- Highly Enantioselective Synthesis of Fused Tri- and Tetrasubstituted Aziridines: aza-Darzens Reaction of Cyclic Imines with α-Halogenated Ketones Catalyzed by Bifunctional Phosphonium Salt
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The first enantioselective aza-Darzens reaction of cyclic imines with α-halogenated ketones was realized under mild reaction conditions by using amino-acid-derived bifunctional phosphonium salts as phase-transfer promoters. A variety of structurally dense tri- and tetrasubstituted aziridine derivatives, containing benzofused heterocycles as well as spiro-structures, were readily synthesized in high yields with excellent diastereo- and enantioselectivities (up to >20:1 d.r. and >99.9 % ee). The highly functionalized aziridine products could be easily transformed into different classes of biologically active compounds.
- Pan, Jianke,Wu, Jia-Hong,Zhang, Hongkui,Ren, Xiaoyu,Tan, Jian-Ping,Zhu, Lixiang,Zhang, Hong-Su,Jiang, Chunhui,Wang, Tianli
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supporting information
p. 7425 - 7430
(2019/05/10)
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- Discovery, synthesis, and structure-activity relations of 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-ones as potassium-competitive acid blockers
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With the aim to discover a gastric antisecretory agent more potent than the existing proton pump inhibitors, novel 3,4-dihydro-1H-spiro(naphthalene-2,2′-piperidin)-1-one derivatives, which could occupy two important lipophilic pockets (described as LP-1 and LP-2) of H+,K+-ATPase and can strongly bind to the K+-binding site, were designed based on a docking model. Among the compounds synthesized, compound 4d showed a strong H+,K+-ATPase-inhibitory activity and a high stomach concentration in rats, resulting in potent inhibitory action on histamine-stimulated gastric acid secretion in rats. Furthermore, 4d exerted significant inhibitory action on histamine-stimulated gastric-acid secretion in rats with a rapid onset and moderate duration of action after the administration. These findings may lead to a new insight into the drug design of potassium-competitive acid blockers.
- Imaeda, Toshihiro,Ono, Koji,Nakai, Kazuo,Hori, Yasunobu,Matsukawa, Jun,Takagi, Terufumi,Fujioka, Yasushi,Tarui, Naoki,Kondo, Mitsuyo,Imanishi, Akio,Inatomi, Nobuhiro,Kajino, Masahiro,Itoh, Fumio,Nishida, Haruyuki
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p. 3719 - 3735
(2017/06/13)
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- Identification of Tricyclic Agonists of Sphingosine-1-phosphate Receptor 1 (S1P1) Employing Ligand-Based Drug Design
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Fingolimod (1) is the first approved oral therapy for the treatment of relapsing remitting multiple sclerosis. While the phosphorylated metabolite of fingolimod was found to be a nonselective S1P receptor agonist, agonism specifically of S1P1 is responsible for the peripheral blood lymphopenia believed to be key to its efficacy. Identification of modulators that maintain activity on S1P1 while sparing activity on other S1P receptors could offer equivalent efficacy with reduced liabilities. We disclose in this paper a ligand-based drug design approach that led to the discovery of a series of potent tricyclic agonists of S1P1 with selectivity over S1P3 and were efficacious in a pharmacodynamic model of suppression of circulating lymphocytes. Compound 10 had the desired pharmacokinetic (PK) and pharmacodynamic (PD) profile and demonstrated maximal efficacy when administered orally in a rat adjuvant arthritis model.
- Xiao, Hai-Yun,Watterson, Scott H.,Langevine, Charles M.,Srivastava, Anurag S.,Ko, Soo S.,Zhang, Yanlei,Cherney, Robert J.,Guo, Wei-Wei,Gilmore, John L.,Sheppeck, James E.,Wu, Dauh-Rurng,Li, Peng,Ramasamy, Duraisamy,Arunachalam, Piramanayagam,Mathur, Arvind,Taylor, Tracy L.,Shuster, David J.,McIntyre, Kim W.,Shen, Ding-Ren,Yarde, Melissa,Cvijic, Mary Ellen,Marino, Anthony M.,Balimane, Praveen V.,Yang, Zheng,Banas, Dana M.,Cornelius, Georgia,D'Arienzo, Celia J.,Warrack, Bethanne M.,Lehman-McKeeman, Lois,Salter-Cid, Luisa M.,Xie, Jenny,Barrish, Joel C.,Carter, Percy H.,Dyckman, Alaric J.,Murali Dhar
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p. 9837 - 9854
(2016/11/19)
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- Heterobicyclic sphingosine 1-phosphate analogs
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Compounds that have agonist activity at one or more of the S1P receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at S1P receptors.
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Page/Page column
(2014/04/18)
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- PPh3·HBr-DMSO mediated expedient synthesis of γ-substituted β,γ-unsaturated α-ketomethylthioesters and α-bromo enals: Application to the synthesis of 2-methylsulfanyl-3(2 H)-furanones
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An efficient chemoselective general procedure for the synthesis of γ-substituted β,γ-unsaturated α-ketomethylthioesters from α,β-unsaturated ketones has been achieved through an unprecedented PPh3·HBr-DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of α-bromoenals from enals. Furthermore, AuCl 3-catalyzed efficient access to 3(2H)-furanones from the above intermediates under extremely mild conditions are described. Copyright
- Mal, Kanchan,Sharma, Abhinandan,Maulik, Prakas R.,Das, Indrajit
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supporting information
p. 662 - 667
(2014/01/23)
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- TETRACYCLIC HETEROCYCLE COMPOUNDS FOR TREATING HEPATITIS C VIRAL INFECTION
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Tetracyclic heterocycle compounds of formula (I) and pharmaceutically acceptable salts thereof are provided, wherein A, A', G, R1, R15, U, V, V', W, W, X, X', Y and Y' are as defined in the invention. The pharmaceutical compositions comprising these compounds and the use of the compounds for treating hepatitis C virus (HCV) infection are also provided.
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Page/Page column 106
(2012/04/17)
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- FUSED TETRACYCLIC HETEROCYCLE COMPOUNDS AND METHODS OF USE THEREOF FOR TREATMENT OF VIRAL DISEASES
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The present invention discloses novel Fused Tetracyclic Heterocycle Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, A', G, R1, R15, U, V, V', W, W', X, X', Y and Y' are as defined herein. The present invention also discloses compositions comprising at least one Fused Tetracyclic Heterocycle Compound, and methods of using the Fused Tetracyclic Heterocycle Compounds for treating or preventing HCV infection in a patient.
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- HETEROBICYCLIC SPHINGOSINE 1-PHOSPHATE ANALOGS
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Compounds that have agonist activity at one or more of the SlP receptors are provided. The compounds are sphingosine analogs that, after phosphorylation, can behave as agonists at SlP receptors.
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Page/Page column 22
(2010/05/14)
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- Environmentally benign electrophilic and radical bromination 'on water': H2O2-HBr system versus N-bromosuccinimide
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A H2O2-HBr system and N-bromosuccinimide in an aqueous medium were used as a 'green' approach to electrophilic and radical bromination. Several activated and less activated aromatic molecules, phenylsubstituted ketones and styrene were efficiently brominated 'on water' using both systems at ambient temperature and without an added metal or acid catalyst, whereas various non-activated toluenes were functionalized at the benzyl position in the presence of visible light as a radical activator. A comparison of reactivity and selectivity of both brominating systems reveals the H2O2-HBr system to be more reactive than NBS for benzyl bromination and for the bromination of ketones, while for electrophilic aromatic substitution of methoxy-substituted tetralone it was higher for NBS. Also, higher yields of brominated aromatics were observed when using H2O2-HBr 'on water'. Bromination of styrene reveals that not just the structure of the brominating reagent but the reaction conditions: amount of water, organic solvent, stirring rate and interface structure, play a key role in defining the outcome of bromination (dibromination vs bromohydroxylation). In addition, mild reaction conditions, a straightforward isolation procedure, inexpensive reagents and a lower environment impact make aqueous brominating methods a possible alternative to other reported brominating protocols.
- Podgor?ek, Ajda,Stavber, Stojan,Zupan, Marko,Iskra, Jernej
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experimental part
p. 4429 - 4439
(2009/10/09)
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- A convenient one-pot synthesis of thiazol-2-imines: application in the construction of pifithrin analogues
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For the first time a reaction intermediate has been isolated giving further insight into the mechanism of thiazol-2-imine formation. The first step of the reaction requires a basic medium, while the second step is an acid mediated E1 elimination reaction. An efficient one-pot synthesis of substituted thiazol-2-imines have been achieved by the condensation of carbonyl compounds with thioureas and 1,3-disubstituted thioureas using 1,1′-(ethane-1,2-diyl)dipyridinium bistribromide (EDPBT). Unsymmetrical 1,3-disubstituted thioureas give regioselective products with symmetrical ketones, which are mainly governed by the pKas of NH protons of thiourea, whereas symmetrical 1,3-disubstituted thioureas give regioselective products with symmetrical carbonyl compounds owing to the regioselective bromination of ketones. The methodology is extended to access novel neurodegenerative drug candidate pifithrin-α analogues in good yields in shorter reaction time. This method is simple, versatile and is applicable for different 1,3-disubstituted thioureas as well as a range of carbonyl compounds.
- Murru, Siva,Singh,Kavala, Veerababurao,Patel, Bhisma K.
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p. 1931 - 1942
(2008/09/17)
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- Halogenation of ketones with N-halosuccinimides under solvent-free reaction conditions
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Several aryl substituted ketones, cyclic ketones, 1,3-diketones and a β-ketoamide were halogenated with N-halosuccinimides under solvent-free reaction conditions (SFRC) at various temperatures (20-80 °C), whereas less enolized ketones required the presence of an acid catalyst (p-toluenesulfonic acid, PTSA). Bromination of substituted acetophenones obeys first order kinetics v=kBr[ketone] and the following correlation with the keto-enol equilibrium constant: log kBr=0.3pKE+C1, less enolized substrates being more reactive; the moderate positive charge developed in the rate determining step was confirmed by the Hammett correlation (ρ=-0.5). On the other hand, in cyclic ketones an opposite relation was observed: log kBr=-0.6pKE+C2, indicating higher reactivity of substrates with higher enolization constant (KE). The important role of the nature of the solvent (MeCN, MeOH) in preorganization of the ketone-NBS-PTSA mixture prior to SFRC bromination was found.
- Pravst, Igor,Zupan, Marko,Stavber, Stojan
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p. 5191 - 5199
(2008/09/21)
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- Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: Potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis
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In this study, the synthesis and biological evaluation of heteroaryl-substituted dihydronaphthalenes and indenes (1-16) is described. The compounds were tested for activity by use of human CYP11B2 expressed in fission yeast and V79 MZh cells and for selectivity by use of human CYP11B1, CYP17, and CYP19. The most active inhibitor was the 6-methoxydihydronaphthalene 4 (IC 50 = 2 nM), showing a Ki value of 1.3 nM and a competitive type of inhibition. The 5-methoxyindene 3 was found to be the most selective CYP11B2 inhibitor (IC50 = 4 nM; CYP11B1 IC50 = 5684 nM), which also showed only marginal inhibition of human CYP3A4 and CYP2D6. Docking and molecular dynamics studies using our homology-modeled CYP11B2 structure were performed to understand some structure-activity relationships. Caco-2 cell experiments revealed highly cell-permeable compounds, and metabolic studies with 4 using rat liver microsomes showed sufficient stability.
- Voets, Marieke,Antes, Iris,Scherer, Christiane,Müller-Vieira, Ursula,Biemel, Klaus,Marchais-Oberwinkler, Sandrine,Hartmann, Rolf W.
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p. 2222 - 2231
(2007/10/03)
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- Tetracyclic compounds as estrogen ligands
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This invention provides estrogen receptor modulators having the structure: wherein R1, R2, R3, R4, Q, n, R8, R9, R10, and R11 have been defined in the specification; o
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Page/Page column 11; 16
(2010/02/15)
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- Directed regioselectivity of bromination of ketones with NBS: solvent-free conditions versus water
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The reaction conditions employed directed the site of functionalisation of ketones with NBS: under solvent-free conditions α-bromination was the exclusive process, while in water, ring functionalisation occurred in the case of methoxy substituted aromatic ketones.
- Pravst, Igor,Zupan, Marko,Stavber, Stojan
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p. 4707 - 4710
(2007/10/03)
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- CONTROL OF PARASITES IN ANIMALS BY THE USE OF IMIDAZO[1,2-B]PYRIDAZINE DERIVATIVES
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Novel imidazo[1,2-b]pyridazine compounds useful for controlling parasites in animals and methods of treatment of parasite infestation in animals using the compounds are disclosed. Formula (I).
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Page/Page column 30
(2008/06/13)
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- Application of directed metallation in synthesis. Part 3: Studies in the synthesis of (±)-semivioxanthin and its analogues
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The synthesis of several analogues of (±)-semivioxanthin including five thiophene analogues, using directed metalation are reported. The strategy consisted of the synthesis of functionalized naphthalene or benzo[b]thiophene as building blocks followed by
- Kamila, Sukanta,Mukherjee, Chandrani,Mondal, Sasanka S.,De, Asish
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p. 1339 - 1348
(2007/10/03)
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- Aryltricyclospirodienones; novel steroid mimics as inhibitors of aromatase
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The aryltricyclospirodienones 16a, 16b, 16c and 18 have been designed as potential inhibitors of aromatase and are synthesised from 6-methoxytetralone; ? compounds 16a and 18 have proved effective inhibitors with activities of the same order as aminoglutethimide.
- Hobbs-Mallyon, David,Li, Warren,Whiting, Donald A.
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p. 1511 - 1516
(2007/10/03)
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- Method of treating diseases susceptable to treatment by blocking NMDA-receptors
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3-Piperidino-1-chromanol derivatives and analogs having the formula STR1 wherein A and B are taken together and are --CH 2 CH 2 -- or A and B are taken separately and are each H;X is CH 2 or O;X 1 is H or OH;Z is H, F, Cl, Br or OH;Z 1 is H, F, Cl, Br or
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- Neuroprotective 3-piperidino-4-hydroxychroman derivatives and analogs
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3-Piperidino-1-chromanol derivatives and analogs having the formula STR1 wherein A and B are taken together and are --CH2 CH2 -- or A and B are taken separately and are each H; X is CH2 or O; X1 is H or OH; Z is
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- TOTAL SYNTHESIS OF NATURAL ESTRONE AND ESTRADIOL METHYL ETHERS IN EXTREMELY HIGH ENANTIOMERIC PURITY VIA AN ASYMMETRIC MICHAEL ADDITION TO AN UNSTURATED SULFOXIDE
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Methoxytetralone enolate ion 1b underwent an asymmetric Michael addition to enantiomerically pure cyclopentenone sulfoxide (S)-(+)-2 with a diastereoslectivity of 91-94percent.A series of eight additional steps led to (+)-estrone methyl ether (11) in over
- Posner, Gary H.,Switzer, Christopher
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p. 1239 - 1244
(2007/10/02)
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