CN103242219A - 2,6-diketone-piperazine (piperidine) type derivative and application thereof - Google Patents
2,6-diketone-piperazine (piperidine) type derivative and application thereof Download PDFInfo
- Publication number
- CN103242219A CN103242219A CN2012100315568A CN201210031556A CN103242219A CN 103242219 A CN103242219 A CN 103242219A CN 2012100315568 A CN2012100315568 A CN 2012100315568A CN 201210031556 A CN201210031556 A CN 201210031556A CN 103242219 A CN103242219 A CN 103242219A
- Authority
- CN
- China
- Prior art keywords
- diketone
- piperidines
- piperazine
- compound
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
Abstract
The invention discloses a 2,6-diketone-piperazine (piperidine) type derivative and an application thereof. The derivative can be applied to preparation of medicines for preventing or treating central nervous system diseases. Animal experiment results show that the derivative has smaller ED50 and stronger action in MK-801-induced high activity and apomorphine-induced climbing animal models as well as has larger ED50 and larger therapeutic indexes in an animal catalepsy model. The derivative is a compound or salt thereof with a general formula (I).
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, be specifically related to a kind of new 2,6-diketone-piperazine (piperidines) their preparation method of analog derivative and the application in the spiritual sacred disease for the treatment of thereof.
Background technology
Schizophrenia is a kind of disease that is split into feature with cognitive power and the emotion degree of depth, shows as the most basic human behavior and is affected, for example language, thought, consciousness and self-perception etc.The scope that the symptom of this disease comprises is wider, and modal is the obstacle of spiritual aspect, such as hallucinate, paranoea and illusion etc.There is 1% people to suffer from schizophrenia in the global range approximately, and in the patient that all are received treatment, has only 5% finally can be returned to one's perfect health.Typical case's antipsychotics (as chlorpromazine, haloperidol) blocking-up d2 dopamine receptor causes comprising EPS (EPS) at serious blocking-up Dopamine Receptors, and tardive dyskinesia and prolactin secretion increase.In addition, typical anti-schizophrenia medicine is invalid to negative symptoms.
Being different from typical antipsychotics, is " atypia " antipsychotic drug of representative with leoponex and risperidone, and EPS (EPS) takes place, and side effects such as tardive dyskinesia are low, and can improve negative symptoms and cognitive disorder effectively.But these medicines have the QT gap to prolong untoward reactions such as hyperprolactinemia and weight increase.Therefore, seek and new can cure treatment schizophrenia effectively and the little antipsychotics of side effect is very important.
The compound of analyzing marketed drug and studying finds that five acceptors are to schizophrenia important effect, i.e. D
2, D
3, 5-HT
1A, 5-HT
2AAnd 5HT
2CD
3The main selectivity of the distribution situation of acceptor in brain is distributed in limbic system, and this system and people's cerebration has close relationship, schizophreniac's D
3The frequency of acceptor gene variation is apparently higher than the contrast crowd, and closely related with the reaction of pharmacological agent.D
3Two main DA nerve pathways are arranged in the R brain, article one, be black substance. striatum path regulation and control motor function, another is midbrain ventral tegmental area-nucleus accumbens septi. prefrontal lobe cortex DA path is closely related with study cognition and affective activity, its dysfunction will cause schizophrenia, this DA path also is the major avenues of approach of reward effect (reward efects) in the brain, D
3RIn two DA nerve pathways, distribution is arranged, and and other DA receptor subtypes between exist complicated the interaction, may be as a target of antipsychotics treatment, selective d
3The antagonistic action of acceptor can reduce schizoid passiveness and cognitive symptom, and this external enwergy stops EPS, comprises tardive dyskinesia, Parkinson's disease.
The serotonin system plays an important role in the function of the prefrontal lobe cortex of regulating (PFC), comprises emotion control, cognitive behavior and working memory.The cone neurone of PFC and GABA relay cell have comprised several have special high-density serotonin receptor subtype 5-HT1A and 5-HT2A.Obtain recently proving that PFC and nmda receptor channel are the targets of 5-HT1AR, these two acceptors are regulated the pallium excitatory neuron, thereby influence cognitive function.In fact, various clinical before data show that 5-HT1AR may be the fresh target of antipsychotic drug development medicine.5-HT1AR avidity on clinical efficacy to the medicine (olanzapine of atypical anti-spirit, aripiprazole) and their low EPS side effect make the serotonin system and in the function of the prefrontal lobe cortex of regulating (PFC), play an important role, comprise emotion control, cognitive behavior and working memory.The cone neurone of PFC and GABA relay cell have comprised several have special high-density seretonine receptor 5 hypotype 5-HT1A and 5-HT2A.Studies show that recently the 5-HT1A agonist is relevant with the atypical antipsychotic treatment, can improve negative symptoms and cognitive disorder.In using atypical antipsychotic leoponex treatment schizophrenia, it is very important to it is found that 5-HT2A plays a part therein, relates to all respects of perception, mood regulation and motion control.Blocking-up 5HT2A acceptor can make the release normalizing of Dopamine HCL, and plays antipsycholic action.In addition, 5HT2C acceptor and weight increase are closely related.
Therefore, seek the mode of a polyceptor combination now, improve the sphere of action of anti-schizophrenia medicine, and can reduce side effect.
Summary of the invention
The purpose of this invention is to provide a kind ofly 2,6-diketone-piperazine (piperidines) analog derivative is to satisfy the needs of clinical application.
Another object of the present invention provides a kind of pharmaceutical composition that contains above-claimed cpd.
A further object of the invention provides the application of above-claimed cpd aspect prevention or treatment central nervous system disease.
Described 2,6-diketone-piperazine (piperidines) analog derivative, for having the compound or its salt of general formula (I):
Wherein:
X is CH or N;
N is 3,4 or 5;
Ar
1Be formula II or formula III:
Ar
2Be formula IV or formula V:
Wherein:
Q is O, S or NH;
L is O or S;
R1, R2, R3, R4 or R5 are hydrogen, halogen, cyano group, nitro, hydroxyl, C respectively independently
1-5The C of alkoxyl group, replacement
1-5Alkyl, unsubstituted C
1-5Alkyl, wherein said C
1-5The substituting group of alkyl is selected from one or more in amino, hydroxyl or the fluorine;
Preferably, described C
1-5Alkoxyl group is methoxyl group, oxyethyl group, propoxy-or butoxy;
Preferably, the C of replacement
1-5Alkyl is trifluoromethyl, fluoro ethyl, methylol or hydroxyethyl;
Preferably, unsubstituted C
1-5Alkyl is methyl, ethyl, propyl group, butyl, n-pentyl, isopentyl or neo-pentyl;
In the formula I compound, Ar
1During for structure I I, R1 and respectively R2 be hydrogen, C
1-5Alkoxyl group, halogen or nitro; Be preferably hydrogen, methoxyl group, chlorine, fluorine or nitro;
Ar
1During for structure III, R3 is preferably hydrogen;
In the formula I compound, Ar
2During for structure I V, R4 is H or halogen, and Q is preferably oxygen or sulphur, and R4 is preferably hydrogen, fluorine;
Ar
2During for structure V, R5 is preferably hydrogen; L is preferably oxygen or sulphur;
In the formula I compound, work as Ar
2During for structure I V, Ar
1Be structure I I, X is CH, and Q is oxygen, R1 for hydrogen n be 3,4 or 5, R4 be fluorine, R1 and R2 independently are hydrogen, C respectively
1-5Alkoxyl group, halogen or nitro;
Preferably, described C
1-5Alkoxyl group is methoxyl group, oxyethyl group, propoxy-or butoxy;
In the formula I compound, work as Ar
2Be structure I V, Ar
1During for structure III, X is CH, and Q is oxygen, and R1 is hydrogen, and n is that 4, R4 is fluorine, and R3 is preferably hydrogen;
In the formula I compound, work as Ar
2Be structure I V, Ar
1During for structure I I, X is nitrogen, and Q is sulphur, and R1 is hydrogen, n be 4 or 5, R4 be fluorine, R1 and R2 independently are hydrogen, methoxyl group, fluorine, chlorine or nitro respectively;
In the formula I compound, work as Ar
2Be structure V, Ar
1During for structure I I, L is oxygen or sulphur, and X is CH, and n is that 4, R1 and R2 independently are hydrogen or chlorine respectively;
Preferably, described 2,6-diketone-piperazine (piperidines) analog derivative is following compound or its salt:
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(4-fluorophenyl)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(phenyl)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(p-methoxy-phenyl)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(2,4 dichloro benzene base)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(nitrophenyl)-piperidines-2, the 6-diketone,
1-(5-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) amyl group)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(5-(4-(3-benzisothiazole)-1-piperazinyl) amyl group)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(3-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) propyl group)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(3-benzisothiazole)-1-piperazinyl) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(benzoxazoles-2 base) piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(benzothiazole-2 base) piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone or
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(1-naphthyl)-piperidines-2, the 6-diketone.
Described salt is for containing pharmaceutically acceptable anion salt: example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol or hydrosulfate, phosphoric acid salt or acid phosphate, acetate, lactic acid salt, Citrate trianion, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoate, esilate, benzene sulfonate, tosilate etc.Preferably salt hydrochlorate or hydrobromate.Described salt preferably contains the crystal water of 0.5-3 molecule.
Animal experiment proves, and is provided by the invention 2, and 6-diketone-piperazine (piperidines) analog derivative can be for the preparation for the treatment of or prevention central nervous system disorder medicine;
Described central nervous system disorder comprise mental disorder, anxiety disorder, personality disorder, dysthymia disorders, manic disorder, migraine, epilepsy, spastic obstacle, the Childhood obstacle, Parkinson's disease, cognitive disorder, neurodegeneration, neurotoxicity or local asphyxia, especially effectively be schizophrenia;
The invention still further relates to a kind of pharmaceutical composition, comprise compound or its salt and the acceptable accessories of the general formula (I) for the treatment of significant quantity;
Described auxiliary material such as tackiness agent be gelatin, W-Gum, Sudan Gum-arabic for example; Vehicle is secondary calcium phosphate for example; Disintegrating agent is W-Gum, yam starch or alginic acid for example; Lubricant is Magnesium Stearate for example; With sweeting agent for example sucrose, lactose.When dosage form is capsule, except the raw material of the above-mentioned type, also can comprise liquid vehicle, for example grease.
Is described preparation of drug combination method conventional, as adopting? the method that handbook provides becomes tablet, capsule, lozenge, suspensoid, syrup etc. with its preparation; Wherein, the weight content of the compound or its salt of general formula (I) is 1～99.9%, preferred 4～70%;
The compound or its salt of general formula (I), and the compound or its salt that contains general formula (I), can put on the patient who needs treatment by any suitable approach, oral as passing through, subcutaneous injection or intravenous approach, or with the form rectal administration of suppository, form applied dermally with the transfer system of paster, every day total dose usually at about 0.05mg between the 2000mg, specifically can be by the state of an illness of doctor according to the patient, decisions such as age, the type and the seriousness that depend on disease or illness, the feature that also depends on object, for example general health, age, sex, body weight and drug tolerance.The technician can determine suitable dosage according to these or other factors.Usually the effective dose of used medicine for central nervous system is that the technician knows.。
The compound of general formula I 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 compound of Formula I, 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 for the treatment of that contains or use them.
The preparation method of the compound of general formula I comprises the steps:
The product that adopts corresponding substituted aroma aldehyde and methyl aceto acetate under the condition of piperidines, to obtain, under the hydrochloric acid effect that potassium hydroxide and the weight concentration of weight concentration 50% is 10-20%, generate corresponding diacid, diacid and urea are 120～170 ℃ of reactions, obtain corresponding imide, again with 1,3-dibromopropane (or 1,4-dibromobutane, 1, pentamethylene bromide) makes under the condition of acid binding agent of salt of wormwood and obtain bromo-derivative, bromo-derivative and corresponding substituted-piperazinyl or piperidines reaction are obtained target product, and reaction expression is as follows:
Extracorporeal receptor shows in conjunction with test, and compound involved in the present invention is to dopamine D 2, D3, and 5HT1A and 5HT2A acceptor have higher avidity, and be low with 5-HT2C (reduce chronic under risk of obesity treatment) avidity.The effect (as improving negative symptoms) that increases medicine reduces side effect, and (as EPS, newborn secretin increases, and weight increase and QI gap prolong.
Animal test results shows that this compounds can obviously improve the high reactivity that MK-801 induces, and can effectively improve the climbing symptom that Apomorphine is induced again, and does not cause EPS under effective dose.Show that it has tangible anti-schizophrenia effect.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 for the treatment of, especially schizophrenia is had therapeutic action.Induce in two animal models of the climbing that high reactivity and apomorphine induce ED50 littler at MK-801, act on byer force, and ED50 is bigger in the cataleptic model of animal, and therapeutic index is bigger.The detailed pharmacological datum of each compound sees Table 1.
Embodiment
The following examples just for the purpose of description and not as restriction of the present invention.Except as otherwise noted, all temperature be centigradetemperature (℃).
Embodiment 1
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2,6-diketone (numbering 1)
(1) in being housed, the 500ml three-necked bottle of reflux exchanger, magnetic agitation and dropping funnel adds the cruel 52g of etheric acid second (0.4mol), 4-chloro-benzaldehyde 28g (0.2mol).Under agitation, drip the ethanol (20ml) of volumetric concentration 95% and the mixed solution of piperidines (2ml), solid dissolves gradually, continues to be stirred to reaction solution and begins again to solidify, and needs lh approximately.When the reactant completion of cure, with electric heating water bath with thermostatic control heating, place 5h in 40 ℃ of lucifuges, make to react completely.With the ethyl alcohol recrystallization of cured article with volumetric concentration 95%, get white, needle-shaped crystals 52.2g, yield 68.2%.Fusing point: 152-155 ℃.
(2) reflux exchanger is being housed, mechanical stirring adds potassium hydroxide 100g in the 500ml three-necked bottle of thermometer, water 100ml, and heated and stirred makes its dissolving, adds to go up step product 23g (0.06mol), heated and stirred backflow 2h in batches.Reaction solution is put cold, is injected the 400ml frozen water, remove by filter water-fast floss, with the 3N hcl acidifying to pH be 5, separate out a large amount of white precipitates, filter, collecting precipitation is with volumetric concentration 50% ethyl alcohol recrystallization, get white crystals 12.3g, yield 84.7%, fusing point: 165-167 ℃.
(3) get the second step product 5g, add 8g urea, be heated to 180 degree reaction 4h, reaction finishes, and is chilled to room temperature, adds 25ml water, filters, and uses the dehydrated alcohol recrystallization, gets white crystals 4.3g, yield, fusing point: 174-176 ℃.
(4) get the 3rd step product, Anhydrous potassium carbonate, TEBA, acetone and 1,4-dibromobutane, heating reflux reaction, 4 hours, be chilled to room temperature, filter, be spin-dried for solvent, cross post and get white solid, fusing point: 71-73 ℃.
(5) get the 4th step product, add 6-fluoro-3-(4-piperidyl)-1, the 2-benzo isoxazole hydrochlorate, Anhydrous potassium carbonate, potassiumiodide and acetonitrile, heating reflux reaction 4 hours is chilled to room temperature, filters, and solvent evaporated is crossed post and is got white solid, is target product.
Fusing point: 158-160 ℃
1H?NMR(CDCl
3)δ1.55-1.56(m，4H)，2.05-2.11(m，6H)，2.41(t，2H，J＝13.6Hz)，2.74-2.81(m，2H)，2.96-3.07(m，5H)，3.33-3.37(m，1H)，3.84(t，2H，J＝14Hz)，7.05-7.35(m，6H)，7.69-7.73(m，1H).MS(ESI)m/z([M+H]
+).
Embodiment 2
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(4-fluorophenyl)-piperidines-2,6-diketone (numbering 2)
Be starting raw material with p-Fluorobenzenecarboxaldehyde, obtain target compound by the method for embodiment 1.Fusing point: 137-139 ℃
1H?NMR(CDCl
3)δ1.52-1.61(m，4H)，2.06-2.12(m，6H)，2.42(t，2H，J＝13.6Hz)，2.75-2.83(m，2H)，2.96-3.07(m，5H)，3.34-3.37(m，1H)，3.83(t，2H，J＝14Hz)，7.03-7.07(m，3H)，7.18-7.24(m，3H)，7.71-7.74(m，1H)
Embodiment 3
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(phenyl)-piperidines-2,6-diketone (numbering 3)
Be starting raw material with phenyl aldehyde, obtain target compound by the method for embodiment 1.Fusing point: 114-116 ℃
1H?NMR(CDCl
3)δ1.55-1.59(m，4H)，2.05-2.13(m，6H)，2.42(t，2H，J＝14.4Hz)，2.77-2.84(m，2H)，2.98-3.08(m，5H)，3.34-3.38(m，1H)，3.84(t，2H，J＝14Hz)，7.03-7.08(m，1H)，7.20-7.40(m，6H)，7.68-7.71(m，1H)
Embodiment 4
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(p-methoxy-phenyl)-piperidines-2,6-diketone (numbering 4)
Be starting raw material with aubepine, obtain target compound by the method for embodiment 1.Fusing point: 136-138 ℃
1H?NMR(CDCl
3)δ1.51-1.61(m，4H)，2.06-2.13(m，6H)，2.41(t，2H，J＝13.6Hz)，2.73-2.80(m，2H)，2.94-3.07(m，5H)，3.30-3.34(m，1H)，3.80-3.83(m，5H)，6.88-6.90(m，2H)，7.02-7.29(m，4H)，7.70-7.74(m，1H)
Embodiment 5
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(2,4 dichloro benzene base)-piperidines-2,6-diketone (numbering 5)
Be starting raw material with 2,4 dichloro benzene formaldehyde, obtain target compound by the method for embodiment 1.Fusing point: 147-149 ℃
1H NMR (CDCl
3) δ 1.57-1.59 (m, 4H), 2.05-2.15 (m, 6H), 2.43 (t, 2H, J=13.6Hz), 2.77-2.81 (m, 2H), 2.99-3.08 (m, 5H), 3.75-3.87 (m, 3H), 7.03-743 (m, 5H), 7.71-7.72 (m, 1H)
Embodiment 6
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(nitrophenyl)-piperidines-2,6-diketone (numbering 6)
Be starting raw material with paranitrobenzaldehyde, obtain target compound by the method for embodiment 1.Fusing point: 149-151 ℃
1H?NMR(CDCl
3)δ1.70-1.74(m，4H)，2.06-2.14(m，6H)，2.43(t，2H，J＝13.6Hz)，2.86-2.91(m，2H)，3.04-3.09(m，5H)，3.50-3.54(m，1H)，4.31(t，2H，J＝13.6Hz)，7.06-7.10(m，1H)，7.23-7.28(m，1H)，7.54-7.59(m，2H)，7.71-7.75(m，1H)，8.12-8.18(m，2H)
Embodiment 7
1-(5-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) amyl group)-4-(4-chloro-phenyl-)-piperidines-2,6-diketone (numbering 7)
Replace 1,4 dibromobutane with pentamethylene bromide, obtain target compound by the method for embodiment 1.Fusing point: 117-119 ℃
1H?NMR(CDCl
3)δ1.31-1.35(m，2H)，1.55-1.58(m，4H)，2.07-2.11(m，6H)，2.37(t，2H，J＝8Hz)，2.77-2.81(m，2H)，.96-3.08(m，5H)，3.33-3.37(m，1H)，3.80(t，2H，J＝14Hz)，7.05-7.35(m，6H)，7.71-7.73(m，1H)
Embodiment 8
1-(5-(4-(3-benzisothiazole)-1-piperazinyl) amyl group)-4-(4-chloro-phenyl-)-piperidines-2,6-diketone (numbering 8)
With 6-fluoro-3-(4-piperidyl)-1, the 2-benzo isoxazole hydrochlorate changes 3-(1-piperazinyl)-1 into, and 2-benzisothia triazole hydrochloride prepares target compound by the method for embodiment 7.Fusing point: 135-137 ℃
1H?NMR(CDCl
3)δ1.34-1.36(m，2H)，1.56-1.58(m，4H)，2.42(t，2H，J＝14.2Hz)，2.67-2.80(m，6H)，2.95-3.01(m，2H)，3.30-3.34(m，1H)，3.56-3.59(m，4H)，3.81(t，2H，J＝14.2Hz)，7.13-7.15(m，2H)，7.33-7.46(m，4H)，7.80-7.82(m，1H)，7.90-7.92(m，1H)
Embodiment 9
1-(3-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) propyl group)-4-(4-chloro-phenyl-)-piperidines-2,6-diketone (numbering 9)
Replace 1,4 dibromobutane with 1,3-dibromopropane, obtain target compound by the method for embodiment 1.Fusing point: 115-117 ℃
1H?NMR(CDCl
3)δ1.77-1.80(m，2H)，2.06-2.14(m，6H)，2.45(t，2H，J＝14.4Hz)，2.75-2.82(m，2H)，2.96-3.09(m，5H)，3.33-3.37(m，1H)，3.88(t，2H，J＝14.8Hz)，7.05-7.36(m，6H)，7.71-7.72(m，1H)
Embodiment 10
1-(4-(4-(3-benzisothiazole)-1-piperazinyl) butyl)-4-(4-chloro-phenyl-)-piperidines-2,6-diketone (numbering 10)
With 6-fluoro-3-(4-piperidyl)-1, the 2-benzo isoxazole hydrochlorate changes 3-(1-piperazinyl)-1 into, and 2-benzisothia triazole hydrochloride prepares target compound by the method for embodiment 1.Fusing point: 163-165 ℃
1H?NMR(CDCl
3)δ1.56-1.72(m，4H)，2.05-2.15(m，6H)，2.45(t，2H，J＝14Hz)，2.67-2.80(m，6H)，2.95-3.01(m，2H)，3.30-3.34(m，1H)，3.56-3.58(m，4H)，3.83(t，2H，J＝14Hz)，7.03-7.43(m，5H)，7.13-7.15(m，2H)，7.33-7.46(m，4H)，7.80-7.82(m，1H)，7.90-7.92(m，1H)
Embodiment 11
1-(4-(4-(benzoxazoles-2 base) piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2,6-diketone (numbering 11)
With 6-fluoro-3-(4-piperidyl)-1, the 2-benzo isoxazole hydrochlorate changes 2-(4-piperidyl)-benzoxazoles into, prepares target compound by the method for embodiment 1.Fusing point: 171-173 ℃
1H?NMR(CDCl
3)δ1.52-1.64(m，4H)，2.01-2.18(m，6H)，2.38(t，2H，J＝14.4Hz)，2.72-2.79(m，2H)，2.95-3.00(m，5H)，3.31-3.34(m，1H)，3.83(t，2H，J＝14Hz)，7.13-7.15(m，2H)，?7.，29-7.35(m，4H)，7.47-7.49(m，1H)，7.67-7.70(m，1H)
Embodiment 12
1-(4-(4-(benzothiazole-2 base) piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2,6-diketone (numbering 12)
With 6-fluoro-3-(4-piperidyl)-1, the 2-benzo isoxazole hydrochlorate changes 2-(4-piperidyl)-benzothiazole into, prepares target compound by the method for embodiment 1.Fusing point: 178-180 ℃
1H?NMR(CDCl
3)δ1.54-1.55(m，4H)，1.94-2.20(m，6H)，2.39(t，2H，J＝14Hz)，2.72-2.79(m，2H)，2.95-3.06(m，5H)，3.31-3.34(m，1H)，3.83(t，2H，J＝14Hz)，7.13-7.15(m，2H)，7.33-7.37(m，3H)，7.43-7.47(m，1H)，7.85-7.87(m，1H)，7.96-7.98(m，1H)
Embodiment 13
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(1-naphthyl)-piperidines-2, the 6-diketone.(numbering 13) is starting raw material with the 1-naphthaldehyde, obtains target compound by the method for embodiment 1.Fusing point: 138-140 ℃
1H?NMR(CDCl3)δ1.59-1.64(m，4H)，2.07-2.16(m，6H)，2.45(t，2H，J＝14.4Hz)，2.91-2.98(m，2H)，3.07-3.20(m，5H)，3.33-3.37(m，1H)，3.89(t，2H，J＝14.8Hz)，7.04-7.05(m，1H)，7.22-7.31(m，2H)，7.45-7.58(m，3H)，7.70-7.99(m，4H)
Embodiment 14
5HT
1AReceptor binding assays
The preparation of film
The rat broken end, cortex is got in operation rapidly on ice, adds the damping fluid (Tris-HCl of 0.05M, pH=7.4) in 4 grades of 3-4s homogenate, homogenate 4 times adds 5ml damping fluid (the Tris-HCl damping fluid of 0.05M) then, in 37 ℃ of hatching 10min, hatch the back test tube and adjusted weight with balance, at 12000r, 4 ℃ of centrifugal 20min abandon supernatant liquor, the Tris-HCl liquid that adds 0.05M, use the vortex mixer mixing, add the Tris-HCl of 0.05M again, centrifugal, triplicate is centrifugal, centrifugal finishing abandons supernatant liquor, will be deposited in-80 ℃ and store for future use.
The receptors bind experiment material:
The isotropic substance aglucon
3H-8-OH-DPAT (67.0Ci/mmol) is available from PerkinElmer company; 5-HT is available from RBI company; The GF/C glass fiber filter paper is available from Whatman company; Tris import packing; PPO, POPOP are available from Shanghai reagent one factory; Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) earlier with the film that the prepares Tris-HCl with an amount of 0.05M, be the suspension of 50ml film with the refiner an amount of homogenate of adding that is uniformly dispersed, standby.
(2) each reaction tubes adds membrane prepare thing 100 μ L respectively, the Tris-HCl 100 μ L of 0.05M.
(3) total binding pipe (TB) adds the Tris-HCl of 100 μ L0.05M, and non-specific binding pipe (NB) adds 5-HT 100 μ L (final concentrations 10
-5M), each test-compound specificity connecting pipe (SB) adds 100 μ L test-compound (final concentrations 10
-5M);
(4) each reaction tubes adds radioligand respectively
3H-8-OH-DPAT 10 μ L (each reaction tubes is all established 2 parallel pipes, and each pipe places on ice during application of sample).
(5) 37 ℃ of temperature of each reaction tubes are incubated 10min, reaction finishes, in conjunction with aglucon filter fast by decompression, fully wash with ice-cold test damping fluid, filter disc is taken out is put in the 3ml scintillating disc toluene scintillation solution and the mixing of adding 2ml;
(6) scintillation vial is put into the liquid scintillation counter counting
Inhibiting rate (I%)=[(total binding pipe cpm-compound c pm)/(the non-specific combination pipe of total binding pipe cpm-cpm)] * 100%
Two multiple pipes are done in the each experiment of compound, carry out twice experiment separately.
Experimental result sees Table 1.
Embodiment 15
5HT
2AReceptor binding assays
5HT
2AThe preparation of film:
The rat broken end, cortex is got in operation rapidly on ice, adds 3ml damping fluid (the Tris-HCl damping fluid of 0.05M: get 6.05gTris and be dissolved in the 1000ml distilled water, transferring PH with dense HCl is 7.5) in 4 grades of 3-4s homogenate, homogenate 4 times adds the 5ml damping fluid then, in 37 ℃ of hatching 10min, hatch the back test tube and adjusted weight with balance, at 12000r, 4 ℃ of centrifugal 20min abandon supernatant liquor, add 3mlA liquid, use the vortex mixer mixing, add the 5ml damping fluid again, centrifugal, (triplicate is centrifugal), centrifugal finishing abandons supernatant liquor, will be deposited in-80 ℃ and store for future use.
The receptors bind experiment material:
The isotropic substance aglucon [
3H]-Ketanserin (67.0Ci/mmol), available from PerkinElmer company; Methysergide is available from RBI company; The GF/C glass fiber filter paper is available from Whatman company; Tris import packing; PPO, POPOP are available from Shanghai reagent one factory; Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) earlier with the film for preparing with an amount of homogenate, be uniformly dispersed with refiner, 15 test tubes are blended in the container of 100ml, add the suspension that an amount of homogenate is the 50ml film, standby.
(2) each reaction tubes adds membrane prepare thing 100 μ L respectively, damping fluid 100 μ L.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds MetHysergide 100 μ L (final concentrations 10
-5M), each test-compound specificity connecting pipe (SB) adds 100 μ L test-compound (final concentrations 10
-5M);
(4) each reaction tubes adds radioligand respectively
3H-Ketanserin 10 μ L (each reaction tubes is all established 2 parallel pipes, and each pipe places on ice during application of sample).
(5) 37 ℃ of temperature of each reaction tubes are incubated 15min, reaction finishes, in conjunction with aglucon filter fast by decompression, fully wash with ice-cold test damping fluid, filter disc is taken out is put in the 3ml scintillating disc toluene scintillation solution and the mixing of adding 2ml;
(6) scintillation vial is put into the liquid scintillation counter counting
Inhibiting rate (I%)=[(total binding pipe cpm-compound c pm)/(the non-specific combination pipe of total binding pipe cpm-cpm)] * 100%
Two multiple pipes are done in the each experiment of compound, carry out twice experiment separately.
Experimental result sees Table 1.
Embodiment 16
The D2 receptor binding assays
The preparation of film
The rat broken end, operation on ice, get brain striatum rapidly, add 3ml damping fluid (the Tris-HCl damping fluid of 0.05M contains NaCl 120mM, KCl 5mM, MgCl21mM, CaCl21mM) in 4 grades of 3-4s homogenate, homogenate 4 times, add the 5ml damping fluid then, the test tube that homogenate is intact is adjusted weight with balance, at 12000r, 4 ℃ of centrifugal 20min, abandon supernatant liquor, add 3mlB liquid, use the vortex mixer mixing, add 5mlB liquid again, centrifugal, triplicate is centrifugal, centrifugal finishing, abandon supernatant liquor, will be deposited in-80 ℃ and store for future use.
The receptors bind experiment material:
The isotropic substance aglucon
3H-Spiperone (67.0Ci/mmol) is available from PerkinElmer company; Butaclamol is available from RBI company; The GF/C glass fiber filter paper is available from Whatman company; Tris import packing; PPO, POPOP are available from Shanghai reagent one factory; Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) earlier with the film for preparing with an amount of homogenate, be uniformly dispersed with refiner, 15 test tubes are blended in the container of 100ml, add the suspension that an amount of homogenate is the 50ml film, standby.
(2) each reaction tubes adds membrane prepare thing 100 μ L respectively, damping fluid 100 μ L.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds 100 μ L Butaclamol (final concentrations 10
-5M), each test-compound specificity connecting pipe (SB) adds 100 μ L test-compound (final concentrations 10
-5M);
(4) each reaction tubes adds radioligand respectively
3H-Spiperone 10 μ L (each reaction tubes is all established 2 parallel pipes, and each pipe places on ice during application of sample).
(5) 37 ℃ of temperature of each reaction tubes are incubated 20min, reaction finishes, in conjunction with aglucon filter fast by decompression, fully wash with ice-cold test damping fluid, filter disc is taken out is put in the 3ml scintillating disc toluene scintillation solution and the mixing of adding 2ml;
(6) scintillation vial is put into the liquid scintillation counter counting
Inhibiting rate (I%)=[(total binding pipe cpm-compound c pm)/(the non-specific combination pipe of total binding pipe cpm-cpm)] * 100%
Two multiple pipes are done in the each experiment of compound, carry out twice experiment separately.
Experimental result sees Table 1.
Embodiment 17
The D3 receptor binding assays
Cell
The HEK-293 cell, through 48-72H (hour) after receptor protein great expression on film, will abandon supernatant behind the centrifugal 5min of cell 1000rpm, receive cell space, deposit in-the 200C refrigerator preserves.Resuspended with Tris-Cl (pH 7.4) during experiment.
Experiment material:
D3 acceptor isotropic substance aglucon [3H]-Spiperone is available from AmersHam company; (+) Butaclamol is available from RBI company; The GF/C glass fiber filter paper is available from Whatman company; Fat-soluble scintillation solution.Tris is by the packing of Ji Tai Science and Technology Ltd..
Experimental technique:
Receptor competition is in conjunction with experiment: testing compound and each 20ul of radioactive ligand and 160ul receptor protein are added in the reaction tube, make test-compound and positive drug final concentration be 10 μ mol/L, after 50min is hatched in 30 ℃ of water-baths, move to ice bath at once and stop its reaction; On Millipore cell sample collector, through GF/C glass fiber filter paper quick suction filtration, and with elutriant (50mM Tris-HCl, PH 7.4) 3ml X 3 times, with microwave oven 4～5min oven dry, filter paper is moved in the 0.5ml centrifuge tube, add the fat-soluble scintillation solution of 500ul.Lucifuge leaves standstill more than the 30min, and counting is measured radioactive intensity.Calculate each compound as follows to the inhibiting rate percentage of isotropic substance aglucon combination:
Inhibiting rate (I%)=[(total binding pipe cpm-compound c pm)/(the non-specific combination pipe of total binding pipe cpm-cpm)] * 100%
Experimental result sees Table 1.
Embodiment 18
5HT
2CReceptor binding assays
The preparation of film
The rat broken end, brain striatum is got in operation rapidly on ice, 2 striatums are incorporated in the centrifuge tube, add 3ml damping fluid (the Tris-HCl damping fluid of 0.05M: get 6.05gTris and be dissolved in the 1000ml distilled water, transferring PH with dense HCl is 7.5) in 4 grades of 3-4s homogenate, homogenate 4 times, add the 5ml damping fluid then, in 37 ℃ of hatching 10min, hatched the back test tube and adjusted weight with balance, at 12000r, 4 ℃ of centrifugal 20min, abandon supernatant liquor, add 3mlA liquid, use the vortex mixer mixing, add the 5ml damping fluid again, centrifugal, (triplicate is centrifugal), centrifugal finishing, abandon supernatant liquor, will be deposited in-80 ℃ and store for future use.
The receptors bind experiment material:
The isotropic substance aglucon [
3H]-mesulergine (67.0Ci/mmol), available from PerkinElmer company; Mianserin is available from RBI company; The GF/C glass fiber filter paper is available from Whatman company; Tris import packing; PPO, POPOP are available from Shanghai reagent one factory; Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) earlier with the film for preparing with an amount of homogenate, be uniformly dispersed with refiner, 15 test tubes are blended in the container of 100ml, add the suspension that an amount of homogenate is the 50ml film, standby.
(2) each reaction tubes adds membrane prepare thing 100 μ L respectively, damping fluid 100 μ L.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds Methysergide100 μ L (final concentration 10
-5M (mol)), each test-compound specificity connecting pipe (SB) adds 100 μ L test-compound (final concentrations 10
-5M);
(4) each reaction tubes add respectively radioligand [
3H]-mesulergine 10 μ L (each reaction tubes is all established 2 parallel pipes, and each pipe places on ice during application of sample).
(5) 37 ℃ of temperature of each reaction tubes are incubated 15min, reaction finishes, in conjunction with aglucon filter fast by decompression, fully wash with ice-cold test damping fluid, filter disc is taken out is put in the 3ml scintillating disc toluene scintillation solution and the mixing of adding 2ml;
(6) scintillation vial is put into the liquid scintillation counter counting
Inhibiting rate (I%)=[(total binding pipe cpm-compound c pm)/(the non-specific combination pipe of total binding pipe cpm-cpm)] * 100%
Two multiple pipes are done in the each experiment of compound, carry out twice experiment separately.
Experimental result sees Table 1.
Embodiment 19
Histamine H1-receptor is in conjunction with test
The preparation of film
Teng mouse broken end, cerebellum is got in operation rapidly on ice, add phosphoric acid buffer (Ph=7.4), use the vortex mixer mixing, at 48000g, 4 ℃ of centrifugal 10min, abandon supernatant liquor, get precipitation, add homogenate F washing again, triplicate is centrifugal, centrifugal finishing abandons supernatant liquor, will be deposited in-80 ℃ and store for future use.
The receptors bind experiment material:
The isotropic substance aglucon [
3H]-pyrilamine (67.0Ci/mmol), available from PerkinElmer company; Mianserin is available from RBI company; The GF/C glass fiber filter paper is available from Whatman company; Tris import packing; PPO, POPOP are available from Shanghai reagent one factory; Fat-soluble scintillation solution.Beckman LS-6500 type full-service fluid scintillation counter.
Experimental technique:
(1) earlier with the film for preparing with an amount of damping fluid, be uniformly dispersed with refiner, 15 test tubes are blended in the container of 100ml, add the suspension that an amount of damping fluid is the 50ml film, standby.
(2) each reaction tubes adds membrane prepare thing 100 μ L respectively, damping fluid 100 μ L.
(3) total binding pipe (TB) adds 100 μ L homogenates, and non-specific binding pipe (NB) adds promethazine100 μ L (final concentration 10
-5M (mol)), each test-compound specificity connecting pipe (SB) adds 100 μ L test-compound (final concentrations 10
-5M);
(4) each reaction tubes add respectively radioligand [
3H]-pyrilamine 10 μ L (each reaction tubes is all established 2 parallel pipes, and each pipe places on ice during application of sample).
(5) 30 ℃ of temperature of each reaction tubes are incubated 60min, reaction finishes, in conjunction with aglucon filter fast by decompression, fully wash with ice-cold test damping fluid, filter disc is taken out is put in the 3ml scintillating disc toluene scintillation solution and the mixing of adding 2ml;
(6) scintillation vial is put into the liquid scintillation counter counting
Experiment in vitro is the result show, 1 pair of four kinds of acceptor of compound (D2, D3,5HT1A, 5HT2A) stronger avidity, suitable with Aripiprazole, and with the avidity of 5HT2C and H1 acceptor less than Aripiprazole.
Embodiment 20
Anti-schizophrenia activity in the high reactivity chemical combination object that MK-801 induces
Laboratory animal and reagent
Healthy Kunming mouse, male and female half and half, body weight (20 ± 2) g is provided by animal cultivation center, Green Dragon mountain, Nanjing.
Xitix, Chemical Reagent Co., Ltd., Sinopharm Group;
MK-801 is produced by U.S. Sigma company, and compound method: the vitamins C with 0.1% is made into the solution of 1mg/ml;
Tried positive drug: haloperidol, leoponex, risperidone, olanzapine, Aripiprazole, Ziprasidone, Kui sulphur are put down;
Tween 80, concentration 10%.
Experimental technique
Selective body overlaps the mouse of lattice, is divided into blank group, model group, positive controls (risperidone group), medicine group at random.Blank group, model group are irritated stomach 10% tween 0.1ml/10g, and positive controls is irritated stomach and given risperidone 0.1mg/kg, and drug component is not irritated stomach and given and the corresponding dosage medicine.The blank group of 1H abdominal injection 0.1% xitix 0.1ml/10g after the administration, model group, positive controls (30min), medicine group abdominal injection MK-801 solution 0.1mg/kg.Measure and respectively organize spontaneous activity in the mouse 90 minutes thereafter.The results are shown in Table 3.
This experimental result shows: compare with model group, risperidone, compound 1 can obviously improve the high reactivity that MK-801 induces, and can effectively improve the climbing symptom that Apomorphine is induced again, and under effective dose, do not cause EPS, show that it has tangible anti-schizophrenia effect.
Embodiment 21
Apomorphine inducing mouse climbing experiment
Laboratory animal
Healthy KM mouse, male, body weight 18～22g is provided by animal cultivation center, Green Dragon mountain, Nanjing.
Main agents
Tried positive drug: haloperidol, leoponex, risperidone, olanzapine, Aripiprazole, Ziprasidone, Kui sulphur are put down;
Apomorphine, Sigma company provides, and faces the dissolving with preceding 0.9%NaCl (containing 0.1% vitamins C), and is now with the current;
Vitamins C, F20061113, Chemical Reagent Co., Ltd., Sinopharm Group;
Sodium chloride injection, H32026305, Xuzhou City the 5th company limited of pharmaceutical factory.
Instrument: self-control climbing cage, stopwatch.
Experimental technique: Apomorphine inducing mouse climbing experiment
The KM mouse, male, body weight 18～22g, be divided into negative control group, model group, each dosage group of positive drug (risperidone, Aripiprazole, Ziprasidone, Kui sulphur are flat, olanzapine, haloperidol, leoponex) and each dosage group of compound (concrete dosage sees the following form 2) at random, 10 every group.Negative control group and model group are irritated stomach and are given the coordinative solvent distilled water, positive drug group filling stomach gives corresponding positive drug and (adds micro-acetic acid during dissolving earlier, add distilled water again), each dosage group of compound is irritated stomach and is given the corresponding dosage compound, irritates the long-pending 0.1ml/10g of being of body of stomach.Subcutaneous injection Apomorphine (1mg/kg) behind the gastric infusion 1H, volume is 0.1ml/10g.Behind the injection Apomorphine, put into the climbing cage immediately, adapt to 5 minutes, 10-11 behind the observation injection Apomorphine, 20-21,30-31 minute behavior, can obviously shorten and continue the total distance number of climbing, with blank group, model group comparing difference statistical significance (P＜0.01) be arranged.Experimental result sees the following form 2.
Embodiment 22
The catalepsy experimental technique
Laboratory animal
Healthy Kunming mouse, male and female half and half, (22 ± 2) g is provided by animal cultivation center, Green Dragon mountain, Nanjing.
Main agents: be subjected to reagent, haloperidol, leoponex, risperidone, olanzapine, Aripiprazole, Ziprasidone
Instrument: excellent equipment is grabbed in self-control: place diameter 0.3cm in the mouse box, be higher than the stainless steel bar of worktable 5cm.
Experimental technique: KM mouse, male and female half and half, body weight 20～24g is divided into negative control group, model group, each dosage group of positive drug (risperidone, Aripiprazole, Ziprasidone, Kui sulphur are flat, olanzapine, haloperidol, leoponex) and each dosage group of compound, 10 every group at random.Negative control group and model group are irritated stomach and are given the coordinative solvent distilled water, positive drug group filling stomach gives corresponding positive drug and (adds micro-acetic acid during dissolving earlier, add distilled water again), each dosage group of compound is irritated stomach and is given the corresponding dosage compound, irritates the long-pending 0.1ml/10g of being of body of stomach.When gastric infusion 30min, 60min, 90min, two fore paws of mouse gently are placed on long 20cm, diameter 0.3cm, be higher than on the spillikin of worktable 5.5cm, again the animal hind leg is put down gently in the box bottom surface, two fore paws of record mouse are in the time length that rod keeps posture, with the stiff motionless positive reaction of 30s.If the mouse fore paw never puts down, stop during 60s observing.Add up each compound dosage group positive reaction number of animals.
Embodiment 23
Studies on acute toxicity
The KM mouse is got in the limit experiment of sequential method, and male and female half and half are divided into some groups at random, and every group of 2-5 only is respectively each compound 2000mg/kg group and group of solvents, presses the 0.2ml/10g gastric infusion.Observe the death condition in the animal 3 days.If (animal had survival more than 3 or 3 in three days, during the life state Non Apparent Abnormality, continue to observe, and experiment finishes after 7 days.If animal when dead 3 or 3 are above in three days, adopts the medium lethal dose method to measure its LD50.)
The KM mouse is got in the trial test of medium lethal dose method, and male and female half and half are divided some groups at random, every group 4, be respectively each compound 1500mg/kg, 1000mg/kg, 500mg/kg group and group of solvents, press the 0.2ml/10g gastric infusion, observe the death condition in animal 1-3 day.
The result: the mouse single gavages 1 LD50 greater than 2000mg/kg, has less acute toxicity.
Embodiment 24
The exemplary embodiments of preparation prescription is as follows:
1. tablet
In the present embodiment, compound 1 can be replaced by any compound equivalent according to the present invention, especially any exemplary compounds of equivalent.
Adopt above-mentioned prescription, can be by means commonly known in the art, preparation becomes tablet.
2. suspension
For the preparation of Orally administered aqueous suspensions, comprise a kind of, the Xylo-Mucine of 50mg, the sodium benzoate of 1mg, 500mg sorb alcohol and water (adding to 1ml) among 1 to 5mg the described embodiment in each milliliter.
3. injection
Prepare parenteral composition by propylene glycol and the water stirring that the activeconstituents among the present invention of 1.5 weight % is placed 10 volume %.
4. suppository:
The mixture that will contain 20mg formula I activeconstituents melts with 100g soybean lecithin and 1400g theobroma oil, pours into and makes its cooling in the mould.Every suppository contains the 20mg activeconstituents.
Will be understood that rational variation does not depart from scope of the present invention.It will be apparent to one skilled in the art that aforesaid the present invention can change in many aspects.
Table 1 compound is to inhibiting rate or the IC50 of each acceptor
Annotate: a represents the IC50 value
Table 2. compound is to the influence of activity distance in the high movable mouse 90min of MK-801
Annotate: compare with model group: * * p＜0.01, compare with the blank group: #p＜0.01 * p＜0.05.
Animal model result in the table 3. preferred compound body
Claims (14)
1.2 6-diketone-piperazine (piperidines) analog derivative is characterized in that, for having the compound or its salt of general formula (I):
Wherein:
X is CH or N;
N is 3,4 or 5;
Ar
1Be formula II or formula III:
Ar
2Be formula IV or formula V:
Wherein:
Q is O, S or NH;
L is O or S;
R1, R2, R3, R4 or R5 are hydrogen, halogen, cyano group, nitro, hydroxyl, C respectively independently
1-5The C of alkoxyl group, replacement
1-5Alkyl, unsubstituted C
1-5Alkyl, wherein said C
1-5The substituting group of alkyl is selected from one or more in amino, hydroxyl or the fluorine.
2. according to claim 12,6-diketone-piperazine (piperidines) analog derivative is characterized in that described C
1-5Alkoxyl group is methoxyl group, oxyethyl group or propoxy-, butoxy.
3. according to claim 12,6-diketone-piperazine (piperidines) analog derivative is characterized in that the C of replacement
1-5Alkyl is trifluoromethyl, fluoro ethyl, methylol or hydroxyethyl.
4. according to claim 12,6-diketone-piperazine (piperidines) analog derivative is characterized in that unsubstituted C
1-5Alkyl is methyl, ethyl, propyl group, butyl, n-pentyl, isopentyl or neo-pentyl.
5. according to claim 22,6-diketone-piperazine (piperidines) analog derivative is characterized in that the C of replacement
1-5Alkyl is trifluoromethyl, fluoro ethyl, methylol or hydroxyethyl.
6. according to claim 42,6-diketone-piperazine (piperidines) analog derivative is characterized in that the C of replacement
1-5Alkyl is trifluoromethyl, fluoro ethyl, methylol or hydroxyethyl.
7. according to claim 2,3 or 5 described 2,6-diketone-piperazine (piperidines) analog derivative is characterized in that the C of replacement
1-5Alkyl is trifluoromethyl, fluoro ethyl, methylol or hydroxyethyl.
8. according to claim 12,6-diketone-piperazine (piperidines) analog derivative is characterized in that, in the formula I compound, works as Ar
1During for structure I I, R1 and R2 are respectively hydrogen, C
1-5Alkoxyl group, halogen or nitro;
Work as Ar
1During for structure III, R3 is hydrogen;
In formula I compound, Ar
2During for structure I V, R4 is H or halogen, and Q is oxygen or sulphur;
Work as Ar
2During for structure V, R5 is hydrogen; L is oxygen or sulphur;
In formula I compound, work as Ar
2During for structure I V, Ar
1Be structure I I, X is CH, and Q is oxygen, R1 for hydrogen n be 3,4 or 5, R4 be fluorine, R1 and R2 independently are hydrogen, C respectively
1-5Alkoxyl group, halogen or nitro;
In the formula I compound, work as Ar
2Be structure I V, Ar
1During for structure III, X is CH, and Q is oxygen, and R1 is hydrogen, and n is that 4, R4 is fluorine, and R3 is hydrogen;
In the formula I compound, work as Ar
2Be structure I V, Ar
1During for structure I I, X is nitrogen, and Q is sulphur, and R1 is hydrogen, n be 4 or 5, R4 be fluorine, R1 and R2 independently are hydrogen, methoxyl group, fluorine, chlorine or nitro respectively;
In the formula I compound, work as Ar
2Be structure V, Ar
1During for structure I I, L is oxygen or sulphur, and X is CH, and n is that 4, R1 and R2 independently are hydrogen or chlorine respectively.
9. according to claim 82,6-diketone-piperazine (piperidines) analog derivative is characterized in that, works as Ar
1During for structure I I, R1 and R2 are respectively hydrogen, methoxyl group, chlorine, fluorine or nitro;
In formula I compound, Ar
2During for structure I V, R4 is H or fluorine, and Q is oxygen or sulphur;
The C of R1 and R2 representative
1-5Alkoxyl group is methoxyl group, oxyethyl group, propoxy-or butoxy.
10.2 6-diketone-piperazine (piperidines) analog derivative is characterized in that, is following compound or its salt:
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(4-fluorophenyl)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(phenyl)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(p-methoxy-phenyl)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(2,4 dichloro benzene base)-piperidines-2, the 6-diketone,
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(nitrophenyl)-piperidines-2, the 6-diketone,
1-(5-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) amyl group)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(5-(4-(3-benzisothiazole)-1-piperazinyl) amyl group)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(3-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) propyl group)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(3-benzisothiazole)-1-piperazinyl) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(benzoxazoles-2 base) piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone,
1-(4-(4-(benzothiazole-2 base) piperidino) butyl)-4-(4-chloro-phenyl-)-piperidines-2, the 6-diketone or
1-(4-(4-(3-(6-fluoro-benzisoxa oxazole))-piperidino) butyl)-4-(1-naphthyl)-piperidines-2, the 6-diketone.
11. according to claim 1～10 each 8 described 2,6-diketone-piperazine (piperidines) analog derivative, it is characterized in that described salt is for containing pharmaceutically acceptable anion salt: example hydrochloric acid salt, hydrobromate, hydriodate, nitrate, vitriol or hydrosulfate, phosphoric acid salt or acid phosphate, acetate, lactic acid salt, Citrate trianion, tartrate, maleate, fumarate, mesylate, gluconate, saccharate, benzoate, esilate, benzene sulfonate, tosilate etc.Preferably salt hydrochlorate or hydrobromate.
12. according to claim 11 2,6-diketone-piperazine (piperidines) analog derivative is characterized in that described salt contains the crystal water of 0.5-3 molecule.
13. each is described 2 for claim 1～12, the application of 6-diketone-piperazine (piperidines) analog derivative in preparation treatment or prevention central nervous system disorder medicine.
14. a pharmaceutical composition, comprising the claim 1～12 for the treatment of significant quantity, each is described 2,6-diketone-piperazine (piperidines) analog derivative and acceptable accessories.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210031556.8A CN103242219B (en) | 2012-02-13 | 2012-02-13 | 2,6-diketone-piperazine (piperidines) analog derivative and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210031556.8A CN103242219B (en) | 2012-02-13 | 2012-02-13 | 2,6-diketone-piperazine (piperidines) analog derivative and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103242219A true CN103242219A (en) | 2013-08-14 |
| CN103242219B CN103242219B (en) | 2016-02-24 |
Family
ID=48922125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210031556.8A Active CN103242219B (en) | 2012-02-13 | 2012-02-13 | 2,6-diketone-piperazine (piperidines) analog derivative and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103242219B (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187794A (en) * | 2016-07-12 | 2016-12-07 | 安徽省逸欣铭医药科技有限公司 | A kind of green industrialized production method of baclofen |
| CN110698338A (en) * | 2019-11-25 | 2020-01-17 | 广西奕安泰药业有限公司 | Preparation method of 3- (4-chlorobenzene) glutaric acid |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2167355A1 (en) * | 1972-01-13 | 1973-08-24 | Synthelabo | 1-(3-aminopropyl)-4-phenylpiperidine-2,6-diones - as non-hypnotic antidepressants |
| CN1058967A (en) * | 1985-05-06 | 1992-02-26 | 布里斯托尔-米尔斯·斯奎布公司 | The preparation method of antipsychotic fused-ring pyridinypiperazine derivatives |
| WO2005118591A1 (en) * | 2004-05-31 | 2005-12-15 | Ranbaxy Laboratories Limited | Condensed piperidine compounds acting as adrenergic receptor antagonists useful in the treatment of prostatic hyperplasia and lower urinary symptoms |
| CN102180872A (en) * | 2011-04-01 | 2011-09-14 | 华中科技大学 | [1, 3 and 4] oxadiazoles derivative and application thereof |
-
2012
- 2012-02-13 CN CN201210031556.8A patent/CN103242219B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2167355A1 (en) * | 1972-01-13 | 1973-08-24 | Synthelabo | 1-(3-aminopropyl)-4-phenylpiperidine-2,6-diones - as non-hypnotic antidepressants |
| CN1058967A (en) * | 1985-05-06 | 1992-02-26 | 布里斯托尔-米尔斯·斯奎布公司 | The preparation method of antipsychotic fused-ring pyridinypiperazine derivatives |
| WO2005118591A1 (en) * | 2004-05-31 | 2005-12-15 | Ranbaxy Laboratories Limited | Condensed piperidine compounds acting as adrenergic receptor antagonists useful in the treatment of prostatic hyperplasia and lower urinary symptoms |
| CN102180872A (en) * | 2011-04-01 | 2011-09-14 | 华中科技大学 | [1, 3 and 4] oxadiazoles derivative and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| RICHARD A. GLENNON等: "Arylpiperazine Derivatives as High-Affinity 5-HTlSAe rotonin Ligands", 《J. MED. CHEM》, vol. 31, 31 December 1988 (1988-12-31), pages 1968 - 1971 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106187794A (en) * | 2016-07-12 | 2016-12-07 | 安徽省逸欣铭医药科技有限公司 | A kind of green industrialized production method of baclofen |
| CN110698338A (en) * | 2019-11-25 | 2020-01-17 | 广西奕安泰药业有限公司 | Preparation method of 3- (4-chlorobenzene) glutaric acid |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103242219B (en) | 2016-02-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102206214B (en) | Benzopyrone derivative and application thereof | |
| JP6294559B1 (en) | Substituted pyrazoles as N-type calcium channel blockers | |
| CN101636397B (en) | Urea compounds, preparation methods and pharmaceutical uses thereof | |
| CN102548983B (en) | Heteroaromatic and aromatic piperazinyl azetidinyl amides as monoacylglycerol lipase inhibitor | |
| CN104955826B (en) | It can be used for treating spiral shell-Quinzolone derivatives of neurological disorder and illness | |
| KR101757100B1 (en) | Neurogenesis-stimulating isoquinoline derivatives | |
| CN102731413A (en) | Urea compound and its preparation method, intermediate and use | |
| WO2012089106A1 (en) | Aromatic alkyne derivative as protein kinase inhibitor and medical use thereof | |
| CN104995182A (en) | Substituted quinoxaline derivatives and their use as positive allosteric modulators of mglur4 | |
| WO2014053409A1 (en) | Benzimidazol.es as cns active agents | |
| CN104854103A (en) | Acylaminocycloalkyl compounds suitable for treating disorders that respond to modulation of dopamine d3 receptor | |
| JP2016505534A (en) | Substituted 1,6-naphthyridine | |
| CN102180872B (en) | [1, 3 and 4] oxadiazoles derivative and application thereof | |
| CN102267971B (en) | Alicyclic-o[c] benzopyrone derivative and application thereof | |
| JP3161737B2 (en) | 4,5-Dihydronaphtho [1,2-c] isoxazole having CNS activity and derivatives thereof | |
| CN103242219B (en) | 2,6-diketone-piperazine (piperidines) analog derivative and application thereof | |
| CN104955809B (en) | The purposes of substituted acetylene-derivative and its positive allosteric modulators as mGluR4 | |
| CN104583210A (en) | Heteroaryl compounds and using methods thereof | |
| CN102267966B (en) | Substituted benzopyrone derivatives and application thereof | |
| CN104955807A (en) | Positive allosteric modulators of mGluR3 | |
| EP2925756B1 (en) | Imidazopyridine derivatives | |
| CN104059046A (en) | Flavonoid derivative and application thereof | |
| TW202140462A (en) | Muscarinic receptor 4 antagonists and methods of use | |
| CA2878435C (en) | Benzisoxazole modulators of neurogenesis | |
| TW200413392A (en) | C6- and C9-substituted isoxazoline derivatives and their use as anti-depressants |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CP02 | Change in the address of a patent holder |
Address after: 221009 Xuzhou Economic Development Zone, Jiangsu, Yang Road, No. 18, No. Patentee after: Jiangsu Nhwa Pharmaceutical Co., Ltd. Address before: 221007 Zhongshan North Road, Jiangsu, No. 289, Patentee before: Jiangsu Nhwa Pharmaceutical Co., Ltd. |
|
| CP02 | Change in the address of a patent holder |