CN102260290A - Quinolinone compounds, and application thereof in preparing antipsychotic drugs - Google Patents
Quinolinone compounds, and application thereof in preparing antipsychotic drugs Download PDFInfo
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- CN102260290A CN102260290A CN2010101812639A CN201010181263A CN102260290A CN 102260290 A CN102260290 A CN 102260290A CN 2010101812639 A CN2010101812639 A CN 2010101812639A CN 201010181263 A CN201010181263 A CN 201010181263A CN 102260290 A CN102260290 A CN 102260290A
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Abstract
The invention relates to quinolinone compounds which can be a partial agonist for dopamine D2 receptor and also a partial agonist for 5-hydroxytryptamine (5-HT) receptor. The quinolinone compounds have a partial agitating action on 5-HT1A receptor, and have an antagonistic action on 5-HT2A. Therefore, the quinolinone compounds or medicine composition containing the quinolinone compounds can be used for improving anxiety, depression, cognitive deficit and negative symptoms.
Description
Technical field
The present invention relates to quinoline quinoline ketone compounds and they in the preparation psychosis medicine purposes in the dysthymia disorders medicine particularly.
Background technology
Dopamine HCL is present in maincenter and peripheral tissues widely as the 3rd acacatechin amine neurotransmitter, and is synthesized at the different sites of maincenter and peripheral tissues.Dopamine Receptors can be divided into D1 and two families of D2; Wherein D1 family comprises D1 and two hypotypes of D5, but its activated adenyl cyclase; D2 family comprises D2, D3 and three hypotypes of D4.Dopamine Receptors plays a major role in the effect of intermediary's antipsychotic drug.At the D2 acceptor, D2 acceptor branch agonist centering limbic brain path can produce functional antagonistic action, can effectively improve the positive symptom that schizophrenia causes because of the D2 over-activity; Centering cortex path can produce functional agonism, improves the caused negative symptoms of D2 hypofunction, cognitive impairment; To the nigrostriatum path, partial agonist is blocked the nigrostriatum path fully unlike antagonist, seldom causes The extrapyramidal symptoms (EPS); To tubercle funnel path,, cause that seldom prolactin level raises because of it is not the activity of blocking tubercle funnel path Dopamine HCL fully.
Serotonin is very high at cerebral cortex and nerve synapse intensive amount, is to regulate neururgic a kind of important substance, and it can have different pharmacological actions by activating different 5-HT receptor subtypes.
Summary of the invention
Technical problem to be solved by this invention provide a kind of quinoline the quinoline ketone compounds, it can be used as the optionally partial agonist of target 5-hydroxytryptamine receptor, d2 dopamine receptor.
For solving above technical problem, the present invention takes following technical scheme:
Compound with general formula (I):
In the formula (I):
R
01, R
02, R
03, R
04, R
05, R
06, R
07, R
08, R
09, be hydrogen or deuterium independently;
R
NFor being selected from a kind of in the following groups:
H、OH、CH
2Ra、OCH
2Ra、COR
c、CHRdRi、(CH
2)nRj、
And
Wherein:
Ra represents H; C1～C5 alkyl; C1～C8 alkyl that one or more fluorine atoms replace; Phenyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing; Perhaps pyridyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for replacing;
R
cExpression H, CH
2Ra, OCH
2Ra, C2～C12 secondary amine, CHRd (NHRe), NReCHRd (COORg), 2-furyl, 1-connection hexahydropyridine base or 1-morpholinyl;
Rd is H or C1～C6 alkyl;
Re is H, CH
2Rf, C1～C7 carbonyl or C1～C7 ester group;
Rg represents H or CH
2Rf;
Rf represents C1～C5 alkyl; C1～C8 alkyl that one or more fluorine atoms replace; Phenyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing; Perhaps Rf represents pyridyl, and it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing;
Ri represents NReCHRd (COORg), OCOCHRd (NHRe) or OCOORg;
Rj represents 2-furyl, 1-connection hexahydropyridine base or 1-morpholinyl;
N is the integer between 1～6, and Y represents C1～C6 alkyl.
According to the present invention, n is preferably 2 or 3.
According to the present invention, representational compound has the compound of formula II, formula III, formula IV, formula (V), formula VI, formula (VII) and formula (VIII) expression.
According to the present invention, described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, maleate, benzene sulfonate, toluenesulfonate, fumarate, tartrate etc.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
The quinoline that the present invention relates to the quinoline ketone compounds be partial agonist at d2 dopamine receptor, simultaneously, its still be serotonin (5-HT) acceptor and partial agonist, the 5-HT1A acceptor is had the part agonism, 5-HT2A is had antagonistic action.Therefore, the present invention or comprise pharmaceutical composition of the present invention and can be used for improving schizoid anxiety, depression, cognitive impairment and negative symptoms.
Embodiment
The present invention will be further described in detail below in conjunction with specific embodiment, but the present invention is not limited to following examples.
Embodiment 1
The compound that present embodiment provides a kind of formula II to represent:
Embodiment 2
The compound that present embodiment provides a kind of formula III to represent:
Embodiment 3
The compound that present embodiment provides a kind of formula IV to represent:
Embodiment 4
Present embodiment provides the compound of a kind of formula (V) expression:
Embodiment 5
The compound that present embodiment provides a kind of formula VI to represent:
Embodiment 6
Present embodiment provides the compound of a kind of formula (VII) expression:
Embodiment 7
Present embodiment provides the compound of a kind of formula (VIII) expression:
Claims (5)
1. the compound and the pharmacologically acceptable salt thereof that have general formula (I):
In the formula (I):
R
01, R
02, R
03, R
04, R
05, R
06, R
07, R
08, R
09, be hydrogen or deuterium independently;
R
NFor being selected from a kind of in the following groups:
H、OH、CH
2Ra、OCH
2Ra、CORc、CHRdRi、(CH
2)nRj、
Wherein:
Ra represents H; C1～C5 alkyl; C1～C8 alkyl that one or more fluorine atoms replace; Phenyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing; Perhaps pyridyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for replacing;
Rc represents H, CH
2Ra, OCH
2Ra, C2～C12 secondary amine, CHRd (NHRe), NReCHRd (COORg), 2-furyl, 1-connection hexahydropyridine base or 1-morpholinyl;
Rd is H or C 1～C6 alkyl;
Re is H, CH
2Rf, C1～C7 carbonyl or C1～C7 ester group;
Rg represents H or CH
2Rf;
Rf represents C1～C5 alkyl; C1～C8 alkyl that one or more fluorine atoms replace; Phenyl, it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing; Perhaps Rf represents pyridyl, and it is perhaps replaced by one or more groups that are selected from fluorine, chlorine, bromine, C1～C6 alkoxyl group, C1～C6 sulfydryl, C1～C6 amido for not replacing;
Ri represents NReCHRd (COORg), OCOCHRd (NHRe) or OCOORg;
Rj represents 2-furyl, 1-connection hexahydropyridine base or 1-morpholinyl;
N is the integer between 1～6, and Y represents C1～C6 alkyl.
2. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: described n is 2 or 3.
3. compound according to claim 1 and pharmacologically acceptable salt thereof is characterized in that: described compound is a kind of in the compound of formula II, formula III, formula IV, formula V, formula VI, formula (VII) and formula (VIII) expression.
4. but described compound of claim 1 and drug salts thereof the purposes in preparation psychosis medicine.
5. purposes according to claim 4 is characterized in that: described psychosis medicine is for improving the medicine of dysthymia disorders, schizophrenia positive symptom, negative symptoms, anxiety-depression, cognitive defect.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101812639A CN102260290A (en) | 2010-05-25 | 2010-05-25 | Quinolinone compounds, and application thereof in preparing antipsychotic drugs |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101812639A CN102260290A (en) | 2010-05-25 | 2010-05-25 | Quinolinone compounds, and application thereof in preparing antipsychotic drugs |
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| CN102260290A true CN102260290A (en) | 2011-11-30 |
Family
ID=45007150
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| WO2014031584A1 (en) * | 2012-08-21 | 2014-02-27 | Janssen Pharmaceutica Nv | Haptens of aripiprazole and their use in immunoassays |
| US10112903B2 (en) | 2009-06-25 | 2018-10-30 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| US10175257B2 (en) | 2012-08-21 | 2019-01-08 | Janssen Pharmaceutica Nv | Antibodies to aripiprazole and use thereof |
| US10379105B2 (en) | 2012-08-21 | 2019-08-13 | Janssen Pharmaceutica Nv | Antibodies to aripiprazole haptens and use thereof |
| US10712353B2 (en) | 2012-08-21 | 2020-07-14 | Janssen Pharmaceutica Nv | Antibodies to olanzapine haptens and use thereof |
| CN113181183A (en) * | 2021-05-20 | 2021-07-30 | 桂林医学院 | Application of cabergoline in preparing medicine composition for treating anxiety disorder |
| US11273158B2 (en) | 2018-03-05 | 2022-03-15 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
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2010
- 2010-05-25 CN CN2010101812639A patent/CN102260290A/en active Pending
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|---|---|---|---|---|
| US10112903B2 (en) | 2009-06-25 | 2018-10-30 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| US11518745B2 (en) | 2009-06-25 | 2022-12-06 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| US10822306B2 (en) | 2009-06-25 | 2020-11-03 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| US10351529B2 (en) | 2009-06-25 | 2019-07-16 | Alkermes Pharma Ireland Limited | Heterocyclic compounds for the treatment of neurological and psychological disorders |
| US10379105B2 (en) | 2012-08-21 | 2019-08-13 | Janssen Pharmaceutica Nv | Antibodies to aripiprazole haptens and use thereof |
| US10488401B2 (en) | 2012-08-21 | 2019-11-26 | Janssen Pharmaceutica Nv | Antibodies to aripiprazole haptens and use thereof |
| US9795685B2 (en) | 2012-08-21 | 2017-10-24 | Janssen Pharmaceutica Nv | Haptens of aripiprazole |
| US10166296B2 (en) | 2012-08-21 | 2019-01-01 | Janssen Pharmaceutica Nv | Haptens of aripiprazole |
| US10175257B2 (en) | 2012-08-21 | 2019-01-08 | Janssen Pharmaceutica Nv | Antibodies to aripiprazole and use thereof |
| US9504682B2 (en) | 2012-08-21 | 2016-11-29 | Janssen Pharmaceutica Nv | Haptens of aripiprazole |
| WO2014031584A1 (en) * | 2012-08-21 | 2014-02-27 | Janssen Pharmaceutica Nv | Haptens of aripiprazole and their use in immunoassays |
| EP3321254A1 (en) * | 2012-08-21 | 2018-05-16 | Janssen Pharmaceutica NV | Haptens of aripiprazole and their use in immunoassays |
| US10712353B2 (en) | 2012-08-21 | 2020-07-14 | Janssen Pharmaceutica Nv | Antibodies to olanzapine haptens and use thereof |
| US10816561B2 (en) | 2012-08-21 | 2020-10-27 | Janssen Pharmaceutica Nv | Antibodies to aripiprazole and use thereof |
| JP2015527363A (en) * | 2012-08-21 | 2015-09-17 | ヤンセン ファーマシューティカ エヌ．ベー． | Aripiprazole haptens and their use in immunoassays |
| CN104822660A (en) * | 2012-08-21 | 2015-08-05 | 詹森药业有限公司 | Haptens of aripiprazole and their use in immunoassays |
| US11105793B2 (en) | 2012-08-21 | 2021-08-31 | Janssen Pharmaceutica Nv | Antibodies to aripiprazole haptens and use thereof |
| US11226345B2 (en) | 2012-08-21 | 2022-01-18 | Janssen Pharmaceutica Nv | Antibodies to olanzapine haptens and use thereof |
| US11273158B2 (en) | 2018-03-05 | 2022-03-15 | Alkermes Pharma Ireland Limited | Aripiprazole dosing strategy |
| CN113181183A (en) * | 2021-05-20 | 2021-07-30 | 桂林医学院 | Application of cabergoline in preparing medicine composition for treating anxiety disorder |
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Application publication date: 20111130 |