- Construction of the Fused Pentacycle of Talatisamine via a Combination of Radical and Cationic Cyclizations
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The fused 6/7/5/6/6-membered (ABCDE) ring system of talatisamine was synthesized in 22 steps. After preparation of the AE-ring structure from 2-(ethoxycarbonyl)cyclohexanone, elaboration of the carboskeleton was realized by sequential additions of allyl magnesium bromide and the lithiated C-ring. The C11-bridgehead radical derived from the ACE-ring underwent the 7-endo cyclization with the enone moiety to form the B-ring in C10-stereoselective and C11-stereospecific manners. The 6-endo cyclization of the remaining D-ring was in turn attained by using the silyl enol ether as the nucleophile and the PhSeCl-activated olefin as the electrophile. These radical and cationic cyclizations were demonstrated to be highly chemoselective, and they significantly contributed to streamlining the route to the intricately fused pentacycle of talatisamine.
- Tabuchi, Toshiki,Urabe, Daisuke,Inoue, Masayuki
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- Expeditious synthesis of the fused hexacycle of puberuline C: Via a radical-based cyclization/translocation/cyclization process
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The fused 6/7/5/6/6/6-hexacyclic ring system of puberuline C was assembled in 18 steps from 2-(ethoxycarbonyl)cyclohexanone. After the azabicyclo[3.3.1]nonane derivative was sequentially coupled with propargyl magnesium bromide, 2-iodo cyclopentenone and allyl bromide, the pentacycle was constructed in a single step via a radical-based cyclization/translocation/cyclization process. The C11-bridgehead radical generated via C-Br homolysis participated in a 7-endo cyclization, and the 1,5-hydrogen translocation of the resultant radical was followed by transannular 6-exo cyclization to simultaneously realize the construction of the two rings and the introduction of the five contiguous stereocenters. The last 6-exo cyclization was induced by the Mukaiyama aldol reaction, and the C16-ketone was stereoselectively reduced by the action of SmI2/t-BuOH, leading for the first time to the synthesis of the entire hexacycle of puberuline C.
- Hagiwara, Koichi,Tabuchi, Toshiki,Urabe, Daisuke,Inoue, Masayuki
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- METHODS AND MATERIALS FOR INCREASING OR MAINTAINING NICOTINAMIDE MONONUCLEOTIDE ADENYLYL TRANSFERASE-2 (NMNAT2) POLYPEPTIDE LEVELS
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This document provides methods and materials for increasing or maintaining NMNAT2 polypeptide levels within cells. For example, compounds (e.g., organic compounds) having the ability to increase or maintain NMNAT2 polypeptide levels within cells, formulations containing compounds having the ability to increase or maintain NMNAT2 polypeptide levels within cells, methods for making compounds having the ability to increase or maintain NMNAT2 polypeptide levels within cells, methods for making formulations containing compounds having the ability to increase or maintain NMNAT2 polypeptide levels within cells, methods for increasing or maintain NMNAT2 polypeptide levels within cells, and methods for treating mammals (e.g., humans) having a condition responsive to an increase in NMNAT2 polypeptide levels are provided (or for preventing said condition).
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Page/Page column 191; 192
(2020/09/08)
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- Tetrahydrocarbazole small molecular organic compounds, application thereof to preparation of antibacterial medicines and preparation method thereof
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The invention discloses tetrahydrocarbazole small molecular organic compounds shown as a structural formula (I), or pharmaceutically acceptable salts and medicinal compositions, application thereof topreparation of antibacterial medicines. The tetrahydrocarbazole small molecular organic compounds can effectively inhibit gram-positive bacteria, and have a very good inhibitory effect on multidrug-resistant staphylococcus aureus and gram-negative bacteria which are clinically difficult to treat, and can be used for preparing highly-efficient anti-bacterial infection medicines. The invention further discloses a preparation method of the tetrahydrocarbazole small molecular organic compounds.
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Paragraph 0160; 0161
(2018/04/03)
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- Tetrahydrocarbazole Inhibitors Of SIRT1 Receptors
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Described are deuterium-substituted tetrahydrocarbazole compounds of Formulae I, II, or III which are inhibitors of sirtuin 1 (SIRT1). Also described are pharmaceutical compositions comprising the deuterium-substituted tetrahydrocarbazole compounds, and methods of use thereof.
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Paragraph 0237-0239
(2017/08/01)
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- Discovery of α-Substituted Imidazole-4-acetic Acid Analogues as a Novel Class of ρ1γ-Aminobutyric Acid Type A Receptor Antagonists with Effect on Retinal Vascular Tone
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The ρ-containing γ-aminobutyric acid type A receptors (GABAARs) play an important role in controlling visual signaling. Therefore, ligands that selectively target these GABAARs are of interest. In this study, we demonstrate that the partial GABAAR agonist imidazole-4-acetic acid (IAA) is able to penetrate the blood–brain barrier in vivo; we prepared a series of α- and N-alkylated, as well as bicyclic analogues of IAA to explore the structure–activity relationship of this scaffold focusing on the acetic acid side chain of IAA. The compounds were prepared via IAA from l-histidine by an efficient minimal-step synthesis, and their pharmacological properties were characterized at native rat GABAARs in a [3H]muscimol binding assay and at recombinant human α1β2γ2Sand ρ1GABAARs using the FLIPR membrane potential assay. The (+)-α-methyl- and α-cyclopropyl-substituted IAA analogues ((+)-6 a and 6 c, respectively) were identified as fairly potent antagonists of the ρ1GABAAR that also displayed significant selectivity for this receptor over the α1β2γ2SGABAAR. Both 6 a and 6 c were shown to inhibit GABA-induced relaxation of retinal arterioles from porcine eyes.
- Krall, Jacob,Brygger, Benjamin M.,Sigureardóttir, Sara B.,Ng, Clarissa K. L.,Bundgaard, Christoffer,Kehler, Jan,Nielsen, Birgitte,Bek, Toke,Jensen, Anders A.,Fr?lund, Bente
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p. 2299 - 2310
(2016/10/25)
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- Design, synthesis, and evaluation of conformationally restricted acetanilides as potent and selective β3 adrenergic receptor agonists for the treatment of overactive bladder
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A series of conformationally restricted acetanilides were synthesized and evaluated as β3-adrenergic receptor agonists (β3-AR) for the treatment of overactive bladder (OAB). Optimization studies identified a five-membered ring as the preferred conformational lock of the acetanilide. Further optimization of both the aromatic and thiazole regions led to compounds such as 19 and 29, which have a good balance of potency and selectivity. These compounds have significantly reduced intrinsic clearance compared to our initial series of pyridylethanolamine β3-AR agonists and thus have improved unbound drug exposures. Both analogues demonstrated dose dependent β3-AR mediated responses in a rat bladder hyperactivity model.
- Moyes, Christopher R.,Berger, Richard,Goble, Stephen D.,Harper, Bart,Shen, Dong-Ming,Wang, Liping,Bansal, Alka,Brown, Patricia N.,Chen, Airu S.,Dingley, Karen H.,Di Salvo, Jerry,Fitzmaurice, Aileen,Gichuru, Loise N.,Hurley, Amanda L.,Jochnowitz, Nina,Miller, Randall R.,Mistry, Shruty,Nagabukuro, Hiroshi,Salituro, Gino M.,Sanfiz, Anthony,Stevenson, Andra S.,Villa, Katherine,Zamlynny, Beata,Struthers, Mary,Weber, Ann E.,Edmondson, Scott D.
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supporting information
p. 1437 - 1453
(2014/03/21)
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- An improved, regioselective synthesis of the radiolabelling precursor for the translocator protein targeting positron emission tomography imaging radiotracer [18F]GE-180
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[18F]GE-180 has been demonstrated to be a promising new positron emission tomography radiotracer for targeting translocator protein. PET imaging of TSPO will enable measurement of neuroinflammation and microglia activity in vivo. The synthetic route used in the initial discovery of GE-180, whilst enabling the rapid evaluation of the structure-activity relationships (SAR) in this molecular class, was not high yielding and not suitable for scale-up. Here we present an optimised route towards GE-180 and the radiolabelling precursor of [18F]GE-180 with significantly improved yields due to a strategy which improves the regioselectivity of the key indole formation step of the synthesis.
- Morisson-Iveson, Véronique,Wadsworth, Harry,Passmore, Joanna,Ewan, Amanda,Nilsen, Sondre,Thaning, Mikkel,Trigg, William
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p. 5141 - 5143
(2014/12/10)
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- PROCESSES FOR THE PREPARATION OF 6-CHLORO-2,3,4,9-TETRAHYDRO-1H-CARBAZOLE-1-CARBOXAMIDE AND OF ITS PRECURSORS
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The invention relates to a novel process for the preparation of rac-6-Chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide (I) through the conversion of a 3-bromo-2-oxo-cyclohexanecarboxylic acid alkyl ester (I'-a) into 6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxylic acid alkyl ester (I'-b), which in turn is processed to yield the final product (I).
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Page/Page column 9
(2013/05/09)
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- GE-180: A novel fluorine-18 labelled PET tracer for imaging Translocator protein 18 kDa (TSPO)
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A series of tricyclic compounds have been synthesised and evaluated in vitro for affinity against Translocator protein 18 kDa (TSPO) and for preferred imaging properties. The most promising of the compounds were radiolabelled and evaluated in vivo to determine biodistribution and specificity for high expressing TSPO regions. Metabolite profiling in brain and plasma was also investigated. Evaluation in an autoradiography model of neuroinflammation was also carried out for the best compound, 12a ([18F]GE-180).
- Wadsworth, Harry,Jones, Paul A.,Chau, Wai-Fung,Durrant, Clare,Fouladi, Naghmeh,Passmore, Joanna,O'Shea, Dennis,Wynn, Duncan,Morisson-Iveson, Veronique,Ewan, Amanda,Thaning, Mikkel,Mantzilas, Dimitrios,Gausemel, Ingvil,Khan, Imtiaz,Black, Andrew,Avory, Michelle,Trigg, William
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scheme or table
p. 1308 - 1313
(2012/04/04)
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- MULTICYCLIC COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are multicyclic compounds, methods of their synthesis, pharmaceutical compositions comprising the compounds, and methods of their use. The compounds provided herein are useful for the treatment, prevention, and/or management of various neurological disorders, including but not limited to, psychosis and schizophrenia.
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Page/Page column 102
(2011/06/25)
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- Phosphine ligands in the Palladium-catalysed methoxycarbonylation of ethene: Insights into the catalytic cycle through an HP NMR spectroscopic Study
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Novel cis-1,2-bis(di-tertbutyl-phosphinomethyl) carbocyclic ligands 6-9 have been prepared and the corresponding palladium complexes [Pd(O 3SCH3)(L-L)][O3SCH3] (L-L = diphosphine) 32-35 synthesised and characterised by NMR spectroscopy and Xray diffraction. These diphosphine ligands give very active catalysts for the palladium-catalysed methoxycarbonylation of ethene. The activity varies with the size of the carbocyclic backbone, ligands 7 and 9, containing four- and six-membered ring backbones giving more active systems. The acid used as co-catalyst has a strong influence on the activity, with excess trifluoroacetic acid affording the highest conversion, whereas excess methyl sulfonic acid inhibits the catalytic system. An in oper-ando NMR spectroscopic mechanistic study has established the catalytic cycle and resting state of the catalyst under operating reaction conditions. Although the catalysis follows the hydride pathway, the resting state is shown to be the hydride precursor complex [Pd(O3SCH3)(L-L)][O3SCH3], which demonstrates that an isolable/detectable hydride complex is not a prerequisite for this mechanism.
- De La Fuente, Veronica,Waugh, Mark,Eastham, Graham R.,Iggo, Jonathan A.,Castillon, Sergio,Claver, Carmen
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scheme or table
p. 6919 - 6932
(2010/08/07)
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- MODULATORS FOR AMYLOID BETA
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The invention relates to compounds of formula wherein R1, R2, R3, R4, X and Y are as defined herein and to pharmaceutically active acid addition salts thereof. The compounds can be used for the treatment of Alzheimer's disease, cerebral amyloid angiopathy, hereditary cerebral hemorrhage with amyloidosis, Dutch-type (HCHWA-D), multi-infarct dementia, dementia pugilistica or Down syndrome.
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Page/Page column 20
(2009/07/25)
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- HYDROXYMETHYL PYRROLIDINES AS BETA 3 ADRENERGIC RECEPTOR AGONISTS
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The present invention provides compounds of Formula I, pharmaceutical compositions thereof, and method of using the same in the treatment or prevention of diseases mediated by the activation of β3-adrenoceptor.
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Page/Page column 34-35
(2009/10/30)
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- Substituted 4,5,6,7-tetrahydrobenzthiazol-2-ylamine compounds
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Substituted 4,5,6,7-tetrahydrobenzothiazol-2-ylamine compounds, a method for their production; pharmaceutical compositions comprising them, and methods of use for modulating biological functions and/or treating or inhibiting various medical conditions such as, e.g., depression and pain.
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- Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1
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High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.
- Napper, Andrew D.,Hixon, Jeffrey,McDonagh, Thomas,Keavey, Kenneth,Pons, Jean-Francois,Barker, Jonathan,Yau, Wei Tsung,Amouzegh, Patricia,Flegg, Adam,Hamelin, Estelle,Thomas, Russell J.,Kates, Michael,Jones, Stephen,Navia, Manuel A.,Saunders, Jeffrey O.,DiStefano, Peter S.,Curtis, Rory
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p. 8045 - 8054
(2007/10/03)
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- SUBSTITUTED 4,5,6,7-TETRAHYDRO-BENZOTHIAZOL-2-YLAMINE COMPOUNDS
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The invention relates to substituted 4,5,6,7-tetrahydro-benzothiazol-2-ylamine compounds, to methods for their production, to medicaments containing said compounds and to the use of said compounds for producing medicaments.
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Page/Page column 65; 67
(2010/02/13)
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- Treating a viral disorder
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Heterocyclic compounds of formula (I) and methods of treating or preventing an HIV-mediated disorder by administering a compound of formula (I) are described herein.
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Page/Page column 20
(2008/06/13)
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- GUANIDINE DERIVATIVES AND USE THEREOF AS NEUROPEPTIDE FF RECEPTOR ANTAGONISTS
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The invention relates to guanidine derivatives of formula (I) where: A = a chain of 3-c6 carbon atoms, one of which can be replaced by -N(R')- or -O- and R' = H or a substituent, where the ring skeleton only contains both double bonds of the thiazole component, the pharmaceutically-acceptable acid addition salts of basic compounds of formula (I), the pharmaceutically-acceptable salts of compounds of formula (I),, comprising acid groups, with bases, the pharmaceutically-acceptable esters of hydroxy or carboxyl group containing compounds of formula (I) and the solvates or hydrates thereof, which are partly known and partly novel and exhibit a neuropeptide FF receptor antagonist effect. The above are suitable for the treatment of pain and hyperalgesia, withdrawal symptoms in alcohol, psychotropic and nicotine dependencies, for improvement or cure of said dependencies, for regulation of insulin excretion, food intake, memory functions, blood pressure, electrolyte and energy management and for treatment of urinary incontinence. The above can be produced using generally used methods and processed to give medicaments.
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- FUSED HETEROCYCLIC DERIVATIVES AS PPAR MODULATORS
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The present invention is directed to compounds represented by the following structural formula, Formula I: wherein (a) X is selected from the group consisting of a single bond, O, S. S(O)2 and N; (b) U is an aliphatic linker; (c) Y is selected from the group consisting of C, O, S, NH and a single bond; (d) E is C(R3) (R4)A or A and wherein (i) A is selected from the group consisting of carboxyl, tetrazole, C1-C6 alkylnitrile, carboxamidek, sulfonamide and acylsulfonamide; (e) B is selected from the group consisting of S, O, C, and N; (f) Z is selected from the group consisting of N and C; with the proviso that when B is C then Z is N.
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- A convenient synthesis of 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine side-chain mimetics
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A convenient synthesis of novel 4-aminomethyl-4,5,6,7-tetrahydro-1,3-benzothiazole arginine side-chain mimetics designed for incorporation into thrombin inhibitors is reported.
- Marinko, Petra,Kastelic, Jo?e,Krbav?i?, Ale?,Kikelj, Danijel
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p. 8911 - 8913
(2007/10/03)
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- The γ-alkylation of cyclic β-ketoesters via their enamine derivatives
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The γ-alkylation - functionalization of cyclic β-ketoesters via their enamine derivatives is discussed with particular emphasis on their preparation from β-ketoesters and their reaction with various electrophiles such as electrophilic olefins, halogenoids, anmd allylic and benzylic halides.Although the amine ring size does not appear to affect reactivity to a great extent, the reaction is very sensitive to β-ketoester ring size, with six-membered rings giving the best results.In the latter case the alkylation-functionalization is general and specific to the γ-position and therefore provides an important complement to the dianion and related methodologies.
- Gravel, Denis,Labelle, Marc
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p. 1874 - 1883
(2007/10/02)
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- A CYCLOPENTANE, CYCLOPENTENE AND CYCLOPENTANONE ANNULATION METHODOLOGY
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The chemistry derived from the dienolates of 1,2-dicarboxylic acid esters is described.New methods for preparing cyclopentane, cyclopentene and cyclopentanone rings affixed to the diesters are discussed.
- Wilkening, David,Mundy, Bradford P.
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p. 227 - 238
(2007/10/02)
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- Synthesis of aminoiderivatives of 4,5,6,7-tetrahydro-benzothiazole. II. 4, 5 and 6-aminomethyl derivatives with cardiovascular activity
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The ethyl esters of 4,5,6,7-tetrahdyro-benzothiazolyl-4 carboxylic acids were synthesized from corresponding ethyl 1-oxo-2 bromo-cyclohexane-carboxylates. Their reduction to alcohols, which were then transformed into tosylates, leads to the aminomethyl derivatives. These derivatives are practically devoid of antihistaminic H2 and dopaminergic activities but have interesting cardiovascular properties.
- Maillard,Delaunay,Langlois,et al.
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p. 457 - 460
(2007/10/02)
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- Condensed Tetrahydrobenzothiazoles: Part I- Synthesis of 2-Substituted Anilino-4,5,6,7-tetrahydrobenzothiazoles and Their 4-Carbethoxy Derivatives
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Condensation of the appropriate 2-halocyclohexanone (I) with arylthiourea (II) affords a number of 2-substituted anilino-4,5,6,7-tetrahydrobenzothiazoles (IIIa) and their 4-carbethoxy esters (IIIb).Influence of steric factors and nucleophilicity of the reactants on the course of this reaction are discussed.
- Balse, Mukta N.,Mahajanshetti, C. S.
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p. 256 - 259
(2007/10/02)
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- 9-Acyl-1,2,3,4-tetrahydrocarbazole-3 and 4-carboxylic acids
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Novel 9-aroyl-1,2,3,4-tetrahydrocarbazoles bearing a carboxy substituent at position 3 or 4 and corresponding esters having antiinflammatory activity, the preparation thereof and novel intermediates therefor are described.
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