CN101575336B - N-aryl piperazine derivative and preparation method thereof and drug composition adopting N-aryl piperazine derivative as active ingredient - Google Patents
N-aryl piperazine derivative and preparation method thereof and drug composition adopting N-aryl piperazine derivative as active ingredient Download PDFInfo
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- CN101575336B CN101575336B CN2009100528628A CN200910052862A CN101575336B CN 101575336 B CN101575336 B CN 101575336B CN 2009100528628 A CN2009100528628 A CN 2009100528628A CN 200910052862 A CN200910052862 A CN 200910052862A CN 101575336 B CN101575336 B CN 101575336B
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- piperazine derivative
- aryl piperazine
- compound
- benzisothiazole
- salt
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Abstract
The invention provides an N-aryl piperazine derivative, i.e. a compound shown in formula (I) or pharmaceutically acceptable salt, wherein n is 1-6. The invention provides the compound shown in formula(I) and a drug composition thereof which have excellent effect in treating nervous and mental diseases caused by central nervous system dopamine and serotonin transmittance disorder.
Description
Technical field
The present invention relates to a kind of D of having
2And 5-HT
2AThe active N-aryl piperazine derivative of dual combination, its preparation method and be the pharmaceutical composition of activeconstituents, and the application of their spirit class diseases of causing in treatment cns Dopamine HCL and the disorder of serotonin mediator with this compound.
Background technology
Psychosis is a kind of neurological disorder property disease, and its main type is a schizophrenia.Schizoid clinical manifestation can be divided into two kinds of positive symptom and negative symptomses.Positive symptom comprises illusion, vain hope and paranoia etc.; Negative symptoms comprises human communication disorders, abepithymia and anhedonia etc.The classical psychotroptic drug of early stage listing such as trilafon, haloperidol etc. are superior to negative symptoms to the curative effect of schizophrenia positive symptom, and their mechanism of effect is to dopamine D
2Acceptor has forceful action, but the effect in mesolimbic system and big brain striatum zone is lacked selectivity, causes the extrapyramidal system untoward reaction.Thereby seeking one type, can to improve the psychosis medicine that insane positive symptom can improve negative symptoms again be the main direction of studying of pharmaceutical field.
At present the atypical antipsychotic agnets of listing such as olanzapine, Ziprasidone, risperidone, Quetiapine, Aripiprazole etc. can the selective exclusion brain in the Dopamine HCL conduction path, and blocking-up or part blocking 5-hydroxytryptamine acceptor comprise 5-HT
2A, 5-HT
2C, 5-HT
1AAcceptor, promptly non-classical psychotroptic drug is D
2, 5-HT
2ADouble inhibitor, thereby can improve positive symptom and negative symptoms simultaneously, and reduced spinoffs such as EPS.This type atypical antipsychotic agnets has replaced classical psychotroptic drug becomes current antipsychotic main medication.
Summary of the invention
The objective of the invention is to overcome the defective of above-mentioned existing classic treatment psychosis medicine, and a kind of new N-aryl piperazine derivative be provided, be i.e. compound or its pharmacy acceptable salt shown in the formula (I):
Wherein: n is an integer among the 1-6.
In the above-mentioned general formula, an integer among the preferred 2-4 of n.
[[4-(1 for 2-for the preferred N-of above-mentioned N-aryl piperazine derivative; 2-benzisothiazole-3-yl)-and the 1-piperazinyl] ethyl]-3; 3-pentamethylene glutarimide, N-[3-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] propyl group]-3, [[4-(1 for 4-for 3-pentamethylene glutarimide or N-; 2-benzisothiazole-3-yl)-and the 1-piperazinyl] butyl]-3,3-pentamethylene glutarimide.
The above-claimed cpd also form of available pharmacy acceptable salt uses; These salt comprise inorganic acid salt and organic acid salt, as: hydrochloride, vitriol, phosphoric acid salt, nitrate salt, PHENRAMINE MALEATE, fumarate, methylsulfonic acid hydrochlorate, tosilate, tartrate etc.
The preparation method of above-claimed cpd is following:
Wherein: n is an integer among the 1-6.
Among the above-mentioned preparation method, raw material 3,3-pentamethylene glutarimide (formula (II) compound), Br (CH
2)
nCl and 1-(1,2-benzisothiazole-3-yl) piperazine (formula (IV) compound) is commercially available getting, and above-mentioned reaction can be carried out under normal pressure.
Compound disclosed by the invention is to D
2And 5-HT
2AHave dual antagonistic action, can improve negative symptoms and positive symptom simultaneously, reduce spinoffs such as EPS, the compound of the spirit class disease that a kind of new treatment cns Dopamine HCL and the disorder of serotonin mediator cause is provided.
The present invention also provides a kind of pharmaceutical composition that is used to treat the spirit type disease that cns Dopamine HCL and the disorder of serotonin mediator cause; Contain above-claimed cpd or its pharmacy acceptable salt of treating significant quantity, and acceptable accessories.
Embodiment
Embodiment 1
N-[3-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] propyl group]-3,3-pentamethylene glutarimide hydrochloride
3,3-pentamethylene glutarimide 0.9g (5mmol), 1-bromo-3-chloropropane 0.79g (5mmol), salt of wormwood 1.5g (11mmol) be 90 ℃ of stirring 2h in 10mlDMF (N), add 1-(1,2-benzisothiazole-3-yl) piperazine 0.87g (4mmol) and continue under this temperature and stir 5h; Reaction is put in the cold backlash entry, uses ethyl acetate extraction, and organic layer is through washing; The salt washing, dried over mgso concentrates dried solvent; Add the Virahol dissolving, add HCl-EtOH (hydrochloric acid-ethanol) solution again and separate out solid to pH=3; Cross and filter white solid 0.7g, mp (fusing point): 250 ℃, ESI-MS (m/z): 440.54 (M+H).
Embodiment 2
N-[4-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] butyl]-3,3-pentamethylene glutarimide hydrochloride
3,3-pentamethylene glutarimide 0.8g (4.4mmol), 1-bromo-4-chlorobutane 0.7g (4.4mmol), salt of wormwood 1.4g (10.3mmol) be 90 ℃ of stirring 2h in 10mlDMF, add 1-(1,2-benzisothiazole-3-yl) piperazine 0.8g (3.7mmol) and continue under this temperature and stir 5h; Reaction is put in the cold backlash entry, uses ethyl acetate extraction, and organic layer is through washing; The salt washing, dried over mgso concentrates dried solvent; Add the Virahol dissolving, add HCl-EtOH solution again, separate out solid to pH=3; Cross and filter white solid 0.6g, mp:200-204 ℃, ESI-MS (m/z): 454.56 (M+H).
Embodiment 3
N-[2-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] ethyl]-3,3-pentamethylene glutarimide
3,3-pentamethylene glutarimide 1g (5.6mmol), 1-bromo-2-monochloroethane 0.9g (5.7mmol), salt of wormwood 1.6g (11.7mmol) be 90 ℃ of stirring 2h in 10mlDMF (N), add 1-(1; 2-benzisothiazole-3-yl) piperazine 1g (4.6mmol) continues under this temperature and stirs 5h; Reaction is put in the cold backlash entry, separates out solid, crosses to filter white solid 0.8g; Mp (fusing point): 280 ℃, ESI-MS (m/z): 431.52 (M+H).
Effect embodiment 1
With the experimental technique of (The Journal of Biological Chemistry, Vol.265, No.8, pp.4507-4514,1990) such as Senogles, measure The compounds of this invention to D
2The avidity of acceptor is used the stably express people dopamine D of recombinating
2LThe Chinese hamster ovary celI of acceptor, under 30 ℃, compound to be measured and/or solvent and cytolemma (concentration is 0.1mg/ml) and 10mM GDP were hatched 20 minutes in the buffered soln at the HEPES (pH 7.4) of gentleness, added the SPA magnetic bead then and hatched 60 minutes again.Reaction by 0.3nM [
35S] GTP γ S starts, and passed through 15 minutes incubation period.Compare with the 1mM Dopamine HCL, testing compound induce [
35S] GTP γ S association reaction increased by 50% or more, represents it possibly have dopamine D
2LReceptor agonist activity.Testing compound if more can make 10 μ M Induced by Dopamine [
35S] GTP γ S association reaction inhibition 50% or more, promptly have receptor antagonist activity.Record under the 30nM concentration test-compound to D
2The combination rate of acceptor, the result is following:
| Compound | Concentration (nM) | Combination rate (%) |
| Embodiment 1 | 30 | 83 |
| Embodiment 2 | 30 | 86 |
| Embodiment 3 | 30 | 92 |
| Aripiprazole | 30 | 96 |
Visible by above-mentioned effect embodiment, 1,2,3 couples of D of embodiment
2The combination rate of acceptor is near Aripiprazole, and therefore, N-aryl piperazine derivative of the present invention is to D
2The combination rate of acceptor is better, and is better for the effect of blocking-up Dopamine HCL conduction path.
Combine experiment with GTP γ S: with CHO-K1 cell transfecting plasmid, stably express goes out people's serotonin 5-HT
2AAcceptor is used to prepare cytolemma, and this operates under gentle Tris-HCl, the pH 7.4 buffered soln conditions and carries out with the standard operation technology.Under 25 ℃, 30 μ g membranins with 0.5nM [
3H] Ketanserin induced 60 minutes, with 1 μ M mianserin assessment non-specific binding.Flushing and filtration cell film each three times.Statistics filtrating component with decide [
3H] combination of Ketanserin specificity.The test test-compound is to 5-HT
2AThe antagonistic action of acceptor, the result is following:
| Compound | Concentration (nM) | Combination rate (%) |
| Embodiment 1 | 30 | 94 |
| Embodiment 2 | 30 | 97 |
| Embodiment 3 | 30 | 91 |
| Aripiprazole | 30 | 80 |
Visible by above-mentioned effect embodiment, 1,2,3 couples of 5-HT of embodiment
2AThe combination rate of acceptor all is higher than Aripiprazole, and therefore, N-aryl piperazine derivative provided by the present invention is to 5-HT
2AThe antagonistic action of acceptor is very good, and is very good to the effect of blocking 5-hydroxytryptamine acceptor.
To sum up, the medicine of the new N-aryl piperazine derivative provided by the present invention spirit class disease that to be a kind of ideal treatment cns Dopamine HCL cause with the disorder of serotonin mediator.
Claims (8)
1. N-aryl piperazine derivative, it is formula (I) compound or its pharmacy acceptable salt:
Wherein: n is an integer among the 1-6.
2. N-aryl piperazine derivative according to claim 1 is characterized in that: n is an integer among the 2-4.
3. N-aryl piperazine derivative according to claim 2; It is characterized in that: said N-aryl piperazine derivative is N-[2-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] ethyl]-3, and [[4-(1 for 3-for 3-pentamethylene glutarimide, N-; 2-benzisothiazole-3-yl)-and the 1-piperazinyl] propyl group]-3; 3-pentamethylene glutarimide or N-[4-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] butyl]-3,3-pentamethylene glutarimide.
4. N-aryl piperazine derivative according to claim 2 is characterized in that: said salt comprises hydrochloride, vitriol, phosphoric acid salt, nitrate salt, PHENRAMINE MALEATE, fumarate, methylsulfonic acid hydrochlorate, tosilate or tartrate.
5. the application of each described N-aryl piperazine derivative of claim 1 to 4 in the medicine of the spirit class disease that preparation treatment cns Dopamine HCL and the disorder of serotonin mediator cause.
6. pharmaceutical composition that is used to treat the spirit type disease that cns Dopamine HCL and the disorder of serotonin mediator cause; It is characterized in that: contain each described compound of claim 1 to 4 or its pharmacy acceptable salt of treating significant quantity, and acceptable accessories.
7. the application of the described pharmaceutical composition of claim 6 in the medicine of the spirit class disease that preparation treatment cns Dopamine HCL and the disorder of serotonin mediator cause.
8. the preparation method of the described N-aryl piperazine derivative of claim 1, said method is with formula (II) compound and Br (CH
2)
nThe Cl reaction makes with the reaction of formula (IV) compound then:
Wherein: n is an integer among the 1-6.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009100528628A CN101575336B (en) | 2009-06-10 | 2009-06-10 | N-aryl piperazine derivative and preparation method thereof and drug composition adopting N-aryl piperazine derivative as active ingredient |
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|---|---|---|---|
| CN2009100528628A CN101575336B (en) | 2009-06-10 | 2009-06-10 | N-aryl piperazine derivative and preparation method thereof and drug composition adopting N-aryl piperazine derivative as active ingredient |
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| CN101575336B true CN101575336B (en) | 2012-03-14 |
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| CN108440520A (en) * | 2018-03-12 | 2018-08-24 | 首都医科大学 | Benzo isothiazole compound and preparation method thereof and the purposes in terms for the treatment of depression |
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