- Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism
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The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its selective D2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in D2R-BRET functional assays.
- Bonifazi, Alessandro,Yano, Hideaki,Ellenberger, Michael P.,Muller, Ludovic,Kumar, Vivek,Zou, Mu-Fa,Cai, Ning Sheng,Guerrero, Adrian M.,Woods, Amina S.,Shi, Lei,Newman, Amy Hauck
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Read Online
- 2-phenylcyclopropyl methylamine derivative, and preparation method and application thereof
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The invention discloses a 2-phenylcyclopropyl methylamine derivative, and a preparation method and application thereof. The 2-phenylcyclopropyl methylamine derivative provided by the invention has a structure as shown in the following formula I, has affinity activity to a dopamine receptor and/or a 5-hydroxytryptamine receptor, and can be used for treating mental diseases.
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Paragraph 0503-0505
(2021/08/21)
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- Synthesis method of high-purity aripiprazole and preparation method of hydrate particles of aripiprazole
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The invention discloses a synthesis method of high-purity aripiprazole and a preparation method of hydrate particles of aripiprazole. The method comprises the following steps: step (1), carrying out Williamson etherification on 7-hydroxyl-3,4-dihydro-2 (1H)-quinolinone and 1,4-dibromobutane under the action of potassium carbonate to obtain 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone; step (2), synthesizing 2,3-dichlorophenyl piperazine hydrochloride from 2,3-dichloroaniline and bis(2-chloroethyl) amine hydrochloride; step (3), carrying out an alkylation coupling reaction of nitrogen on 7-(4-bromobutoxy)-3,4-dihydro-2(1H)-quinolinone and 1-(2,3-dichlorophenyl) piperazine hydrochloride, so as to prepare aripiprazole; (4) refining: recrystallizing aripiprazole by using ethyl acetate to obtain high-purity anhydrous aripiprazole; and (5) preparation of aripiprazole hydrate particles: refluxing and dissolving anhydrous aripiprazole in an ethanol-water system, and controlling the stirring rate and the cooling rate to obtain the aripiprazole hydrate particles.
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Paragraph 0026; 0053; 0117-0130
(2021/08/07)
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- Acetylcholinesterase inhibition of diversely functionalized quinolinones for alzheimer’s disease therapy
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In this communication, we report the synthesis and cholinesterase (ChE)/monoamine oxidase (MAO) inhibition of 19 quinolinones (QN1-19) and 13 dihydroquinolinones (DQN1-13) designed as potential multitarget small molecules (MSM) for Alzheimer’s disease therapy. Contrary to our expectations, none of them showed significant human recombinant MAO inhibition, but compounds QN8, QN9, and DQN7 displayed promising human recombinant acetylcholinesterase (hrAChE) and butyrylcholinesterase (hrBuChE) inhibition. In particular, molecule QN8 was found to be a potent and quite selective non-competitive inhibitor of hrAChE (IC50 = 0.29 μM), with Ki value in nanomolar range (79 nM). Pertinent docking analysis confirmed this result, suggesting that this ligand is an interesting hit for further investigation.
- Bautista-Aguilera, óscar M.,Ismaili, Lhassane,Chioua, Mourad,Andrys, Rudolf,Schmidt, Monika,Bzonek, Petr,Martínez-Grau, María ángeles,Beadle, Christopher D.,Vetman, Tatiana,López-Mu?oz, Francisco,Iriepa, Isabel,Refouvelet, Bernard,Musilek, Kamil,Marco-Contelles, José
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- The one-pot synthesis of butyl-1H-indol-3-alkylcarboxylic acid derivatives in ionic liquid as potent dual-acting agent for management of BPH
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Based on the SAR of both α1-AR antagonists and 5α-reductase (5AR) inhibitors, the dual-acting agent 4-(1-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-1H-indol-3-yl)butanoic acid 4aaa was designed against BPH and synthesized by two steps of N-alkylation. One-pot protocol towards 4aaa was newly developed. With IL [C6min]Br as solvent, the yield of 4aaa was increased to 75.1% from 16.0% and the reaction time was shortened in 1.5 h from 48 h. 25 derivatives structurally based on arylpiperazine and indolyl butyric acid with alkyl linker were prepared. The protocol was futher extended to get another 14 derivatives wherein O-alkylation was involved, and applied to the synthesis of biologically efficient molecules DPQ and Aripiprazole. Expectedly, compound 4aaa exhibited dual inhibition of α1-AR and 5α-reductase, and exhibited no obvious cytotoxicity against human cells. The pharmacokinetic properties of 4aaa was also determined.
- Chen, Kaixuan,Jiang, Zhenzhou,Liu, Shuwen,Xi, Baomin,Yang, Fubiao,Zeng, Li-Yan,Zeng, Yunong
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- Industry-Oriented Route Evaluation and Process Optimization for the Preparation of Brexpiprazole
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Efforts toward route evaluation and process optimization for the preparation of brexpiprazole (1) are described. Starting from commercially available dihydroquinolinone 11, a three-step synthesis route composed of O-alkylation, oxidation, and N-alkylation was selected for industry-oriented process development aiming to reduce side reactions and achieve better impurity profiles. The reaction conditions of the three steps were investigated, and the control strategy for the process-related impurities was established. The optimized process was validated on the kilogram scale and now is viable for commercialization, with the results of not less than 99.90% purity of 1 (by HPLC) and not more than 0.05% of persistent impurities 15 and 16.
- Chen, Weiming,Suo, Jin,Liu, Yongjian,Xie, Yuanchao,Wu, Mingjun,Zhu, Fuqiang,Nian, Yifeng,Aisa, Haji A.,Shen, Jingshan
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p. 852 - 857
(2019/04/01)
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- Design, synthesis, molecular docking, and in vitro antidiabetic activity of novel PPARγ agonist
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Abstract: The present work describes the design, synthesis, molecular docking, biological evaluation, and assessment of structure–activity relationship of new derivatives based upon the molecular skeleton of the drug pioglitazone, a compound which is currently used for the management of type 2 diabetes mellitus. Pioglitazone has several side effects such as weight gain, edema, congestive heart failure, and bladder cancer. Therefore, there is a strong demand for identification of new lead candidates in the treatment of type 2 diabetes mellitus. A series of 24 compounds were prepared and evaluated for their peroxisome proliferator-activated receptor-γ (PPARγ) binding affinity assay and the IC50 values were determined. Among these compounds, six compounds exhibited promising IC50 values as compared to standard drugs pioglitazone and rosiglitazone. Furthermore, in order to confirm the target of these molecules, molecular docking study was carried out with peroxisome proliferator-activated receptor-γ (PPARγ) protein. Molecular modeling studies suggested that these compounds appropriately interact in the active sites of receptor. Graphical abstract: [Figure not available: see fulltext.].
- Chaturvedi, Radha Nandan,Pendem, Krishnaiah,Patel, Vipul P.,Sharma, Mukta,Malhotra, Sunita
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p. 2069 - 2084
(2018/08/22)
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- Method for synthesizing aripiprazole
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The invention discloses a method for synthesizing aripiprazole. The method comprises making 4-halogenated-3-nitrophenol react with an ethylenation reagent under palladium catalysis conditions to obtain 3-nitro-4-vinylphenol; making the 3-nitro-4-vinylphenol and 1,4-dihalogenated butane reacting with alkali to obtain 4-(4-halobutoxy)-2-nitro-1-styrene; making the 4-(4-halobutoxy)-2-nitro-1-styreneand 1-(2,3-dichlorophenyl)piperazine salt reacting with the alkali to obtain 1-(2,3-dichlorophenyl)-4-(4-(3-nitro-4-vinylphenoxy)butyl)piperazine; making the 1-(2,3-dichlorophenyl)-4-(4-(3-nitro-4-vinylphenoxy)butyl)piperazine reacting with CO to form the aripiprazole. The method for synthesizing the aripiprazole has the total yield of up to 77% and is simple in post treatment.
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- PROCESSES FOR THE PREPARATION OF 7-{4-[4-(1-BENZOTHIOPHEN-4-YL)PIPERAZIN-1-YL]BUTOXY}QUINOLIN-2(1H)-ONE
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The Present Invention relates to process for the preparation of 7-{4-[4-(1-benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one represented by the following structural formula-1.
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Page/Page column 36-37
(2018/05/27)
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- Design, synthesis and biological evaluation of 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives as new multipotent cholinesterase/monoamine oxidase inhibitors for the treatment of Alzheimer's disease
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A new family of multitarget molecules able to interact with acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), as well as with monoamino oxidase (MAO) A and B, has been synthesized. Novel 3,4-dihydro-2(1H)-quinoline-O-alkylamine derivatives have been designed using a conjunctive approach that combines the JMC49 and donepezil. The most promising compound TM-33 showed potent and balance inhibitory activities toward ChE and MAO (eeAChE, eqBuChE, hMAO-A and hMAO-B with IC50 values of 0.56?μM, 2.3?μM, 0.3?μM and 1.4?μM, respectively) but low selectivity. Both kinetic analysis of AChE inhibition and molecular modeling study suggested that TM-33 binds simultaneously to the catalytic active site and peripheral anionic site of AChE. Furthermore, our investigation proved that TM-33 could cross the blood-brain barrier (BBB) in vitro, and abided by Lipinski's rule of five. The results suggest that compound TM-33, an interesting multi-targeted active molecule, offers an attractive starting point for further lead optimization in the drug-discovery process against Alzheimer's disease.
- Sang, Zhipei,Pan, Wanli,Wang, Keren,Ma, Qinge,Yu, Lintao,Liu, Wenmin
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p. 3006 - 3017
(2017/05/29)
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- Method for synthesizing aripiprazole using m-amino phenol as raw material
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The present invention discloses a method for synthesizing aripiprazole using m-amino phenol as a raw material. The synthesis method comprises: step 1, performing a substitution reaction on the m-amino phenol and 3-methoxy propionyl chloride in an aqueous solution of a strong base; step 2, performing electrophilic substitution on the product obtained in the first step using boron trifluoride diethyl ether as a catalyst; step 3, performing a substitution reaction on the product obtained in the second step and 4-bromine-1-butyl iodide under catalysis of the strong base in solvent composed of DMSO, DMF and water; and step 4, performing a substitution reaction on the product obtained in the third step and 1-(2, 3-dichloro phenyl) piperazine under catalysis of the strong base in solvent composed of DMSO, DMF and water; Tert-butyl benzenesulfonic acid 4-chloro butyl ester and 7-hydroxy-3, 4-2 (1H) dihydroquinolinone are used for a substitution reaction. Since tert-butyl benzenesulfonyloxy and chlorine respectively in 1, 4-position carbon atoms in 4-bromine-1-butyl iodide have different substitution activity, iodine is preferably substituted by hydroxy, and in this way dimerized quinolinone by-products are reduced, thereby improving the purity of the product and ensuring the yield.
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- The method of producing crystals B aripiprazole anhydride (by machine translation)
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PROBLEM TO BE SOLVED: aripiprazole anhydride of B-type crystal in an easy and safe operation, without using a solvent of high toxicity, without being mixed with other crystalline form of high-purity, high yield. SOLUTION: 2 θ = 16.3 °, 21.8 °, 22.2 °, in X-ray diffraction spectrum 23.3 ° and 24.5 ° shows a peak having a powder, a melting point of 148 ±3 °C, aripiprazole 0.05-0.30% moisture content in the crystal, and benzyl alcohol dissolved in a mixed solvent of amyl acetate, recrystallization to aripiprazole anhydride-B. Selected drawing: fig. 2 (by machine translation)
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Paragraph 0019; 0020
(2017/01/31)
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- Efficient synthesis of deuterium labeled hydroxyzine and aripiprazole
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Hydroxyzine and aripiprazole are active pharmaceutical ingredients that have been largely acknowledged for their antipsychotic properties. Deuterium labeled isotopes of hydroxyzine and aripiprazole are internal standards that can aid in the further research of non-isotopic forms via quantification analysis using HPLC-MS/MS. The synthesis of hydroxyzine-d8 was accomplished by coupling piperazine-d8 with 4-chlorobenzhydryl chloride followed by the reaction of the first intermediate with 2-(2-chloroethoxy) ethanol to afford 11.7% of hydroxyzine-d8 with 99.5% purity. The synthesis of aripiprazole-d8 was also achieved in two steps. 1,4-Dibromobutane-d8 reacted with 7-hydroxy-3,4-dihydro-2(1H)-quinolinone. The first intermediate was then coupled with 1-(2, 3-dichlorophenyl)piperazine hydrochloride to produce 33.4% of aripiprazole-d8 with 99.93% purity.
- Vohra, Mohit,Sandbhor, Mahendra,Wozniak, Andrew
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p. 304 - 307
(2015/06/25)
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- Synthesis and biological evaluation of a novel sigma-1 receptor antagonist based on 3,4-dihydro-2(1H)-quinolinone scaffold as a potential analgesic
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The synthesis and sigma-1 receptor (σ1R) antagonist activity of a new series of 3,4-dihydro-2(1H)-quinolinone derivatives are reported. The new compounds were evaluated in vitro in sigma-1 and sigma-2 receptor-binding assays in guinea pig brain membranes. The structure-activity relationship led us to the promising derivative 7-(3-(piperidin-1-yl)propoxy)-1- (4-fluorobenzyl)-3,4-dihydro-2(1H)-quinolinone (35). The compounds with highest affinity and greatest selectivity were further profiled, and compound 35 had a high binding constant for sigma-1 receptor (Kiσ1 = 1.22 nM) and high sigma-1/2 selectivity (1066-fold). Thus, compound 35, which proved to be an antagonist of sigma-1 receptor, emerged as the most interesting candidate. In addition, compound 35 exerted dose-dependent anti-nociceptive effects in the formalin test. These characteristics suggested that the potent and selective compound 35 could be a potent candidate for pain treatment.
- Lan, Yu,Chen, Yin,Xu, Xiangqing,Qiu, Yinli,Liu, Shicheng,Liu, Xin,Liu, Bi-Feng,Zhang, Guisen
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p. 216 - 230
(2014/05/06)
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- Diversified synthesis of novel quinoline and dibenzo thiazepine derivatives using known active intermediates
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The novel drug development to control resisting infections in conventional drug therapy is a need of today. Few antiulcer relative derivatives developed by approaching convergent synthesis. The derivatives synthesized successfully are dibenzo thiazepine-pyridine (SLN11-SLN15) and benzimidazole-hydroquinoline based derivatives (SLN16-SLN20). It involved the coupling through microwave, sonication and conventional techniques at final step. The efficient technology identified as sonication technique basically time and yield. The reported compounds were structural characterized by elemental analysis and spectral studies such as 1H, 13C NMR and MS.
- Sharada,Satyanarayana Reddy,Sammaiah,Sumalatha
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p. 7959 - 7966
(2013/09/23)
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- HETEROARYL COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are heteroaryl compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. In one embodiment, the compounds provided herein are useful for the treatment, prevention, and/or management of various disorders, such as CNS disorders and neurological disorders, including, but not limited to, e.g., psychosis, schizophrenia, depression, movement disorders, and Parkinson's disease.
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Paragraph 00287; 00288; 00367; 00368
(2013/12/03)
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- FUNCTIONALLY SELECTIVE LIGANDS OF DOPAMINE D2 RECEPTORS
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The present invention relates to novel functionally selective ligands of dopamine D2 receptors, including agonists, antagonists, and inverse agonists. The invention further relates to the use of these compounds for treating central nervous system disorders related to D2 receptors.
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Page/Page column 45
(2012/01/15)
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- Synthesis of novel 3,4-dihydroquinolin-2(1H)-one guanidines as potential antihypertensive agents
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Hydroxy-3,4-dihydroquinolin-2(1H)-ones (4a-c) were synthesized by intramolecular Friedel Craft alkylation of N-(methoxyphenyl)-3- chloropropionamides (3a-c), obtained by acylation of anisidine with chloropropionyl chloride. The hydroxy-3,4-dihydro quinolin-2(1H)- ones (4a-c) were treated with various dibromo alkanes under phase transfer catalyst conditions at room temperature to give bromoalkyloxy- 3,4-dihydroquinolin-2(1H)- ones (5a-l) which on further reaction with guanidine hydrochloride in dimethyl formamide afforded N-{4- [(2-oxo-1,2,3,4-tetrahydroquinolin-5-yl)oxy]alkyl} guanidines (6a-l). These compounds were synthesized as potential antihypertensive agents.
- Pai,Samel
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p. 1655 - 1660
(2012/01/06)
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- IMPROVED PROCESS FOR THE PREPARATION OF 7.(4-BROMOBUTOXY) 3,4-DIHYDROCARBOSTYRIL, A PRECURSOR OF ARIPIPRAZOLE
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Disclosed herein is an improved process for the preparation of 7-(4-bromobutoxy) 3,4-dihydrocarbostyril, a key intermediate used in the preparation of Aripiprazole.
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Page/Page column 8
(2011/04/18)
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- ARYLPIPERAZINE MODULATORS OF D2 RECEPTORS, 5-HT1A RECEPTORS, AND/OR 5-HT2A RECEPTORS
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The present invention relates to new arylpiperazine modulators of D2 receptors, 5-HT1A receptors, and/or 5-HT2A receptors, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 26
(2010/04/23)
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- PROCESS FOR PREPARING CRYSTALLINE ARIPIPRAZOLE
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The present invention relates the process for preparation of stable polymorph of aripiprazole and in particular the present invention is related to an improved process for the preparation of crystalline anhydrous aripiprazole and its hydrochloride salt.
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Page/Page column 4-5
(2010/05/13)
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- PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
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The present invention relates to an improved process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)-1-piper-azinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone of Formula (I).
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Page/Page column 3
(2010/06/14)
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- A PROCESS FOR PURIFICATION OF 7-(4-BROMOBUTOXY)-3,4 DIHYDROCARBOSTYRIL, AN INTERMEDIATE FOR MANUFACTURE OF ARIPIRAZOLE
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A process for the purification of 7- (4-bromobutoxy)-3,4- dihydrocarbostyril, substantially free of dimer impurity, said process comprising providing a solution of crude 7- (4-bromobutoxy)-3,4- dihydrocarbostyril containing the dimer impurity in an organic solvent selected from the group of halogenated hydrocarbon solvent, aromatic hydrocarbon, alcohols, alkyl esters of C1-C4 alkanoic acids, ethers, diethyl ester and ketones ; converting to a salt by the addition of an inorganic acid; separation of 1,4-bis [3,4-dihydro-2 (1H)-quinolinone-7-oxy] butane salt (dimer impurity salt) from the mixture, based on the difference in at least one physical property of 7- (4-bromobutoxy)-3,4- dihydrocarbostyril salt and the salt of dimer impurity; liberating the 7- (4-bromobutoxy)-3,4- dihydrocarbostyril salt by treating with an inorganic base; precipitating 7- (4-bromobutoxy)-3,4- dihydrocarbostyril by adding an anti-solvent.
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Page/Page column 8-9
(2010/11/30)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE
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The present invention relates to an improved process for the preparation of 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone of Formula (I).
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Page/Page column 6-10
(2009/01/20)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE ARIPIPRAZOLE
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The invention relates to an improved process for preparing substantially pure aripiprazole (HPLC >99.8 %), wherein 7,7'-[tetramethylenebis(oxy)]bis(3,4- dihydroquinolin-2(lH)-one) is present in pure aripiprazole in 0.01 % (w/w).
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Page/Page column 8-9
(2008/06/13)
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- COMPSITIONS, SYNTHESIS, AND METHODS OF USING QUINOLINE BASED ATYPICAL ANTIPSYCHOTIC AGENTS
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The present invention provides novel quinolinone derivatives which can be advantageously used for treating schizophrenia and related psychoses such as acute manic, bipolar disorder, autistic disorder, and depression.
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Page/Page column 24
(2009/01/20)
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- A PROCESS FOR THE PREPARATION OF ARIPIPRAZOLE AND INTERMEDIATES THEREOF
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The present invention is related to the process for the preparation aripiprazole and intermediates thereof. The process comprises reacting 7-hydroxy-3,4-dihydro-2(1H)-quinolinone with 1-bromo-4-chlorobutane in aqueous solvent in the presence of a phase transfer catalyst and a base.
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Page/Page column 7-8
(2010/11/28)
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- Process for the preparation of aripiprazole
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The present invention relates to an improved process for the preparation of 7-[4[-(2,3-dichlorophenyl) -1-piperazinyl]butoxy]3,4-dihydro-2-(1H) quinolinone (Aripiprazole) having dimer impurity less than 0.15%, particularly, the present invention relates to an improved process for the preparation of 7-(4-chlorobutoxy)-3,4-dihydrocarbostyril of formula (I) having dimer impurity less than 0.5% comprising a step of, reacting 7-hydroxy-tetrahydroquinolinone of formula (III) with 1-bromo-4-chlorobutane in the presence of a base in a solvent.
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Page/Page column 3-5
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF POLYMORPHS, SOLVATES OF ARIPIPRAZOLE USING ARIPIPRAZOLE ACID SALTS
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The present invention relates to Aripiprazole, a useful agent for antipsychotic. The present invention also provides new acid addition salts of Aripiprazole and process for the preparation of polymorphs and solvates of Aripiprazole using Aripiprazole acid salts, their interconversion and the process for preparation of Aripiprazole acid salts.
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Page/Page column 22-26; 28
(2008/06/13)
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- Synthesis and bioactivity of aripiprazole derivatives
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Ten aripirazole (CAS 129722-12-9) derivatives were prepared and examined for dopamine receptor antagonist activity. The structures of these newly synthesized compounds were confirmed by their elemental analyses and by IR, 1H-NMR and mass spectra. It was demonstrated that all the new compounds have dopamine receptor antagonist activity to a certain extent. Three compounds showed more potent activity than aripiprazole. ECV · Editio Cantor Verlag.
- Ge, Hai-Xia,Wang, Li-Chen,Jiang, Zhen-Zhou,Ni, Sheng-Liang
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p. 673 - 677
(2007/10/03)
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- Processes for preparing and purifying carbostyril compounds such as aripiprazole and 7-(4-halobutoxy)-3,4-dihydro-2(1H)-quinolinones
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The present invention provides several improved processes for preparing aripiprazole, wherein the first step comprising reacting 7-HQ with a 1,4-disubstituted-butane in biphasic reaction mixture or in a single phase solvent to obtain a 7-(4-halobutoxy)-3,4-dihydro-(1H)-quinolinone (7-HBQ) and the second step comprising reacting the 7-HBQ and 1-(2,3-dichlorophenyl)piperazine or an acid addition salt thereof in a biphasic reaction medium containing water and a water-immiscible solvent to obtain aripiprazole. Also provided are methods of purifying the 7-HBQs and aripiprazole.
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Page/Page column 11
(2008/06/13)
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- Synthesis and characterization of N-oxides and metabolites of anti-psychotic drug, Aripiprazole
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Aripiprazole is a recently developed anti-psychotic drug used for the treatment of schizophrenia. Aripiprazole and its N-oxides exhibit a strong activity for influencing the neurotransmission of dopamine receptors and are devoid of side effects induced by the known drugs useful for the treatment of schizophrenia. Further, Aripiprazole is metabolized by different biotransformation pathways as dehydrogenation, hydroxylation and N-dealkylation giving rise to different metabolites. The present work details the development of a simple and novel process for the preparation of Aripiprazole N-oxides as Aripiprazole-4-N-oxide, Aripiprazole-1-N-oxide and Aripiprazole-1,4-di-N-oxide and Aripiprazole metabolites such as dehydro Aripiprazole and Aripiprazole hydroxy metabolite.
- Satyanarayana, Bollikonda,Sumalatha, Yasareni,Kumar, Sythana Suresh,Venkatraman, Sundaram,Reddy, Ghanta Mahesh,Reddy, Padi Pratap
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p. 485 - 490
(2007/10/03)
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- Novel antipsychotic agents with dopamine autoreceptor agonist properties: Synthesis and pharmacology of 7-[4-(4-phenyl-1- piperazinyl)butoxy]-3,4-dihydro-2(1H)-quinolinone derivatives
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To develop a novel antipsychotic agent which is an agonist of dopamine (DA) autoreceptors and an antagonist of postsynaptic DA receptors, a series of 7-[4-[4-(substituted phenyl)-1-piperazinyl]butoxy]-3,4-dihydro-2(1H)- quinolinones was synthesized and their dual activities were examined. The postsynaptic DA receptor antagonistic activities of the compounds were evaluated by their ability to inhibit stereotypy induced by apomorphine in mice, and the autoreceptor agonist activities were determined by their effects on the γ-butyrolactone (GBL)-induced increase in L- dihydroxyphenylalanine (DOPA) synthesis in the mouse brain. Many compounds inhibited the stereotypic behavior, and several compounds reversed the GBL- induced increase in the DOPA synthesis. Among them, 7-[4-[4-(2,3- dichlorophenyl)-l-piperazinyl]butoxy]-3,4-dihydro-2(1H)-quinolinone (28, aripiprazole, OPC-14597) was found to have these two activities. This compound reversed the GBL-induced DOPA synthesis (ED50 values of 5.1 μmol/kg po) and inhibited the APO induced stereotypy (ED50 values of 0.6 μmol/kg po). Compound 28 induced catalepsy at 10 times higher dose than that required for the antagonism of APO-induced stereotypy (ED50 value of 7.8 μmol/kg po).
- Oshiro, Yasuo,Sato, Seiji,Kurahashi, Nobuyuki,Tanaka, Tatsuyoshi,Kikuchi, Tetsuro,Tottori, Katsura,Uwahodo, Yasufumi,Nishi, Takao
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p. 658 - 667
(2007/10/03)
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- CARBOSTYRIL DERIVATIVES
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A novel carbostyril derivative and salt thereof represented by the formula (1) STR1 (wherein R is a group of the formula STR2 ((wherein R. sup.1 is a C 1-C 3 alkoxy group)), a group of the formula STR3 ((wherein R 2 and R 3 are each, at the same time, a chlorine atom, a bromine atom; and R 4 is a hydrogen atom or a chlorine atom)), 2-methyl-3-nitrophenyl group, 3,5-dichlorophenyl group, or a group of the formula STR4 ((wherein R 5 is a chlorine atom or a bromine atom; and R 6 is a methyl group)); the carbon-carbon bond between 3-and 4-position in the carbostyril skeleton is a single or double bond).
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