- Synthesis of chiral 5-substituted 2-pyrrolidinones: An unusual one-step transformation
-
An efficient methodology for the enantioselective synthesis of γ-lactams, using a one-pot reaction of chiral N-alkoxycarbonyl γ-amino α,β-unsaturated carboxylates with magnesium in methanol, afforded the target chiral compounds in high chemical yield (87-95%) and optical purity (96-99% ee).
- Wei, Zhong-Yong,Knaus, Edward E.
-
-
Read Online
- Biotransformation of Licochalcone A by transgenic crown galls of Panax quinquefolium
-
Licochalcone A, as main constituent of Chinese Gancao (Glycyrrhiza inflate Bat), is responsible for thechemopreventive effect of the herbal. In order to get the bioactive modified molecules of Licochalcone A,it was biotransformed using transgenic crown galls of Panax quinquefolium to afford 9 products includinga new alkaloid together with 8 known compounds. Their structures were elucidated by physicochemicaland spectral methods as: methyl(12S)-1-[(5-formylfuran-2-yl)methyl]-5-oxopyrrolidine-2-carboxylate(1), methyl(12S)-1-[2-(furan-2-yl)-2-oxoethyl]-5-oxopyrrolidine-2-carboxylate (2), 5-hydroxymethyl-2-furfural (3), (S)-methylpyroglutamate (4), 4-hydroxy-2-methoxy-5-(2-methylbut-3-en-2-yl) benz-aldehyde (5), 4-hydroxybenzoicacid (6), dibutyl phthalate (7), 3β,6α,12β,25-tetrahydroxy-(20S,24R)-epoxy-dammarane (8), β-sitosterol (9).Among them, compounds 5 and 6 were transformed from Licochalcone A, while 14 and 8 were derivedfrom the culture medium stimulated by the substrate. Furthermore, their cancer chemopreventive effectwere tested by the assay of NQO1 (NAD(P)H: quinine oxidoreductase 1) inducing activities in Hepa 1c1ccells.
- Li, Jiayuan,Li, Ning,Huang, Bing,Zhao, Weihong,Wang, Wenli,Si, Yingying,Yan, Chunyan
-
-
Read Online
- A catalytic one-step process for the chemo- and regioselective acylation of monosaccharides
-
An organocatalytic method for the chemo- and regioselective acylation of monosaccharides has been developed. Treatment of octyl β-D-glucopyranoside with isobutyric anhydride in the presence of 10 mol % of a C2- symmetric chiral 4-pyrrolidinopyridine catalyst (1) at -50°C gave the 4-O-isobutyryl derivative as the sole product in 98% yield. Thus, chemoselective acylation, favoring a secondary hydroxyl group in the presence of a free primary hydroxyl group, and regioselective acylation, favoring one of three secondary hydroxyl groups, took place with perfect selectivity. A competitive acylation between octyl β-D-glucopyranoside and a primary alcohol (2-phenylethanol) with 1.1 equiv of isobutyric anhydride in the presence of 1 gave the 4-O-isobutyrate of octyl β-D-glucopyranoside with 99% regioselectivity in 98% yield, which indicates that acylation of the secondary hydroxyl group at C(4) of the carbohydrate proceeds in an accelerative manner. A possible mechanism, involving multiple hydrogen-bonding between 1 and the monosaccharide, is proposed for the chemo- and regioselective acylation.
- Kawabata, Takeo,Muramatsu, Wataru,Nishio, Tadashi,Shibata, Takeshi,Schedel, Hartmut
-
-
Read Online
- Studies on pyrrolidinones: Some attempts to improve the synthesis of methyl N-(3,4,4′,5-tetramethoxybenzhydryl)pyroglutamate (HEI 81) by using N-acyl iminium salts methodologies
-
Some ways to use the N-acyl iminium salt methodologies to synthesize a new inhibitor of tubulin polymerization, methyl N-(3,4,4′,5-tetramethoxybenzhydryl)pyroglutamate (HEI 81) were studied. The most interesting reactions utilize a new pyroglutamic lactone (3-(3,4,5-trimethoxyphenyl)dihydropyrrolo[1,2-c]oxazole-1,5-dione).
- Bourry, Anne,Pitard, Franck,Rigo, Benoit,Sanz, Gerard,Camus, Fabrice,Norberg, Bernadette,Durant, Francois,Couturier, Daniel
-
-
Read Online
- Revised Structure of Anthelvencin A and Characterization of the Anthelvencin Biosynthetic Gene Cluster
-
Anthelvencins A and B are pyrrolamide metabolites produced by Streptomyces venezuelae ATCC 14583 and 14585. Isolated in 1965, they were reported to exhibit anthelmintic and moderate antibacterial activities. In this study, we revise the structure of anthelvencin A and identify a third anthelvencin metabolite, bearing two N-methylated pyrrole groups, which we named anthelvencin C. We sequenced the genome of S. venezuelae ATCC 14583 and identified a gene cluster predicted to direct the biosynthesis of anthelvencins. Functional analysis of this gene cluster confirmed its involvement in anthelvencin biosynthesis and allowed us to propose a biosynthetic pathway for anthelvencins. In addition to a nonribosomal peptide synthetase (NRPS), the assembly of anthelvencins involves an enzyme from the ATP-grasp ligase family, Ant23. We propose that Ant23 uses a PCP-loaded 4-aminopyrrole-2-carboxylate as substrate. As observed for the biosynthesis of the other pyrrolamides congocidine (produced by Streptomyces ambofaciens ATCC 25877) and distamycin (produced by Streptomyces netropsis DSM 40846), the NRPS assembling anthelvencins is composed of stand-alone domains only. Such NRPSs, sometimes called type II NRPSs, are less studied than the classical multimodular NRPSs. Yet, they constitute an interesting model to study protein-protein interactions in NRPSs and are good candidates for combinatorial biosynthesis approaches.
- Aubry, Céline,Clerici, Paolo,Gerbaud, Claude,Lautru, Sylvie,Micouin, Laurent,Pernodet, Jean-Luc
-
-
Read Online
- Design, synthesis and evaluation of hydrazine and acyl hydrazone derivatives of 5-pyrrolidin-2-one as antifungal agents
-
Twenty-eight 5-pyrrolidine-2-ones decorated by hydrazine or acyl hydrazones groups have been designed, synthesized and evaluated as antifungal agents on a panel of twelve fungal strains and three non albicans candida yeasts species which have demonstrated reduced susceptibility to commonly used antifungal drugs. Half of the target compounds exhibited good to high antifungal activities on at least one strain with MIC50 lower than the control antifungal agent – hymexazol or ketoconazole. 5-Arylhydrazino-pyrrolidin-2-ones were found active and the –NH-NH- linker proved to be essential to maintain the antifungal potential. Compound 2a is a broad-spectrum antifungal, active on 60% of the tested strains. Replacing the hydrazine linker by an acylhydrazone one narrowed the spectrum of activity but pyroglutamylaryl hydrazones, mainly aromatic ones, exhibited good activity, adequate “fungicide-like” properties and were devoted of cytotoxicity.
- Billamboz, Muriel,Dascalu, Anca-Elena,Fayeulle, Antoine,Furman, Christophe,Ghinet, Alina,Lipka, Emmanuelle,Rigo, Beno?t
-
-
Read Online
- Enantioselective N-heterocyclic carbene-catalysed intermolecular crossed benzoin condensations: Improved catalyst design and the role of in situ racemisation
-
The enantioselective intermolecular crossed-benzoin condensation mediated by novel chiral N-heterocyclic carbenes derived from pyroglutamic acid has been investigated. A small library of chiral triazolium ions were synthesised. Each possessed a tertiary alcohol H-bond donor and a variable N-aryl substituent. It was found that increasing both the steric requirement and the electron-withdrawing characteristics of the N-aryl ring led to more chemoselective, efficient and enantioselective chemistry, however both quenching the reaction at different times and deuterium incorporation experiments involving the product revealed that this is complicated by product racemisation in situ (except in the case of benzoin itself), which explains the dependence of enantioselectivity on the electrophilicity of the reacting aldehydes common in the literature. Subsequent protocol optimisation, where one reacting partner was an o-substituted benzaldehyde, allowed a range of crossed-benzoins to be synthesised in moderate-good yields with moderate to excellent enantioselectivity.
- Delany, Eoghan G.,Connon, Stephen J.
-
supporting information
p. 248 - 258
(2021/01/14)
-
- Identification of a Pyrrole Intermediate Which Undergoes C-Glycosidation and Autoxidation to Yield the Final Product in Showdomycin Biosynthesis
-
Showdomycin is a C-nucleoside bearing an electrophilic maleimide base. Herein, the biosynthetic pathway of showdomycin is presented. The initial stages of the pathway involve non-ribosomal peptide synthetase (NRPS) mediated assembly of a 2-amino-1H-pyrrole-5-carboxylic acid intermediate. This intermediate is prone to air oxidation whereupon it undergoes oxidative decarboxylation to yield an imine of maleimide, which in turn yields the maleimide upon acidification. It is also shown that this pyrrole intermediate serves as the substrate for the C-glycosidase SdmA in the pathway. After coupling with ribose 5-phosphate, the resulting C-nucleoside undergoes a similar sequence of oxidation, decarboxylation and deamination to afford showdomcyin after exposure to air. These results suggest that showdomycin could be an artifact due to aerobic isolation; however, the autoxidation may also serve to convert an otherwise inert product of the biosynthetic pathway to an electrophilic C-nucleotide thereby endowing showdomycin with its observed bioactivities.
- Kim, Minje,Liu, Hung-wen,Ren, Daan,Wang, Shao-An
-
supporting information
p. 17148 - 17154
(2021/06/28)
-
- Enantiopure 5-CF3-Proline: Synthesis, Incorporation in Peptides, and Tuning of the Peptide Bond Geometry
-
The straightforward synthesis of enantiopure 5-(R)-and 5-(S)-trifluoromethylproline is reported. The key steps are a Ruppert-Prakash reagent addition on l-pyroglutamic esters followed by an elimination reaction and a selective reduction. The solution-phase and solid-phase incorporation of this unprotected enantiopure fluorinated amino acid in a short peptide chain was demonstrated. Compared to proline, the CF3 group provides a decrease of the trans to cis amide bond isomerization energy and an increase of the cis conformer population.
- Sanchez, Clément A.,Gadais, Charlène,Chaume, Grégory,Girard, Sylvaine,Chelain, Evelyne,Brigaud, Thierry
-
supporting information
p. 382 - 387
(2021/01/13)
-
- Discovery of SY-5609: A Selective, Noncovalent Inhibitor of CDK7
-
CDK7 has emerged as an exciting target in oncology due to its roles in two important processes that are misregulated in cancer cells: cell cycle and transcription. This report describes the discovery of SY-5609, a highly potent (sub-nM CDK7 Kd) and selective, orally available inhibitor of CDK7 that entered the clinic in 2020 (ClinicalTrials.gov Identifier: NCT04247126). Structure-based design was leveraged to obtain high selectivity (>4000-times the closest off target) and slow off-rate binding kinetics desirable for potent cellular activity. Finally, incorporation of a phosphine oxide as an atypical hydrogen bond acceptor helped provide the required potency and metabolic stability. The development candidate SY-5609 displays potent inhibition of CDK7 in cells and demonstrates strong efficacy in mouse xenograft models when dosed as low as 2 mg/kg.
- Alnemy, Sydney,Bradley, Michael J.,Chuaqui, Claudio,Ciblat, Stephane,Hamman, Kristin B.,Hu, Shanhu,Kabro, Anzhelika,Ke, Nan,Malojcic, Goran,Marineau, Jason J.,Mihalich, Janessa,Roy, Stephanie,Savinainen, Anneli,Schmidt, Darby,Waters, Nigel J.,Whitmore, Kenneth Matthew,Wilsily, Ashraf,Winter, Dana K.,Zahler, Robert
-
-
- N-Heterocyclic carbene triazolium salts containing brominated aromatic motifs: Features and synthetic protocol
-
In this work, we provide a brief overview of the role of N-aryl substituents on triazolium N-heterocyclic carbene (NHC) catalysis. This synopsis provides context for the disclosed synthetic protocol for new chiral N-heterocyclic carbene (NHC) triazolium salts with brominated aromatic motifs. Incorporating brominated aryl rings into NHC structures is challenging, probably due to the substantial steric and electronic influence these substituents exert throughout the synthetic protocol. However, these exact characteristics make it an interesting N-aryl substituent, because the electronic and steric diversity it offers could find broad use in organometallic- A nd organo-catalysis. Following the synthetic reaction by NMR guided the extensive modification of a known protocol to enable the preparation of these challenging NHC pre-catalysts.
- Raed, Anas Abo,Dhayalan, Vasudevan,Barkai, Shahar,Milo, Anat
-
p. 878 - 882
(2020/12/25)
-
- INHIBITORS OF CYCLIN-DEPENDENT KINASE 7 (CDK7)
-
The present invention provides various compositions, including compounds of Formula (I) or (la), or a species thereof, and pharmaceutically acceptable salts, solvates (e.g., hydrates), stereoisomer, tautomers, isotopic and other specified forms thereof. Also provided are methods (or uses) and kits involving the compounds or pharmaceutically acceptable compositions containing them for treating or preventing a disease (e.g., a proliferative disease such as cancer) in a subject. Administration of a compound or pharmaceutical composition described herein is expected to inhibit cyclin-dependent kinase 7 (CDK7), and thereby, induce apoptosis in tumor cells in the subject.
- -
-
Paragraph 122-123
(2020/05/28)
-
- Design and Synthesis of 56 Shape-Diverse 3D Fragments
-
Fragment-based drug discovery is now widely adopted for lead generation in the pharmaceutical industry. However, fragment screening collections are often predominantly populated with flat, 2D molecules. Herein, we describe a workflow for the design and synthesis of 56 3D disubstituted pyrrolidine and piperidine fragments that occupy under-represented areas of fragment space (as demonstrated by a principal moments of inertia (PMI) analysis). A key, and unique, underpinning design feature of this fragment collection is that assessment of fragment shape and conformational diversity (by considering conformations up to 1.5 kcal mol?1 above the energy of the global minimum energy conformer) is carried out prior to synthesis and is also used to select targets for synthesis. The 3D fragments were designed to contain suitable synthetic handles for future fragment elaboration. Finally, by comparing our 3D fragments with six commercial libraries, it is clear that our collection has high three-dimensionality and shape diversity.
- Atobe, Masakazu,Blakemore, David C.,Bond, Paul S.,Chan, Ngai S.,De Fusco, Claudia,Downes, Thomas D.,Firth, James D.,Hubbard, Roderick E.,Jones, S. Paul,Klein, Hanna F.,O'Brien, Peter,Roughley, Stephen D.,Vidler, Lewis R.,Waddelove, Laura,Whatton, Maria Ann,Wheldon, Mary C.,Woolford, Alison J.-A.,Wrigley, Gail L.
-
supporting information
(2020/07/13)
-
- INHIBITORS OF APOL1 AND METHODS OF USING SAME
-
The disclosure provides at least one entity chosen from compounds of formula (I), solid state forms of the same, compositions comprising the same, and methods of using the same, including use in treating focal segmental glomerulosclerosis (FSGS) and/or non-diabetic kidney disease (NDKD).
- -
-
Paragraph 00306
(2020/07/14)
-
- Practical Synthesis of Chiral N-Heterocyclic Carbene Triazolium Salts Containing a Hydroxy Functional Handle
-
A library of functionalized chiral pyrrolidine-based N-heterocyclic carbene triazolium salts containing a hydroxy handle is prepared from readily accessible chiral (S)-pyroglutamic acid in eight steps. This improved synthetic protocol affords increased yields for known structures and 18 new NHCs are prepared by this method. The presence of a hydroxy handle offers potential for further functionalization and for non-covalent control over catalytic reactions in which the NHCs can serve as organocatalysts or ligands for organometallic catalysis.
- Dhayalan, Vasudevan,Mal, Kanchan,Milo, Anat
-
p. 2845 - 2864
(2019/07/04)
-
- Organocatalytic Decarboxylation of Amino Acids as a Route to Bio-based Amines and Amides
-
Amino acids obtained by fermentation or recovered from protein waste hydrolysates represent an excellent renewable resource for the production of bio-based chemicals. In an attempt to recycle both carbon and nitrogen, we report here on a chemocatalytic, metal-free approach for decarboxylation of amino acids, thereby providing a direct access to primary amines. In the presence of a carbonyl compound the amino acid is temporarily trapped into a Schiff base, from which the elimination of CO2 may proceed more easily. After evaluating different types of aldehydes and ketones on their activity at low catalyst loadings (≤5 mol%), isophorone was identified as powerful organocatalyst under mild conditions. After optimisation many amino acids with a neutral side chain were converted in 28–99 % yield in 2-propanol at 150 °C. When the reaction is performed in DMF, the amine is susceptible to N-formylation. This consecutive reaction is catalysed by the acidity of the amino acid reactant itself. In this way, many amino acids were efficiently transformed to the corresponding formamides in a one-pot catalytic system.
- Claes, Laurens,Janssen, Michiel,De Vos, Dirk E.
-
p. 4297 - 4306
(2019/08/26)
-
- Synthesis and bioactivities evaluation of L-pyroglutamic acid analogues from natural product lead
-
A series of L-pyroglutamic acid analogues from natural product lead were designed and synthesized, as well as their antifungal activities against Phytophthora infestans, neuritogenic activities, antibacterial activities and anti-inflammatory activities are described. The bioassays and SAR study showed that the majority of L-pyroglutamic acid esters have a significant antifungal activity against P. infestans, especially 2d and 2j demonstrated the best activities with EC50 values of 1.44 and 1.21 μg mL?1, which were about seven times that of commercial azoxystrobin (7.85 μg mL?1). Moreover, compounds 2e, 2g and 4d displayed anti-inflammatory activity against LPS-induced NO production in BV-2 microglial cells; neuritogenic activity in NGF-induced PC-12 cells is the same activity. This study demonstrates that compounds 2d and 2j are potential drugs to control P. infestans.
- Gang, Fang-li,Zhu, Feng,Li, Xiao-ting,Wei, Jie-lu,Wu, Wen-jun,Zhang, Ji-wen
-
p. 4644 - 4649
(2018/08/21)
-
- Discovery of a Potent Thiazolidine Free Fatty Acid Receptor 2 Agonist with Favorable Pharmacokinetic Properties
-
Free fatty acid receptor 2 (FFA2/GPR43) is a receptor for short-chain fatty acids reported to be involved in regulation of metabolism, appetite, fat accumulation, and inflammatory responses and is a potential target for treatment of various inflammatory and metabolic diseases. By bioisosteric replacement of the central pyrrolidine core of a previously disclosed FFA2 agonist with a synthetically more tractable thiazolidine, we were able to rapidly synthesize and screen analogues modified at both the 2- and 3-positions on the thiazolidine core. Herein, we report SAR exploration of thiazolidine FFA2 agonists and the identification of 31 (TUG-1375), a compound with significantly increased potency (7-fold in a cAMP assay) and reduced lipophilicity (50-fold reduced clogP) relative to the pyrrolidine lead structure. The compound has high solubility, high chemical, microsomal, and hepatocyte stability, and favorable pharmacokinetic properties and was confirmed to induce human neutrophil mobilization and to inhibit lipolysis in murine adipocytes.
- Hansen, Anders H?jgaard,Sergeev, Eugenia,Bolognini, Daniele,Sprenger, Richard R.,Ekberg, Jeppe Hvidtfeldt,Ejsing, Christer S.,McKenzie, Christine J.,Rexen Ulven, Elisabeth,Milligan, Graeme,Ulven, Trond
-
supporting information
p. 9534 - 9550
(2018/10/24)
-
- INHIBITORS OF CYCLIN DEPENDNT KINASE 7 (CDK7)
-
The present invention provides novel compounds of Formula (I) and pharmaceutically acceptable salts, solvates, hydrates, tautomers, stereoisomers, isotopically labeled derivatives, and compositions thereof. Also provided are methods and kits involving the compounds or compositions for treating or preventing proliferative diseases (e.g., cancers (e.g., leukemia, melanoma, multiple myeloma), benign neoplasms, angiogenesis, inflammatory diseases, autoinflammatory diseases, and autoimmune diseases) in a subject. Treatment of a subject with a proliferative disease using a compound or composition of the invention may inhibit the aberrant activity of cyclin-dependent kinase 7 (CDK7), and therefore, induce cellular apoptosis and/or inhibit transcription in the subject.
- -
-
Paragraph 323
(2018/02/28)
-
- 2-PYRROLIDINE PHENYLHYDRAZIDES ANTIBACTERIAL AGENTS
-
2-Pyrrolidine phenylhydrazides antibacterial agents The present invention relates to 2-pyrrolidine phenylhydrazide compounds of formula (I), which are selective antibacterials specifically agalnstAcineto barter baumannii.The invention also relates to their therapeutic use as antibacterials, to a process for their preparation and to pharmaceutical compositions containing them.
- -
-
Page/Page column 54
(2018/02/28)
-
- Zirconium-catalysed N-acylation of lactams using unactivated carboxylic acids
-
A large number of chemicals including surfactants, nootropic drugs and pesticides contain an N-acylated lactam moiety in their molecular structure. In this work, the direct, catalytic N-acylation of a number of lactams with various unactivated carboxylic
- Hulsbosch, Joris,Claes, Laurens,De Vos, Dirk E.
-
supporting information
p. 1646 - 1650
(2018/04/06)
-
- Enantiospecific Total Synthesis of (+)-3-epi-Epohelmin A Using a Nitrogen-Substituted Donor–Acceptor Cyclopropane
-
The enantiospecific total synthesis of (+)-3-epi-epohelmin was accomplished by rapid construction of the pyrrolizidine core starting from enantiopure l-pyrroglutamic acid. The key reaction included a highly regio- and stereoselective intramolecular cyclopropanation reaction, regioselective ring opening of a nitrogen-substituted donor–acceptor cyclopropane, stereoselective reduction of a ketone, chemoselective organolithium addition to a Weinreb amide, and chemoselective oxidation of an allylic alcohol.
- Gharpure, Santosh J.,Nanda, Laxmi Narayan,Kumari, Dimple
-
supporting information
p. 3917 - 3920
(2017/07/28)
-
- Supercritical fluid chromatography approach for a sustainable manufacture of new stereoisomeric anticancer agent
-
Two routes aimed at the manufacture of unprecedented stereoisomeric combretastatin A-4 analogue were described: flash chromatography vs supercritical fluid chromatography. The latter has many advantages over liquid chromatography and was therefore chosen for the small scale separation of methyl 1-[(3-hydroxy-4-methoxyphenyl) (3,4,5-trimethoxyphenyl)methyl]-5-oxo-L-prolinate 5, with potential antitumoral activity. After a screening of six different polysaccharide based chiral stationary phases and four co-solvents, the percentage of co-solvent, the flow-rate and the outlet pressure were optimized through a design of experiments (DoE). The preparation of 50 mg of each stereoisomer was achieved successfully on a Chiralpak AD-H with isopropanol as a co-solvent. Productivity (kkd), solvent usage and environmental factor (E Factor) were calculated. Flash chromatography and supercritical fluid chromatography approaches were compared in terms of yield and purity of each stereoisomer manufactured.
- Ghinet, Alina,Zehani, Yasmine,Lipka, Emmanuelle
-
p. 845 - 853
(2017/08/22)
-
- Compounding method for LCZ696 midbody
-
The invention discloses a compounding method for a LCZ696 midbody. The compounding route is as follows: wherein R1 is Me, Et or i-Pr; X is Cl, Br or I; R2 is Ms, Ts or Tf. According to the compounding method for the LCZ696 midbody disclosed by the invention, the methylating difficulty is reduced, the midbody is configured and overturned through the consequent reaction, the proportion of the required configuration is greatly increased, the product yield, purity and use ratio are increased and the industrial large-scale production is benefited.
- -
-
Paragraph 0048-0049
(2017/11/16)
-
- Synthesis of Bicyclic and Tricyclic Chiral Guanidinium Salts by an Intramolecular Alkylation Approach
-
Synthetic studies leading to three new types of chiral guanidinium scaffolds are described. Structures of interest include bicyclic guanidine derivatives with various substitution patterns around the guanidine core, as well as a highly rigid tricyclic scaffold. The challenging targets were accessed by application of mercury(II)-promoted guanylation of N-Boc-substituted thioureas and Ishikawa's desulfurative cyclization. In addition to our synthetic logics, a scalable synthesis of the tricyclic guanidinium salt is presented.
- Turo?kin, Aleksej,Raven, William,Selig, Philipp
-
supporting information
p. 296 - 305
(2017/01/24)
-
- As hepatitis c inhibitor spiro compound and its use in medicine
-
The invention provides a spiro compound serving as a hepatitis c inhibitor and application thereof in a medicine. The compound is a compound as shown in a formula (I) or a stereisomer, a geometric isomer, a tautomer, nitric oxide, an aquo-complex, a solvate, a metabolite, pharmaceutically acceptable salt or prodrug of the compound as shown in the formula (I). The invention also provides a pharmaceutical composition containing the compound, application of the compound and the pharmaceutical composition in inhibition of HCV (Hepatitis C Virus) copy and HCV virus protein, as well as the application of the compound and the pharmaceutical composition in prevention, handling, treatment or relieving of HCV infection or hepatitis c disease for a patient. The formula I is as shown in the specification.
- -
-
Paragraph 1140-1142
(2017/12/28)
-
- Discovery of Indolinone-Based Multikinase Inhibitors as Potential Therapeutics for Idiopathic Pulmonary Fibrosis
-
Idiopathic pulmonary fibrosis (IPF) is a serious and deadly disease for which treatment options are limited. The recent approval of antifibrosis agent nintedanib represents one of the first therapeutic approaches for the treatment of IPF. Here, we report novel indolinone-based multikinase inhibitors that target angiogenesis and fibrosis pathways and may serve as potential therapeutics for IPF. KBP-7018 is a novel, tyrosine kinase-selective inhibitor with potent effects on three fibrotic kinases (c-KIT, PDGFR, and RET). The pharmacokinetics (PK) properties of KBP-7018 were favorable in mice, rats, and dogs. In a bleomycin (BLM)-induced mouse pulmonary fibrosis model, 10, 30, and 100 mg/kg daily doses (q.d.) of KBP-7018 improved the 28-day survival rate in a dose-dependent manner. The improved efficacy of KBP-7018 compared to nintedanib provided a certain level of chemical validation for the involvement of PDGFR, c-KIT, and RET in IPF. Thus, KBP-7018 represents a novel multikinase inhibitor with differentiated activity, highly enhanced selectivity, and acceptable PK profiles that will enter phase I clinical trials.
- Huang, Zhenhua,Li, Heran,Zhang, Qian,Lu, Fangzheng,Hong, Mei,Zhang, Zhigang,Guo, Xiaocui,Zhu, Yuanju,Li, Sanming,Liu, Hongzhuo
-
supporting information
p. 1142 - 1147
(2017/11/15)
-
- Debio-1143: Inhibitor of apoptosis protein (IAP) antagonist Cancer therapy
-
Inhibitors of apoptosis proteins (IAPs) block caspases, modulate nuclear factor NF-êB signaling pathways and are involved in resistance to cancer therapies. Debio-1143, a mimetic of an endogenous IAP inhibitor (second mitochondriaderived activator of caspases [SMAC]), may help to overcome treatment resistance and has demonstrated antitumor activity in various cancer cell lines and xenograft models, alone or in combination with chemotherapy, radiotherapy or immunotherapies. So far, about 150 cancer patients have been enrolled in 5 registered early-phase clinical trials testing Debio-1143. Tolerability was acceptable even when the drug was used in combination therapies. In monotherapy, pharmacokinetics was linear, but varied considerably among patients in combination settings. High tumor penetration and on-target activity were consistently shown in patient surrogate tissues and tumor biopsies. Tumor responses to second-(or higher) line monotherapy in patients with various advanced cancers were rather weak, but currently followed approaches as an adjunct to existing cancer therapies look encouraging. Still, to identify ideal target populations and concomitant regimens remains challenging.
- Ray-Coquard,Bourhis,Delord,Vuagniaux,Zanna,Lu,Wang
-
p. 745 - 755
(2018/03/21)
-
- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
-
The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
- -
-
Paragraph 1803
(2017/05/14)
-
- BIS-HETEROARYL DERIVATIVES AS MODULATORS OF PROTEIN AGGREGATION
-
The present invention relates to certain bis-heteroaryl compounds, pharmaceutical compositions containing them, and methods of using them, including methods for preventing, reversing, slowing, or inhibiting protein aggregation, and methods of treating diseases that are associated with protein aggregation, including neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, Lewy body disease, Parkinson's disease with dementia, fronto- temporal dementia, Huntington's Disease, amyotrophic lateral sclerosis, and multiple system atrophy, and cancer including melanoma.
- -
-
Paragraph 0156
(2017/02/24)
-
- A Catalyst Designed for the Enantioselective Construction of Methyl- and Alkyl-Substituted Tertiary Stereocenters
-
Tertiary methyl-substituted stereocenters are present in numerous biologically active natural products. Reported herein is a catalytic enantioselective method for accessing these chiral building blocks using the Mukaiyama-Michael reaction between silyl ketene thioacetals and acrolein. To enable remote enantioface control on the nucleophile, a new iminium catalyst, optimized by three-parameter tuning and by identifying substituent effects on enantioselectivity, was designed. The catalytic process allows rapid access to chiral thioesters, amides, aldehydes, and ketones bearing an α-methyl stereocenter with excellent enantioselectivities, and allowed rapid access to the C4-C13 segment of (-)-bistramide A. DFT calculations rationalized the observed sense and level of enantioselectivity.
- Claraz, Aurlie,Sahoo, Gokarneswar,Berta, Dnes,Madarsz, dm,Ppai, Imre,Pihko, Petri M.
-
supporting information
p. 669 - 673
(2016/02/27)
-
- As tyrosine kinase inhibitors substituted indolinone derivatives
-
The invention belongs to the technical field of a medicine, and particularly relates to a substituted indole ketone derivative as a tyrosine kinase inhibitor shown in a general formula (I), a pharmaceutically acceptable salt, a deuterated article or a stereoisomer thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, Ra, Rb, Rc, Rd, n, n1, n2, n3, n4, a ring A and a ring B are defined in the specification. The invention also relates to a preparation method of the compound, a drug preparation containing the compound, and application of the compound in preparation of a drug for preventing or treating a fibrosis disease and treating an excessive hyperplasia disease.
- -
-
Paragraph 0361-0363
(2016/10/24)
-
- Impact of Functional Groups on the Copper-Initiated N-Arylation of 5-Functionalized Pyrrolidin-2-ones and Their Vinylogues
-
The electronic effects governing the N-arylation of pyrrolidone were investigated. The generalization of our preliminary findings on a copper(I)-catalyzed Csp2-N coupling process was first improved with a wide variety of aryl and heteroaryl halides and methyl pyroglutamate. The optimized protocol was further extended to pyrrolidin-2-ones substituted at the C5-position with an aryl group bearing an electron-donating or electron-withdrawing group as well as to some of their substituted enaminoester vinylogues. The impact of substituents at the N- and C5-position on these coupling processes seemed to be pivotal for determining both the reaction profiles and yields.
- Baudelet, Davy,Da?ch, Adam,Rigo, Beno?t,Lipka, Emmanuelle,Gautret, Philippe,Homerin, Germain,Claverie, Christelle,Rousseau, Jolanta,Abuhaie, Cristina-Maria,Ghinet, Alina
-
supporting information
p. 2226 - 2244
(2016/07/15)
-
- Stereo- and Chemodivergent NHC-Promoted Functionalisation of Arylalkylketenes with Chloral
-
Stereo- and chemodivergent enantioselective reaction pathways are observed upon treatment of alkylarylketenes and trichloroacetaldehyde (chloral) with N-heterocyclic carbenes, giving selectively either β-lactones (up to 88:12 dr, up to 94% ee) or α-chloroesters (up to 94% ee). Either 2-arylsubstitution or an α-branched iPr alkyl substituent within the ketene favours the chlorination pathway, allowing chloral to be used as an electrophilic chlorinating reagent in asymmetric catalysis.
- Douglas, James J.,Churchill, Gwydion,Slawin, Alexandra M. Z.,Fox, David J.,Smith, Andrew D.
-
supporting information
p. 16354 - 16358
(2015/11/09)
-
- Synthesis and evaluation of a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane scaffold as a mimic of Xaa-trans-Pro in poly-l-proline type II helix conformation
-
We describe the development of a small-molecule mimic of Xaa-trans-Pro dipeptide in poly-l-proline type II helix conformation, based upon a (3R,6S,9S)-2-oxo-1-azabicyclo[4.3.0]nonane core structure. Stereoselective synthesis of the mimic from l-pyroglutamic acid is achieved in twelve linear steps and 9.9% yield. Configurational and conformational analyses are conducted using a combination of 1H NMR spectroscopy, X-ray crystallography and circular dichroism spectroscopy; and evaluation of the mimic as a promising surrogate dipeptide, in a protein-protein interaction between the SH3 domain of human Fyn kinase (Fyn SH3) and peptidomimetics of its biological ligand, are conducted by 1H-15N HSQC NMR titration experiments.
- Aillard, Boris,Kilburn, Jeremy D.,Blaydes, Jeremy P.,Tizzard, Graham J.,Findlow, Stuart,Werner, J?rn M.,Bloodworth, Sally
-
p. 4562 - 4569
(2015/04/14)
-
- SPIRO COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS
-
Disclosed are spiro compounds of formula (I), or stereomers, geometric isomers, tautomers, nitrogen oxides, hydrates, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof. The compounds can be used to treat hepatitis C virus (HCV) infection or hepatitis C disease. Furthermore disclosed are pharmaceutical compositions containing the compounds and the method of using the compounds or pharmaceutical compositions in the treatment of HCV infection or hepatitis C disease.
- -
-
Paragraph 0635
(2015/11/09)
-
- Bridged Ring compounds As Hepatitis C Virus (HCV) Inhibitors And Pharmaceutical Applications Thereof
-
Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
- -
-
Paragraph 0748; 0749; 0750; 0751; 0752
(2015/03/28)
-
- Chemoselective Intramolecular Functionalization of Methyl Groups in Nonconstrained Molecules Promoted by N-Iodosulfonamides
-
Mechanistic evidence observed in Hofmann-L?ffler-Freytag-type reactions has been crucial to achieve the chemoselective functionalization of methyl groups under mild conditions. Radical-mediated methyl iodination and subsequent oxidative deiodination are the key steps in this functionalization, where iodine chemistry has a pivotal role on the formation of the C-N bond. The concepts of single hydrogen atom transfer (SHAT) and multiple hydrogen atom transfer (MHAT) are introduced to describe the observed chemoselectivity. (Chemical Equation Presented).
- Paz, Nieves R.,Rodríguez-Sosa, Dionisio,Valdés, Haydee,Marticorena, Ricardo,Melián, Daniel,Copano, M. Belén,González, Concepción C.,Herrera, Antonio J.
-
supporting information
p. 2370 - 2373
(2015/06/02)
-
- Flexible and modular syntheses of enantiopure 5-cis-substituted prolinamines from l-pyroglutamic acid
-
A wide range (25 examples) of 5-cis-substituted prolinamines is prepared in five to ten steps starting from cheap l-pyroglutamic acid. Three routes, differing mainly in the order of introduction of the substituents at the 5-cis position, the pyrrolidine nitrogen atom, and the exocyclic amino function, are successfully developed.
- Prause, Felix,Kaldun, Johannes,Arensmeyer, Benjamin,Wennemann, Benedikt,Fr?hlich, Benjamin,Scharnagel, Dagmar,Breuning, Matthias
-
p. 575 - 586
(2015/02/19)
-
- A new class of non-C2-symmetric ligands for oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones
-
We report the discovery, synthesis, and application of a new class of non-C2-symmetric phosphoramidite ligands derived from pyroglutamic acid for use in both oxidative and redox-neutral palladium-catalyzed asymmetric allylic alkylations of 1,3-diketones. The resulting chiral products are typically obtained in high yield with good to excellent levels of enantioselectivity.
- Trost, Barry M.,Donckele, Etienne J.,Thaisrivongs, David A.,Osipov, Maksim,Masters, James T.
-
supporting information
p. 2776 - 2784
(2015/03/04)
-
- An cost-effective and safe process of L-cis-4,5-methanoproline amide, the key synthetic intermediate of saxagliptin, via an improved Simmons-Smith reaction
-
L-cis-4,5-Methanoproline amide, a key intermediate of saxagliptin, was synthesized by an improved Simmons-Smith reaction. The zinc carbenoid was formed through Zn/CuBr and CH2I2, under the optimized condition, the title compound was gained with 68% yield and excellent diastereomeric selectivity (40:1 d.r.). The absence of the flammable and expensive ZnEt2 makes this procedure very attractive in large scale production.
- Ding, Ding,Pan, Xianhua,Yu, Wansheng,Li, Xiaojun,Chen, Suke,Liu, Feng
-
p. 719 - 726
(2015/05/05)
-
- FUSED MORPHOLINOPYRIMIDINES AND METHODS OF USE THEREOF
-
The present disclosure relates to Fused Morpholinopyrimidines, pharmaceutical compositions comprising an effective amount of a Fused Morpholinopyrimidine and methods for using a Fused Morpholinopyrimidine in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of a Fused Morpholinopyrimidine.
- -
-
Paragraph 1238
(2015/08/03)
-
- Design, syntheses, and pharmacological characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan analogues as opioid receptor ligands
-
A series of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) analogues were synthesized and pharmacologically characterized to study their structure-activity relationship at the mu opioid receptor (MOR). The competition binding assay showed two-atom spacer and aromatic side chain were optimal for MOR selectivity. Meanwhile, substitutions at the 1′- and/or 4′-position of the isoquinoline ring retained or improved MOR selectivity over the kappa opioid receptor while still possessing above 20-fold MOR selectivity over the delta opioid receptor. In contrast, substitutions at the 6′- and/or 7′-position of the isoquinoline ring reduced MOR selectivity as well as MOR efficacy. Among this series of ligands, compound 11 acted as an antagonist when challenged with morphine in warm-water tail immersion assay and produced less significant withdrawal symptoms compared to naltrexone in morphine-pelleted mice. Compound 11 also antagonized the intracellular Ca2+ increase induced by DAMGO. Molecular dynamics simulation studies of 11 in three opioid receptors indicated orientation of the 6′-nitro group varied significantly in the different 'address' domains of the receptors and played a crucial role in the observed binding affinities and selectivity. Collectively, the current findings provide valuable insights for future development of NAQ-based MOR selective ligands.
- Yuan, Yunyun,Zaidi, Saheem A.,Stevens, David L.,Scoggins, Krista L.,Mosier, Philip D.,Kellogg, Glen E.,Dewey, William L.,Selley, Dana E.,Zhang, Yan
-
supporting information
p. 1701 - 1715
(2015/03/30)
-
- BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS (HCV) INHIBITORS AND PHARMACEUTICAL APPLICATIONS THEREOF
-
Provided herein is a compound having Formula (I), or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are pharmaceutical compositions comprising the compounds disclosed herein, which can be used for treating HCV infection or a HCV disorder.
- -
-
Paragraph 00346
(2014/02/16)
-
- FUSED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
Provided are fused tricyclic compounds effective to inhibit the function of the NS5A protein of formula (I), wherein X, X', Y, Y', A, A',Q1, Q2, R1-R4, X4, R5a, f and W are defined as in the description. Also provided herein are pharmaceutical compositions thereof, and uses in the manufacture of a medicament for treating HCV infection or a HCV disorder thereof.
- -
-
Paragraph 00353; 00354; 00487; 00488
(2014/06/23)
-
- SPIRO RING COMPOUND AS HEPATITIS C VIRUS (HCV) INHIBITOR AND USES THEREOF FIELD OF THE INVENTION
-
A compound of formula (I) or a stereoisomer, a geometric isomer. a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof is provided, which can be used for treating HCV infection or a HCV disorder. Also a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof are provided, which can also be used for treating HCV infection or a HCV disorder.
- -
-
Page/Page column 149; 150
(2014/06/23)
-
- BRIDGED RING COMPOUNDS AS HEPATITIS C VIRUS INHIBITORS, PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
-
Provided herein is a compound of formula (I) or a stereoisomer, a geometric isomer, a tautomer, an N-oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, which can be used for treating HCV infection or a HCV disorder. Also provided herein are a pharmaceutical composition comprising the compound and the use of the compound and the pharmaceutical composition thereof, which can also be used for treating HCV infection or a HCV disorder.
- -
-
Page/Page column 118
(2014/09/16)
-
- BICYCLIC AROMATIC CARBOXAMIDE COMPOUNDS USEFUL AS PIM KINASE INHIBITORS
-
The present disclosure describes bicyclic aromatic carboxamide derivatives, as well as their compositions and methods of use. The compounds inhibit the activity of the Pim kinases, and are useful in the treatment of diseases related to the activity of Pim kinases including, e.g., cancer and other diseases.
- -
-
Paragraph 0682
(2014/07/23)
-
- Methanesulfonic acid mediated cyclization and meyer-schuster rearrangement of γ-amino-ynones: Access to enantiopure pyrrolidine exocyclic vinylogous amides
-
α- and β-Amino-ynones have been largely used to prepare heterocyclic rings in the presence of various electrophiles such as protic acids or gold(I). Herein we disclose the unprecedented formation of pyrrolidine exocyclic vinylogous amides, in place of the expected azepinones or piperidinones, starting from γ-amino-ynones derived from amino acids. The process involves a tandem 1,2-addition of the protected nitrogen to the carbonyl group followed by a Meyer-Schuster rearrangement, which efficiently afforded enantiopure pyrrolidine exocyclic vinylogous amides. The sequence is poorly catalyzed by gold salts, but proved to be very efficient in the presence of methanesulfonic acid. Copyright
- Vu, Huy-Dinh,Renault, Jacques,Roisnel, Thierry,Gouault, Nicolas,Uriac, Philippe
-
p. 4506 - 4514
(2014/08/05)
-
- Straightforward synthesis of non-natural l-chalcogen and l-diselenide N-Boc-protected-γ-amino acid derivatives
-
The synthesis of new chiral seleno-, telluro-, and thio-N-Boc-γ-amino acids is described herein. These new compounds were prepared through a simple and short synthetic route, from the inexpensive and commercially-available amino acid l-glutamic acid. The products, with a highly modular character, were obtained in good to excellent yields, via hydrolysis of chalcogen pyroglutamic derivatives with overall retention of the l-glutamic acid stereochemistry. Also, an l-diselenide-N-Boc-γ-amino acid was prepared in good yield. This new synthetic route represents an efficient method for preparing new l-chalcogen- and l-diselenide-γ-amino acids with biological potential.
- Kawasoko, Cristiane Y.,Foletto, Patricia,Rodrigues, Oscar E. D.,Dornelles, Luciano,Schwab, Ricardo S.,Braga, Antonio L.
-
p. 5173 - 5183
(2013/08/15)
-
- The fluorine-NHC gauche effect: A structural and computational study
-
Herein, we report the synthesis and X-ray structural analysis of a collection of fluorinated metal N-heterocyclic carbenes (Ag, Au, Pd, Rh, Ir) and their precursor salts. The common structural feature of these species is a flanking fluoroethyl group, which is either freely rotating or embedded within a bicyclic framework. Solid state analysis confirmed a gauche conformational preference in all cases with the fluorine adopting a syn clinal arrangement (φ[NCCF]～60°) with respect to the triazolium nitrogen at the vicinal position of the NHC. A density functional theory analysis was employed to quantify these effects and evaluate the influence of electronic modulation of the carbenic carbon [(CN+); neutral carbene (C:); metal-bound carbene (CM)], on the relative gauche/anti preference, thus highlighting the potential of this conformational phenomenon as a useful molecular design strategy for controlling the topology of organometallic complexes.
- Paul, Susann,Schweizer, W. Bernd,Rugg, Graham,Senn, Hans Martin,Gilmour, Ryan
-
p. 5647 - 5659
(2013/07/11)
-
- First total synthesis of oteromycin utilizing one-pot four-step cascade reaction strategy
-
The first total synthesis of oteromycin was investigated. Our previously reported convergent strategy for the synthesis of α-acyl-γ-hydroxy- γ-lactams was first applied for the total synthesis, however, the final deprotection of the methoxyaminal moiety could not be achieved since an unexpected intramolecular Diels-Alder (IMDA) reaction occurred. Therefore, a novel one-pot four-step cascade reaction starting from α-selenolactam was investigated. The efficient synthetic strategy was successfully developed to afford the desired oteromycin, and its complete structure elucidation including the stereochemistry at C24 position was also accomplished.
- Uchiro, Hiromi,Shionozaki, Nobuhiro,Tanaka, Ryo,Kitano, Hiroyuki,Iwamura, Naoki,Makino, Kimiko
-
p. 506 - 511
(2013/02/23)
-
- Total reflection fluorescent observation device
-
A device and method for fluorescence observation have good operability, high sensitivity, and high acid reliability. The device is used for fluorescence observation using evanescent light. The angle of incidence of the excitation light is adjusted so that the excitation light is totally reflected from the surface of a substrate irrespective of the angle of the substrate surface. The method includes a step of shining the excitation light on the observation substrate while continuously varying the angle of the excitation light with respect to the observation substrate. In addition, the method includes a step of sensing the shone excitation light via optical sensors, and a step of setting the angle of total reflection according to the result of the sensing by the optical sensors. In the present device and method, the direction in which the shone excitation light travels varies with the angle of incidence.
- -
-
-
