CN106966953A - A kind of preparation method and applications of novel dopamine D3 receptor selective ligands - Google Patents
A kind of preparation method and applications of novel dopamine D3 receptor selective ligands Download PDFInfo
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- CN106966953A CN106966953A CN201710130807.0A CN201710130807A CN106966953A CN 106966953 A CN106966953 A CN 106966953A CN 201710130807 A CN201710130807 A CN 201710130807A CN 106966953 A CN106966953 A CN 106966953A
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- piperazine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/38—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D277/82—Nitrogen atoms
Abstract
The invention discloses a kind of preparation method and applications of novel dopamine D3 receptor selective ligands; BIDA is led by piperazine compounds and N (4 brombutyl) phthalimide reaction generation piperazine; by deprotection, with CDI and aromatic amine coupling generation end-product piperazine carbamide compounds.Compared to the prior art, the dopamine D 3 receptor selective ligands that the present invention is described selectively are higher than 10000 times；Piperazine aromatic amides class compound compared to before, piperazine aryl urea compound of the invention has higher dissolubility, bioavilability and the ability for penetrating blood-brain barrier；The combination of the compound of the present invention not only to D3 acceptor specificities, but also the downstream signaling pathway of the activation D3 acceptors of selectivity, and to the signal path of D2 acceptors and D4 acceptors without effect, therefore distribution, result and the function of D3 acceptors can be studied as molecular probe and tool molecule.
Description
Technical field
The present invention relates to biomedicine field, specifically a kind of preparation method of novel dopamine D3 receptor selective ligands
And its application.
Background technology
Dopamine is Catecholamines Neurotransmitters in Blood, and dopamine receptor is transferred to by nerve synapse, activates downstream signal
Path and play regulation motion, cognition, the effect of the physiological function such as emotion.According to function and structure, dopamine receptor mainly divides
For two classes, D1 classes and D2 classes.D1 classes include D1 acceptors and D5 acceptors, are mainly coupled and activated adenyl cyclase and second with Gs
Courier；D2 classes include D2 acceptors, D2 acceptors and D4 acceptors, suppress adenyl cyclase and second messenger.D2 acceptors are mainly distributed
In carious tooth class and the caudate putamen and nucleus accumbens septi of primate, the distribution at other positions is reduced, and these regions are mainly with fortune
Dynamic function is related.Compared to the distribution of D2 acceptors, D3 acceptors are relatively low in the distribution density of respective regions, but D3 acceptors are in veutro
Globus pallidus, black substance, the distribution of thalamus and habenula are far above D2 acceptors, and only have D3 acceptors to be distributed and nothing in dorsal part corpus straitum
D2 acceptors are distributed], and these regions and cognitive, emotion are closely bound up.Therefore, D3 acceptors and the close phase of a variety of neuropsychopathys
Close, such as Parkinson's, sex dysfunction, schizophrenia, pharmacological dependence and drug habit.D2 acceptors and D3 acceptors in D2 classes
With very high similitude and homology, thus clinical conventional antipsychotics has very low selection to D2R and D3R
Property, therefore, these medicines can have certain side effect, such as the extrapyramidal symptoms, hyperprolactinemia etc..Anti-Parkinson's drug
Thing shows the pair work such as Nausea and vomiting, abalienation and postural hypotension also in that selectively relatively low to D2R and D3R
With.
D3 receptor selective ligands will not produce above-mentioned adverse reaction, and selective ligands are sought by mediated brain source nerve
The foster factor plays neuroprotection and nerve regneration function.The dopamine of mesolimbic system is found in schizophreniac's intracerebral
D3 receptor expression levels are raised, therefore D3 receptor-selective inhibitor is expected to improve and treats schizoid positive symptom,
And the extrapyramidal symptoms of typical D2 acceptor inhibitors will not be brought.The inhibitor of D3 acceptors can mediate frontal cortex acetyl courage
The release of alkali, therefore, is conducive to regulation notice, work and Social Memory power, that is, improves negative schizophrenia.Preclinical examination
Test and show：D3 receptor-selective inhibitor S333138 are in psychotolytic effective dosage ranges without the mandatory faintness of discovery
Side effect.Importantly, compared to non-selective part, D3 receptor selective ligands do not find pharmacological dependence and medicine into
The characteristic of addiction.D3 acceptors are to reduce ***e addiction, effectively treat the target of opium, nicotine and ethanol dependence.
The postmortem of PD patient finds the D3R horizontal down-regulations 45% of basal ganglion, and D2R levels only lower 15-25%；Clothes
With non-anti- PD medicines, D3R horizontal down-regulation 48%, and anti-PD medicines are taken, D3R levels up-regulation 25%.Therefore, D3 acceptor selections
Property activator turned into the new strategy for the treatment of Parkinson, and D3R selective agonist can mitigate the fortune that levodopa amine is caused
Dynamic obstacle, and long-term taking D3R selective agonists can reduce PD dyskinesia.Gene knockout D3 acceptors cause long-term
Depressed and anxiety symptom, this also illustrates that D3 receptor stimulating agents contribute to treatment anxiety and depression.
Clinical at present and market medication lacks the dopamine D 3 R parts of high selectivity, sigma-aldrich and selleck
Decile word bank also lacks high selectivity D3R part, seriously hinders the distribution of dopamine D 3 receptor and the research of function.Cause
This, D3 acceptor high selectivity parts are the molecular probes for studying dopamine D 3 receptor function, and its related neurological disease cause of disease.
For the research of D3 receptor selective ligands, not only academia lets a hundred schools contend, and major pharmacy giants are also numerous and confused
March the field.(piperazine) pyridine of azepine [3,1,0] bis cyclohexane of GlaxoSmithKline PLC research, BASF and Abbott Laboratories' research takes
The benzsulfamide in generation, piperidines piperazine, benzene (pyridine) and the isoxazole piperazine of Roche research, the benzene of Pfizer is for morpholine class, Pierre
The chromene formamide selectivity of method uncle is not high, more non-functional selectivity].Research finds Aripiprazole homologue
UNC0006, UNC9975 and UNC9994 selectivity mediating dopamine D2 receptoroid β-arrestin signal paths, but to D2 by
The selectivity of body and D3 receptor signaling pathways is relatively low.Germany scientist finds o-diazepamate -3- formaldoximation compounds 8b selections
Property mediating dopamine acceptor gα protein signal path, but the same selectivity to D2 acceptors and D3 acceptors is relatively low.
Dopamine D 3 receptor selective ligands have a class to be 4- phenylpiperazines-amides compound, cause lipophilicity higher,
So water-soluble and bioavilability is relatively low.Also many selective ligands are chipal compounds, and separation is difficult, production cost
It is high, it is difficult to enter industrialized production and enter clinical.
The content of the invention
It is an object of the invention to provide a kind of preparation method of novel dopamine D3 receptor selective ligands, with solution
State the problem of being proposed in background technology.
To achieve the above object, the present invention provides following technical scheme：
A kind of preparation method of novel dopamine D3 receptor selective ligands, comprises the steps：
(1) by piperazine compounds, N- (4- brombutyls) phthalimide, K2CO3It is dissolved in acetonitrile, flows back with NaI
Reaction 6-8 hours, generates piperazine-neck BIDA, and reaction equation is as follows：
(2) piperazine-phthalimide ethanol is dissolved, adds Hydrazine, it is small in 60 DEG C of back flow reaction 6-8
When, piperazine-fatty amine is obtained, reaction equation is as follows：
(3) aromatic amine is added dropwise in CDI DCM solution, reacts at room temperature 6h, after TLC detection reactions completely, volatilization
Dry solvent, is dissolved, back flow reaction 6-8 hours after adding piperazine-fatty amine, DIEA with acetonitrile, is detected and reacted using TLC, obtained
End-product piperazine-carbamide compounds, reaction equation is as follows：
As scheme of the invention further, in step (1), piperazine class compound, N- (4- brombutyls) phthalyl are sub-
Amine, K2CO3Mol ratio with NaI is 1：1.05:3:0.3.
As scheme of the invention further, in step (2), piperazine-phthalimide and Hydrazine mole
Than for 1:3.
As scheme of the invention further, in step (3), aromatic amine, CDI, piperazine-fatty amine and DIEA mol ratio
For 1：1.4:1：1.6.
Described novel dopamine D3 receptor selective ligands are applied to treatment Nervous and mental diseases, including psychoneural
Class disease includes Parkinson's, dyskinesia, emotion and motivation obstacle, sex dysfunction, schizophrenia, pharmacological dependence
With drug habit etc..
Compared with prior art, the beneficial effects of the invention are as follows：The dopamine D 3 receptor selective ligands that the present invention is described
Selectivity is higher than 10000 times, there was only 13 times and 59 times compared to the selective highest ligand selectivity of document report before；Compare
Piperazine before-aromatic amides class compound, piperazine-aryl urea compound of the invention has higher dissolubility, biology
Availability and the ability for penetrating blood-brain barrier；Before without any document and patent report D3 function of receptors alternative cpds,
The combination of the compound of the present invention not only to D3 acceptor specificities, but also the downstream signal of the activation D3 acceptors of selectivity is logical
Road, and to the signal path of D2 acceptors and D4 acceptors without effect, therefore D3 can be studied as molecular probe and tool molecule
Distribution, result and the function of acceptor.
Brief description of the drawings
Fig. 1 be piperazine-phthalimide derivatives (100nM) Competitive assays experiment in radioligand
[3H]-Sulpiride substitution percentage.
Fig. 2 be piperazine-(3- quinolyls) carbamide compounds (100nM) Competitive assays experiment in radioligand
[3H]-Sulpiride substitution percentage.
Fig. 3 is that piperazine-(2-[4-morpholinodithio base) carbamide compounds (100nM) are matched somebody with somebody in Competitive assays experiment to radioactivity
Body [3H]-Sulpiride substitution percentage.
Fig. 4 be (4- chlorphenyls) piperazine compounds (100nM) Competitive assays experiment in radioligand [3H]-
The substitution percentage of Sulpiride.
Fig. 5 is piperazine-phthalimide representative compound 3h to D3R and D2R selectivity.
Fig. 6 is piperazine-aryl urea representative compound to one of D3R and D2R selectivity test result schematic diagrams.
Fig. 7 is piperazine-aryl urea representative compound to the two of D3R and D2R selectivity test result schematic diagrams.
Fig. 8 is piperazine-aryl urea representative compound to the three of D3R and D2R selectivity test result schematic diagrams.
Fig. 9 is piperazine-aryl urea representative compound to the four of D3R and D2R selectivity test result schematic diagrams.
Figure 10 is piperazine-aryl urea representative compound to the five of D3R and D2R selectivity test result schematic diagrams.
Figure 11 is piperazine-aryl urea representative compound to the six of D3R and D2R selectivity test result schematic diagrams.
Figure 12 is piperazine-aryl urea representative compound to the seven of D3R and D2R selectivity test result schematic diagrams.
Figure 13 is piperazine-aryl urea representative compound to the eight of D3R and D2R selectivity test result schematic diagrams.
Figure 14 is one of Parkinson's rat roller bearing experimental result that D3R selectivity 5e are induced 6- hydroxyl dopamines.
Figure 15 is the two of Parkinson's rat roller bearing experimental result that D3R selectivity 5e are induced 6- hydroxyl dopamines.
Figure 16 is one of Parkinson's rat roller bearing experimental result that D3R selectivity 5eHCl are induced 6- hydroxyl dopamines.
Figure 17 is the two of Parkinson's rat roller bearing experimental result that D3R selectivity 5eHCl are induced 6- hydroxyl dopamines.
Figure 18 is one of feature amount effect curve schematic diagram of D3R specificity part 5e and its hydrochloride.
Figure 19 is the two of the feature amount effect curve schematic diagram of D3R specificity part 5e and its hydrochloride.
Embodiment
The technical scheme in the embodiment of the present invention will be clearly and completely described below, it is clear that described implementation
Example only a part of embodiment of the invention, rather than whole embodiments.Based on the embodiment in the present invention, this area is common
The every other embodiment that technical staff is obtained under the premise of creative work is not made, belongs to the model that the present invention is protected
Enclose.
Experimental example 1：Selective screening of the piperazine-phthalimide class representative compound to D3R and D2R
Fig. 1 be piperazine-phthalimide derivatives (100nM) Competitive assays experiment in radioligand
[3H]-Sulpiride substitution percentage.
Experimental example 2：Selective screening of piperazine-(3- quinolyls) the carbamide compounds class representative compound to D3R and D2R
Fig. 2 be piperazine-(3- quinolyls) carbamide compounds (100nM) Competitive assays experiment in radioligand
[3H]-Sulpiride substitution percentage.
Experimental example 3：Selectivity of piperazine-(2-[4-morpholinodithio base) the carbamide compounds class representative compound to D3R and D2R
Screening
Fig. 3 is that piperazine-(2-[4-morpholinodithio base) carbamide compounds (100nM) are matched somebody with somebody in Competitive assays experiment to radioactivity
Body [3H]-Sulpiride substitution percentage.
Experimental example 4：Selective screening of (4- chlorphenyls) the piperazines class compounds representative compound to D3R and D2R
Fig. 4 be (4- chlorphenyls) piperazine compounds (100nM) Competitive assays experiment in radioligand [3H]-
The substitution percentage of Sulpiride.
Experimental example 5：Piperazine-phthalimide class representative compound is to D3R and D2R selectivity tests
Fig. 5 is piperazine-phthalimide representative compound 3h to D3R and D2R selectivity.
Comparative example 1：
Piperazine-aryl urea representative compound is to D3R and D2R selectivity tests
A few width figures of top are piperazine-aryl urea representative compound 5e, 5h, control compound 1 and 2 and its hydrochloride
To D3R and D2R selectivity.
The D3R ligand compounds of famous periodical J.Med.Chem. reports have very high selectivity, therefore are used as controlization
Compound.The drifting alkaloids affinity reduction of the two, many times, the hydrochloric acid of the two are improved by being prepared into hydrochloride affinity
Salt is selectively respectively 59 times and 13 times.And piperazine-aryl urea representative compound 5e, 5h and its hydrochloride are selectively respectively
>10000 times and 5000 times.
Experimental example 6：Effect of the D3 receptor selective ligands to neuropsychopathy
Figure 14-15 is Parkinson's rat roller bearing experimental result that D3R selectivity 5e are induced 6- hydroxyl dopamines.
Figure 16-17 is Parkinson's rat roller bearing experimental result that D3R selectivity 5eHCl are induced 6- hydroxyl dopamines.
In roller bearing experiment test, the Parkinson rat that D3R selective agonists 5e and its hydrochloride are induced 6-OHDA
The frequency that drops has reduction effect, to being separated with increasing action between dropping, and the effect with positive control medicine apomorphine is similar.
Experimental example 7：D3R specificities ligand function selectivity
Figure 18-19 is the feature amount effect curve of D3R specificity part 5e and its hydrochloride.
In functional test, compound 5e and its hydrochloric acid salt activator D3R downstream signaling pathways, without activating under D2R and D4R
Swim signal path.It therefore, it can the molecular probe and tool molecule as research dopamine D 3 receptor structure, distribution and function.
Experimental example 7：D3R selective ligands solubility tests
Solubility of the compound 5e of table 1 in absolute ethyl alcohol
| Concentration in ethanol | 10mg/mL | 5mg/mL | 3.3mg/mL |
| 5e | - | - | + |
Note：- represent that compound is insoluble or can not be completely dissolved ,+represent that compound can be completely dissolved
Solubility of the compound 5eHCl of table 2 in absolute ethyl alcohol
| Concentration in ethanol | 25.6mg/mL | 12.8mg/mL | 8.53mg/mL | 6.4mg/mL |
| 5e·HCl | - | - | - | + |
Note：- represent that compound is insoluble or can not be completely dissolved ,+represent that compound can be completely dissolved
By 2 forms above it is known that D3R selective ligands compounds 5e is through being prepared into hydrochloride, in absolute ethyl alcohol
In solubility improve 1 times.
The solubility of the compound 5e of table 3 and its hydrochloride in water-soluble
| Solubility in water | 12mg/mL | 6mg/mL | 3mg/mL | 1mg/mL |
| 5e | - | - | - | + |
| 5e·HCl | + | + | + | + |
Note：- represent that compound is insoluble or can not be completely dissolved ,+represent that compound can be completely dissolved
As seen from the above table, D3R selective ligands compound 5e is through being prepared into hydrochloride, and the solubility in water improves 12
Times.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit is required rather than described above is limited, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that for clarity, those skilled in the art should
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It may be appreciated other embodiment.
Claims (6)
1. a kind of preparation method of novel dopamine D3 receptor selective ligands, it is characterised in that comprise the steps：
(1) by piperazine compounds, N- (4- brombutyls) phthalimide, K2CO3It is dissolved in NaI in acetonitrile, back flow reaction
6-8 hours, piperazine-neck BIDA is generated, reaction equation is as follows：
(2) piperazine-phthalimide ethanol is dissolved, adds Hydrazine, in 60 DEG C of back flow reactions 6-8 hours, obtained
To piperazine-fatty amine, reaction equation is as follows：
(3) aromatic amine is added dropwise in CDI DCM solution, reacts at room temperature 6h, after TLC detection reactions completely, volatilization is dry molten
Agent, is dissolved, back flow reaction 6-8 hours after adding piperazine-fatty amine, DIEA with acetonitrile, is detected and reacted using TLC, obtains whole production
Thing piperazine-carbamide compounds, reaction equation is as follows：
2. the preparation method of novel dopamine D3 receptor selective ligands according to claim 1, it is characterised in that step
(1) in, piperazine class compound, N- (4- brombutyls) phthalimide, K2CO3Mol ratio with NaI is 1：1.05:3:0.3.
3. the preparation method of novel dopamine D3 receptor selective ligands according to claim 1, it is characterised in that step
(2) in, piperazine-phthalimide and Hydrazine mol ratio are 1:3.
4. the preparation method of novel dopamine D3 receptor selective ligands according to claim 1, it is characterised in that step
(3) in, aromatic amine, CDI, piperazine-fatty amine and DIEA mol ratio are 1：1.4:1：1.6.
5. a kind of application of novel dopamine D3 receptor selective ligands, it is characterised in that the novel dopamine D3 acceptors choosing
Selecting property part is used to treat Nervous and mental diseases.
6. the application of novel dopamine D3 receptor selective ligands according to claim 2, it is characterised in that psychoneural
Class disease includes Parkinson's, dyskinesia, emotion and motivation obstacle, sex dysfunction, schizophrenia, pharmacological dependence
And drug habit.
Priority Applications (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710130807.0A CN106966953A (en) | 2017-03-07 | 2017-03-07 | A kind of preparation method and applications of novel dopamine D3 receptor selective ligands |
| US16/488,533 US20200087264A1 (en) | 2017-02-24 | 2018-02-11 | Novel selective ligand for dopamine d3 receptor, preparation method therefor, and pharmaceutical application thereof |
| JP2019567773A JP7017797B2 (en) | 2017-02-24 | 2018-02-11 | Novel Dopamine D3 Receptor Selective Ligands and Methods for Preparation and Pharmaceutical Use |
| PCT/CN2018/076341 WO2018153297A1 (en) | 2017-02-24 | 2018-02-11 | Novel selective ligand for dopamine d3 receptor, preparation method therefor, and pharmaceutical application thereof |
| EP18757064.3A EP3587398A1 (en) | 2017-02-24 | 2018-02-11 | Novel selective ligand for dopamine d3 receptor, preparation method therefor, and pharmaceutical application thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108329282A (en) * | 2018-01-16 | 2018-07-27 | 新乡医学院 | A kind of phenylpiperazine analog derivative and its preparation method and application |
| WO2018153297A1 (en) * | 2017-02-24 | 2018-08-30 | 深圳市灵兰生物医药科技有限公司 | Novel selective ligand for dopamine d3 receptor, preparation method therefor, and pharmaceutical application thereof |
| CN116057049A (en) * | 2020-05-29 | 2023-05-02 | 大邱庆北尖端医疗产业振兴财团 | Carboxamide derivatives and pharmaceutical composition for preventing or treating mental diseases containing the same as active ingredient |
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|---|---|---|---|---|
| WO2003028728A1 (en) * | 2001-09-28 | 2003-04-10 | Richter Gedeon Vegyészeti Gyár Rt. | 4-(4-substituted piperazinyl-1yl)-butylcarboxamides as d3 dopamine subtype selective ligands |
| CN1784395A (en) * | 2003-05-07 | 2006-06-07 | 埃科特莱茵药品有限公司 | Piperazine-alkyl-ureido derivatives |
| CN104755083A (en) * | 2012-10-11 | 2015-07-01 | 南方研究所 | Urea and amide derivatives of aminoalkylpiperazines and use thereof |
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2017
- 2017-03-07 CN CN201710130807.0A patent/CN106966953A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2003028728A1 (en) * | 2001-09-28 | 2003-04-10 | Richter Gedeon Vegyészeti Gyár Rt. | 4-(4-substituted piperazinyl-1yl)-butylcarboxamides as d3 dopamine subtype selective ligands |
| CN1784395A (en) * | 2003-05-07 | 2006-06-07 | 埃科特莱茵药品有限公司 | Piperazine-alkyl-ureido derivatives |
| CN104755083A (en) * | 2012-10-11 | 2015-07-01 | 南方研究所 | Urea and amide derivatives of aminoalkylpiperazines and use thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018153297A1 (en) * | 2017-02-24 | 2018-08-30 | 深圳市灵兰生物医药科技有限公司 | Novel selective ligand for dopamine d3 receptor, preparation method therefor, and pharmaceutical application thereof |
| CN108329282A (en) * | 2018-01-16 | 2018-07-27 | 新乡医学院 | A kind of phenylpiperazine analog derivative and its preparation method and application |
| CN108329282B (en) * | 2018-01-16 | 2022-01-07 | 新乡医学院 | Phenylpiperazine derivative and preparation method and application thereof |
| CN116057049A (en) * | 2020-05-29 | 2023-05-02 | 大邱庆北尖端医疗产业振兴财团 | Carboxamide derivatives and pharmaceutical composition for preventing or treating mental diseases containing the same as active ingredient |
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