- Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer
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Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
- Long, Huan,Hu, Xiaolong,Wang, Baolin,Wang, Quan,Wang, Rong,Liu, Shumeng,Xiong, Fei,Jiang, Zhenzhou,Zhang, Xiao-Qi,Ye, Wen-Cai,Wang, Hao
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p. 12089 - 12108
(2021/09/06)
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- Rational modifications, synthesis and biological evaluation of new potential antivirals for RSV designed to target the M2-1 protein
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Respiratory syncytial virus (RSV) is the main cause of lower respiratory tract diseases in infants and young children, with potentially serious and fatal consequences associated with severe infections. Despite extensive research efforts invested in the identification of therapeutic measures, no vaccine is currently available, while treatment options are limited to ribavirin and palivizumab, which both present significant limitations. While clinical and pre-clinical candidates mainly target the viral fusion protein, the nucleocapsid protein or the viral polymerase, our focus has been the identification of new antiviral compounds targeting the viral M2-1 protein, thanks to the presence of a zinc-ejecting group in their chemical structure. Starting from an anti-RSV hit we had previously identified with an in silico structure-based approach, we have designed, synthesised and evaluated a new series of dithiocarbamate analogues, with which we have explored the antiviral activity of this scaffold. The findings presented in this work may provide the basis for the identification of a new antiviral lead to treat RSV infections.
- Bassetto, Marcella,Benato, Sara,Brancale, Andrea,Ferla, Salvatore,Jochmans, Dirk,Manganaro, Roberto,Neyts, Johan,Paulissen, Jasmine
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supporting information
(2020/03/13)
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- Development of 2-amino-4-phenylthiazole analogues to disrupt myeloid differentiation factor 88 and prevent inflammatory responses in acute lung injury
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Myeloid differentiation primary response protein 88 (MyD88), an essential adapter protein used by toll-like receptors (TLR), is a promising target molecule for the treatment of respiratory inflammatory diseases. Previous studies explored the activities of novel 2-amino-4-phenylthiazole analogue (6) in inflammation-induced cancer, and identified the analogue as an inhibitor of MyD88 toll/interleukin-1 receptor (TIR) homology domain dimerization. Here, we describe the synthesis of 47 new analogues by modifying different sites on this lead compound and assessed their anti-inflammatory activities in lipopolysaccharide-induced mouse primary peritoneal macrophages (MPMs). The most promising compound, 15d, was found to effectively interact with MyD88 protein and prevented formation of the MyD88 homodimeric complex. Furthermore, 15d showed in vivo anti-inflammatory activity in LPS-caused model of acute lung injury. This work provides new candidates as MyD88 inhibitors to combat inflammation diseases.
- Chen, Lingfeng,Chen, Hongjin,Chen, Pengqin,Zhang, Wenxin,Wu, Chao,Sun, Chuchu,Luo, Wu,Zheng, Lulu,Liu, Zhiguo,Liang, Guang
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- Sulfonamides incorporating piperazine bioisosteres as potent human carbonic anhydrase I, II, IV and IX inhibitors
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Starting from the molecular simplification of (R) 4-(3,4-dibenzylpiperazine-1-carbonyl)benzenesulfonamide 9a, a compound endowed with selectivity for human Carbonic Anhydrase (hCA) IV, a series of piperazines and 4-aminopiperidines carrying a 4-sulfamoylb
- Chiaramonte, Niccolò,Bua, Silvia,Angeli, Andrea,Ferraroni,Picchioni, Ilaria,Bartolucci, Gianluca,Braconi,Dei, Silvia,Teodori, Elisabetta,Supuran, Claudiu T.,Romanelli, Maria Novella
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- Design, synthesis, and evaluation of genipin derivatives for the treatment of Alzheimer's Disease
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Twenty-two novel genipin derivatives have been designed, synthesized, and evaluated for their inhibitory activity against acetylcholinesterase (AChE). As a result, compound 13a bearing ligustrazine moiety displayed the most potent AChE inhibitory activity in this series with IC50 value of 218?nm. Besides, MTT assay was performed to investigate the neuroprotection of these compounds against PC12 cells injured by Amyloid β-protein 1–42 (Aβ1–42). Among them, 8a showed higher inhibition rate (%Inhibition?=?22.29) than the positive reference Donepezil (%Inhibition?=?17.65).
- Huang, Weijun,Wang, Yujun,Li, Jiaming,Zhang, Yanchun,Ma, Xiaodong,Zhu, Panhu,Zhang, Yang
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p. 110 - 122
(2018/12/11)
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- The synthesis and biological evaluation of novel gardenamide A derivatives as multifunctional neuroprotective agents
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A novel series of gardenamide A derivatives was synthesized as potential anti-Alzheimer's disease agents. The neuroprotective effects of these multifunctional agents against oxygen-glucose deprivation (OGD)-induced neurotoxicity in rat cortical neurons, and hydrogen peroxide (H2O2)- A nd amyloid-β1-42 (Aβ1-42)-induced neurotoxicity in rat hippocampal neurons were evaluated. In vitro studies revealed that these compounds demonstrated moderate to good multifunctional neuroprotective activity. Among the entire series, compounds 10e, 10j, 10n and 10p appeared to be the most active multifunctional neuroprotective agents. Studies indicate that compounds 10e, 10f, 10h, 10i, 10j, 10n and 10p exhibit significant activities against OGD-induced neurotoxicity in rat cortical neurons, and 10e, 10j, 10n and 10p show prominent activities against H2O2- A nd Aβ1-42-induced neurotoxicity in rat hippocampal neurons. Moreover, these derivatives did not exert conspicuous neurotoxicity in rat cortical neurons. Thus, the present study evidently shows that 10e, 10j, 10n and 10p are potent multifunctional neuroprotective agents, which may serve as promising lead candidates for anti-Alzheimer's disease drug development.
- Zhang, Zuzhi,Wang, Yujun,Zhang, Yanchun,Li, Jiaming,Huang, Weijun,Wang, Lei
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p. 1180 - 1186
(2019/07/25)
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- N?-Acryloyllysine Piperazides as Irreversible Inhibitors of Transglutaminase 2: Synthesis, Structure-Activity Relationships, and Pharmacokinetic Profiling
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Transglutaminase 2 (TGase 2)-catalyzed transamidation represents an important post-translational mechanism for protein modification with implications in physiological and pathophysiological conditions, including fibrotic and neoplastic processes. Consequently, this enzyme is considered a promising target for the diagnosis of and therapy for these diseases. In this study, we report on the synthesis and kinetic characterization of N?-acryloyllysine piperazides as irreversible inhibitors of TGase 2. Systematic structural modifications on 54 new compounds were performed with a major focus on fluorine-bearing substituents due to the potential of such compounds to serve as radiotracer candidates for positron emission tomography. The determined inhibitory activities ranged from 100 to 10?000 M-1 s-1, which resulted in comprehensive structure-activity relationships. Structure-activity correlations using various substituent parameters accompanied by covalent docking studies provide an advanced understanding of the molecular recognition for this inhibitor class within the active site of TGase 2. Selectivity profiling of selected compounds for other transglutaminases demonstrated an excellent selectivity toward transglutaminase 2. Furthermore, an initial pharmacokinetic profiling of selected inhibitors was performed, including the assessment of potential membrane permeability and liver microsomal stability.
- Wodtke, Robert,Hauser, Christoph,Ruiz-Gómez, Gloria,J?ckel, Elisabeth,Bauer, David,Lohse, Martin,Wong, Alan,Pufe, Johanna,Ludwig, Friedrich-Alexander,Fischer, Steffen,Hauser, Sandra,Greif, Dieter,Pisabarro, M. Teresa,Pietzsch, Jens,Pietsch, Markus,L?ser, Reik
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supporting information
p. 4528 - 4560
(2018/05/07)
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- Design, synthesis and evaluation against Mycobacterium tuberculosis of azole piperazine derivatives as dicyclotyrosine (cYY) mimics
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Three series of azole piperazine derivatives that mimic dicyclotyrosine (cYY), the natural substrate of the essential Mycobacterium tuberculosis cytochrome P450 CYP121A1, were prepared and evaluated for binding affinity and inhibitory activity (MIC) against M. tuberculosis. Series A replaces one phenol group of cYY with a C3-imidazole moiety, series B includes a keto group on the hydrocarbon chain preceding the series A imidazole, whilst series C explores replacing the keto group of the piperidone ring of cYY with a CH2-imidazole or CH2-triazole moiety to enhance binding interaction with the heme of CYP121A1. The series displayed moderate to weak type II binding affinity for CYP121A1, with the exception of series B 10a, which displayed mixed type I binding. Of the three series, series C imidazole derivatives showed the best, although modest, inhibitory activity against M. tuberculosis (17d MIC = 12.5 μg/mL, 17a 50 μg/mL). Crystal structures were determined for CYP121A1 bound to series A compounds 6a and 6b that show the imidazole groups positioned directly above the haem iron with binding between the haem iron and imidazole nitrogen of both compounds at a distance of 2.2 ?. A model generated from a 1.5 ? crystal structure of CYP121A1 in complex with compound 10a showed different binding modes in agreement with the heterogeneous binding observed. Although the crystal structures of 6a and 6b would indicate binding with CYP121A1, the binding assays themselves did not allow confirmation of CYP121A1 as the target.
- El-wahab, Hend A.A. Abd,Accietto, Mauro,Marino, Leonardo B.,McLean, Kirsty J.,Levy, Colin W.,Abdel-Rahman, Hamdy M.,El-Gendy, Mahmoud A.,Munro, Andrew W.,Aboraia, Ahmed S.,Simons, Claire
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p. 161 - 176
(2017/11/29)
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- Design, synthesis and biological evaluation of new phthalimide and saccharin derivatives with alicyclic amines targeting cholinesterases, beta-secretase and amyloid beta aggregation
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The complexity of Alzheimer's disease (AD) calls for search of multifunctional compounds as potential candidates for effective therapy. A series of phthalimide and saccharin derivatives linked by different alicyclic fragments (piperazine, hexahydropyrimidine, 3-aminopyrrolidine or 3-aminopiperidine) with phenylalkyl moieties attached have been designed, synthesized, and evaluated as multifunctional anti-AD agents with cholinesterase, β-secretase and β-amyloid inhibitory activities. In?vitro studies showed that the majority of saccharin derivatives with piperazine moiety and one phthalimide derivative with 3-aminopiperidine fragment exhibited inhibitory potency toward acetylcholinesterase (AChE) with EeAChE IC50values ranging from 0.83?μM to 19.18?μM. The target compounds displayed inhibition of human β-secretase-1 (hBACE1) ranging from 26.71% to 61.42% at 50?μM concentration. Among these compounds, two multifunctional agents (26, [2-(2-(4-benzylpiperazin-1-yl)ethyl)benzo[d]isothiazol-3(2H)-one 1,1-dioxide] and 52, 2-(2-(3-(3,5-difluorobenzylamino)piperidin-1-yl)ethyl)isoindoline-1,3-dione) have been identified. Compound 26 exhibited the highest inhibitory potency against EeAChE (IC50?=?0.83?μM) and inhibitory activity against hBACE1 (33.61% at 50?μM). Compound 52 is a selective AChE inhibitor (IC50 AChE?=?6.47?μM) with BACE1 inhibitory activity (26.3% at 50?μM) and it displays the most significant Aβ anti-aggregating properties among all the obtained compounds (39% at 10?μM). Kinetic and molecular modeling studies indicate that 26 may act as non-competitive AChE inhibitor able to interact with both catalytic and peripheral active site of the enzyme.
- Panek, Dawid,Wi?ckowska, Anna,Wichur, Tomasz,Bajda, Marek,Godyń, Justyna,Jończyk, Jakub,Mika, Kamil,Janockova, Jana,Soukup, Ondrej,Knez, Damijan,Korabecny, Jan,Gobec, Stanislav,Malawska, Barbara
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p. 676 - 695
(2016/10/13)
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- Synthesis and bioactive evaluations of novel benzotriazole compounds as potential antimicrobial agents and the interaction with calf thymus DNA
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A novel series of benzotriazole derivatives were synthesized and characterized by NMR, IR and MS spectra. The bioactive assay manifested that most of the new compounds exhibited moderate to good antibacterial and antifungal activities against the tested strains in comparison to reference drugs chloromycin, norfloxacin and fluconazole. Especially, 2,4-dichlorophenyl substituted benzotriazole derivative 6f displayed good antibacterial activity against MRSA with MIC value of 4 μg/mL, which was 2-fold more potent than Chloromycin, and it also displayed 3-fold stronger antifungal activity (MIC = 4 μg/mL) than fluconazole (MIC = 16 μg/mL) against Beer yeast. The preliminary interactive investigations of compound 6f with calf thymus DNA revealed that compound 6f could effectively intercalate into DNA to form compound 6f-DNA complex which might block DNA replication to exert antimicrobial activities. Molecular docking experiments suggested that compound 6f projected into base-pairs of DNA hexamer duplex forming two hydrogen bonds with guanine of DNA. The theoretical calculations were in accordance with the experimental results.
- Ren, Yu,Zhang, Hui Zhen,Zhang, Shao Lin,Luo, Yun Lei,Zhang, Ling,Zhou, Cheng He,Geng, Rong Xia
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p. 2251 - 2260
(2016/01/09)
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- Design, synthesis, and biological activity of novel 1,4-disubstituted piperidine/piperazine derivatives as CCR5 antagonist-based HIV-1 entry inhibitors
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A series of novel 1,4-disubstituted piperidine/piperazine derivatives were designed, synthesized and evaluated for their in vitro activities against HIV-1 Bal (R5) infection in CEMX174 5.25M7 cells. A majority of these compounds showed potent anti-HIV-1 activities with IC50 at nanomolar levels. N-(4-Fluoro-benzyl)piperazine analog B07 hydrochloride exhibited potency against HIV-1 activity similar to that of TAK-220 hydrochloride, but it had much better water solubility (25 mg/ml in phosphate sodium buffer at 25 °C) and oral bioavailability (56%) than TAK-220 hydrochloride (a solubility of 2 mg/ml and oral bioavailability of 1.4%). These results suggest that B07 hydrochloride may serve as a better lead for the development of new anti-HIV-1 therapies or microbicides for treatment and prevent of HIV-1 infection.
- Dong, Ming-Xin,Lu, Lu,Li, Haitao,Wang, Xiaohua,Lu, Hong,Jiang, Shibo,Dai, Qiu-Yun
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scheme or table
p. 3284 - 3286
(2012/06/18)
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- Gas-phase nucleophilic aromatic substitution between piperazine and halobenzyl cations: Reactivity of the methylene arenium form of benzyl cations
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Methylene arenium involved in SNAr: The gas-phase nucleophilic aromatic substitution reactions of halobenzyl cations with piperazine through a cationic σ complex were studied using ESI mass spectrometry. This study demonstrates that the methylene arenium form of halobenzyl cations exhibits nucleophilic substitution reactivity at the phenyl ring (see scheme). Copyright
- Chai, Yunfeng,Jiang, Kezhi,Sun, Cuirong,Pan, Yuanjiang
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body text
p. 10820 - 10824
(2011/11/07)
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- Exploration of (S)-3-aminopyrrolidine as a potentially interesting scaffold for discovery of novel Abl and PI3K dual inhibitors
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Based on the literature-reported compensatory effect of PI3K on Abl inhibition and the improved preclinical effect of drug combination of Abl and PI3K inhibitors, a series of compounds bearing novel scaffold of (S)-3-aminopyrrolidine was identified as Abl and PI3K dual inhibitors through support vector machine screening tool, which were subsequently synthesized and tested. Most compounds demonstrated promising cytoxicity against a CML leukemia cell-line K562 and moderate inhibition against Abl and PI3K kinases. These compounds induced no apoptosis in K562 cell-line, suggesting that their cytotoxic activities are unlikely duo to other known anti-CML mechanisms. Molecular docking study further showed that the compound 5k could bind with both Abl and PI3K, but the weaker binding with Abl compared to Imatinib is consistent with its low kinase inhibitory rates. These plus literature-reported evidences suggest that the promising cytotoxic effect of our novel compounds might be due to the collective effect of Abl and PI3K inhibition.
- Zhang, Cunlong,Tan, Chunyan,Zu, Xuyu,Zhai, Xin,Liu, Feng,Chu, Bizhu,Ma, Xiaohua,Chen, Yuzong,Gong, Ping,Jiang, Yuyang
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experimental part
p. 1404 - 1414
(2011/04/22)
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- NOVEL BENZODIOXANE AND BENZOXAZINE DERIVATIVES USEFUL AS CC CHEMOKINE RECEPTOR LIGANDS
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The present invention relates to benzodioxane and benzoxazine derivatives that act as ligands for CC chemokine receptors, such as CCR1. The invention also relates to methods of preparing the compounds, compositions containing the compounds, and to methods of treatment using the compounds.
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Page/Page column 22
(2010/06/22)
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- DESIGN, SYNTHESIS AND EVALUATION OF PROCASPASE ACTIVATING COMPOUNDS AS PERSONALIZED ANTI-CANCER DRUGS
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Compositions and methods are disclosed in embodiments relating to induction of cell death such as in cancer cells. Compounds and related methods for synthesis and use thereof, including the use of compounds in therapy for the treatment of cancer and selective induction of apoptosis in cells are disclosed. Compounds are disclosed that have lower neurotoxicity effects than other compounds.
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Page/Page column 42
(2010/08/18)
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- Discovery of novel protease activated receptors 1 antagonists with potent antithrombotic activity in vivo
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Protease activated receptors (PARs) or thrombin receptors constitute a class of G-protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation of these receptors. In humans, thrombin-induced platelet aggregation is mediated by one subtype of these receptors, termed PAR1. This article describes the discovery of new antagonists of these receptors and more specifically two compounds: 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3- dienyl]benzonitrile 36 (F 16618) and 3-(2-chlorophenyl)-1-[4-(4-fluorobenzyl) piperazin-1-yl]propenone 39 (F 16357), obtained after optimization. Both compounds are able to inhibit SFLLR-induced human platelet aggregation and display antithrombotic activity in an arteriovenous shunt model in the rat after iv or oral administration. Furthermore, these compounds are devoid of bleeding side effects often observed with other types of antiplatelet drugs, which constitutes a promising advantage for this new class of antithrombotic agents. 2009 American Chemical Society.
- Perez, Michel,Lamothe, Marie,Maraval, Catherine,Mirabel, Etienne,Loubat, Chantal,Planty, Bruno,Horn, Clemens,Michaux, Julien,Marrot, Sebastien,Letienne, Robert,Pignier, Christophe,Bocquet, Arnaud,Nadal-Wollbold, Florence,Cussac, Didier,De Vries, Luc,Le Grand, Bruno
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experimental part
p. 5826 - 5836
(2010/03/24)
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- Procaspase-3 activation as an anti-cancer strategy: Structure-activity relationship of procaspase-activating compound 1 (PAC-1) and its cellular co-localization with caspase-3
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A goal of personalized medicine as applied to oncology is to identify compounds that exploit a defined molecular defect in a cancerous cell. A compound called procaspase-activating compound 1 (PAC-1) was reported that enhances the activity of procaspase-3 in vitro and induces apoptotic death in cancer cells in culture and inmouse xenograft models. Experimental evidence indicates that PAC-1 activates procaspase-3 in vitro through chelation of inhibitory zinc ions. Described herein is the synthesis and biological activity of a family of PAC-1 derivativeswhere key functional groups have been systematically altered. Analysis of these compounds reveals a strong correlation between the in vitro procaspase-3 activating effect and their ability to induce death in cancer cells in culture. Importantly, we also show that a fluorescently labeled version of PAC-1 co-localizes with sites of caspase-3 activity in cancer cells. The data presented herein further bolster the hypothesis that PAC-1 induces apoptosis in cancer cells through the direct activation of procaspase-3, has implications for the design and discovery of next-generation procaspase-3 activating compounds, and sheds light on the anti-apoptotic role of cellular zinc.
- Peterson, Quinn P.,Hsu, Danny C.,Goode, David R.,Novotny, Chris J.,Totten, Ryan K.,Hergenrother, Paul J.
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supporting information; scheme or table
p. 5721 - 5731
(2010/02/28)
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- Synthesis and antimalarial activity of hydroxyethylpiperazine derivatives
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The antimalarial activity of hydroxyethylpiperazine derivatives, synthesized from the reaction of (2S,3S)Boc-phenylalanine epoxide with benzylpiperazines in good yields (76-96%), has been evaluated in vitro against the Plasmodium falciparum W2 clone (chlo
- Cunico, Wilson,Gomes, Claudia R.B.,Moreth, Marcele,Manhanini, Diogo P.,Figueiredo, Isabela H.,Penido, Carmen,Henriques, Maria G.M.O.,Varotti, Fernando P.,Krettli, Antoniana U.
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body text
p. 1363 - 1368
(2009/09/27)
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- INHIBITORS OF STEAROYL-COA DESATURASE
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of diseases such as, for example, obesity.
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- CINNAMOYL-PIPERAZINE DERIVATIVES AND THEIR USE AS PAR- I ANTAGONISTS
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The present invention relates to compounds of general formula (I), wherein: R1 represents halogen, CN or NO2; R2 represents hydrogen or halogen; n represents 1 or 2; R3 represents phenyl substituted by one or mo
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Page/Page column 8
(2008/06/13)
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- Synthesis and evaluation of fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives for dopamine D4 receptor imaging
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Seven fluorine-substituted 1H-pyrrolo[2,3-b]pyridine derivatives were synthesized based on a lead ligand, 3-[[4-(4-iodophenyl)piperazin-1-yl]-methyl]- 1H-pyrrolo[2,3-b]pyridine (L-750,667) and evaluated as potential dopamine D 4 receptor imagin
- Oh, Seung-Jun,Lee, Kyo Chul,Lee, Sang-Yoon,Ryu, Eun Kyoung,Saji, Hideo,Choe, Yearn Seong,Chi, Dae Yoon,Kim, Sang Eun,Lee, Jeewoo,Kim, Byung-Tae
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p. 5505 - 5513
(2007/10/03)
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- Synthesis and preliminary pharmacological evaluation of 4′-arylmethyl analogues of clozapine. I - The effect of aromatic substituents
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As part of a research program to develop compounds with mixed dopamine D4 and serotonin 5-HT2A antagonist activity with potential for the treatment of schizophrenia, we report a family of compounds based on structural modification of the atypical antipsychotic, clozapine (2). The chemical synthesis, structural characterization and pharmacological evaluation of a series 4′-arylmethyl analogues of clozapine are described. Preliminary receptor binding data are presented, examining primarily the electronic and positional effects of substituents on the introduced arylmethyl group, and secondarily the nature of the aryl ring.
- Capuano, Ben,Crosby, Ian T.,Lloyd, Edward J.,Taylor, David A.
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p. 565 - 576
(2007/10/03)
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- Certain substituted 1-aryl-3-piperazin-1′-yl propanones
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Disclosed are compounds of formula I: wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar1and Ar2independently represent aryl groups; and Y is hydrogen; o
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- Pyrimidine derivatives
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Pyrimidine derivatives useful as a gastrointestinal prokinetic agent, represented by formula STR1 wherein X is O or NR5, Y is O, S or NR5 wherein R5 is a hydrogen atom, a C1 -C6 alkyl group or the like; R1 and R2 may be the same or different and each is a hydrogen atom, a C1 -C6 alkyl group or the like; R3 is CN, or COOR6 wherein R6 is a C1 -C6 alkyl group, a C3 -C6 cycloalkyl group, an aryl group or the like; R4 is --SR7 or --NR8 R9 wherein R7 is a C1 -C6 alkyl group; R8 is a C1 -C6 alkyl group or the like; R9 is a hydrogen atom, a C1 -C6 alkyl group or the like, or R8 and R9 may represent, together with the nitrogen atom to which they are attached, an N-substituted piperazine ring of formula (X) STR2 wherein R10 represents a C1 -C6 alkyl group or the like or a pharmacologically acceptable salt thereof. The above-mentioned compounds are useful as a gastrointestinal prokinetic agent used for the therapy of digestive tract diseases.
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- Use of polymer supported reagents for clean multi-step organic synthesis: Preparation of amines and amine derivatives from alcohols for use in compound library generation
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The automated sequential application of polymer supported perruthenate (PSP) and polymer supported cyanoborohydride (PSCBH) in an oxidation-reductive amination procedure allowed the efficient transformation of simple alcohols into more complex amines which can be further derivatised by the use of polymer bound amino sulfonylpyridinium chlorides.
- Ley, Steven V.,Bolli, Martin H.,Hinzen, Berthold,Gervois, Anne-Geraldine,Hall, Beverley J.
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p. 2239 - 2241
(2007/10/03)
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- Certain substituted 1-aryl-3-piperazin-1'-yl propanones to treat Alzheimer's Disease
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Disclosed are compounds of formula I: STR1 or the pharmaceutically acceptable salts thereof wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar1 and Ar2 i
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- Substituted 1-aryl-3-piperazin-1'-yl propanones
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Disclosed are compounds of formula I: STR1 wherein X is a carbonyl, sulfonyl, methylene, or methylene substituted with optionally substituted phenyl; Z is nitrogen or CH; Ar1 and Ar2 independently represent aryl groups; and Y is hydr
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- Bis(piperazinyl or homopiperazinyl)alkanes
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Compounds of the formula STR1 wherein R1, R2, R3, R4, R5, and R6 are independently hydrogen, alkyl of 1 to 4 carbon atoms, hydroxyl, alkoxy of 1 to 4 carbon atoms, alkanoyloxy of 1 to 4 carbon atoms, halogen, trihalomethyl, di(lower alkyl of 1 to 4 carbon atoms)amino, (alkoxy of 1 to 4 carbon atoms)carbonyl, nitro, cyano or alkanoyl of 1 to 3 carbon atoms; R7 and R8 are independently hydrogen, methyl, hydroxyl, carboxyl, (alkoxy of 1 to 4 carbon atoms)carbonyl, hydroxymethyl, phenyl, or p-chlorophenyl; R9 and R10 are independently hydrogen or methyl; j and k are independently 0, 1, 2, or 3, their sum being no more than 4; m and n are independently 0, 1, 2, or 3, their sum being no more than 4; A is --CH2 -- or --CH2 --CH2 --; R7 and R9 together are oxo, provided k is other than o; R8 and R10 together are oxo, provided m is other than o; R11 and R12 independently represent hydrogen or one to four methyl substituents on the carbon atoms of the piperazine ring (A=--CH2 --); R13, R14, R15, and R16 are independently hydrogen or methyl; R13 and R14 together are oxo; R15 and R16 together are oxo; and X is alkylene of 1 to 2 carbon atoms, optionally hydroxy-substituted; or a non-toxic, pharmacologically acceptable acid addition salt thereof, are useful as antiallergic and anti-inflammatory agents.
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