- A new approach to 4-aryl-1,3-butanediols by cobalt-catalyzed sequential radical cyclization-arylation reaction of silicon-tethered 6-iodo-1-hexene derivatives
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Treatment of 6-iodo-4-oxa-3-sila-1-hexene derivatives with arylmagnesium bromide in the presence of a catalytic amount of a cobalt-diamine complex in THF afforded the corresponding benzyl-substituted oxasilacyclopentanes in good yield. The products were converted to 4-aryl-1,3-diols after Tamao-Fleming oxidation. Georg Thieme Verlag Stuttgart.
- Someya, Hidenori,Kondoh, Azusa,Sato, Akinori,Ohmiya, Hirohisa,Yorimitsu, Hideki,Oshima, Koichiro
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Read Online
- An efficient synthesis of the orally-active GpIIb/IIIa antagonist FR184764
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An efficient synthesis of the orally-active GpIIb/IIIa antagonist FR184764 was achieved. The key intermediate, an optically active ethynyl β-amino ester, was synthesized efficiently by utilizing a lipase catalyzed kinetic resolution step.
- Yamanaka, Toshio,Ohkubo, Mitsuru,Takahashi, Fumie,Kato, Masayuki
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Read Online
- Synthesis and antiplasmodial activity of streptocyanine/peroxide and streptocyanine/4-aminoquinoline hybrid dyes
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Two series of streptocyanine dyes incorporating cyclic peroxide or 4-aminoquinoline moieties are prepared and X-ray diffraction structures for three compounds are determined. All hybrid dyes show good antiplasmodial activity (0.06 to 0.66 μM) and are not
- Maether, Marie-Pierre,Bernat, Virginie,Maturano, Marie,Andre-Barres, Christiane,Ladeira, Sonia,Valentin, Alexis,Vial, Henri,Payrastre, Corinne
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Read Online
- Novel spiroindoline HDAC inhibitors: Synthesis, molecular modelling and biological studies
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This paper describes the rational development of a series of novel spiroindoline derivatives endowed with selective inhibitory activity on the HDAC6 isoform. A convenient multicomponent one-pot protocol was applied for the assembly of the desired N1-substituted spiroindoline core which allowed a straightforward analoging. Computational studies and in vitro determination of inhibitory potency for the developed compounds against HDAC6 and HDAC1 isoforms were flanked by cell-based studies on histone H3 and α-tubulin acetylation. The effects on cancer cell cycle and apoptosis of the best performing derivatives were assessed on cancer cell lines highlighting a promising antitumor potential. In view of cell-based data and calculated drug-like properties, the selective HDAC6 inhibitor 5b, with a spiroindoline-based hydroxamate bearing a tert-butyl carbamate functionality, was selected to be further investigated for its potential in inhibiting tumor cells migration. It was able to potently inhibit cell migration in SH-SY5Y neuroblastoma cells and did not display toxicity in NIH3T3 mouse fibroblasts. Taken together, these data foster further investigation and optimization for this class of compounds as novel anticancer agents.
- Brindisi, Margherita,Senger, Johanna,Cavella, Caterina,Grillo, Alessandro,Chemi, Giulia,Gemma, Sandra,Cucinella, Dora Mariagrazia,Lamponi, Stefania,Sarno, Federica,Iside, Concetta,Nebbioso, Angela,Novellino, Ettore,Shaik, Tajith Baba,Romier, Christophe,Herp, Daniel,Jung, Manfred,Butini, Stefania,Campiani, Giuseppe,Altucci, Lucia,Brogi, Simone
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Read Online
- Piperidine-based glycodendrons as protein N-glycan prosthetics
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The generation of homogeneously glycosylated proteins is essential for defining glycoform-specific activity and improving protein-based therapeutics. We present a novel glycodendron prosthetic which can be site-selectively appended to recombinant proteins to create ‘N-glycosylated’ glycoprotein mimics. Using computational modeling, we designed the dendrimer scaffold and protein attachment point to resemble the native N-glycan architecture. Three piperidine–melamine glycodendrimers were synthesized via a chemoenzymatic route and attached to human growth hormone and the Fcregion of human IgG. These products represent a new class of engineered biosimilars bearing novel glycodendrimer structures.
- Hudak, Jason E.,Belardi, Brian,Appel, Mason J.,Solania, Angelo,Robinson, Peter V.,Bertozzi, Carolyn R.
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Read Online
- A CLASS OF BIFUNCTIONAL CHIMERIC HETEROCYCLIC COMPOUNDS FOR TARGETED DEGRADATION OF ANDROGEN RECEPTORS AND USE THEREOF
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The present invention relates to a class of bifunctional chimeric heterocyclic compounds for targeted degradation of androgen receptors and use thereof, and specifically provides a compound of formula (I), or an isotopic compound thereof, or an optical isomer thereof, or a tautomer thereof, or a pharmacologically acceptable salt thereof, or a prodrug thereof, or a solvate thereof, wherein ARB is an androgen receptor recognition/binding part, L is a link part, and U is a ubiquitin protease recognition/binding part; and the three parts are connected by means of chemical bonds. The compound can perform the targeted degradation on androgen receptors in prostate cancer cells, and suppress the proliferation of the prostate cancer cells, and also show good metabolic stability and pharmacokinetic properties. The compound has good application prospect in the preparation of targeted chimeras for protein degradation of androgen receptors and in the preparation of drugs for treating the related diseases regulated by the androgen receptors.
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- BIFUNCTIONAL MOLECULES CONTAINING AN E3 UBIQUITINE LIGASE BINDING MOIETY LINKED TO A BCL6 TARGETING MOIETY
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Bifunctional compounds, which find utility as modulators of B-cell lymphoma 6 protein (BCL6; target protein), are described herein. In particular, the bifunctional compounds of the present disclosure contain on one end a Von Hippel-Lindau, cereblon, Inhibitors of Apotosis Proteins or mouse double-minute homolog 2 ligand that binds to the respective E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The bifunctional compounds of the present disclosure exhibit a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.
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Paragraph 00475; 00476
(2021/04/23)
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- Expansion of substrate scope for nitroxyl radical/copper-catalyzed aerobic oxidation of primary alcohols: A guideline for catalyst selection
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Four distinctive sets of optimum nitroxyl radical/copper salt/additive catalyst combinations have been identified for accommodating the aerobic oxidation of various types of primary alcohols to their corresponding aldehydes. Interestingly, less nucleophilic catalysts exhibited higher catalytic activities for the oxidation of particular primary allylic and propargylic alcohols to give α,β-unsaturated aldehydes that function as competent Michael acceptors. The optimum conditions identified herein were successful in the oxidation of various types of primary alcohols, including unprotected amino alcohols and divalent-sulfur-containing alcohols in good-to-high yields. Moreover, N-protected alaninol, an inefficient substrate in the nitroxyl radical/ copper-catalyzed aerobic oxidation, was oxidized in good yield. On the basis of the optimization results, a guideline for catalyst selection has been established.
- Iwabuchi, Yoshiharu,Nagasawa, Shota,Sasaki, Ryota,Sasano, Yusuke,Yamaichi, Aoto
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p. 488 - 497
(2021/05/27)
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- C-H Alkylation of Aldehydes by Merging TBADT Hydrogen Atom Transfer with Nickel Catalysis
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Catalyst controlled site-selective C-H functionalization is a challenging but powerful tool in organic synthesis. Polarity-matched and sterically controlled hydrogen atom transfer (HAT) provides an excellent opportunity for site-selective functionalization. As such, the dual Ni/photoredox system was successfully employed to generate acyl radicals from aldehydes via selective formyl C-H activation and subsequently cross-coupled to generate ketones, a ubiquitous structural motif present in the vast majority of natural and bioactive molecules. However, only a handful of examples that are constrained to the use of aryl halides are developed. Given the wide availability of amines, we developed a cross-coupling reaction via C-N bond cleavage using the economic nickel and TBADT catalyst for the first time. A range of alkyl and aryl aldehydes were cross-coupled with benzylic and allylic pyridinium salts to afford ketones with a broad spectrum of functional group tolerance. High regioselectivity toward formyl C-H bonds even in the presence of α-methylene carbonyl or α-amino/oxy methylene was obtained.
- Murugesan, Vetrivelan,Ganguly, Anirban,Karthika, Ardra,Rasappan, Ramesh
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supporting information
p. 5389 - 5393
(2021/07/21)
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- 1,3-Alkyl Transposition in Allylic Alcohols Enabled by Proton-Coupled Electron Transfer
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A method is described for the isomerization of acyclic allylic alcohols into β-functionalized ketones via 1,3-alkyl transposition. This reaction proceeds via light-driven proton-coupled electron transfer (PCET) activation of the O?H bond in the allylic al
- Knowles, Robert R.,Seidler, Gesa,Zhao, Kuo
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supporting information
p. 20190 - 20195
(2021/08/13)
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- C10-ALKYLENE SUBSTITUTED 13-MEMBERED MACROLIDES AND USES THEREOF
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Provided are 13-membered macrolides for the treatment of infectious diseases. The 13-membered macrolides described herein are azaketolides. Also provided are methods for preparing the 13- membered macrolides, pharmaceutical compositions comprising the 13-membered macrolides, and methods of treating infectious diseases, and in particular, disease resulting from Gram negative bacteria using the disclosed macrolides. Formula (I)
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- A pH-Switchable Aqueous Organocatalysis with Amphiphilic Secondary Amine–Porphyrin Hybrids
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A series of amphiphilic 5-(cyclic-secondary-amine)-10,15,20-tris(4-sulfonatophenyl)porphyrins, designed with the aim of using the amphiphilic porphyrin moiety for the modulation of the aggregation state of the compound by the pH of the medium, have been synthesised, and the relationship between their supramolecular behaviour in acidic aqueous media and their organocatalytic activity in Michael and aldol reactions has been investigated. In particular, we have found that the catalytic activity of the pyrrolidine moiety in an amphiphilic isoindoline–porphyrin hybrid for the aldol reaction of cyclohexanone with 4-nitrobenzaldehyde can be selectively and reversibly switched on and off by adjusting the homogeneity of its solutions through pH variations. The catalysis of the aldol reaction by the secondary amine moiety would otherwise take place regardless of the pH of the medium. We have demonstrated that the aggregation behaviour of these amine–porphyrin hybrids can be also used for the recovery and reutilization of the catalysts.
- Arlegui, Aitor,Crusats, Joaquim,Cuesta, Victor,Moyano, Albert,Torres, Pol
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supporting information
(2020/07/08)
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- Stereoselective Activity of 1-Propargyl-4-styrylpiperidine-like Analogues That Can Discriminate between Monoamine Oxidase Isoforms A and B
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The resurgence of interest in monoamine oxidases (MAOs) has been fueled by recent correlations of this enzymatic activity with cardiovascular, neurological, and oncological disorders. This has promoted increased research into selective MAO-A and MAO-B inhibitors. Here, we shed light on how selective inhibition of MAO-A and MAO-B can be achieved by geometric isomers of cis-and trans-1-propargyl-4-styrylpiperidines. While the cis isomers are potent human MAO-A inhibitors, the trans analogues selectively target only the MAO-B isoform. The inhibition was studied by kinetic analysis, UV-vis spectrum measurements, and X-ray crystallography. The selective inhibition of the MAO-A and MAO-B isoforms was confirmed ex vivo in mouse brain homogenates, and additional in vivo studies in mice show the therapeutic potential of 1-propargyl-4-styrylpiperidines for central nervous system disorders. This study represents a unique case of stereoselective activity of cis/trans isomers that can discriminate between structurally related enzyme isoforms.
- Knez, Damijan,Colettis, Natalia,Iacovino, Luca G.,Sova, Matej,Pi?lar, Anja,Konc, Janez,Le?nik, Samo,Higgs, Josefina,Kamecki, Fabiola,Mangialavori, Irene,Dol?ak, Ana,?akelj, Simon,Trontelj, Jurij,Kos, Janko,Binda, Claudia,Marder, Mariel,Gobec, Stanislav
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p. 1361 - 1387
(2020/03/10)
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- Visible light photoredox catalyzed deprotection of 1,3-oxathiolanes
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An efficient visible light photoredox catalyzed aerobic deprotection of 1,3-oxathiolanes using organic dye Eosin Y as a photocatalyst is disclosed. The deprotection procedure features the use of a metal-free catalyst, mild conditions, a broad range of substrate scope, and good functional group tolerance. 35 examples were tested under the standard conditions and most of them afforded the deprotected products in modest to high yields.
- Yang, Mingyang,Xing, Zhimin,Fang, Bowen,Xie, Xingang,She, Xuegong
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supporting information
p. 288 - 291
(2020/01/13)
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- Synthesis method of 4-ethynyl-tetrahydropyran or 4-ethynyl piperidine
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The invention relates to the technical field of organic synthesis. For solving the problems that a conventional synthesis method of 4-ethynyl-tetrahydropyran and 4-ethynyl piperidine is complex in operation, high in cost and unsuitable for industrial production in the prior art, the invention provides a synthesis method of 4-ethynyl-tetrahydropyran or 4-ethynyl piperidine, wherein the synthesis method comprises the following steps: carrying out Wittig reaction on carbonyl of a compound represented by the formula (I) and phosphorus ylide salt under the action of a strong alkali to generate a compound represented by the formula (II), wherein the reaction temperature is 0-50 DEG C; (2) hydrolyzing the compound represented by the formula (II) to generate a compound represented by the formula (III), wherein the reaction temperature is 20-60 DEG C; (3) carrying out a Corey-Fuchs reaction on the compound represented by the formula (III) to obtain a compound represented by the formula (IV), wherein the reaction temperature is -20 to 40 DEG C; and (4) carrying out a reaction of the compound represented by the formula (IV) with a strong alkali, and carrying out a reaction with a silica reagent to generate a compound represented by the formula (V), wherein the reaction temperature is -70 to 20 DEG C. The method has the advantages of simple and accessible raw materials, low cost, simple synthesis steps and high yield, and is suitable for laboratory small-scale preparation and industrial production.
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- Axial-to-Central Chirality Transfer for Construction of Quaternary Stereocenters via Dearomatization of BINOLs
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All-carbon quaternary stereocenters are versatile building blocks, and their asymmetric construction has attracted much attention. Herein, we disclose an axial-to-central chirality transfer strategy for the synthesis of chiral quaternary stereocenters via dearomatization of (S)-BINOLs. The reaction proceeded smoothly with a wide range of propargyl carbonates to afford chiral spiro-compounds in high yields with excellent enantioselectivities. In addition, the strategy was extended to kinetic resolution of rac-BINOLs albeit with moderate s value.
- Min, Xiao-Long,Xu, Xu-Ran,He, Ying
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supporting information
p. 9188 - 9193
(2019/11/14)
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- 3-HYDROXY-N-(3-(7H-PYRROLO[2,3-D]PYRIMIDIN-4-YL)PHENYL)PYRROLIDINE-1-CARBOXAMIDE DERIVATIVES
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The invention relates to compounds of the formula (I) or a pharmaceutically acceptable salt thereof, wherein the substituents are as defined in the specification; to intermediates in the preparation of the compounds, to pharmaceutical compositions compris
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Page/Page column 108
(2019/10/23)
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- Nickel-Catalyzed Selective Reduction of Carboxylic Acids to Aldehydes
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The direct reduction of carboxylic acids to aldehydes is a fundamental transformation in organic synthesis. The combination of an air-stable Ni precatalyst, dimethyl dicarbonate as an activator, and silane reductant effects this reduction for a wide variety of substrates, including pharmaceutically relevant structures, in good yields and with no overreduction to alcohols. Moreover, this methodology is scalable, allows access to deuterated aldehydes, and is also compatible with one-pot utilization of the aldehyde products.
- Iosub, Andrei V.,Morav?ík, ?tefan,Wallentin, Carl-Johan,Bergman, Joakim
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supporting information
p. 7804 - 7808
(2019/10/14)
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- Photochemical Homologation for the Preparation of Aliphatic Aldehydes in Flow
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Cheap and readily available aqueous formaldehyde was used as a formylating reagent in a homologation reaction with nonstabilized diazo compounds, enabled by UV photolysis of bench-stable oxadiazolines in a flow photoreactor. Various aliphatic aldehydes were synthesized along with the corresponding derivatized alcohols and benzimidazoles. No transition-metal catalyst or additive was required to affect the reaction, which proceeded at room temperature in 80 min.
- Chen, Yiding,Leonardi, Marco,Dingwall, Paul,Labes, Ricardo,Pasau, Patrick,Blakemore, David C.,Ley, Steven V.
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p. 15558 - 15568
(2019/01/04)
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- A N - Boc - 4 - piperidine formaldehyde preparation method (by machine translation)
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The invention discloses a N - Boc - 4 - piperidine formaldehyde preparation method, which belongs to the technical field of organic chemistry. From the N - Boc - 4 - piperidone as the starting point, and the toluene shPs reaction generating diethylketohydrazone, then add the butyl lithium/tetramethyl ethylenediamine/formylation reagent reaction to obtain the 1 - Boc - 4 - formyl - 3, 6 - dihydro - 2 H - pyridine, then palladium carbon to catalyze hydrogenation to obtain N - Boc - 4 - piperidine formaldehyde. The invention has simple operation, higher yield, use of the starting raw material is cheap, is preparing N - Boc - 4 - piperidine formaldehyde suitable method. (by machine translation)
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Paragraph 0019; 0039; 0041
(2018/03/26)
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- Antimalarial agents against both sexual and asexual parasites stages: structure-activity relationships and biological studies of the Malaria Box compound 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine (MMV019918) and analogues
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Therapies addressing multiple stages of Plasmodium falciparum life cycle are highly desirable for implementing malaria elimination strategies. MMV019918 (1, 1-[5-(4-bromo-2-chlorophenyl)furan-2-yl]-N-[(piperidin-4-yl)methyl]methanamine) was selected from the MMV Malaria Box for its dual activity against both asexual stages and gametocytes. In-depth structure-activity relationship studies and cytotoxicity evaluation led to the selection of 25 for further biological investigation. The potential transmission blocking activity of 25 versus P. falciparum was confirmed through the standard membrane-feeding assay. Both 1 and 25 significantly prolonged atrioventricular conduction time in Langendorff-isolated rat hearts, and showed inhibitory activity of Ba2+ current through Cav1.2 channels. An in silico target-fishing study suggested the enzyme phosphoethanolamine methyltransferase (PfPMT) as a potential target. However, compound activity against PfPMT did not track with the antiplasmodial activity, suggesting the latter activity relies on a different molecular target. Nevertheless, 25 showed interesting activity against PfPMT, which could be an important starting point for the identification of more potent inhibitors active against both sexual and asexual stages of the parasite.
- Vallone, Alessandra,D'Alessandro, Sarah,Brogi, Simone,Brindisi, Margherita,Chemi, Giulia,Alfano, Gloria,Lamponi, Stefania,Lee, Soon Goo,Jez, Joseph M.,Koolen, Karin J.M.,Dechering, Koen J.,Saponara, Simona,Fusi, Fabio,Gorelli, Beatrice,Taramelli, Donatella,Parapini, Silvia,Caldelari, Reto,Campiani, Giuseppe,Gemma, Sandra,Butini, Stefania
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p. 698 - 718
(2018/03/24)
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- Two novel donepezil-lipoic acid hybrids: Synthesis, anticholinesterase and antioxidant activities and theoretical studies
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Alzheimer disease (AD) is a complex disease related to multiple pathogenic mechanisms. A strategy to develop effective drugs is based on the so-called multi-Target directed ligands (MTDL) by using hybrid compounds. So, in the present study, we have designed and synthesized two hybrids, containing the indanone-piperidine moiety of donepezil, a drug approved for the treatment of AD, and the lipoic acid scaffold, an antioxidant compound endowed with neuroprotective effects. One hybrid was synthesized in four steps with 42percent global yield, and the other hybrid in six steps with 19percent global yield. The latter hybrid displayed moderate inhibitory activity against human acetylcholinesterase (hAChE) and greater activity against human butyrylcholinesterases (hBuChE). The selectivity for hBuChE was further rationalized by theoretical study. Importantly, the second hybrid showed a good antioxidant activity, exhibiting better ability in scavenging 2,2-diphenyl- 1 picrylhydrazyl (DPPH) radicals than lipoic acid.
- Terra, Bruna S.,Da Silva, Pedro H. C.,Tramarin, Anna,Franco, Lucas L.,Da Cunha, Elaine F. F.,Macedo, Fernando,Ramalho, Teodorico C.,Bartolini, Manuela,Bolognesi, Maria L.,De Fátima, ?ngelo
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p. 738 - 747
(2018/02/07)
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- TETRAHYDROISOQUINOLINE KAPPA OPIOID ANTAGONISTS
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Potent opioid receptor antagonists of formula (I) and their use as pharmacotherapies for treating depression, anxiety, schizophrenia, eating disorders, and addiction to cocaine, methamphetamine, nicotine, alcohol, and opiates are disclosed. More specifically, the disclosure provides potent and selective kappa opioid receptor antagonist compounds, pharmaceutical compositions of those compounds and uses of those compounds to ameliorate or treat addictions, eating disorders, etc.
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Paragraph 00317
(2018/04/12)
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- DISUBTITUTED AZETIDINES, PYRROLIDINES, PIPERIDINES AND AZEPANES AS INHIBITORS OF MONOAMINE OXIDASE B FOR THE TREATMENT OF NEURODEGENERATIVE DISEASES
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This invention relates to new inhibitors of MAO-Bwith the general formula I, where substituents are described in patent description. Compounds can be in the form of pure enantiomers or as racemic mixtures, or in the form of pharmaceutically acceptable salts. The present invention relates to the use of these inhibitors for the alleviation of symptoms and treatment of acute and chronic neurological disorders, cognitive and neurodegenerative diseases.
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Page/Page column 18
(2018/04/20)
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- NOVEL COMPOUNDS AS GPR119 AGONISTS
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The present invention relates to novel compounds of formula (I) as GPR119 agonist, composition compositions containing such compounds and method of preparation thereof.
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- 4 - piperidinyl - 1H - pyrrole - 3 - carboxamides hydrochloride synthetic method
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The invention discloses a synthesis method of 4-piperidyl-1H-pyrrole-3-formamide compound hydrochloride. The method comprises the following steps: reacting a compound I Boc-4-hydroxymethyl piperidine with oxalyl chloride to obtain a compound II, and reacting the compound II with triethyl phosphonoacetate to obtain a compound III; reacting the compound III with p-toluenesulfonylmethyl isocyanide to obtain a compound IV; reacting the compound IV with 2-(trimethylsilyl)-ethoxymethyl chloride to generate a compound V; hydrolyzing the compound V to obtain a compound VI, and reacting the compound VI with an amino compound to generate a compound VII; acting on the compound VII with tetrabutylammonium fluoride to generate a compound VIII; and acting on the compound VIII with HCI to generates a compound IX, namely 4-piperidyl-1H-pyrrole-3-formamide compound hydrochloride. According to the method, piperidyl and acylamino are introduced at the positions 3 and 4 on a pyrrole ring, the reaction route is simple and feasible, and the obtained compound has a plurality of reactive groups and good water solubility and has potentials for development of medical intermediates.
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Paragraph 0025; 0026
(2017/08/25)
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- A Mild TEMPO-Catalyzed Aerobic Oxidative Conversion of Aldehydes into Nitriles
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An efficient method to prepare nitriles from aldehydes using hexamethyldisilazane (HMDS) as the nitrogen source has been developed. The reactions were performed with 2,2,6,6-tetramethylpiperidine l-oxyl (TEMPO) as the catalyst, NaNO2 or TBN as the co-catalyst, and molecular oxygen as the terminal oxidant under mild conditions. A variety of aromatic, heteroaromatic, aliphatic and allylic aldehydes could be converted into their corresponding nitriles in good to excellent yields.
- Fang, Chaojie,Li, Meichao,Hu, Xinquan,Mo, Weimin,Hu, Baoxiang,Sun, Nan,Jin, Liqun,Shen, Zhenlu
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p. 1157 - 1163
(2016/04/19)
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- Benzimidazole-2-piperazine compound, its pharmaceutical composition and its preparation and use
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The invention relates to a benzimidazole-2-piperazine derivative and a preparing method and application of the benzimidazole-2-piperazine derivative in medicine, in particular to a novel benzimidazole-2-piperazine derivative shown in the general formula (I), a preparing method of the derivative, a pharmaceutical composition containing the derivative and application of the derivative serving as a therapeutic agent, especially serving as a poly (ADP-ribose) polymerase (PARP) inhibitor. In the general formula (I), R refers to hydrogen or halogen, G refers to carbonyl or methylene, m is 1-2, n is 1-3, and Q refers to hydrogen or C1-C4 alkyl. When X is methylene and Y is NR1 or methylene, X is NR1; R1 refers to hydrogen, C1-C6 alkyl, benzyl, COR2 or SO2R2; R2 refers to the following groups which are not substituted or groups substituted by 1-3 substituent groups, including C1-C6 alkyl, C3-C8 naphthenic base, phenyl, benzyl, naphthyl and C5-C10 aromatic heterocycle base, heterocycle in the C5-C10 aromatic heterocycle base comprises 1-3 heteroatoms selected from N, O and S, and the substituent groups are selected from the following atoms or groups of C1-C6 alkyl, C1-C6 alkoxy, halogen, amidogen, nitryl, sulfydryl, hydroxyl, cyanogroup and trifluoromethyl. The general formula (I) is shown in the specification.
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Paragraph 0209; 0374; 0377; 0378
(2016/10/20)
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- Synthesis and in vitro evaluation of donepezil-based reactivators and analogues for nerve agent-inhibited human acetylcholinesterase
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Poisoning by organophosphorus nerve agents and pesticides is a serious public and military health issue with over 200 000 fatalities annually worldwide. Conventional emergency treatment consists of rapid administration of atropine and pyridinium oxime as an antidote. The reactivation of acetylcholinesterase (AChE) in the central nervous system (CNS) by the oxime is inefficient due to the fact that positively charged pyridiniums do not readily cross the blood brain barrier (BBB). Herein, we described the synthesis and in vitro evaluation of four donepezil-based non quaternary reactivators. The compounds 1-4 have been prepared in 7-8 linear steps in 1-9% overall yields and oximes 1-3 show better ability (8 fold higher) than pralidoxime to reactivate VX-inhibited human AChE (VX-hAChE). Besides, oxime 2 is 5 to 11 fold more efficient than pralidoxime and HI-6 respectively for the reactivation of VX-inhibited human butyrylcholinesterase (VX-hBChE).
- Renou, Julien,Dias, José,Mercey, Guillaume,Verdelet, Tristan,Rousseau, Catherine,Gastellier, Anne-Julie,Arboléas, Mélanie,Touvrey-Loiodice, Mélanie,Baati, Rachid,Jean, Ludovic,Nachon, Florian,Renard, Pierre-Yves
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p. 17929 - 17940
(2016/03/01)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula (I) and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
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- Bilastine preparation method
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The invention discloses a Bilastine preparation method. The Bilastine preparation method includes that 2-nitroaniline which is low in price and easy to obtain is taken as a raw material which is subjected to reduction-n-cyclohexylmaleimide reaction, alkyl
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Paragraph 0087; 0088; 0089; 0090; 0091; 0092
(2017/04/14)
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- Spiro aryl phosphorus oxide or sulfide
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The invention discloses a spiro aryl phosphorus oxide or sulfide as ALK inhibitor, and in particular discloses a compound shown in a formula (I) as an ALK inhibitor or a pharmaceutically acceptable salt thereof.
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Paragraph 0692; 0693; 0694; 0695
(2016/10/08)
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- A base promoted multigram synthesis of aminoisoxazoles: Valuable building blocks for drug discovery and peptidomimetics
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A practical multigram metal free synthesis of isoxazole-containing building blocks from commercially available amino acids was elaborated. The key reaction was a regioselective [3 + 2]-cycloaddition of in situ generated nitrile oxides with alkynes/enamines. The obtained building blocks were used in the preparation of bioactive compounds and peptidomimetics.
- Chalyk, Bohdan A.,Kandaurova, Inna Y.,Hrebeniuk, Kateryna V.,Manoilenko, Olga V.,Kulik, Irene B.,Iminov, Rustam T.,Kubyshkin, Vladimir,Tverdokhlebov, Anton V.,Ablialimov, Osman K.,Mykhailiuk, Pavel K.
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p. 25713 - 25723
(2016/03/25)
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- Piperidine compound and preparation method thereof
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The invention relates to a piperidine compound and a preparation method thereof. The compound is N-BOC-4-(1-amino-3-hydroxypropenyl) piperidine, and 4-piperidine methanol is used as a staring material, and the compound is synthesized through reactions in six steps, is an important intermediate for preparing a kinase inhibitor and has wide application prospects in preparing medicine for preventing and treating diabetes. The preparation method has the advantages of cheap raw materials and easiness in obtaining the raw materials, and a synthetic method is simple, is a novel method for synthesizing the piperidine compound and is suitable for large-scale industrial production.
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Paragraph 0023; 0031
(2017/03/14)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and chronic kidney disease and conditions associated with excessive salt and water retention.
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- Copper(I)-catalyzed enantioselective nucleophilic borylation of aldehydes: An efficient route to enantiomerically enriched α-alkoxyorganoboronate esters
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The first catalytic enantioselective nucleophilic borylation of a
- Kubota, Koji,Yamamoto, Eiji,Ito, Hajime
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supporting information
p. 420 - 424
(2015/01/30)
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- Discovery of novel 2,5-dioxoimidazolidine-based P2X7 receptor antagonists as constrained analogues of KN62
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Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1β ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1β ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis.
- Park, Jin-Hee,Lee, Ga-Eun,Lee, So-Deok,Hien, Tran Thi,Kim, Sujin,Yang, Jin Won,Cho, Joong-Heui,Ko, Hyojin,Lim, Sung-Chul,Kim, Yoon-Gyoon,Kang, Keon-Wook,Kim, Yong-Chul
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supporting information
p. 2114 - 2134
(2015/03/30)
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- Development of Fluorine-18 Labeled Metabolically Activated Tracers for Imaging of Drug Efflux Transporters with Positron Emission Tomography
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Increased activity of efflux transporters, e.g., P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), at the blood-brain barrier is a pathological hallmark of many neurological diseases, and the resulting multiple drug resistance represents a major clinical challenge. Noninvasive imaging of transporter activity can help to clarify the underlying mechanisms of drug resistance and facilitate diagnosis, patient stratification, and treatment monitoring. We have developed a metabolically activated radiotracer for functional imaging of P-gp/BCRP activity with positron emission tomography (PET). In preclinical studies, the tracer showed excellent initial brain uptake and clean conversion to the desired metabolite, although at a sluggish rate. Blocking with P-gp/BCRP modulators led to increased levels of brain radioactivity; however, dynamic PET did not show differential clearance rates between treatment and control groups. Our results provide proof-of-concept for development of prodrug tracers for imaging of P-gp/BCRP function in vivo but also highlight some challenges associated with this strategy.
- Sander, Kerstin,Galante, Eva,Gendron, Thibault,Yiannaki, Elena,Patel, Niral,Kalber, Tammy L.,Badar, Adam,Robson, Mathew,Johnson, Sean P.,Bauer, Florian,Mairinger, Severin,Stanek, Johann,Wanek, Thomas,Kuntner, Claudia,Kottke, Tim,Weizel, Lilia,Dickens, David,Erlandsson, Kjell,Hutton, Brian F.,Lythgoe, Mark F.,Stark, Holger,Langer, Oliver,Koepp, Matthias,?rstad, Erik
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p. 6058 - 6080
(2015/08/24)
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- Nickel-Catalyzed Reductive Cross-Coupling of (Hetero)Aryl Iodides with Fluorinated Secondary Alkyl Bromides
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A mild and efficient nickel-catalyzed reductive cross-coupling between fluorinated secondary alkyl bromides and (hetero)aryl iodides is described. The use of FeBr2 as an additive successfully overcomes the hydrodebromination and β-fluorine elim
- Li, Xuefei,Jiang, Zhong-Xing,Feng, Zhang,Zhang, Xingang
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supporting information
p. 5570 - 5573
(2015/12/17)
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- Searching for Dual Inhibitors of the MDM2-p53 and MDMX-p53 Protein-Protein Interaction by a Scaffold-Hopping Approach
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Two libraries of substituted benzimidazoles were designed using a 'scaffold-hopping' approach based on reported MDM2-p53 inhibitors. Substituents were chosen following library enumeration and docking into an MDM2 X-ray structure. Benzimidazole libraries were prepared using an efficient solution-phase approach and screened for inhibition of the MDM2-p53 and MDMX-p53 protein-protein interactions. Key examples showed inhibitory activity against both targets.
- Zaytsev, Andrey,Dodd, Barry,Magnani, Matteo,Ghiron, Chiara,Golding, Bernard T.,Griffin, Roger J.,Liu, Junfeng,Lu, Xiaohong,Micco, Iolanda,Newell, David R.,Padova, Alessandro,Robertson, Graeme,Lunec, John,Hardcastle, Ian R.
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p. 180 - 189
(2015/02/19)
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- Highly chemoselective aerobic oxidation of amino alcohols into amino carbonyl compounds
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The direct oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has often posed serious challenges in organic synthesis and has constrained chemists to adopting an indirect route, such as a protection/deprotection strategy, to attain their goal. Described herein is a highly chemoselective aerobic oxidation of unprotected amino alcohols to their amino carbonyl compounds in which 2-azaadamantane N-oxyl (AZADO)/copper catalysis is used. The catalytic system developed leads to the alcohol-selective oxidation of various unprotected amino alcohols, carrying a primary, secondary, or tertiary amino group, in good to high yield at ambient temperature with exposure to air, thus offering flexibility in the synthesis of nitrogen-containing compounds. Strong as an ox: The highly chemoselective aerobic oxidation of unprotected amino alcohols to their corresponding amino carbonyl compounds has been achieved by using 2-azaadamantane N-oxyl (AZADO)/copper catalysis. This catalytic system oxidizes not only alcohols with tertiary amino groups but also those with secondary and primary amines in good to high yield at ambient temperature in air. bpy=2,2-bipyridyl, DMAP=4-(N,N-dimethylamino)pyridine.
- Sasano, Yusuke,Nagasawa, Shota,Yamazaki, Mai,Shibuya, Masatoshi,Park, Jaiwook,Iwabuchi, Yoshiharu
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supporting information
p. 3236 - 3240
(2014/04/03)
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- PYRROLO[2,3-B]PYRIDINE CDK9 KINASE INHIBITORS
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Disclosed are compounds of Formula (IIa), wherein R1, R2, R3A, R3B, R3C, R3D, R3E, and R4 are as defined in the specification, and pharmaceutically acceptable salts thereof. The compounds may be used as agents in the treatment of diseases, including cancer. Also provided are pharmaceutical compositions comprising one or more compounds of Formula (IIa)
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Page/Page column 362
(2014/09/29)
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- INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
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- SPIRO - FUSED PIPERIDINE DERIVATIVES FOR USE AS INHIBITORS OF THE RENAL OUTER MEDULLARY POTASSIUM CHANNEL
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The present invention provides compounds of Formula I and the pharmaceutically acceptable salts thereof, which are inhibitors of the ROMK (Kir1.1) channel. The compounds may be used as diuretic and/or natriuretic agents and for the therapy and prophylaxis of medical conditions including cardiovascular diseases such as hypertension, heart failure and conditions associated with excessive salt and water retention.
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- Novel spiroketal pyrrolidine GSK2336805 potently inhibits key hepatitis C virus genotype 1b mutants: From lead to clinical compound
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Rapid clinical progress of hepatitis C virus (HCV) replication inhibitors, including these selecting for resistance in the NS5A region (NS5A inhibitors), promises to revolutionize HCV treatment. Herein, we describe our explorations of diverse spiropyrrolidine motifs in novel NS5A inhibitors and a proposed interaction model. We discovered that the 1,4-dioxa-7-azaspiro[4.4]nonane motif in inhibitor 41H (GSK2236805) supported high potency against genotypes 1a and 1b as well as in genotype 1b L31V and Y93H mutants. Consistent with this, 41H potently suppressed HCV RNA in the 20-day RNA reduction assay. Pharmacokinetic and safety data supported further progression of 41H to the clinic.
- Kazmierski, Wieslaw M.,Maynard, Andrew,Duan, Maosheng,Baskaran, Sam,Botyanszki, Janos,Crosby, Renae,Dickerson, Scott,Tallant, Matthew,Grimes, Rick,Hamatake, Robert,Leivers, Martin,Roberts, Christopher D.,Walker, Jill
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p. 2058 - 2073
(2014/04/03)
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- Discovery of 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating of chronic kidney diseases
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We identified 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted ureas as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating chronic kidney diseases. Compound 19 exhibited excellent sEH inhibitory activity a
- Kato, Yuko,Fuchi, Nobuhiro,Nishimura, Yutaka,Watanabe, Ayano,Yagi, Mai,Nakadera, Yasuhito,Higashi, Eriko,Yamada, Masateru,Aoki, Takumi,Kigoshi, Hideo
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p. 565 - 570
(2014/01/23)
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- CDK9 KINASE INHIBITORS
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Disclosed are compound of Formula (Ia), wherein R1A, R1, R2, R10, J, L, T, X, Y, and Z are as defined in the specification, and pharmaceutically acceptable salts thereof. The compounds may be used as agents in the treatment of diseases, including cancer. Also provided are pharmaceutical compositions, comprising one or more compounds of Formula (Ia).
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Paragraph 0540
(2014/09/30)
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- NITROGENATED HETEROCYCLIC COMPOUND
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A nitrogen-containing heterocyclic compound represented by formula (I-A): (wherein R1A represents lower alkyl which may be substituted with lower alkoxy, R3A represents lower alkyl substituted with fluorine atom(s), and RqA represents an optionally substituted aromatic heterocyclic group) or the like, or a pharmaceutically acceptable salt thereof; and the like, are provided.
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Paragraph 0097
(2014/11/27)
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- Synthesis and nanostructures of 5,10,15,20-tetrakis(4-piperidyl)porphyrin
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A new water-soluble porphyrin, 5,10,15,20-tetrakis(4-piperidyl)porphyrin (T(4-Pip)P), has been synthesized. T(4-Pip)P is related to the extensively studied water-soluble porphyrin 5,10,15,20-tetrakis(4-pyridyl)porphyrin (T(4-Py)P) but has substituents with different electronic and hydrogen-bonding properties and is soluble over a much larger pH range due to the higher pK a of its conjugate acid T(4-H-Pip)P4+. Investigations of the ionic self-assembly reactions of T(4-H-Pip)P4+ with anionic water-soluble porphyrins reveal that it forms nanoscale materials.
- Jacobsen, John L.,Berget, Patrick E.,Varela, Michael C.,Vu, Tony,Schore, Neil E.,Martin, Kathleen E.,Shelnutt, John A.,Santos, Luís M.,Medforth, Craig J.
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p. 10507 - 10515
(2013/11/19)
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- ANTIBACTERIAL PIPERIDINYL SUBSTITUTED 3,4-DIHYDRO-1H-[1,8]NAPHTHYRIDINONES
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The present invention is related to novel compounds of formula (I) that inhibit the activity of the Fab1 enzyme which are therefore useful in the treatment of bacterial infections. It further relates to pharmaceutical compositions comprising these compounds, and chemical processes for preparing these compounds.
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Page/Page column 26
(2013/03/26)
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- Discovery of vinylcycloalkyl-substituted benzimidazole TRPM8 antagonists effective in the treatment of cold allodynia
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Thermosensitive transient receptor potential melastatin 8 (TRPM8) antagonists are considered to be potential therapeutic agents for the treatment of cold hypersensitivity. The discovery of a new class of TRPM8 antagonists that shows in vivo efficacy in the rat chronic constriction injury (CCI)-induced model of neuropathic pain is described.
- Calvo, Raul R.,Meegalla, Sanath K.,Parks, Daniel J.,Parsons, William H.,Ballentine, Shelley K.,Lubin, Mary Lou,Schneider, Craig,Colburn, Raymond W.,Flores, Christopher M.,Player, Mark R.
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p. 1903 - 1907
(2012/04/04)
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- Application of flow chemistry to the selective reduction of esters to aldehydes
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The reduction of esters to aldehydes is an important transformation in organic chemistry and several reducing agents have been described. However, the use of this reaction in medicinal and natural product chemistry is limited due to the instability of the intermediates and the high reactivity of the reaction products. In the current article, the general and selective reduction of esters with diisobutyl-tert-butoxyaluminum hydride in flow is reported. This reagent allows esters to be reduced in the presence of different functional groups, including those considered to be of similar or higher reactivity. Copyright
- De Munoz, Juan M.,Alcazar, Jesus,De La Hoz, Antonio,Diaz-Ortiz, Angel
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supporting information; experimental part
p. 260 - 263
(2012/02/16)
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- Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists
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Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the β2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.
- Sasmal, Sanjita,Balaji, Gade,Kanna Reddy, Hariprasada R.,Balasubrahmanyam,Srinivas, Gujjary,Kyasa, Shivakumar,Sasmal, Pradip K.,Khanna, Ish,Talwar, Rashmi,Suresh,Jadhav, Vikram P.,Muzeeb, Syed,Shashikumar, Dhanya,Harinder Reddy,Sebastian,Frimurer, Thomas M.,Rist, ?ystein,Elster, Lisbeth,H?gberg, Thomas
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scheme or table
p. 3157 - 3162
(2012/06/04)
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