), 3.85 (, J=6.4HZ, 2H, O-CH2) and 3.60-3.72 (2H, piperazine-H), 3.21-3.53 (m, 6H), 2.84 (t, J=8HZ, 2H), 2.39 (t, J=8HZ, 2H) 1.83-2.01 (m, 4H)
MS：m/z 488
Embodiment 9
I-97-[4-(4-(5-methoxyl group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 5-methoxyl group-Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 25H 30N 4O 3(theoretical value %:C 57.36, and H 6.16, and N 10.70 for 2HCl; Experimental value %C 57.13, H 6.13, N 10.65).
1HNMR (DMSO-d 6): δ 9.92 (s, 1H, CONH), 8.04-6.48, (6H, aromatic ring-H), 4.05-4.10 (2H, piperazine-H), 3.80 (b, 5H, O-CH2) 3.59-3.62 (2H, piperazine-H), 3.20-3.50 (m, 6H), 2.78 (t, J=8HZ, 2H) 2.41 (t, J=8HZ, 2H) 1.73-1.93 (m, 4H)
MS：m/z 450
Embodiment 10
I-107-[4-(4-(5-cyano group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 5-cyano group-Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 25H 27N 5O 3(theoretical value %:C 57.92, and H 5.64, and N 13.51 for 2HCl; Experimental value %C 57.80, H 5.62, N 13.48).
1HNMR (DMSO-d 6): δ 10.05 (s, 1H, CONH), 7.94-6.48, (6H, aromatic ring-H), 3.95-4.07 (2H, piperazine-H), 3.99 (t, J=6.4HZ, 2H, O-CH2,) 3.54-3.60 (2H, piperazine-H), 3.11-3.49 (m, 6H), 2.67 (t, J=8HZ, 2H), 2.39 (t, J=8HZ, 2H) 1.81-1.98 (m, 4H)
MS：m/z 445
Embodiment 11
I-117-[4-(4-(5-bromo-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 5-bromo-Whitfield's ointment is starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 24H 27BrN 4O 3(theoretical value %:C 50.37, and H 5.11, and N 9.79 for 2HCl; Experimental value %C 50.16, H 5.08, N 9.75).
1HNMR (DMSO-d 6): δ 10.01 (s, 1H, CONH), 8.01-6.48 (6H, aromatic ring-H), 4.12-4.23 (2H, piperazine-H), 3.89 (t, J=6.4HZ, 2H, O-CH2) 3.50-3.54 (2H, piperazine-H), 3.11-3.51 (m, 6H), 2.80 (t, J=8HZ, 2H), 2.33 (t, J=8HZ, 2H) 1.77-1.93 (m, 4H)
MS：m/z 498
Embodiment 12
I-127-[4-(4-(7-bromo-6-methoxyl group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
Think starting raw material, by the synthetic target compound that makes of the method for preparing I-1
Ultimate analysis: C 25H 29BrN 4O 4(theoretical value %:C 49.85, and H 5.19, and N 9.30 for 2HCl; Experimental value %C 49.70, H 6.11, N 10.61).
1HNMR (DMSO-d 6): δ 9.93 (s, 1H, CONH), 7.98-6.48, (5H, aromatic ring-H), 4.05-4.10 (2H, piperazine-H), 3.95 (m, J=6.4HZ, 5H, O-CH2,) 3.59-3.62 (2H, piperazine-H), 3.20-3.50 (m, 6H), 2.78 (t, J=8HZ, 2H) 2.41 (t, J=8HZ, 2H) 1.73-1.93 (m, 4H)
MS：m/z 528
Embodiment 13
II-17-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 1-ethanoyl-4-(2,4 difluorobenzene formyl radical) piperidines
With 1,3-two fluorobenzene (6.7g, 58.7mmol) and ammonia chloride (13.3g 250mmol) joins in the methylene dichloride of 15ml, is cooled to room temperature.Be dissolved with 1-ethanoyl-4-piperidyl dicarbonyl chloride (9.8g, methylene dichloride 50ml 51.8mmol), back flow reaction 3 hours to wherein dripping.After reaction finishes mixture is poured in the ice and the mixture of hydrochloric acid, methylene dichloride 20ml*3 extraction separates organic phase, and anhydrous magnesium sulfate drying filters, and evaporate to dryness gets product 5.01g, yield 36%.
B) preparation 2,4 difluorobenzene base-(4-piperidyl) methane keto hydrochloride
(5.6g 20.9mmol) adds in the 6N hydrochloric acid of 19ml, refluxes 5 hours with 1-ethanoyl-4-(2,4 difluorobenzene formyl radical) piperidines.Evaporated under reduced pressure, the 2-propyl alcohol of interpolation 20ml stirs in residue, filters, and drying gets product 4.67g, yield 85%.
C) preparation 2,4--difluorophenyl-(4-piperidyl) methane ketoxime hydrochloride
(3.0g, 11.5mmol) (3.0g 42.8mmol) is added in the ethanol of 5ml and oxammonium hydrochloride with 2,4 one difluorophenyls (4 one piperidyl) methane keto hydrochloride.To the N that wherein drips 3ml, the N-dimethylethanolamine stirs under the room temperature, refluxes then 3 hours.Reaction finishes postcooling to room temperature, filtering-depositing, drying, the title compound of product 2.6g, it is white crystal (productive rate 96%).
D) preparation 4-(6-fluoro-1,2-benzisoxa oxazole)-piperidines
With 2, (5.52g 20mmol) is added in 25ml 50% potassium hydroxide 4-difluorophenyl (4-piperidyl)-methane ketoxime hydrochloride, refluxes 4 hours, be cooled to room temperature, toluene 25ml*2 extraction merges the organic phase anhydrous magnesium sulfate drying, filters, evaporated under reduced pressure, the ether recrystallization gets product 3.3g, yield 75%.
E) preparation 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone
With 1-bromo-4-chloro-butane (3.4g, 20mmol), the Anhydrous potassium carbonate powder (4.14g, 30mmol) with 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (1.63g, 10mmol) join in the 10ml acetone, backflow 24h, the reaction solution evaporate to dryness distributes with methylene dichloride and each 20ml of water, organic layer extracts with water 20ml*2, saturated aqueous common salt 20ml successively, anhydrous magnesium sulfate drying, evaporate to dryness gets buff powder, the gained powder is washed with normal hexane 20ml*3 making beating, filter, drying gets 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone 1.98g, yield 78%.
F) preparation 7-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 7-(4-chlorine butoxy)-3, and 4-dihydro-2 (1H)-quinolinone (297mg, 1mmol), 4-(6-fluoro-1,2-benzisoxa oxazole)-and piperidines (242mg, 1.1mmol), (414mg 3.3mmol) joins 10ml to the Anhydrous potassium carbonate powder, back flow reaction 24h, the evaporate to dryness reaction solution distributes with methylene dichloride and each 20ml of water, organic layer is successively with water 20ml*2, saturated aqueous common salt 20ml extraction, anhydrous magnesium sulfate drying, evaporate to dryness gets buff powder, dissolve with acetone 5ml, put in the ice bath and stir, separate out white solid, filter, the small amount of acetone washing, drying gets white powder 260mg, and it is dissolved in the dehydrated alcohol, drip HCl/EtOH to PH=2, separate out white precipitate, leach, the dehydrated alcohol recrystallization, get product 200mg, yield 42%.
Ultimate analysis: C 25H 28FN 3O 3(theoretical value %:C 63.35, and H 6.17, and N 8.87 for HCl; Experimental value %C 63.22, H6.11, N 8.80).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
8.00-6.38 (6H, aromatic ring-H)
3.94(t，J＝6.4HZ，2H，O-CH 2)
3.20 (m, 2H, piperidines-H)
1.51-3.02(17H，-CH 2)
MS：m/z 437。
Embodiment 14
II-27-[3-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-positive propoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 1,3-two fluorobenzene and 1-bromo-3-chloro-propane are starting raw material, by the synthetic target compound that makes of the method for preparing II-1
Ultimate analysis: C 24H 26FN 3O 3(theoretical value %:C 62.67, and H 5.92, and N 9.14 for HCl; Experimental value %C 62.60, H5.95, N 9.20.
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
7.95-6.52 (6H, aromatic ring-H)
3.91(t，J＝6.4HZ，2H，O-CH 2)
3.26 (m, 2H, piperidines-H)
1.55-2.83(15H，-CH 2)
MS：m/z 423
Embodiment 15
II-37-[5-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-pentyloxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 1,3-two fluorobenzene and 1-bromo-5-chloro-pentane are starting raw material, by the synthetic target compound that makes of the method for preparing II-1
Ultimate analysis: C 26H 30FN 3O 3(theoretical value %:C 63.99, and H 6.40, and N 8.61 for HCl; Experimental value %C 63.90, H6.44, N 8.60.
1HNMR(DMSO-d 6)：δ10.02(B，1H，CONH)
8.12-6.56, (6H, aromatic ring-H)
3.81(t，J＝6.4HZ，2H，O-CH 2)
3.20 (m, 2H, piperidines-H)
1.46-2.91(19H，-CH 2)
MS(APCI)：m/z 451[M+H] +
Embodiment 16
II-47-[(4-benzisoxa oxazole-piperidino)-and n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 4-(2-fluoro-phenyl)-1-methyl piperidine
The N2 protection down; to adding Mg powder (55.7g; 2.3mol) and the tetrahydrofuran (THF) 250ml of small amount of bromine ethane in slowly drip 4-chloro-N-methyl piperidine (245g; 1.8mol) THF solution 800ml, drip off back back flow reaction 1 hour, in reaction solution, splash into 2-fluorobenzene cyanogen (222g; 1.8mol) THF solution 440ml; drip off the back and refluxed 3 hours, and at room temperature reacted 13 hours, reaction solution is poured into and is contained 700g NH 4In the 2.3L water of Cl, refluxed 2 hours, the cooling back is with extracted with diethyl ether, and extraction liquid merges evaporate to dryness, and 124 cuts are collected in fractionation, get product 224g.
B) preparation 3-(1-methyl-4-piperidyl)-1,2-benzisothia triazole hydrochloride
To 4-(2-fluoro-phenyl)-1-methyl piperidine hydrochloride (28.2g, 0.13mmol) and oxammonium hydrochloride (19.2g, ethyl di-alcohol (400ml) 0.28mol)--add 85% KOH (80.8g in water (200ml) solution; 1.2mol) aqueous solution 200ml; back flow reaction is 5 hours under the N2 protection, pours into after reacting completely in the 1000ml water, with extracted with diethyl ether; extraction liquid merges; drying, the small amount of acetone dissolving, HCl/EtOH transfers pH=2; separate out a large amount of white precipitates, with EtOH-H 2The O recrystallization gets product 15.4g
C) preparation 3-(4-piperidyl)-1,2 benzisothia triazole hydrochloride
To 3-(1-methyl-4-piperidyl)-1; add benzene oxygen formyl chloride (8.8g in the toluene solution of 2-benzisothiazole (12.3g); 0.056mol), the N2 protection was reacted 16 hours down, cooling; filter; filtrate concentrate oily matter, it is dissolved in the ether, drip sherwood oil; separate out white solid; extracting waste solid 5g is dissolved in the KOH solution, and backflow 16h boils off ethanol; get brown oil; it is dissolved in the small amount of acetone, drips HCl/EtOH to ph=2, separate out white solid; the methanol-water recrystallization gets product 2.0g
D) preparation 7-[4-(4-benzisoxa oxazole-piperidino)-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 7-(4-chlorine butoxy)-3, and 4-dihydro-2 (1H)-quinolinone (297mg, 1mmol), 3-(4-piperidyl)-1,2 benzisothiazoles (220mg, 1mmol), (414mg 3.3mmol) joins 10ml to the Anhydrous potassium carbonate powder, back flow reaction 24h, the evaporate to dryness reaction solution distributes with methylene dichloride and each 20ml of water, organic layer is successively with water 20ml*2, saturated aqueous common salt 20ml extraction, anhydrous magnesium sulfate drying, evaporate to dryness gets buff powder, dissolve with acetone 5ml, put in the ice bath and stir, separate out white solid, filter, the small amount of acetone washing, drying gets white powder 260mg, and it is dissolved in the dehydrated alcohol, drip HCl/EtOH to PH=2, separate out white precipitate, leach, the dehydrated alcohol recrystallization, get product 200mg, yield 44%.
Ultimate analysis: C 25H 29N 3O 3(theoretical value %:C 65.85, and H 6.63, and N 9.22 for HCl; Experimental value %C65.82, H6.60, N 9.25).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
7.91-6.38 (6H, aromatic ring-H)
3.87(t，J＝6.4HZ，2H，O-CH 2)
3.22 (m, 2H, piperidines-H)
1.58-2.99(18H，-CH 2)
MS：m/z 419。
Embodiment 17
II-57-[4-(4-(6-chloro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 1-chloro-3-fluorobenzene is raw material, by the synthetic target compound that makes of the method for preparing II-1
Ultimate analysis: C 23H 28ClN 3O 3(theoretical value %:C 61.23, and H 5.96, and N 8.57 for HCl; Experimental value %C 61.20, H5.93, N 8.60.
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
8.08-6.40 (6H, aromatic ring-H)
3.89(t，J＝6.4HZ，2H，O-CH 2)
3.14 (m, 2H, piperidines-H)
1.40-2.95(17H，-CH 2)
MS：m/z 453。
Embodiment 18
II-67-[4-(4-(5-methoxyl group-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation (4-(2-hydroxy-5-methyl oxygen base phenyl) (1-ethanoyl-piperidyl) methane ketoxime hydrochloride
With the 4-methoxyphenol is raw material, makes (4-(2-hydroxy-5-methyl oxygen base phenyl) (1-ethanoyl-piperidyl) methane ketoxime hydrochloride according to the A among the method II-1, B, C scheme
B) preparation 1-ethanoyl-4-(5-methoxyl group-1,2 benzisoxa oxazole) piperidines
With free (4-(2-hydroxy-5-methyl oxygen base phenyl) (1-ethanoyl-piperidyl) methane ketoxime 0.034mol and 4.5ml diacetyl oxide na60 reaction 1.5h; boil off diacetyl oxide; obtain acylate; it is joined suspendible NaH (1.1g is arranged; 0.023mol) DMF80ml in; room temperature reaction 16 hours; pour in the 300ml water,, ethyl acetate extraction; organic phase is water successively; the saturated common salt washing; anhydrous MgSO4 drying gets oily matter, and the ether crystallization gets the 3.7g solid; toluene-hexanaphthene recrystallization gets 1-ethanoyl-4-(5-methoxyl group-1,2 benzisoxa oxazole) piperidines 2.1g
C) preparation 4-(5-methoxyl group-1,2 benzisoxa oxazole) piperidine hydrochlorate
The 6NHCl of 1-ethanoyl-4-(5-methoxyl group-1,2 benzisoxa oxazole) piperidines 0.07mol and 110ml was refluxed 6 hours, and room temperature is placed, and separates out a large amount of white precipitates, and ethyl alcohol recrystallization gets 4-(5-methoxyl group-1,2 benzisoxa oxazole) piperidine hydrochlorate
D) preparation 7-[4-(4-(5-methoxyl group-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
Make 7-[4-(4-(5-methoxyl group-benzisoxa oxazole)-piperidino)-n-butoxy according to D step in the method example 13]-3,4-dihydro-2 (1H)-quinolinone hydrochloride, yield 52%
Ultimate analysis: C 26H 31N 3O 4(theoretical value %:C 64.25, and H 6.64, and N 8.15 for HCl; Experimental value %C 64.22, H6.51, N 8.19).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
7.95-6.38 (6H, aromatic ring-H)
3.92(t，J＝6.4HZ，2H，O-CH 2)
3.18 (m, 2H, piperidines-H)
1.54-3.02(20H，-CH 2)
MS：m/z 449。
Embodiment 19
II-77-[4-(4-(5-fluoro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With the 4-fluorophenol is raw material, by the synthetic target compound that makes of the method for preparing II-1
Ultimate analysis: C 25H 28FN 3O 3(theoretical value %:C 63.35, and H 6.17, and N 8.87 for HCl; Experimental value %C 63.31, H6.15, N 8.85).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
7.96-6.38 (6H, aromatic ring-H)
3.95(t，J＝6.4HZ，2H，O-CH 2)
3.27 (m, 2H, piperidines-H)
1.56-2.83(18H，-CH 2)
MS：m/z 437。
Embodiment 20
II-87-[4-(4-(5,6-dimethoxy-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 3, the 4-syringol is a raw material, by the synthetic target compound that makes of the method for preparing II-1
Ultimate analysis: C 27H 34N 3O 5(theoretical value %:C 62.84, and H 6.64, and N 8.14 for HCl; Experimental value %C 62.82, H6.62, N 8.16).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
8.08-6.40 (5H, aromatic ring-H)
3.89-3.35(m，8H，O-CH 2)
3.20 (m, 2H, piperidines-H)
1.53-2.97(17H，-CH 2)
MS：m/z 479。
Embodiment 21
II-97-[4-(5-hydroxyl-benzisoxa oxazole)-piperidino)-and n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 1-ethanoyl-4-(the 5-methoxyl group-1 that obtains among the embodiment 18; 2 benzisoxa oxazoles) the HBr solution of piperidines 2.1g and 25ml48% refluxed 4 hours; and the 10h of continuation reaction at room temperature; separate out white precipitate; leach; methyl alcohol-ether recrystallization gets 5-hydroxyl-3-(4-piperidyl)-1; 2 benzisoxa oxazole hydrobromate 1.0g; below make 7-[4-(4-(5-hydroxyl-benzisoxa oxazole)-piperidino)-n-butoxy according to D step in the method example 13]-3; 4-dihydro-2 (1H)-quinolinone hydrochloride, yield 49.3%
Ultimate analysis: C 25H 29N 3O 4(theoretical value %:C 63.62, and H 6.41, and N 8.90 for HCl; Experimental value %C 63.58, H6.30, N 8.97).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
8.08-6.40 (6H, aromatic ring-H)
5.13 (b, 1H, hydroxyl-H)
3.89(t，J＝6.4HZ，2H，O-CH 2)
3.14 (m, 2H, piperidines-H)
1.40-2.95(17H，-CH 2)
MS：m/z 435
Embodiment 22
II-107-[4-(5,6-dihydroxyl-benzisoxa oxazole)-piperidino)-and n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With the 1-ethanoyl-4-(5 that obtains among the embodiment 20; 6-dimethoxy-1; 2 benzisoxa oxazoles) the HBr solution of piperidines 2.1 and 25ml48% refluxed 4 hours; and the 10h of continuation reaction at room temperature; separate out white precipitate; leach; methyl alcohol-ether recrystallization gets 5-hydroxyl-3-(4-piperidyl)-1; 2 benzisoxa oxazole hydrobromate 1.0g; below make 7-[4-according to D step in the method example 13 (4-(5; 6-dihydroxyl benzo isoxzzole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride, yield 61%.
Ultimate analysis: C 25H 29N 3O 5(theoretical value %:C 61.53, and H 6.20, and N 8.61 for HCl; Experimental value %C 61.43, H6.30, N 8.71).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
8.08-6.40 (5H, aromatic ring-H)
5.20 (b, 2H, hydroxyl-H)
3.80(t，J＝6.4HZ，2H，O-CH 2)
3.21 (m, 2H, piperidines-H)
1.50-2.93(17H，-CH 2)
MS：m/z 451
Embodiment 23
II-117-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-n-butylamine-based]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 1,3-two fluorobenzene and 7-amino-3,4-dihydro-2 (1H)-quinolinone is a raw material, by the synthetic target compound that makes of the method for preparing II-1
Ultimate analysis: C 25H 29FN 4O 2(theoretical value %:C 58.94, and H 6.13, and N 11.00 for 2HCl; Experimental value %C 58.83, H6.11, N 10.89).
1HNMR(DMSO-d 6)：δ9.88(B，1H，CONH)
(8.10-6.38 7H, aromatic ring-H, proton on the PhNH nitrogen)
3.94(t，J＝6.4HZ，2H，O-CH 2)
3.20 (m, 2H, piperidines-H)
1.51-3.02(17H，-CH 2)
MS：m/z 437(M ++H)
Embodiment 24
III-17-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl)--n-butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone
With 1-bromo-4-chloro-butane (3.4g, 20mmol), the Anhydrous potassium carbonate powder (4.14g, 30mmol) with 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (1.63g, 10mmol) join in the 10ml acetone, backflow 24h, the reaction solution evaporate to dryness distributes with methylene dichloride and each 20ml of water, organic layer extracts with water 20ml*2, saturated aqueous common salt 20ml successively, anhydrous magnesium sulfate drying, evaporate to dryness gets buff powder, the gained powder is washed with normal hexane 20ml*3 making beating, filter, drying gets 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone 1.98g, yield 78%.
B) preparation 4-(1,2-benzisothiazole-3-yl)-1-piperazine
With 3-chloro-(1, the 2-benzisothiazole) (14g, 200mmol) and Piperazine anhydrous (6.8g 40mmol) places eggplant-shape bottle, and 125 ℃ of heating 24 hours, the reaction back that finishes adds the cancellation of 52ml frozen water, adds 50% NaOH solution 3.2g again, stirs 5min, with CH 2Cl 250ml*3 extraction, organic layer respectively frozen water with 50ml*2 wash, 50 ml*2 of saturated aqueous common salt wash anhydrous MgSO 4Drying gets 4-(1,2-benzisothiazole-3-yl)-1-piperazine.
C) preparation 7-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
With 7-(4-chlorine butoxy)-3, and 4-dihydro-2 (1H)-quinolinone (297mg, 1mmol), 4-(1,2-benzisothiazole-3-yl)-and the 1-piperidines (242mg, 1.1mmol), (414mg 3.3mmol) joins 10ml to the Anhydrous potassium carbonate powder, back flow reaction 24h, the evaporate to dryness reaction solution distributes with methylene dichloride and each 20ml of water, organic layer is successively with water 20ml*2, saturated aqueous common salt 20ml extraction, anhydrous magnesium sulfate drying, evaporate to dryness gets buff powder, dissolve with acetone 5ml, put in the ice bath and stir, separate out white solid, filter, the small amount of ethanol dissolving, HCl/EtOH transfers PH=2, separates out white precipitate, leaches, get product 260mg, yield 59%.
Ultimate analysis: C 24H 28N 4O 2(theoretical value %:C 66.03, and H 6.46, and N 12.80 for S2HCl; Experimental value %C 66.10, H 6.40, and N 12.70
1HNMR (DMSO-d 6): δ 9.98 (s, 1H, CONH), 8.13-6.45, (7H, aromatic ring-H), 4.05-4.10 (2H, piperazine-H), 3.95 (t, J=6.4HZ, 2H, O-CH2,) 3.59-3.62 (2H, piperazine-H), 3.20-3.50 (m, 6H), 2.78 (t, J=8HZ, 2H) 2.41 (t, J=8HZ, 2H) 1.73-1.93 (m, 4H)
MS：437[M+H] +
Embodiment 25
III-27-[3-(1, the 2-benzisothiazole)-1-piperazinyl)--positive propoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
With 1-bromo-3-chloro-propane is raw material, makes target product according to example 23 methods
Ultimate analysis: C 23H 26N 4O 2(theoretical value %:C 55.75, and H 5.70, and N 11.31 for S2HCl; Experimental value %C 55.69, H 5.81, and N 11.30
1HNMR (DMSO-d 6): δ 10.02 (s, 1H, CONH), 8.05-6.50, (7H, aromatic ring-H), 4.07-4.12 (2H, piperazine-H), 3.95 (t, J=6.4HZ, 2H, O-CH2,) 3.62-3.66 (2H, piperidines-H), 3.15-3.47 (m, 6H), 2.80 (t, J=8HZ, 2H), 2.47 (t, J=8HZ, 2H) 1.89-2.15 (m, 2H)
MS：m/z 423[M+H] +
Embodiment 26
III-37-[2-(1, the 2-benzisothiazole)-1-piperazinyl)--oxyethyl group]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
With 1-bromo-2-chloro-ethane is raw material, makes target product according to example 23 methods
Ultimate analysis: C 22H 24N 4O 2(theoretical value %:C 54.88, and H 5.44, and N 11.64 for S2HCl; Experimental value %C 54.87, H 5.40, and N 11.60
1HNMR (DMSO-d 6): δ 10.02 (s, 1H, CONH), 8.01-6.50, (7H, aromatic ring-H), 4.12-4.18 (2H, piperazine-H), 3.99 (t, J=6.4HZ, 2H, O-CH2) 3.69-3.78 (2H, piperidines-H), 3.25-3.57 (m, 6H), 2.74 (t, J=8HZ, 2H), 2.68 (t, J=8HZ, 2H)
MS：m/z 409[M+H] +
Embodiment 27
III-47-[4-(6-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 6-methoxyl group-1, the 2-benzisothiazole)-the 1-piperazine
With reference to the preparation of J.Med.Chem.1991.34.3316-3328 method, yield 20%
B) 7-[4-(6-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
Make 7-[4-(6-methoxyl group-1,2-benzisothiazole)-1-piperazinyl according to g step operation among the embodiment 1)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride, yield 40%
Ultimate analysis: C 25H 30N 4O 3(theoretical value %:C 55.65, and H 5.98, and N 10.38 for S2HCl; Experimental value %C 55.60, H 5.95, and N 10.30.
1HNMR (DMSO-d 6): δ 10.01 (s, 1H, CONH), 8.21-6.56, (6H, aromatic ring-H), 4.08-4.15 (2H, piperazine-H), 3.79 (m, 5H, O-CH2) 3.52-3.60 (2H, piperazine-H), 3.16-3.48 (m, 6H), 2.79 (t, J=8HZ, 2H), 2.47 (t, J=8HZ, 2H) 1.82-2.01 (m, 4H)
MS：m/z 466
Embodiment 28
III-57-[4-(7-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride:
A) preparation 7-methoxyl group-1, the 2-benzisothiazole)-the 1-piperazine
With reference to the preparation of J.Med.Chem.1991.34.3316-3328 method, yield 20%
B) 7-[4-(7-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
Make 7-[4-(7-methoxyl group-1,2-benzisothiazole)-1-piperazinyl according to g step operation among the embodiment 1)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride, yield 40%
Ultimate analysis: C 25H 30N 4O 3(theoretical value %:C 55.65, and H 5.98, and N 10.38 for S2HCl; Experimental value %C 55.62, H 5.75, and N 10.37.
1HNMR (DMSO-d 6): δ 10.05 (s, 1H, CONH), 8.16-6.50, (6H, aromatic ring-H), 4.10-4.18 (2H, piperazine-H), 3.89 (m, 5H, O-CH2) 3.51-3.60 (2H, piperazine-H), 3.22-3.48 (m, 6H), 2.76 (t, J=8HZ, 2H), 2.44 (t, J=8HZ, 2H) 1.72-1.96 (m, 4H)
MS：m/z 466
Embodiment 29
III-67-[4-(5-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 5-methoxyl group-1, the 2-benzisothiazole)-the 1-piperazine
With reference to the preparation of J.Med.Chem.1991.34.3316-3328 method, yield 20%
B) 7-[4-(5-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
Make 7-[4-(5-methoxyl group-1,2-benzisothiazole)-1-piperazinyl according to g step operation among the embodiment 1)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride, yield 39%
Ultimate analysis: C 25H 30N 4O 3(theoretical value %:C 55.65, and H 5.98, and N 10.38 for S2HCl; Experimental value %C 55.62, H 5.75, and N 10.37.
1HNMR (DMSO-d 6): δ 10.00 (s, 1H, CONH), 8.17-6.39 (6H, aromatic ring-H), 4.12-4.18 (2H, piperazine-H), 3.91 (m, 5H, O-CH2) 3.54-3.60 (2H, piperazine-H), 3.18-3.47 (m, 6H), 2.69 (t, J=8HZ, 2H), 2.45 (t, J=8HZ, 2H) 1.79-1.98 (m, 4H)
MS：m/z 466
Embodiment 30
III-77-[4-(4-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 4-methoxyl group-1, the 2-benzisothiazole)-the 1-piperazine
With reference to the preparation of J.Med.Chem.1991.34.3316-3328 method, yield 20%
B) preparation 7-[4-(4-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
Make 7-[4-(4-methoxyl group-1,2-benzisothiazole)-1-piperazinyl according to g step operation among the embodiment 1)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride, yield 39%
Ultimate analysis: C 25H 30N 4O 3(theoretical value %:C 55.65, and H 5.98, and N 10.38 for S2HCl; Experimental value %C 55.63, H 5.71, and N 10.36.
1HNMR (DMSO-d 6): δ 10.02 (s, 1H, CONH), 8.14-6.49, (6H, aromatic ring-H), 4.10-4.16 (2H, piperazine-H), 3.87 (m, 5H, O-CH2) 3.60-3.68 (2H, piperazine-H), 3.19-3.54 (m, 6H), 2.75 (t, J=8HZ, 2H), 2.42 (t, J=8HZ, 2H) 1.71-1.80 (m, 4H)
MS：m/z 466
Embodiment 31
IV-17-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 7-[4-(2-methyl-4-tertbutyloxycarbonyl-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
With 7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone and 2-methyl-4-tert-butoxycarbonyl-piperazine are raw material, make target product according to the g step reaction among the embodiment 1, yield 72.4%
B) preparation 7-[4-(2-methyl-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrobromate
With 7-[4-(2-methyl-4-tertbutyloxycarbonyl-piperazinyl)-n-butoxy]-3, (4.17g 10mmol) adds among the 30%HBr aqueous solution 100ml 4-dihydro-2 (1H)-quinolinone, 60 ℃ were stirred 3 hours, put coldly, separated out yellow mercury oxide, the dehydrated alcohol recrystallization gets product 3.5g, yield 73%
C) preparation 7-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-3, the preparation of 4-dihydro-2 (1H)-quinolinone hydrochloride
With free 7-[4-(2-methyl-4-tertbutyloxycarbonyl-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone (470mg, 1mmol) with 3-chlorobenzene and isothiazole (170mg, 1mmol) the 1200c frit reaction is 12 hours, and reaction is put after finishing cold, adds 1NHCl solution 50ml, anhydrous diethyl ether 30ml*3 extraction, water layer transfers to ph=8 with 5NNaOH, methylene dichloride 30ml*3 extraction, and extraction liquid is washed successively, the saturated common salt washing, anhydrous MgSO4 drying, get yellow powder, the small amount of ethanol dissolving, HCl/EtOH transfers ph=2, separates out white precipitate, leach, the dehydrated alcohol recrystallization gets product 300mg, yield 57%.
Ultimate analysis: C 25H 30N 4O 2(theoretical value %:C 57.36, and H 6.16, and N 10.70 for S2HCl; Experimental value %C57.335.63, H 6.20, and N 10.78.
1HNMR (DMSO-d 6): δ 9.96 (s, 1H, CONH), 8.20-6.48, (7H, aromatic ring-H), 4.05-4.10 (2H, piperazine-H), 3.95 (t, J=6.4HZ, 2H, O-CH2,) 3.59-3.62 (1H, piperazine-H), 3.20-3.50 (m, 6H), 2.78 (t, J=8HZ, 2H) 2.41 (t, J=8HZ, 2H) 1.73-1.93 (m, 7H)
MS：m/z 450。
Embodiment 32
IV-27-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy] preparation of-2 (1H)-quinolinone hydrochlorides
Make 7-(4-chloro-n-butoxy)-2 (1H)-quinolinones with reference to the CN1839134 method, and make target product according to embodiment 30 methods.
Ultimate analysis: C 25HN 4O 2(theoretical value %:C 57.58, and H 5.80, and N 10.74 for S2HCl; Experimental value %C 57.50, H5.83, N 10.71.
1HNMR (DMSO-d 6): δ 10.02 (s, 1H, CONH), 8.34-6.40, (9H, aromatic ring-H, two keys-H), 4.05-4.10 (2H, piperazine-H), 3.95 (t, J=6.4HZ, 2H, O-CH2) and 3.59-3.62 (1H, piperazine-H), 3.20-3.50 (m, 2H), 2.78 (t, J=8HZ, 2H) 2.41 (t, J=8HZ, 2H) 1.73-1.93 (m, 7H)
MS：m/z 448
Embodiment 33
IV-37-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy] preparation of-2 (1H)-3-toluquinoline keto hydrochlorides
Make 7-(4-chloro-n-butoxy)-2 (1H)-3-toluquinoline ketone with reference to the CN1839134 method, and make target product according to embodiment 30 methods.
Ultimate analysis: C 26H 30N 4O 2(theoretical value %:C 67.50, and H 6.54, and N 12.11 for S2HCl; Experimental value %C 67.55, H 6.52, and N 12.08.
1HNMR (DMSO-d 6): δ 10.02 (s, 1H, CONH), 7.97-6.45, (9H, aromatic ring-H, two keys-H), 4.12-4.18 (2H, piperazine-H), 3.99 (t, J=6.4HZ, 2H, O-CH2) and 3.59-3.62 (1H, piperazine-H), 3.16-3.47 (m, 2H), 2.75 (t, J=8HZ, 2H), 2.50 (t, J=8HZ, 2H) 1.85-1.99 (m, 9H)
MS：m/z 462
Embodiment 34
IV-47-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy] preparation of-2 (1H)-4-toluquinoline keto hydrochlorides
Make 7-(4-chloro-n-butoxy)-2 (1H)-4 toluquinoline ketone with reference to the CN1839134 method, and make target product according to embodiment 30 methods.
Ultimate analysis: C 26H 30N 4O 2(theoretical value %:C 67.50, and H 6.54, and N 12.11 for S2HCl; Experimental value %C 67.51, H 6.51, and N 12.08.
1HNMR (DMSO-d 6): δ 10.01 (s, 1H, CONH), 7.96-6.45, (9H, aromatic ring-H, two keys-H), 4.10-4.20 (2H, piperazine-H), 3.96 (t, J=6.4HZ, 2H, O-CH2) and 3.49-3.58 (1H, piperazine-H), 3.16-3.47 (m, 2H), 2.8 (3t, J=8HZ, 2H), 2.50 (t, J=8HZ, 2H) 1.81-1.93 (m, 9H)
MS：m/z 462
Embodiment 35
V-17-[4-(4 (6-fluoro-benzisoxa oxazoles)-5,6-dihydro piperazinyl)--n-butoxy]-preparation of 3-4-dihydro-2 (1H)-quinolinone hydrochloride
A) preparation 7-(4-bromine butoxy)-3,4-dihydro-2 (1H)-quinolinone
With 7-hydroxyl-3, (16.3g 0.1mol) joins 1 to 4-dihydro-2 (1H) quinolinone, in the mixing solutions of 4-dibromobutane 10ml and 40ml acetone, add K2CO313.8g, 40 ℃ were reacted 10 hours, stopped reaction, add 50ml water and 50ml normal hexane, stir, a large amount of white precipitates occur, leach, a small amount of normal hexane washing gets product 20.5g, yield 69%.
B) preparation 2,4 difluorobenzene base-4-pyridyl-methane ketone
With sulfur oxychloride (219ml, 3mol) slowly be added drop-wise to pyridine-4-formic acid (246.2, among dichloromethane solution 500ml 2mol), back flow reaction 4 hours, boil off the excess chlorination sulfoxide, add 1,3-two fluorobenzene (392ml, 4mol) with the 533g aluminum trichloride (anhydrous), back flow reaction 5 hours is poured reaction solution in the 3kg mixture of ice and water into after reaction finishes, and stirs 0.5 hour, the 200ml washed with dichloromethane, free with 40%NaOH solution 500ml, methylene dichloride 100ml*3 extraction, extraction liquid merges, washing successively, the saturated common salt washing, anhydrous magnesium sulfate drying gets product 178g.Yield 41%.
C) preparation 2,4 difluorobenzene base-4-pyridyl-methane ketoxime
133.6g yellow soda ash and 62.9 gram oxammonium hydrochlorides are joined 178g2, in the ethanol liquid of 4-difluorophenyl-4-pyridyl-methane ketone, back flow reaction 1 hour, the reaction solution evaporate to dryness adds 500ml water, stirs, and precipitation leaches, and oven dry gets product 181g, yield 94%.
D) preparation 6-fluoro-3-pyridyl-benzisoxa oxazole
With 181 grams 2,4-difluorophenyl-4-pyridyl-methane ketoxime join be suspended with NaH (19g, 50%oil is among tetrahydrofuran (THF) 500ml 0.4mol), stirring at room 10 hours, reaction solution is poured in the 500ml mixture of ice and water, ethyl acetate 50ml*3 extraction, and extraction liquid merges, washing successively, saturated common salt washing, anhydrous magnesium sulfate drying, recrystallizing methanol gets 6-fluoro-3-pyridyl-benzisoxa oxazole 53g, yield 32g.
E) preparation 7-[4-(4-benzisothiazole)-5,6-dihydro piperidines piperazine base)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone hydrochloride
Under the ice bath to 6-fluoro-3-pyridyl-benzisoxa oxazole (2.14g, drip 7-(4-bromine butoxy)-3 among acetonitrile solution 30ml 10mmol), 4-dihydro-2 (1H)-quinolinone (2.97g, 10mmol) acetonitrile 20ml solution drips off back back flow reaction 1 hour, and the reaction solution evaporate to dryness gets yellow solid, add methyl alcohol 50ml, ice bath slowly adds NaBH4 powder 2g down, adds the back and continues room temperature reaction 1 hour, slowly drips 10% citric acid solution 100ml, evaporate to dryness, add methylene dichloride and each 50ml of water, tell organic phase, water layer continues to extract with methylene dichloride 20ml*2, wash i successively, the saturated common salt washing, anhydrous magnesium sulfate drying, get buff powder, it is dissolved in small amount of ethanol, dripping hydrochloric acid ethanol is to ph=2, separate out white precipitate, leach, get product 3.23g, yield 59.7%.
Ultimate analysis: C 25H 26N 3O 3(theoretical value %:C 63.62, and H 5.77, and N 8.90 for FHCl; Experimental value %C 63.69, H5.70, N 8.90.
1HNMR(DMSO-d 6)：δ9.87(B，1H，CONH)
8.08-6.40 (6H, aromatic ring-H)
5.95 (m, 1H, two keys-H)
3.89(t，J＝6.4HZ，2H，O-CH 2)
3.14 (m, 2H, piperidines-H)
1.40-2.95(14H，-CH 2)
MS：m/z 435
Embodiment 36
V-27-[4-(4-(benzisothiazole)-5,6-dihydro piperidyl)--n-butoxy]-preparation of 3-4-dihydro-2 (1H)-quinolinone hydrochloride
With the fluorobenzene is raw material, makes target product according to embodiment 34 methods.
Ultimate analysis: C 25H 27N 3O 28(theoretical value %:C 69.26, and H 6.18, and N 9.69 for HCl; Experimental value %C 69.36, H6.15, N 9.67.
1HNMR(DMSO-d 6)：δ10.01(B，1H，CONH)
8.15-6.38 (7H, aromatic ring-H)
5.73 (m, 1H, two keys-H)
3.82(t，J＝6.4HZ，2H，O-CH 2)
3.17 (m, 2H, piperidines-H)
1.50-2.89(14H，-CH 2)
MS：m/z 433
Embodiment 37
VI-17-[4-(4-(s, s-dioxy-1,2 benzisothiazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
(4-(1 with 7-[4-, the 2-benzisothiazole)-the 1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone (4.36g, 10mmol) be dissolved in the 50ml methylene dichloride, slowly add metachloroperbenzoic acid (1.80g, 10mmol), added the back stirring at room 10 hours, wash with 10% sodium hydrogen carbonate solution 50ml*3 successively, washing, saturated common salt washing, anhydrous magnesium sulfate drying, get buff powder, it is dissolved in a small amount of dehydrated alcohol, dripping hydrochloric acid ethanol is to ph=2, separate out white precipitate, leach, get product 2.31g, yield 42.5%.
Ultimate analysis: C 24H 28N 4O 4(theoretical value %:C 53.23, and H 5.28, and N 10.35 for S2HCl; Experimental value %C 53.20, H 5.25, and N 10.32.
1HNMR (DMSO-d 6): δ 10.05 (s, 1H, CONH), 8.35-6.56, (7H, aromatic ring-H), 4.12-4.18 (2H, piperazine-H), 3.87 (t, J=6.4HZ, 2H, O-CH2) 3.60-3.68 (2H, piperazine-H), 3.15-3.47 (m, 6H), 2.73 (t, J=8HZ, 2H), 2.46 (t, J=8HZ, 2H) 1.78-2.11(m，4H)
MS：m/z 468
Embodiment 38
VI-27-[3-(4-(s, s-dioxy-1,2 benzisothiazole)-1-piperazinyl)-positive propoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
(4-(1 with 7-[3-, the 2-benzisothiazole)-the 1-piperazinyl)--positive propoxy]-3,4-dihydro-2 (1H)-quinolinone (4.36g, 10mmol) be dissolved in the 50ml methylene dichloride, slowly add metachloroperbenzoic acid (1.80g, 10mmol), added the back stirring at room 10 hours, wash with 10% sodium hydrogen carbonate solution 50ml*3 successively, washing, saturated common salt washing, anhydrous magnesium sulfate drying, get buff powder, it is dissolved in a small amount of dehydrated alcohol, dripping hydrochloric acid ethanol is to ph=2, separate out white precipitate, leach, get product 2.31g, yield 42.5%.
Ultimate analysis: C 23H 26N 4O 4(theoretical value %:C 52.37, and H 5.35, and N 10.62 for S2HCl; Experimental value %C 53.20, H 5.25, and N 10.32.
1HNMR (DMSO-d 6): δ 10.07 (s, 1H, CONH), 8.38-6.67, (7H, aromatic ring-H), 4.16-4.22 (2H, piperazine-H), 3.89 (t, J=6.4HZ, 2H, O-CH2,) 3.61-3.72 (2H, piperazine-H), 3.11-3.45 (m, 6H), 2.67 (t, J=8HZ, 2H), 2.52 (t, J=8HZ, 2H) 1.61-2.12.(m，2H)
MS：m/z 454。
Embodiment 39
VII-17-[4-(4-(6-fluoro-benzisoxa oxazole)-2,5-lupetazin base)--n-butoxy]-preparation of 3-4-dihydro-2 (1H)-quinolinone hydrochloride
With 4-fluoro-Whitfield's ointment, 2, the 5-lupetazin is a starting raw material, press the I-1 method synthetic target product
Ultimate analysis: C 26H 31N 4O 3(theoretical value %:C 57.89, and H 6.17, and N 10.39 for F2HCl; Experimental value %C 57.88, H 6.19, and N 10.32.
1HNMR (DMSO-d 6): δ 10.03 (s, 1H, CONH), 8.19-6.50, (6H, aromatic ring-H), 4.11-4.23 (2H, piperazine-H), 3.87 (t, J=6.4HZ, 2H, O-CH2,) 3.61-3.68 (2H, piperazine-H), 3.14-3.49 (m, 4H), 2.83 (t, J=8HZ, 2H), 2.44 (t, J=8HZ, 2H) 1.89-2.10 (m, 10H)
MS：m/z 466
Embodiment 40
VII-27-[4-(4-benzisothiazole)-2,5-lupetazin base)--n-butoxy]-preparation of 3-4-dihydro-2 (1H)-quinolinone hydrochloride
With 3-chlorobenzene and isothiazole, 2, the 5-lupetazin is a raw material, makes target product by embodiment 1 step e, f, g
Ultimate analysis: C 26H 32N 4O 2(theoretical value %:C 58.09, and H 6.38, and N 10.42 for S2HCl; Experimental value %C 58.00, H 6.35, and N 10.45.
1HNMR (DMSO-d 6): δ 10.10 (s, 1H, CONH), 8.21-6.62 (7H, aromatic ring-H), 4.14-4.25 (2H, piperazine-H), 3.98 (t, J=6.4HZ, 2H, O-CH2) 3.51-3.60 (2H, piperazine-H), 3.17-3.55 (m, 4H), 2.89 (t, J=8HZ, 2H), 2.50 (t, J=8HZ, 2H), and 1.78-1.99 (m, 10H)
MS：m/z 464
Embodiment 41
Tablet: derivative 25mg of the present invention
Sucrose 155mg
W-Gum 65mg
Magnesium Stearate 5mg
The preparation method: activeconstituents is mixed with sucrose, W-Gum, and it is moistening to add water, stirs, and drying, crushing screening adds Magnesium Stearate, mixes compressing tablet.Every heavy 250mg, active component content is 25mg.
Embodiment 42
Injection: derivative 10mg of the present invention
Water for injection 90mg
The preparation method: activeconstituents is dissolved in water for injection, mixes, filter, the solution that is obtained is sub-packed in the ampoule under aseptic condition, every bottle of 10mg, active component content are the 1mg/ bottle.
Embodiment 43
D2 dopamine receptor is in conjunction with test
Experiment material:
D2 acceptor isotropic substance aglucon [3H] Spiperone (77.0Ci/mmol); (+) Butaclamol; The GF/C glass fiber filter paper; Fat-soluble scintillation solution; The D2 receptor protein of sf9 cell expressing.
Experimental technique
Containing 100mMNaCl, 1mM MgCl 2With carry out in the 50mMTris-Hcl damping fluid of the 250 μ M1 of the Ph=7.4 of 1%DMSO ( 3H] the grand and CHO-hD of spiral shell group 2LThe combination test of the membrane product of cell.At room temperature will contain testing compound, 0.4nM ( 3H] spiral shell group swells and the proteinic bipartite sample of about 12ug is incubated 120 minutes.Under reduced pressure carry out quick filtering separation bonded radioligand, by the radioactivity that keeps on the liquid scintillation spectrophotometry filter by the Whatman GF/B glass fibre filter of handling with 0.3% polymine in advance.Use the hereinafter title compound among the embodiment of above-mentioned experimental test, at first the competition inhibiting rate of each compound 10umol/L concentration to [3H] Spiperone and D2R receptors bind measured in scalping; Inhibiting rate is higher than the receptor binding assays that 95% compound carries out a series of concentration, determines half amount of suppression (IC50 suppresses 50%[3H] Spiperone and D2 receptors bind required compound concentration).Every concentration determination two looped pipelines, each compound carries out independent experiment twice.Test-results shows that under 10uM all compounds embody occupation rate more than 95%, the IC that all different compounds show to the D2 acceptor 50Value all less than or etc. the 500nM (table 1 that vide infra.The KIC that the preferred embodiment of The compounds of this invention preferably shows 50Value is not more than 100nM, more preferably no more than 50nM, even more preferably no more than 25nM, most preferably is not more than 10Nm.
Table 2 related compound is to the D2 receptor affinity
Numbering IC 50 (nM) Numbering IC 50 (nM) Numbering IC 50 (nM) Numbering IC 50 (nM)
I-1 25.7 I-11 77.8 II-9 78.8 VI-2 Do not survey
I-2 56.8 I-12 10.2 II-10 45.6 VI-3 12.3
I-3 99.3 II-1 5.66 III-1 5.23 VI-4 15.3
I-4 10.2 II-2 16.2 III-2 76.8 V-1 58.2
I-5 53.6 II-3 202 III-3 Do not survey V-2 77.4
I-6 Do not survey II-4 23.6 III-4 17.9 VI-1 Do not survey
I-7 289.6 II-5 15.8 III-5 15.8 VI-2 Do not survey
I-8 156.8 II-6 277 III-6 15.0 VII-1 Do not survey
I-9 25.0 II-7 12.6 III-7 168.3 VII-2 Do not survey
I-10 Do not survey II-8 23.8 VI-1 38.9
Embodiment 44
The test of D2 receptor antagonism
One, experiment material:
The Chinese hamster ovary celI of stably express rD2R; Forskolin, IBMX, Dopamine, Haloperidol are available from Sigma; All the other reagent are available from Shanghai chemical reagents corporation of traditional Chinese medicines group.
Two, experimental technique:
The CHO-rD2 cell is inoculated in 96 orifice plates, overnight incubation with 30000/hole; Each medicine dissolution adds in the cell in 37 ℃ of preincubate 30min in the serum-free F12 training liquid that contains 100 μ MIBMX; Add the serum-free F12 training liquid reaction 8min that contains 10 μ M Forskolin and 10 μ M Dopamine, add the 1M HClO of 100 μ l precoolings 4Termination reaction is put ice 40min, adds 20 μ l 2M K 2CO 3Neutralization reaction liquid, 4 ℃ of centrifugal 15min of 3000rpm abandon KClO 4Precipitation is got a certain amount of supernatant and is diluted in the 0.05M acetate buffer solution, measures the cAMP growing amount with radioimmunoassay.[ 125I] the cAMP radioimmunological kit is available from Shanghai Univ. of Traditional Chinese Medicine nuclear medicine experimental center, and concrete steps can be referring to its specification sheets.Every concentration determination two looped pipelines of each compound, each compound carries out twice independent experiment at least.Test-results is seen Fig. 1～Fig. 4.Among Fig. 1, Haloperidol is a haloperidol.
The ordinate zou of amount effect curve represents that compound antagonism DA reduces the per-cent of cAMP growing amount.
Table 2 part of compounds antagonistic action result
Numbering EC50(μM)
Haloperidol 0.346
II-1 56.4
III-1 3.38
IV-l 1.98
Embodiment 45
Be used for the inherent agonist activity of D2 [ 3H] adenosine uptake examination face
Experimental technique
Remove serum deprivation by the substratum washed twice pair cell that uses 200 μ l not contain serum, the substratum that 90 μ l is not contained serum joins in each hole. flat board is incubated 2-3 hour.To join in each hole as substratum, carrier (substratum that does not contain serum), negative control (antagonist) or the test compounds in the substratum that does not contain serum and the standard substance (final concentration is the 10uM solution of the 10 μ l of 1uM) that 10 μ of positive control contain serum. flat board is turned back in the insulation can.After 18 hours, add [ 3H] adenosine (0.5 μ Ci/ hole) do not contain in the substratum of serum at 10 μ l, and flat board turned back in the insulation can.After 4 hours, add trypsin 0.25%) (100 μ l/ hole).Flat board is turned back in the insulation can.After 1 hour, by filtering termination test fast through Whatman GF/B glass fibre filter.For example use Brandel MLR-96T cell harvestor, with 500ml 50mM Tris-HCIpH7.0 damping fluid washing nozzle.For example, use the radioactivity (50% significant quantity) of the reservation on the Wallac 1205Betaplate liquid scintillation counter assessment filter.Intrinsic activity is defined as total intake (1 μ M Kui pyrrole sieve) deducts the substratum that does not contain serum, test compounds and 1 μ M Kui pyrrole sieve that is categorized as 100% intrinsic activity (DA agonist fully) are compared.All tests are all preferably according to carrying out in triplicate, and wherein every kind of medicine accounts for complete row in each flat board.Compound of the present invention preferably shows the intrinsic activity of 1%-90% at least, the more preferably activity of 10%-90% at least, the more preferably activity of 10%-80% at least, the more preferably intrinsic activity of 20%-60%, more preferably at least 30% one 50% intrinsic activity at least.Test-results is seen Fig. 5.
Embodiment 46
Anti-schizophrenia activity test in the Compound I I-1 body
Test materials
1. the preparation of reagent and solution and dosage
Apomorphine: Apomorphine is dissolved in 0.1% the xitix, is made into the solution of 10mg/kg dosage.
Aripiprazole is dissolved in the physiological saline, is made into the solution of 5mg/kg dosage, ultrasonicly makes dissolving.
Risperidone is dissolved in the physiological saline, is made into the solution of 0.25mg/kg dosage.
Compound I I-1 is made into 20mg/kg, and is now with the current.
2. experimental animal and grouping
Female KM mouse, 18-22g. when test mouse are divided into solvent control group, model control group, positive controls at random, and respectively are subjected to the reagent group.Behavior observation is tested every group of 5 mouse.Movable observing is tested every group of 4 mouse.
3. test method
3.1 mouse administration: irritate stomach by 0.1ml/10g respectively for the group mouse and give respectively to be subjected to reagent.
3.2 mouse modeling: giving to be subjected to after the reagent 30 minutes, is the Apomorphine solution of 10mg/kg with concentration, carries out abdominal injection with 0.1ml/10g mouse body weight respectively.
After 3.3 stereotypic behavior observation mouse gives Apomorphine, whether mouse perpendicular tail occurs, smells, gnaws, jumps, climbs stereotypic behaviors such as wall, new line in observed and recorded preceding 30 seconds in the time of the 5th, 10,15,20,25,30 minutes respectively, and mark by following standard: 0 grade, no above-mentioned behavior appearance in 30 seconds that observe; 1 grade, the appearance of the above-mentioned behavior of discontinuous moderate in 30 seconds that observe; 2 groups, the appearance of the above-mentioned behavior that successive is strong in 30 seconds that observe.
4. the processing of test-results
Statistics is respectively organized the stereotyped movement number of 6 time point accumulative totals of mouse, calculates the mean value of every mouse, and its result represents with mean ± SD.
5 statistical methods
The stereotypic behavior test-results adopts the LSD method to add up; The movable number of times of mouse is observed and is adopted the variance analysis and the Q-test of replicate measurement to add up.
6, stereotyped movement behavior observation experimental result (seeing Fig. 6 and Fig. 7), among Fig. 6,1 is model group, and 2 is the risperidone group, and 3 is group of solvents, and 4 is A Li piperazine azoles group, 5 are Compound I I-1 group.
This test-results shows: compare with model group, risperidone, A Li piperazine azoles, Compound I I-1 can obviously reduce each time point stereotyped movement number and the accumulative total stereotyped movement number of mouse, show that it has tangible antipsychotic effect.
Embodiment 47
The studies on acute toxicity of II-1:
With Bliss method statistics, the mouse single gavages the LD of II-1 50Greater than 2000mg/kg, suitable with Aripiprazole (1400mg/kg) and Ziprasidone (1600mg/kg), well below risperidone (83.2mg/kg), have less acute toxicity.
Embodiment 48
The Ames test of II-1
Bacterial classification: mouse Salmonellas Histidine nutrient defect mutation strain TA 97, TA 98, TA 100And TA 102
The result: experiment comprises-S 9With+S 9Two parts are at no S 9TA in the test macro 98With add S 9TA in the test macro 975000 μ g/ wares have bacteriostatic action.Other dosage does not all have bacteriostatic action to all bacterial strains, and the growth background is good.No matter all proof loads are at no S 9Or add S 9In the experimental system, do not cause that all any bacterium colony returns parameter and obviously increases, the Salmonella reversion test feminine gender.
The above results shows that II-1 has antischizophrenic effect, and oral absorption is better.The Salmonella reversion test feminine gender has less acute toxicity, possesses the potential value as the research and development of class novel anti spirit sacred disease.

Claims (15)

1. aralkyl piperidines (piperazine) derivative, for having the compound shown in general structure (1) and the free alkali or the salt of this compound:
Figure A2007100405450002C1
Wherein:
A is-(CH 2) n-,-(CH 2) nO-or-(CH 2) nNH-, n are the integer of 2--5, wherein-and (CH 2) n-,-(CH 2) nO-and-(CH 2) nTwo substituting groups replacements that one of the carbon of NH-or nitrogen-atoms or two can choose wantonly and be replaced or is connected with same carbon atom by one or two substituting group that is independently selected from fluorine and methyl independently, these two substituting groups can also form Spirocyclopropyl or volution butyl ring with the carbon that they connected;
Z is N, CH or C; Condition is when Z is N, and each is connected by singly-bound with the covalently bound carbon atom of Z;
P is O, S, SO or SO 2
Q is N, C or CH;
Be--CH=CH--,--CH 2-CH 2-,--CH 2-NH--,--NH-CH 2--,--N=CH--,--CH=N--,--O-CH 2--or--CH 2-O--wherein
Figure A2007100405450002C3
Can on any available binding site, choose wantonly by 1--4 substituent R 2, R 2', R 3And R 3' replace;
R 1Be H or OH;
R 2, R 2',, R 3And R 3' be independently selected from hydrogen, halogen, cyano group, oxo, hydroxyl,--C (=O) CH 3, (C 1--C 4) alkyl and (C 1--C 4) alkoxyl group, wherein (C 1--C 4) alkyl, (C 1--C 4) alkoxyl group and-C (=O) CH 3The moieties of group can be chosen wantonly by 1--3 fluorine atom replacement and can also choose wantonly by amino or hydroxyl substituent and replace;
R 4, R 5Be independently selected from hydrogen, halogen, cyano group, oxo, hydroxyl,--C (=O) CH 3, (C 1--C 4) alkyl and (C 1--C 4) alkoxyl group, wherein (C 1--C 4) alkyl, (C 1--C 4) alkoxyl group and-C (=O) CH 3The moieties of group can be chosen wantonly by 1--3 fluorine atom replacement and can also choose wantonly by amino or hydroxyl substituent and replace;
R 6, R 7Select hydrogen and methyl independently;
R 8, R 9Be independently selected from hydrogen, halogen, cyano group, oxo, hydroxyl ,-C (=O) CH 3, (C 1-C 4) alkyl and (C 1-C 4) alkoxyl group, wherein (C 1-C 4) alkyl, (C 1-C 4) alkoxyl group and-C (=O) CH 3The moieties of group can be chosen wantonly by 1--3 fluorine atom replacement and can also choose wantonly by amino or hydroxyl substituent and replace.
2. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that, Z is that CH, Q are C, and P is O.
3. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that, Z is that N, Q are C, and P is S or SO 2
4. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that Z is C, and Q is C, and P is O, and adjacent carbons links to each other with two keys on Z and the b ring.
5. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that Z is N, R 6Or R 7Be methyl.
6. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that Z is N, R 6And R 7Be methyl.
7. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that Z is N, and Q is N,
Figure A2007100405450003C1
For-CH 2-CH 2-or-CH=CH-, and R1, R4 and R5 are hydrogen.
8. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that Z is N, and Q is N,
Figure A2007100405450003C2
For-C (CH 3)=CH-, R 6, R 7Be hydrogen.
9. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that, described salt is for containing pharmaceutically acceptable anionic salt.
10. aralkyl piperidines according to claim 9 (piperazine) derivative is characterized in that said salt is hydrochloride or hydrogen bromide salt.
11. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that said salt contains the crystal water of 0.5-3 molecule.
12. aralkyl piperidines according to claim 1 (piperazine) derivative is characterized in that, described aralkyl piperidines (piperazine) derivative is:
I-1 7-[4-(4-(6-chloro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-2 7-[4-(4-(5-chloro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-3 7-[4-(4-(benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-4 7-[4-(4-(6-fluoro-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-5 7-[4-(4-(6-trifluoromethyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-6 7-[4-(4-(6-methyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-7 7-[4-(4-(5-methyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-8 7-[4-(4-(6-hydroxyl-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-9 7-[4-(4-(5-methoxyl group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-10 7-[4-(4-(5-cyano group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-11 7-[4-(4-(5-bromo-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
I-12 7-[4-(4-(7-bromo-6-methoxyl group-benzisoxa oxazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-1 7-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-2 7-[3-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-positive propoxy]-3,4-dihydro-2 (1H)-quinolinone
II-3 7-[2-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone
II-4 7-[2-(4-benzisoxa oxazole-piperidino)-oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone
II-5 7-[4-(4-(6-chloro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-6 7-[4-(4-(5-methoxyl group-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-7 7-[4-(4-(5-fluoro-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-8 7-[4-(4-(5,6-dimethoxy-benzisoxa oxazole)-piperidino)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-9 7-[4-(5-hydroxyl-benzisoxa oxazole)-piperidino)-and n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-10 7-[4-(5,6-dihydroxyl-benzisoxa oxazole)-piperidino)-and n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
II-11 7-[4-(4-(6-fluoro-benzisoxa oxazole)-piperidino)-n-butylamine-based]-3,4-dihydro-2 (1H)-quinolinone
III-1 7-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-2 7-[3-(1, the 2-benzisothiazole)-1-piperazinyl)--positive propoxy]-3,4-dihydro-2 (1H)-quinolinone
III-3 7-[2-(1, the 2-benzisothiazole)-1-piperazinyl)--oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone
III-4 7-[4-(6-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-5 7-[4-(7-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-6 7-[4-(5-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
III-7 7-[4-(4-methoxyl group-1,2-benzisothiazole)-1-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
IV-1 7-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
IV-2 7-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-2 (1H)-quinolinones
IV-3 7-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-2 (1H)-3-toluquinoline ketone
IV-4 7-[4-(4-benzisothiazole)-2-methyl-piperazinyl)--n-butoxy]-2 (1H)-4-toluquinoline ketone
V-1 7-[4-(4 (6-fluoro-benzisothiazoles)-5,6-dihydro piperazinyl)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone
V-2 7-[4-(4 (6-fluoro-benzisothiazoles)-5,6-dihydro piperazinyl)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone
VI-1 7-[4-(4-(s, s-dioxy-1,2 benzisothiazole)-1-piperazinyl)-n-butoxy]-3,4-dihydro-2 (1H)-quinolinone
VI-2 7-[3-(4-(s, s-dioxy-1,2 benzisothiazole)-1-piperazinyl)-positive propoxy]-3,4-dihydro-2 (1H)-quinolinone
VII-1 7-[4-(4-(6-fluoro-benzisoxa oxazole)-2,5-lupetazin base)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone
VII-2 7-[4-(4-benzisothiazole)-2,5-lupetazin base)--n-butoxy]-3-4-dihydro-2 (1H)-quinolinone.
13. contain the pharmaceutical composition of each described aralkyl piperidines (piperazine) derivative of claim 1～12 for the treatment of significant quantity and medically acceptable carrier.
14. the application of each described aralkyl piperidines (piperazine) derivative of claim 1～12 in the neural spiritual class disease medicament of preparation treatment.
15. application according to claim 14 is characterized in that, the spiritual class disease of described nerve is a schizophrenia.
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CN105801511A (en) * 2016-04-22 2016-07-27 山西大学 Preparation method of 1,2-benzisothiazole-3-ketone
CN111518019A (en) * 2019-02-01 2020-08-11 江苏豪森药业集团有限公司 Preparation method of paliperidone palmitate intermediate
CN111518019B (en) * 2019-02-01 2023-10-24 江苏豪森药业集团有限公司 Preparation method of paliperidone palmitate intermediate

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