- Benzyne-Induced Ring Opening Reactions of DABCO: Synthesis of 1,4-Disubstituted Piperazines and Piperidines
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The 2-(4-phenylpiperazin-1-yl)ethan-1-amine scaffold is a structurally important motif that occurs frequently in medicinal and pharmaceutical chemistry. Despite the significance of this moiety, general strategies for its synthesis to date have required mu
- Seo, Jeongseob,Kim, Daegeun,Ko, Haye Min
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p. 2739 - 2743
(2020/05/25)
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- Piperazine-and piperidine-containing thiazolo[5,4-d]pyrimidine derivatives as new potent and selective adenosine a2a receptor inverse agonists
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The therapeutic use of A2A adenosine receptor (AR) antagonists for the treatment of neurodegenerative disorders, such as Parkinson and Alzheimer diseases, is a very promising approach. Moreover, the potential therapeutic role of A2A AR antagonists to avoid both immunoescaping of tumor cells and tumor development is well documented. Herein, we report on the synthesis and biological evaluation of a new set of piperazine-and piperidine-containing 7-amino-2-(furan-2-yl)thiazolo[5,4-d]pyrimidine derivatives designed as human A2A AR antagonists/inverse agonists. Binding and potency data indicated that a good number of potent and selective hA2A AR inverse agonists were found. Amongst them, the 2-(furan-2-yl)-N5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazolo[5,4-d]pyrimidine-5,7-diamine 11 exhibited the highest A2A AR binding affinity (Ki = 8.62 nM) as well as inverse agonist potency (IC50 = 7.42 nM). In addition, bioinformatics prediction using the web tool SwissADME revealed that 8, 11, and 19 possessed good drug-likeness profiles.
- Varano, Flavia,Catarzi, Daniela,Vigiani, Erica,Vincenzi, Fabrizio,Pasquini, Silvia,Varani, Katia,Colotta, Vittoria
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- ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase
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The serine hydrolase monoacylglycerol lipase (MAGL) is involved in a plethora of pathological conditions, in particular pain and inflammation, various types of cancer, metabolic, neurological and cardiovascular disorders, and is therefore a promising target for drug development. Although a large number of irreversible-acting MAGL inhibitors have been discovered over the past years, there are only few compounds known so far which inhibit the enzyme in a reversible manner. Therefore, much effort is put into the development of novel chemical entities showing reversible inhibitory behavior, which is thought to cause less undesired side effects. To explore a wide range of chemical structures as MAGL binders, we have applied a virtual screening approach by docking small molecules into the crystal structure of human MAGL (hMAGL) and envisaged a library of 45 selected compounds which were then synthesized. Biochemical investigations included the determination of the inhibitory potency on hMAGL and two related hydrolases, i.e. human fatty acid amide hydrolase (hFAAH) and murine cholesterol esterase (mCEase). The most promising candidates from theses analyses, i.e. three ω-quinazolinonylalkyl aryl ureas bearing alkyl spacers of three to five methylene groups, exhibited IC50 values of 20–41 μM and reversible, detergent-insensitive behavior towards hMAGL. Among these compounds, the inhibitor 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyl)urea (96) was selected for further kinetic characterization, yielding a dissociation constant Ki = 15.4 μM and a mixed-type inhibition with a pronounced competitive component (α = 8.94). This mode of inhibition was further supported by a docking experiment, which suggested that the inhibitor occupies the substrate binding pocket of hMAGL.
- Dato, Florian M.,Neud?rfl, J?rg-Martin,Gütschow, Michael,Goldfuss, Bernd,Pietsch, Markus
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supporting information
(2019/11/13)
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- Development of novel multipotent compounds modulating endocannabinoid and dopaminergic systems
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Polypharmacology approaches may help the discovery of pharmacological tools for the study or the potential treatment of complex and multifactorial diseases as well as for addictions and also smoke cessation. In this frame, following our interest in the de
- Grillo, Alessandro,Chemi, Giulia,Brogi, Simone,Brindisi, Margherita,Relitti, Nicola,Fezza, Filomena,Fazio, Domenico,Castelletti, Laura,Perdona, Elisabetta,Wong, Andrea,Lamponi, Stefania,Pecorelli, Alessandra,Benedusi, Mascia,Fantacci, Manuela,Valoti, Massimo,Valacchi, Giuseppe,Micheli, Fabrizio,Novellino, Ettore,Campiani, Giuseppe,Butini, Stefania,Maccarrone, Mauro,Gemma, Sandra
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- Identification of N-Benzyl 3,5-Dinitrobenzamides Derived from PBTZ169 as Antitubercular Agents
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A series of benzamide scaffolds were designed and synthesized by the thiazinone ring opening of PBTZ169, and N-benzyl 3,5-dinitrobenzamides were finally identified as anti-TB agents in this work. 3,5-Dinitrobenzamides D5, 6, 7, and 12 exhibit excellent in vitro activity against the drug susceptive Mycobacterium tuberculosis H37Rv strain (MIC: 0.0625 μg/mL) and two clinically isolated multidrug-resistant strains (MIC 0.016-0.125 μg/mL). Compound D6 displays acceptable safety and better pharmacokinetic profiles than PBTZ169, suggesting its promising potential to be a lead compound for future antitubercular drug discovery.
- Li, Linhu,Lv, Kai,Yang, Yupeng,Sun, Jingquan,Tao, Zeyu,Wang, Apeng,Wang, Bin,Wang, Hongjian,Geng, Yunhe,Liu, Mingliang,Guo, Huiyuan,Lu, Yu
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p. 741 - 745
(2018/07/05)
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- Design, synthesis and antimycobacterial activity of novel imidazo[1,2-a]pyridine-3-carboxamide derivatives
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We report herein the design and synthesis of “novel imidazo [1,2-a]pyridine-3-carboxamides (IPAs)” bearing a variety of different linkers, based on the structure of IMB-1402 discovered in our lab. Results reveal that 2,6-dimethyl-N-[2-(phenylamino)ethyl] IPAs with an electron-donating group on the benzene ring as a potent scaffold. Compounds 26g and 26h have considerable activity (MIC: 0.041–2.64 μM) against drug-sensitive/resistant MTB strains, and they have acceptable safety indices against MTB H37Rv with the SI values of 4395 and 1405, respectively. Moreover, N-[2-(piperazin-1-yl)ethyl] moiety was also identified as a potentially alternative linker (compound 31), opening a new direction for further SAR studies.
- Lv, Kai,Li, Linhu,Wang, Bo,Liu, Mingliang,Wang, Bin,Shen, Weiyi,Guo, Huiyuan,Lu, Yu
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p. 117 - 125
(2017/06/05)
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- New derivatives of quinoline-4-carboxylic acid with antiplasmodial activity
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New analogues of the recently published compound DDD107498 were prepared. Their activities were examined in vitro against the chloroquine-sensitive NF54 strain. The most active were also tested against the multiresistant K1 strain of Plasmodium falciparum. A couple of the newly synthesized compounds showed promising antiplasmodial activity and selectivity. A single compound showed adequate reduction of parasitaemia (98.1%) in mice infected with Plasmodium berghei. Survival time was doubled compared to control. The results of the biological tests of the novel compounds were compared with the activities of drugs in use. Structure-activity relationships were discussed.
- Hochegger, Patrick,Faist, Johanna,Seebacher, Werner,Saf, Robert,M?ser, Pascal,Kaiser, Marcel,Weis, Robert
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p. 2251 - 2259
(2017/03/23)
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- Small-Molecule Inhibition of the UNC119–Cargo Interaction
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N-Terminal myristoylation facilitates membrane binding and activity of proteins, in particular of Src family kinases, but the underlying mechanisms are only beginning to be understood. The chaperones UNC119A/B regulate the cellular distribution and signal
- Mejuch, Tom,Garivet, Guillaume,Hofer, Walter,Kaiser, Nadine,Fansa, Eyad K.,Ehrt, Christiane,Koch, Oliver,Baumann, Matthias,Ziegler, Slava,Wittinghofer, Alfred,Waldmann, Herbert
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supporting information
p. 6181 - 6186
(2017/05/22)
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- Binding kinetics of ZM241385 derivatives at the human adenosine A 2A receptor
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Classical drug design and development rely mostly on affinity- or potency-driven structure-activity relationships (SAR). Thus far, a given compound's binding kinetics have been largely ignored, the importance of which is now being increasingly recognized. In the present study, we performed an extensive structure-kinetics relationship (SKR) study in addition to a traditional SAR analysis at the adenosine A2A receptor (A 2AR). The ensemble of 24 A2AR compounds, all triazolotriazine derivatives resembling the prototypic antagonist ZM241385 (4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino) ethyl)phenol), displayed only minor differences in affinity, although they varied substantially in their dissociation rates from the receptor. We believe that such a combination of SKR and SAR analyses, as we have done with the A 2AR, will have general importance for the superfamily of G protein-coupled receptors, as it can serve as a new strategy to tailor the interaction between ligand and receptor. Above and beyond: Insight into the binding kinetics of ZM241385 derivatives at the human adenosine A2A receptor has provided additional information beyond a traditional structure-activity relationship (SAR) analysis. The strategy, combining a structure-kinetics relationship investigation and SAR, can serve as an important tool for more directed medicinal chemistry efforts in the future.
- Guo, Dong,Xia, Lizi,Van Veldhoven, Jacobus P. D.,Hazeu, Marc,Mocking, Tamara,Brussee, Johannes,Ijzerman, Adriaan P.,Heitman, Laura H.
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p. 752 - 761
(2014/05/06)
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- Enhancing a CH-π interaction to increase the affinity for 5-HT 1A receptors
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An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared t
- Liegeois, Jean-Francois,Lespagnard, Marc,Meneses Salas, Elsa,Mangin, Floriane,Scuvee-Moreau, Jacqueline,Dilly, Sebastien
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p. 358 - 362
(2014/05/06)
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- Synthesis and pharmacological evaluation of [(4-Arylpiperazin-1-yl)-alkyl]- carbamic acid ethyl ester derivatives as potential anxiolytic agents
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On the basis of our earlier studies, a series of N-{4-[4-(aryl) piperazin-1-yl]-phenyl}-amine derivatives containing terminal carbamoyl fragment with alkyl spacer of different lengths (15-20) were synthesized as ligands, for 5-hydroxytryptamine-1A (5-HT1A
- Khatri, Manisha,Rai, Santosh K.,Ranbhor, Ranjit,Kishore, Krishna,Tiwari, Manisha
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p. 1143 - 1152
(2012/11/07)
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- Chemical modifications on 4-arylpiperazine-ethyl carboxamide derivatives differentially modulate affinity for 5-HT1A, D4.2, and α2A receptors: Synthesis and in vitro radioligand binding studies
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A series of substituted 4-aryl-piperazine-ethyl heteroarylcarboxamides were prepared and tested in in vitro radioligand binding studies. The presence of a quinoxaline has a favourable impact in terms of serotonin 5-HT1A versus dopamine D4.2 receptor selectivity. Compounds with a 3-CF3 group at the distal phenyl ring are the most effective in terms of affinity and selectivity for 5-HT1A versus D4.2 receptors. A 4-phenyl-1,2,3,6- tetrahydropyridine in place of the corresponding 4-phenyl-piperazine side chain is also favourable not only for the affinity for 5-HT1A and D4.2 receptors but also in some cases for α2A-adrenoceptors.
- Graulich, Amaury,Lonard, Marc,Rsimont, Mlissa,Huang, Xi-Ping,Roth, Bryan L.,Ligeois, Jean-Franois
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experimental part
p. 56 - 67
(2010/05/18)
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- Synthesis and biological evaluation of oxazole derivatives as T-type calcium channel blockers
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T-type calcium channel is one of therapeutic targets for the treatment of cardiovascular diseases and neuropathic pain. In this study, as a part of our ongoing efforts to develop potent T-type calcium channel blockers, we designed oxazole derivatives subs
- Lee, Jie Eun,Koh, Hun Yeong,Seo, Seon Hee,Baek, Yi Yeon,Rhim, Hyewhon,Cho, Yong Seo,Choo, Hyunah,Pae, Ae Nim
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scheme or table
p. 4219 - 4222
(2010/09/04)
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- 3-IMIDAZOLYL-INDOLES FOR THE TREATMENT OF PROLIFERATIVE DISEASES
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The invention relates to 3-heterocyclyl indolyl compounds capable of inhibiting the interaction between p53, or variants thereof, and MDM2 and/or MDM4, or variants thereof, respectively, said compounds having the formula (I) wherein R1, R2, R3, R4, RA, Y and Y are as defined in the specification. Due to their activity, the compounds are useful in the treatment of various disorders and diseases mediated by the activity of MDM2 and/or MDM4, or variants thereof, such as inflammatory or proliferative diseases or in the protection of cells.
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Page/Page column 141
(2008/12/04)
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- Further structure-activity relationships study of hybrid 7-{[2-(4-phenylpiperazin-1-yl)ethyl]propylamino}-5,6,7,8-tetrahydronaphthalen-2- ol analogues: identification of a high-affinity D3-preferring agonist with potent in vivo activity with long duration
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This paper describes an extended structure-activity relationships study of aminotetralin-piperazine-based hybrid molecules developed earlier for dopamine D2/D3 receptors. Various analogues as positional isomers have been developed where location of the ph
- Biswas, Swati,Zhang, Suhong,Fernandez, Fernando,Ghosh, Balaram,Zhen, Juan,Kuzhikandathil, Eldo,Reith, Maarten E. A.,Dutta, Aloke K.
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p. 101 - 117
(2008/09/20)
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- Synthesis and biological evaluation of novel T-type Ca2+ channel blockers
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A small molecule library of piperazinylalkylisoxazole derivatives containing about 600 compounds was designed, synthesized and evaluated for blocking effects on T-type Ca2+ channel. Several ligands were identified to possess high inhibitory activity against the T-type Ca 2+ channel. The compound 21 with trifluoromethyl substituents at C3-position of phenyl group (R1) and C2- position of phenyl group (R2) showed the highest inhibitory activity with IC50 value of 1.02μM, which is comparable to that of mibefradil.
- Jung, Hee Kyung,Doddareddy, Munikumar Reddy,Cha, Joo Hwan,Rhim, Hyewhon,Cho, Yong Seo,Koh, Hun Yeong,Jung, Bong Young,Pae, Ae Nim
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p. 3965 - 3970
(2007/10/03)
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- Synthesis and biological characterization of novel hybrid 7-{[2-(4-phenyl-piperazin-1-yl)-ethyl]-propyl-amino}-5,6,7,8-tetrahydro- naphthalen-2-ol and their heterocyclic bioisosteric analogues for dopamine D2 and D3 receptors
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In a recent preliminary communication we described the development of a series of hybrid molecules for the dopamine D2 and D3 receptor subtypes. The design of these compounds was based on combining pharmacophoric elements of aminotetralin and piperazine m
- Dutta, Aloke K.,Venkataraman, Sylesh K.,Fei, Xiang-Shu,Kolhatkar, Rohit,Zhang, Shijun,Reith, Maarten E.A.
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p. 4361 - 4373
(2007/10/03)
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- Hybrid 2-aminotetralin and aryl-substituted piperazine compounds and their use in altering cns activity
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Hybrid compounds containing in aminotetralin moiety or a heterocyclic and/or open chain analog thereof linked through an alkylene group to an aryl ring system-substituted piperidiene moiety exhibit high levels of CNS activity, in some cases exhibiting especially high relative binding efficiencies between D3 and D2 dopaminergic receptor subtypes.
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- A novel series of hybrid compounds derived by combining 2-aminotetralin and piperazine fragments: Binding activity at D2 and D3 receptors
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A series of 7-hydroxy-2-[N-alkyl-(N-(4-phenylpiperazine)-alkyl)amino]tetralins was developed based on a novel hybrid approach that combined 2-aminotetralin and arylpiperazine pharmacophoric moieties. Our preliminary study revealed that a four-methylene bu
- Dutta, Aloke K,Fei, XiangShu,Reith, Maarten E.A
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p. 619 - 622
(2007/10/03)
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- New arylpiperazine derivatives as antagonists of the human cloned 5-HT4 receptor isoforms
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New derivatives of arylpiperazine 9 were designed from ML 10302, a potent 5-HT4 receptor agonist in the gastrointestinal system. Compounds were synthesized by condensation of a number of available arylpiperazines or heteroarylpiperazines with 2
- Curtet,Soulier,Zahradnik,Giner,Berque-Bestel,Mialet,Lezoualc'h,Donzeau-Gouge,Sicsic,Fischmeister,Langlois
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p. 3761 - 3769
(2007/10/03)
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- Quantitative structure-activity analyses of novel hydroxyphenylurea derivatives as antioxidants
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A series of substituted hydroxyphenylureas was synthesized, the chemical structure of which was designed based on structures of natural antioxidants, vitamin E (α-tocopherol) and uric acid. They exhibited high inhibitory activity against lipid peroxidation. In order to gain an insight into the mechanism of the inhibition reaction, we analyzed their structure-activity relationships quantitatively. Electronic and steric effects of substituents on the phenolic hydroxyl group were shown to be of importance in governing the inhibitory potency. An increase in the electron donating property of substituents toward the phenolic hydroxyl group enhanced the antioxidative activity by the stabilization of an electron-deficient radical-type transition state. The steric shielding by ortho-substituents stabilized the phenoxy radicals formed following the transition state. Derivatives having the carboxyl group were only weakly active presumably because of an intermolecular ion-dipole interaction of the phenolic hydroxyl group with the carboxylate anion which could retard the formation of the transition state. Copyright (C) 1998 Elsevier Science Ltd.
- Nakao, Kazuya,Shimizu, Ryo,Kubota, Hitoshi,Yasuhara, Mikiko,Hashimura, Yoshimasa,Suzuki, Toshikazu,Fujita, Toshio,Ohmizu, Hiroshi
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p. 849 - 868
(2007/10/03)
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- 5-HT and DA receptor affinity of arylpiperazine derivatives with terminal benzamide fragment
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The synthesis of some arylpiperazines with a benzamide moiety on N-4 alkyl chain was accomplished and their dopaminergic and serotonergic affinity was assayed by in vitro receptor binding. The results of such investigation showed a moderate affinity on D-
- Perrone,Berardi,Leopoldo,Tortorella,Lograno,Daniele,Govoni
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p. 567 - 572
(2007/10/02)
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- N-(amino)alkyl)-1-pyrrolidine, 1-piperidine and 1-homopiperidinecarboxamides (and thiocarboxamides) with sulfur linked substitution in the 2, 3 or 4-positions
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Novel pyrrolidine, piperidine and homopiperidinecarboxamide and thiocarboxamide compounds having the formula: STR1 wherein X is --S--, --S(O)-- or --S(O)2 --; A is a loweralkalene chain and A1 and A2 are alkalene chains when p and d are one; R, R1 and R2 are hydrogen, loweralkyl, phenyl cycloalkyl or phenylalkyl and R1 and R2 may form a heterocyclic residue with the adjacent nitrogen atom; Q is a selected aromatic radical, and the pharmaceutically acceptable acid addition salts useful as cardiac antiarrhythmia agents are disclosed. Novel chemical intermediates, unsubstituted on pyrrolidine, piperidine and homopiperidine nitrogen but with --(A2)p --X--(A2)d --Q side chain are also disclosed.
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- 1-[(aminoalkyl and aminoalkylamino)carbonyl and thiocarbonyl]-α,α-diarylpyrrolidine, piperidine and homopiperidineacetamides and acetonitriles
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Novel 1-[(aminoalkyl and aminoalkylamino)carbonyl and thiocarbonyl]-α,α-diaryl-pyrrolidine, piperidine and homopiperidineacetamides and acetonitriles having the formula: STR1 wherein; n is zero, one or two; X is oxygen or sulfur; Z is STR2 p is 0 to 5 inclusive with the proviso that when Z is STR3 p is at least one; Y is aminocarbonyl or cyano; Ar1 and Ar2 are 2, 3 or 4-pyrido, phenyl or substituted phenyl; R is hydrogen or loweralkyl; R1, R2 and R3 are hydrogen, cycloalkyl, loweralkyl, phenyl, substituted phenyl, phenylloweralkyl, and R2 and R3 taken with the adjacent nitrogen may form a heterocyclic residue, and diastereoisomers when possible and pharmaceutical salts; and the method and pharmaceutical compositions for treating cardiac arrhythmias therewith are disclosed.
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- N-[(amino)alkyl]-1-pyrrolidine, 1-piperidine and 1-homopiperidinecarboxamides (and thiocarboxamides) with sulfur linked substitution in the 2, 3 or 4-position
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Novel pyrrolidine, piperidine and homopiperidinecarboxamide and thiocarboxamide compounds having the formula: STR1 wherein X is --S--, --S(O)-- or --S(O)2 --; A is a loweralkalene chain and A1 and A2 are alkalene chains when p and d are one; R, R1 and R2 are hydrogen, loweralkyl, phenyl cycloalkyl or phenylalkyl and R1 and R2 may form a heterocyclic residue with the adjacent nitrogen atom; Q is a selected aromatic radical, and the pharmaceutically acceptable acid addition salts useful as cardiac antiarrhythmia agents are disclosed. Novel chemical intermediates, unsubstituted on pyrrolidine, piperidine and homopiperidine nitrogen but with --(A2)p --X--(A2)d --Q side chain are also disclosed.
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- Method of treating cardiac disorders with N-(aryloxyalkyl)-N'-(aminoalkyl)ureas
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N-(Aryloxyalkyl)-N'-(aminoalkyl)ureas and thioureas having the formula: STR1 wherein R1 and R2 are hydrogen, loweralkyl, cycloalkyl, phenyl or phenyllower alkyl, and R3 and R4 are hydrogen, loweralkyl, phenyl and phenylalkyl or R3 and R4 taken together with the adjacent nitrogen form a heterocyclic residue are disclosed in a method of suppressing cardiac arrhythmias.
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- 1-Heterocyclic alkyl-1,2,3,4-tetrahydroquinazolinones and analgesic intermediates thereof
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1-Heterocyclic alkyl-1,2,3,4-tetrahydroquinazolinones, acid addition salts thereof, and intermediate compounds having analgesic properties. A representative quinazolinone compound is 1-[2-(1-phenyl-4-piperazinyl)-ethyl]-2-phenyl-1,2,3,4-tetrahydro-4-quinazolinone. A representative analgesic intermediate is 2-[2-(4-[1-phenyl]piperazinyl)ethylamino] bezamide.
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- 1-Heterocyclic alkyl-1,2,3,4-tetrahydroquinazolinones and analgesic intermediates thereof
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1-heterocyclic alkyl-1,2,3,4-tetrahydroquinazolinones, acid addition salts thereof, and intermediate compounds having analgesic properties. A representative quinazolinone compound is 1-[2-(1-phenyl-4-piperazinyl)-ethyl]-2-phenyl-1,2,3,4-tetrahydro-4-quinazolinone. A representative analgesic intermediate is 2-[2-(4-[1-phenyl]piperazinyl)ethylamino]benzamide.
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