- Synthesis and crystal structure of 5-chloro-3,4-dihydroxy-3-(2-hydroxyethyl) isobenzofuran-1(3H)-one
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5-Chloro-3,4-dihydroxy-3-(2-hydroxyethyl)isobenzofuran-1(3H)-one (C10H9ClO5, Mr=244.63) has been synthesized using 2-chloro-5-trifluoromethylphenol as starting material through esterification, Friedel-Crafts acylation, hydrolysis, and cyclization reaction. The compound was characterized by infrared (IR), 1H nuclear magnetic resonance (NMR), 13C NMR, and elemental analysis. The single crystal structure of the title compounds has been further determined by X-ray diffraction. The crystal belongs to the triclinic system, space group P1 with a=7.8111(16) ?, b=7.8164(16) ?, c=8.5660(17) ?, α=82.50(3)°, β=71.28(3)°, γ=68.22(3)°, V=459.93(16) ?3, Z=2, Dc=1.766 g/cm3, μ=0.418 mm?1, F(000)=252, the final R1=0.0792, and wR2(I>2σ(I))=0.2209. The existence of π-π conjunction effect resulted in correlative bond length shorter than typical bond length in the crystal. The title compound is assembled into a three-dimensional supramolecular structure by two intermolecular hydrogen bonds and one intramolecular hydrogen bond.
- Fu, Ying,Wang, Kui,Wang, Peng,Zhao, Ze-Yu,Wang, Yun-Kai,Ye, Fei
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p. 329 - 333
(2018/09/29)
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- NOVEL INHIBITORS OF MAP4K1
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The invention relates to novel inhibitors of MAP4K1 (HPK1) useful for the treatment of diseases or disorders characterised by dysregulation of the signal transduction pathways associated with MAPK activation, including hyperproliferative diseases, diseases of immune system dysfunction, inflammatory disorders, neurological diseases, and cardiovascular diseases. The invention further relates to pharmaceutical compositions comprising the same and methods of treatment of said diseases and disorders. The inhibitors are of formula (I) wherein the definitions for A, D, E, F, R5, R6, R7, Z, ring Q, n, x and y are as given in the application.
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Page/Page column 63
(2018/12/13)
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- Structure-Based Design and Biological Characterization of Selective Histone Deacetylase 8 (HDAC8) Inhibitors with Anti-Neuroblastoma Activity
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Histone deacetylases (HDACs) are important modulators of epigenetic gene regulation and additionally control the activity of non-histone protein substrates. While for HDACs 1-3 and 6 many potent selective inhibitors have been obtained, for other subtypes much less is known on selective inhibitors and the consequences of their inhibition. The present report describes the development of substituted benzhydroxamic acids as potent and selective HDAC8 inhibitors. Docking studies using available crystal structures have been used for structure-based optimization of this series of compounds. Within this study, we have investigated the role of HDAC8 in the proliferation of cancer cells and optimized hits for potency and selectivity, both in vitro and in cell culture. The combination of structure-based design, synthesis, and in vitro screening to cellular testing resulted in potent and selective HDAC8 inhibitors that showed anti-neuroblastoma activity in cellular testing.
- Heimburg, Tino,Kolbinger, Fiona R.,Zeyen, Patrik,Ghazy, Ehab,Herp, Daniel,Schmidtkunz, Karin,Melesina, Jelena,Shaik, Tajith Baba,Erdmann, Frank,Schmidt, Matthias,Romier, Christophe,Robaa, Dina,Witt, Olaf,Oehme, Ina,Jung, Manfred,Sippl, Wolfgang
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p. 10188 - 10204
(2018/01/10)
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- Synthesis, structure-activity relationships, and biological evaluation of a series of benzamides as potential multireceptor antipsychotics
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In the present study, a series of benzamides, endowed with potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)-piperidin-1-yl)butoxy)-N-methylbenzamide (21) and its fluoro-substituted analogue (22) held the best pharmacological binding profiles. They not only presented potent activities for D2, 5-HT1A, and 5-HT2A receptors, but were also endowed with low activities for 5-HT2C, H1 receptors and hERG channels, suggesting a low propensity of inducing weight gain and QT prolongation. In animal models, compounds 21 and 22 reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. It thus provides potential candidates for further preclinical studies.
- Yang, Feipu,Jiang, Xiangrui,Li, Jianfeng,Wang, Yu,Liu, Yongjian,Bi, Minghao,Wu, Chunhui,Zhao, Qingjie,Chen, Weiming,Yin, Jingjing,Zhang, Jian,Xie, Yuanchao,Hu, Tianwen,Xu, Mingshuo,Guo, Shuang,Wang, Zhen,He, Yang,Shen, Jingshan
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supporting information
p. 3141 - 3147
(2016/06/13)
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- The Catalyst-Controlled Regiodivergent Chlorination of Phenols
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Different catalysts are demonstrated to overcome or augment a substrate's innate regioselectivity. Nagasawa's bis-thiourea catalyst was found to overcome the innate para-selectivity of electrophilic phenol chlorination, yielding ortho-chlorinated phenols that are not readily obtainable via canonical electrophilic chlorinations. Conversely, a phosphine sulfide derived from 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) was found to enhance the innate para-preference of phenol chlorination.
- Maddox, Sean M.,Dinh, Andrew N.,Armenta, Felipe,Um, Joann,Gustafson, Jeffrey L.
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supporting information
p. 5476 - 5479
(2016/11/17)
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- Ring Opening of Bicyclo[3.1.0]hexan-2-ones: A Versatile Synthetic Platform for the Construction of Substituted Benzoates
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Described is the development of a highly efficient 2πdisrotatory ring-opening aromatization sequence using bicyclo[3.1.0]hexan-2-ones. This unprecedented transformation efficiently proceeds under thermal conditions and allows facile construction of uniquely substituted and polyfunctionalized benzoates. In the presence of either amines or alcohols formation of substituted anilines or ethers, respectively, is achieved. Additionally, the utility of this method was demonstrated in a short synthesis of sekikaic acid methyl ester. Cracked open: A highly efficient thermal 2πdisrotatory ring-opening aromatization sequence of bicyclo[3.1.0]hexan-2-ones is described. The transformation proceeds in sulfolane to give uniquely substituted benzoates. In the presence of either amines or alcohols, formation of substituted anilines or ethers, respectively, is achieved.
- Feierfeil, Johannes,Grossmann, Adriana,Magauer, Thomas
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supporting information
p. 11835 - 11838
(2015/10/05)
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- Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis B virus infection
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The invention provides novel compounds having the general formula: wherein R1, R2, R3, R4, R5 and R6 are as described herein, compositions including the compounds and methods of using the compounds.
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Paragraph 1502; 1503
(2015/08/04)
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- NOVEL DIHYDROQUINOLIZINONES FOR THE TREATMENT AND PROPHYLAXIS OF HEPATITIS B VIRUS INFECTION
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The invention provides novel compounds having the general formula (I) wherein R1, R2 R3, R4, R5 and R6 are as described herein, compositions including the compounds and methods of using the compounds in the treatment of the hepatitis B virus.
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Page/Page column 211; 212
(2015/09/23)
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- HETEROCYCLIC COMPOUNDS FOR THE INHIBITION OF PASK
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Disclosed herein are new heterocyclic compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.
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Paragraph 0175
(2014/05/24)
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- GAMMA-AMINO-BUTYRIC ACID DERIVATIVES AS GABAB RECEPTOR LIGANDS
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Gamma-amino-butyric acid derivatives that are GABAB receptor ligands, pharmaceutical compositions comprising such derivatives, and methods of using such derivatives and pharmaceutical compositions thereof for treating diseases are disclosed.
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Page/Page column 54
(2010/11/03)
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- Deuterated chemiluminescent 1,2-dioxetanes
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Deuterium-based i.e. isotopic hydrogen chemiluminescent 1,2-dioxetanes derived from the photo-oxidation of new novel alkenes which are synthesized by the coupling reaction of (a) a saturated or unsaturated cyclic, polycylic, normal or branched chain alkyl, cycloalkyl and spiro-fused and (b) substituted aromatic esters or ketones wherein (a) or (b) or both at least have a deuterium atom or a deuterium atom-containing group. These deuterium-based 1,2-dioxetanes may also have electron donating or withdrawing groups at the four-membered peroxide ring. Thus, the added electronic charge and the isotopic hydrogen or isotopic hydrogen-containing group hereof affects the light producing efficiency of 1,2-dioxetanes.
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Page/Page column 25
(2009/05/29)
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- Advances toward new antidepressants with dual serotonin transporter and 5-HT1A receptor affinity within a class of 3-aminochroman derivatives. Part 2
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Novel compounds combining a 5-HT1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affin
- Hatzenbuhler, Nicole T.,Baudy, Reinhardt,Evrard, Deborah A.,Failli, Amedeo,Harrison, Boyd L.,Lenicek, Steven,Mewshaw, Richard E.,Saab, Annmarie,Shah, Uresh,Sze, Jean,Zhang, Minsheng,Zhou, Dahui,Chlenov, Michael,Kagan, Michael,Golembieski, Jeannette,Hornby, Geoffrey,Lai, Margaret,Smith, Deborah L.,Sullivan, Kelly M.,Schechter, Lee E.,Andree, Terrance H.
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experimental part
p. 6980 - 7004
(2009/11/30)
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- Chemiluminescent 1,2-dioxetanes
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A method of generating light through chemiluminescence involves providing a stable 1,2-dioxetane of the formula: Wherein (a) R1 and R2 are each, individually, a chemical reactive site or when fused together form a chemical reactive site, and R3 and R4 are each, individually, a chemical reactive site or when fused together form a chemical reactive or (b) R1 has at least two hetero atoms with chemical reactive site and R3 and R4 are inactive site and R2 is a chemical reactive site.
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- 3-AMINO CHOMAN AND 2-AMINO TETRALIN DERIVATIVES
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3-Amino chroman and 2-amino tetralin derivatives and compositions containing such compounds are disclosed. Methods of using the 3-amino chroman and 2-amino tetralin compounds and compositions containing such compounds in the treatment of serotonin disorders, such as depression and anxiety, are also disclosed.
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Page/Page column 66
(2010/02/10)
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- Structural requirements for factor Xa inhibition by 3-oxybenzamides with neutral P1 substituents: Combining X-ray crystallography, 3D-QSAR, and tailored scoring functions
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The design, synthesis, and structure-activity relationship of 3-oxybenzamides as potent inhibitors of the coagulation protease factor Xa are described on the basis of X-ray structures, privileged structure motifs, and SAR information. A total of six X-ray structures of fXa/inhibitor complexes led us to identify the major protein-ligand interactions. The binding mode is characterized by a lipophilic dichlorophenyl substituent interacting with Tyr228 in the protease S1 pocket, while polar parts are accommodated in S4. This alignment in combination with docking allowed derivation of 3D-QSAR models and tailored scoring functions to rationalize biological affinity and provide guidelines for optimization. The resulting models showed good correlation coefficients and predictions of external test sets. Furthermore, they correspond to binding site topologies in terms of steric, electrostatic, and hydrophobic complementarity. Two approaches to derive tailored scoring functions combining binding site and ligand information led to predictive models with acceptable predictions of the external set. Good correlations to experimental affinities were obtained for both AFMoC (adaptation of fields for molecular comparison) and the novel TScore function. The SAR information from 3D-QSAR and tailored scoring functions agrees with all experimental data and provides guidelines and reasonable activity estimations for novel fXa inhibitors.
- Matter, Hans,Will, David W.,Nazaré, Marc,Schreuder, Herman,Laux, Volker,Wehner, Volkmar
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p. 3290 - 3312
(2007/10/03)
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- Chemiluminescent 1,2-dioxetanes
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A method of generating light through chemiluminescence involves providing a stable 1,2-dioxetane of the formula: Wherein (a) R1 and R2 are each, individually, a chemical reactive site or when fused together form a chemical reactive site, and R3 and R4 are each, individually, a chemical reactive site or when fused together form a chemical reactive or (b) R1 has at least two hetero atoms with chemical reactive site and R3 and R4 are inactive site and R2 is a chemical reactive site.
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- Chemiluminescent 1,2-dioxetanes
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The present invention provides novel 1,2-dioxetanes derived from spiro-fused ketones with or without π-electrons in the ring or with carbon-carbon double bond(s) in the spiro-fused ring. Additionally, these new dioxetanes have electron donating or withdrawing groups at the four-membered peroxide ring to render these dioxetanes active at all sites.
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- New oxybenzamide derivatives useful for inhibiting factor Xa or VIIa
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The present invention relates to compounds comprising the following formula: R0—Q—X—Q′—W—U—V—G—M??(I) These compounds are useful as pharmacologically active compounds. They exhibit an antithrombotic effect and are suitable, for example, for the therapy and prophylaxis of cardiovascular disorders such as thromboembolic diseases or restenoses. These compounds are reversible inhibitors of the blood clotting enzymes factor Xa (FXa) and/or factor VIIa (FVIIa), and can generally be used to treat, prevent, or cure conditions in which an undesired activity of factor Xa and/or factor VIIa is present, or where inhibition of factor Xa and/or factor VIIa is intended. The invention further relates to processes for the preparation of these compounds, methods of their use (e.g., as active ingredients in pharmaceuticals), and pharmaceutical preparations comprising them.
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- Synthesis and biological activity of the metabolites of syn-3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]non-9-yl 4-Chlorobenzoate hydrochloride
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Five metabolites of syn-3-ethyl-7-methyl-3,7-diazabicyclo[3.3.1]non-9-yl 4-chlorobenzoate hydrochloride (YUTAC) (1) were prepared and examined for Na+ current blocking activity in guinea pig ventricular myocytes. These metabolites showed lower
- Yamawaki,Bukovac,Sunami
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p. 2365 - 2369
(2007/10/02)
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