CN101607959A - The dihydroquinoline ketone derivatives, its preparation method and be the pharmaceutical composition of activeconstituents with this compound - Google Patents
The dihydroquinoline ketone derivatives, its preparation method and be the pharmaceutical composition of activeconstituents with this compound Download PDFInfo
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- CN101607959A CN101607959A CNA2009100533556A CN200910053355A CN101607959A CN 101607959 A CN101607959 A CN 101607959A CN A2009100533556 A CNA2009100533556 A CN A2009100533556A CN 200910053355 A CN200910053355 A CN 200910053355A CN 101607959 A CN101607959 A CN 101607959A
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Abstract
The invention provides a kind of new dihydroquinoline ketone derivatives, promptly compound or its pharmacy acceptable salt are right formula shown in the formula (I), and wherein: n is an integer among the 1-6, and A is that formula (II) or formula (III) structure are right formula.The pharmaceutical composition that contains formula (I) compound has better curative effect in the spiritual class disease that treatment central nervous system Dopamine HCL and the disorder of serotonin mediator cause.
Description
Technical field
The present invention relates to a kind of D of having
2And 5-HT
2AThe active dihydroquinoline ketone derivatives of dual combination, its preparation method and be the pharmaceutical composition of activeconstituents, and the application of their spiritual class diseases of causing in treatment central nervous system Dopamine HCL and the disorder of serotonin mediator with this compound.
Background technology
Psychosis is a kind of neurological disorder 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 antipsychotic drug of early stage listing such as trilafon, haloperidol etc. are better than 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 a class, 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 antipsychotic drug is D
2, 5-HT
2ADouble inhibitor, thereby can improve positive symptom and negative symptoms simultaneously, and reduced side effects such as extrapyramidal symptoms.This class atypical antipsychotic agnets has replaced classical antipsychotic 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 dihydroquinoline ketone derivatives 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, and A is formula (II) or formula (III) structure:
In the above-mentioned general formula, an integer among the preferred 2-4 of n.
The preferred 7-[2-[4-of above-mentioned dihydroquinoline ketone derivatives (6-fluoro-1,2-benzoisoxazole-3-yl)-and piperidino] oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone, 7-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-and piperidino] propoxy-]-3,4-dihydro-2 (1H)-quinolinone, 7-[4-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-and piperidino] butoxy]-3,4-dihydro-2 (1H)-quinolinone, 7-[2-[4-(1,2-benzisothiazole-3-yl)-and the 1-piperazinyl] oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone, 7-[3-[4-(1,2-benzisothiazole-3-yl)-and the 1-piperazinyl] propoxy-]-3,4-dihydro-2 (1H)-quinolinone or 7-[4-[4-(1,2-benzisothiazole-3-yl)-and the 1-piperazinyl] butoxy]-3,4-dihydro-2 (1H)-quinolinone.
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, maleate, fumarate, methylsulfonic acid hydrochlorate, tosilate, tartrate etc.
The preparation method of above-claimed cpd is as follows:
Wherein A, n are identical with above-mentioned definition, and X is Cl or Br.
Among the above-mentioned preparation method, 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone (formula (IV) compound) is commercially available getting, saturated dihalide
AH also 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 side effects such as extrapyramidal symptoms, the compound of the spiritual class disease that a kind of new treatment central nervous system Dopamine HCL and the disorder of serotonin mediator cause is provided.
The present invention also provides a kind of new pharmaceutical composition that is used for the treatment of the spiritual class disease that central nervous system Dopamine HCL and the disorder of serotonin mediator cause, contain above-claimed cpd or its pharmacy acceptable salt for the treatment of significant quantity, and acceptable accessories.
Embodiment
The preparation of intermediate
Embodiment 1:7-(2-chloroethoxy)-3, the preparation of 4-dihydro-2 (1H)-quinolinone
7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone 5g, salt of wormwood 8.5g, 1,2-ethylene dichloride 50ml is backflow 12h in 25mlDMF (dimethyl formamide), reaction solution pours in the water, ethyl acetate extraction, and organic layer is washed once with 10% sodium hydroxide solution, washing again, use dried over mgso subsequently, concentrating under reduced pressure, residual solid adds toluene and stirs, filter, oven dry gets white powder 3.3g, mp (fusing point): 130-132 ℃.
Embodiment 2:7-(3-chlorine propoxy-)-3, the preparation of 4-dihydro-2 (1H)-quinolinone
7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone 5g, salt of wormwood 8.5g, 1-bromo-3-chloropropane 9.4g be 70 ℃ of stirring 3h in 25mlDMF, and reaction solution pours in the water, stir and moments later separate out solid, filter, filter cake is recrystallization in methyl alcohol, get white powder 5.7g, mp:116-120 ℃.
Embodiment 3:7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone
7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone 5g, salt of wormwood 8.5g, 1-bromo-4-chlorobutane 10.5g be 70 ℃ of stirring 3h in 25mlDMF, and reaction solution pours in the water, stir and moments later separate out solid, filter, filter cake is recrystallization in methyl alcohol, get white powder 5.0g, mp:102-104 ℃.
The preparation of dihydroquinoline ketone derivatives
Embodiment 4
7-[2-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-piperidino] oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
7-(2-chloroethoxy)-3,4-dihydro-2 (1H)-quinolinone 0.5g, 4-(6-fluoro-1,2-benzoisoxazole-3-yl) piperidine hydrochlorate 0.5g, salt of wormwood 0.55g be 100 ℃ of stirring 4h in 10mlDMF, reaction solution pours in the water, use ethyl acetate extraction, washing again, salt washing, use dried over mgso subsequently, concentrate, resistates adds the HCl-ethanolic soln to pH=3, filters, get pale yellow powder 0.4g, mp:218-221 ℃.
ESI-MS(m/z)：409.38(M+H)
1H?NMR(DMSO-d6，400M)
δ：2.24-2.52(m，5H)，2.79(t，2H)，3.13(m，4H)，3.63(m，2H)，4.02(t，2H)，6.51(m，2H)，7.06(d，1H)，7.33(m，1H)，7.70(dd，1H)，8.16(dd，1H)，9.96(s，1H).
Embodiment 5
7-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-piperidino] propoxy-]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
7-(3-chlorine propoxy-)-3,4-dihydro-2 (1H)-quinolinone 1.1g, 4-(6-fluoro-1,2-benzoisoxazole-3-yl) piperidine hydrochlorate 1.0g, salt of wormwood 1.1g be 100 ℃ of stirring 4h in 10mlDMF, reaction solution pours in the water, uses ethyl acetate extraction, and organic layer is through washing, salt washing, dried over mgso, concentrate 2.2g oily matter, add dissolve with ethanol, drip HCl-ethanol to pH=3, separate out solid, filter, get pale yellow powder 1.5g, mp:163-166 ℃.
ESI-MS(m/z)：423.48(M+H)
1H?NMR(DMSO-d6，400M)
δ：2.21-2.44(m，9H)，2.79(t，2H)，3.13(m，4H)，3.63(m，2H)，4.02(t，2H)，6.51(m，2H)，7.06(d，1H)，7.33(m，1H)，7.70(dd，1H)，8.16(dd，1H)，9.96(s，1H).
Embodiment 6
7-[4-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-piperidino] butoxy]-3,4-dihydro-2 (1H)-quinolinone hydrochloride
7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone 0.55g, 4-(6-fluoro-1,2-benzoisoxazole-3-yl) piperidine hydrochlorate 0.5g, salt of wormwood 0.55g be 100 ℃ of stirring 4h in DMF10ml, reaction solution pours in the water, uses ethyl acetate extraction, and organic layer is through washing, the salt washing, dried over mgso concentrates, resistates adds acetone solution, drip HCl-ethanol to pH=3, separate out solid, filter, get pale yellow powder 0.5g, mp:120-124 ℃.
ESI-MS(m/z)：437.54(M+H)
1H?NMR(DMSO-d6，400M)
δ：1.76-1.92(m，4H)，2.21-2.44(m，7H)，2.79(t，2H)，3.13(m，4H)，3.63(m，2H)，3.94(t，2H)，6.50(m，2H)，7.05(d，1H)，7.33(m，1H)，7.70(dd，1H)，8.19(dd，1H)，9.93(s，1H).
Embodiment 7
7-[2-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone
7-(2-chloroethoxy)-3,4-dihydro-2 (1H)-quinolinone 1.4g, 1-(1,2-benzisothiazole-3-yl) piperazine 0.91g, salt of wormwood 0.87g be 100 ℃ of stirring 8h in DMF10ml, reaction solution pours in the water, use ethyl acetate extraction, organic layer is through washing, and salt is washed, dried over mgso, be evaporated to the 5ml volume, separate out solid, filtering drying, get white solid 0.5g, mp:190-192 ℃.
ESI-MS(m/z)：408.54(M+H)
1H?NMR(CDCl
3，400M)
δ：2.61(t，2H)，2.80-2.92(m，8H)，3.59(t，4H)，4.14(t，2H)，6.32(d，1H)，6.57(dd，1H)，7.05(d，1H)，
7.33-7.48(m，2H)，7.54(s，1H)，7.80(m，1H)，7.90(d，1H).
Embodiment 8
7-[3-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] propoxy-]-3,4-dihydro-2 (1H)-quinolinone
7-(3-chlorine propoxy-)-3,4-dihydro-2 (1H)-quinolinone 1.44g, 1-(1,2-benzisothiazole-3-yl) piperazine 1.1g, salt of wormwood 0.83g be 100 ℃ of stirring 5h in DMF10ml, and reaction is poured in the water, use ethyl acetate extraction, organic layer is through washing, and salt is washed, dried over mgso, be concentrated into the 5ml volume, separate out solid, filtering drying gets white solid 1.26g, mp:145-147 ℃.
ESI-MS(m/z)：422.34(M+H)
1H?MR(CDCl
3，400M)
δ：1.98(m，2H)，2.59-2.71(m，8H)，2.89(t，2H)3.57(t，4H)，4.03(t，2H)，6.31(d，1H)，6.54(dd，1H)，
7.03(d，1H)，7.43-7.47(m，2H)，7.67(s，1H)，7.79(m，1H)，7.89(m，1H).
Embodiment 9
7-[4-[4-(1,2-benzisothiazole-3-yl)-1-piperazinyl] butoxy]-3,4-dihydro-2 (1H)-quinolinone
7-(4-chlorine butoxy)-3,4-dihydro-2 (1H)-quinolinone 1.52g, 1-(1,2-benzisothiazole-3-yl) piperazine 1.1g, salt of wormwood 0.83g 100 ℃ of stirring 5h in DMF10ml, reaction is poured in the water, add ethyl acetate, stir a moment, separate out product, filter product 1.2g, mp:173-176.
ESI-MS(m/z)：436.24(M+H)
1H?NMR(CDCl
3，400M)
δ：1.69-1.87(m，4H)，2.47-2.91(m，10H)，3.55(t，4H)，3.97(t，2H)，6.28(d，1H)，6.52(dd，1H)，7.15(d，1H)，7.32-7.47(m，2H)，7.51(s，1H)，7.79(d，1H)，7.89(d，1H).
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 is 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 may 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 as follows:
| Compound | Concentration (nM) | Combination rate (%) |
| Embodiment 5 | ??30 | ??87 |
| Embodiment 6 | ??30 | ??92 |
| Embodiment 8 | ??30 | ??83 |
| Embodiment 9 | ??30 | ??96 |
| Aripiprazole | ??30 | ??96 |
By above-mentioned effect embodiment as seen, 5,6,8 couples of D of embodiment
2The combination rate of acceptor is near Aripiprazole, 9 couples of D of embodiment
2The combination rate and the Aripiprazole of acceptor are suitable, and therefore, dihydroquinoline ketone derivatives 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.
With GTP γ S in conjunction with experiment: 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 membranin 0.5nM[
3H] Ketanserin induced 60 minutes, with 1 μ M mianserin assessment non-specific binding.Flushing and filtration cell film each three times, add up the filtrate component with decide [
3H] combination of Ketanserin specificity.The test test-compound is to 5-HT
2AThe antagonistic action of acceptor, the result is as follows:
| Compound | Concentration (nM) | Combination rate (%) |
| Embodiment 5 | ??30 | ??97 |
| Embodiment 6 | ??30 | ??74 |
| Embodiment 8 | ??30 | ??88 |
| Embodiment 9 | ??30 | ??86 |
| Aripiprazole | ??30 | ??80 |
By above-mentioned effect embodiment as seen, 6 couples of 5-HT of embodiment
2AThe combination rate of acceptor is near Aripiprazole, 5,8,9 couples of 5-HT of embodiment
2AThe combination rate of acceptor all is higher than Aripiprazole, and therefore, dihydroquinoline ketone derivatives 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, new dihydroquinoline ketone derivatives provided by the present invention is the medicine of the spiritual class disease that causes of a kind of ideal treatment central nervous system Dopamine HCL and the disorder of serotonin mediator.
Claims (8)
1. dihydroquinoline ketone derivatives, it is formula (I) compound or its pharmacy acceptable salt:
Wherein: n is an integer among the 1-6, and A is formula (II) or formula (III) structure:
2. dihydroquinoline ketone derivatives according to claim 1 is characterized in that: n is an integer among the 2-4.
3. dihydroquinoline ketone derivatives according to claim 2, it is characterized in that: described dihydroquinoline ketone derivatives is a 7-[2-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-and piperidino] oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone, 7-[3-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-and piperidino] propoxy-]-3,4-dihydro-2 (1H)-quinolinone, 7-[4-[4-(6-fluoro-1,2-benzoisoxazole-3-yl)-and piperidino] butoxy]-3,4-dihydro-2 (1H)-quinolinone, 7-[2-[4-(1,2-benzisothiazole-3-yl)-and the 1-piperazinyl] oxyethyl group]-3,4-dihydro-2 (1H)-quinolinone, 7-[3-[4-(1,2-benzisothiazole-3-yl)-and the 1-piperazinyl] propoxy-]-3,4-dihydro-2 (1H)-quinolinone or 7-[4-[4-(1,2-benzisothiazole-3-yl)-and the 1-piperazinyl] butoxy]-3,4-dihydro-2 (1H)-quinolinone.
4. dihydroquinoline ketone derivatives according to claim 2 is characterized in that: described salt comprises hydrochloride, vitriol, phosphoric acid salt, nitrate, maleate, fumarate, methylsulfonic acid hydrochlorate, tosilate or tartrate.
5. the application of the spiritual class disease that causes in treatment central nervous system Dopamine HCL and the disorder of serotonin mediator of each described dihydroquinoline ketone derivatives of claim 1 to 4.
6. pharmaceutical composition that is used for the treatment of the spiritual class disease that central nervous system 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 for the treatment of significant quantity, and acceptable accessories.
7. the application of the spiritual class disease that causes in treatment central nervous system Dopamine HCL and the disorder of serotonin mediator of the described pharmaceutical composition of claim 6.
8. the preparation method of the described dihydroquinoline ketone derivatives of claim 1, described method is with formula (IV) compound and saturated dihalide
Reaction makes with the reaction of AH compound then:
Wherein n is an integer among the 1-6, and X is Cl or Br, and A is formula (II) or formula (III) structure:
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101693711B (en) * | 2009-10-23 | 2011-08-17 | 杜玉民 | 3-(1-piperazinyl)-1,2-benzisothiazole derivative as well as synthesizing method and application thereof |
| WO2012130153A1 (en) * | 2011-03-31 | 2012-10-04 | 江苏恒谊药业有限公司 | Quinolinone derivatives and use thereof as medicament against schizophrenia |
-
2009
- 2009-06-18 CN CNA2009100533556A patent/CN101607959A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101693711B (en) * | 2009-10-23 | 2011-08-17 | 杜玉民 | 3-(1-piperazinyl)-1,2-benzisothiazole derivative as well as synthesizing method and application thereof |
| WO2012130153A1 (en) * | 2011-03-31 | 2012-10-04 | 江苏恒谊药业有限公司 | Quinolinone derivatives and use thereof as medicament against schizophrenia |
| CN102718758A (en) * | 2011-03-31 | 2012-10-10 | 江苏恒谊药业有限公司 | Quinolinone derivative and application thereof as anti-schizophrenic drug |
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Open date: 20091223 |