- An Alternate Synthesis of Deethylvincadifformine
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A synthesis of 20-deethylvincadifformine from methyl nicotinylacetate is described.The reaction scheme involved a fast construction of the pentacyclic nucleus of the Aspidosperma alkaloids and the early incorporation of the 16-carbomethoxy group common to these bases.
- Wenkert, Ernest,Orito, Kazuhiko,Simmons, Dana P.,Ardisson, Janick,Kunesch, Nicole,Poisson, Jacques
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- PHOSPHORUS-CONTAINING PRODRUGS OF GEMCITABINE
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This invention relates to phosphorus-containing prodrugs of gemcitabine and their use in the treatment of cancer and viral infectious diseases. Compared with the parent drug (i.e., Gemcitabine), the prodrugs of present invention show a significant overall
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Page/Page column 28; 29
(2020/01/24)
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- NEW ANALOGS AS ANDROGEN RECEPTOR AND GLUCOCORTICOID RECEPTOR MODULATORS
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The present invention relates to novel dihydropyridine derivatives of formula (I): as modulators of nuclear receptors selected from androgen receptor and glucocorticoid receptor, to processes for their preparation, to pharmaceutical compositions comprising said compounds and to the use of said for manufacturing a medicament for the treatment of pathological conditions or diseases that can improve by modulation of androgen receptor and/or glucocorticoid receptor, selected from cancer, metastasizing cancers, benign prostate hyperplasia, polycystic ovary syndrome (PCOS), hair loss, hirsutism, acne, hypogonadism, muscle wasting diseases, cachexia, Cushing's syndrome, anti-psychotic drug induced weight gain, obesity, post-traumatic stress disorder and alcoholism.
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Paragraph 0276; 0277; 0278; 0279
(2019/05/16)
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- COMPOUNDS
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Provided are benzoxazolinone sulfonamide derivatives that inhibit Na v1.7 activity, pharmaceutical compositions containing them and their use in therapy for the treatment of diseases mediated by Na v1.7 activity.
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Page/Page column 39; 40
(2018/12/03)
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- Quinone-Fused Pyrazoles through 1,3-Dipolar Cycloadditions: Synthesis of Tricyclic Scaffolds and in vitro Cytotoxic Activity Evaluation on Glioblastoma Cancer Cells
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A novel and straightforward synthesis of highly substituted isoquinoline-5,8-dione fused tricyclic pyrazoles is reported. The key step of the synthetic sequence is a regioselective, Ag2CO3 promoted, 1,3-dipolar cycloaddition of C-heteroaryl-N-aryl nitrilimines and substituted isoquinoline-5,8-diones. The broad functional group tolerability and mild reaction conditions were found to be suitable for the preparation of a small library of compounds. These scaffolds were designed to interact with multiple biological residues, and two of them, after brief synthetic elaborations, were analyzed by molecular docking studies as potential anticancer drugs. In vitro studies confirmed the potent anticancer effects, showing promising IC50 values as low as 2.5 μm against three different glioblastoma cell lines. Their cytotoxic activity was finally positively correlated to their ability to inhibit PI3K/mTOR kinases, which are responsible for the regulation of diverse cellular processes in human cancer cells.
- Bertuzzi, Giulio,Crotti, Simone,Calandro, Pierpaolo,Bonini, Bianca Flavia,Monaco, Ilaria,Locatelli, Erica,Fochi, Mariafrancesca,Zani, Paolo,Strocchi, Elena,Mazzanti, Andrea,Chiariello, Mario,Franchini, Mauro Comes
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supporting information
p. 1744 - 1750
(2018/09/11)
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- The guareschi pyridine scaffold as a valuable platform for the identification of selective PI3K inhibitors
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A novel series of 4-aryl-3-cyano-2-(3-hydroxyphenyl)-6-morpholino-pyridines have been designed as potential phosphatidylinositol-3-kinase (PI3K) inhibitors. The compounds have been synthesized using the Guareschi reaction to prepare the key 4-aryl- 3-cyano-2,6-dihydroxypyridine intermediate. A different selectivity according to the nature of the aryl group has been observed. Compound 9b is a selective inhibitor against the PI3Kα isoform, maintaining a good inhibitory activity. Docking studies were also performed in order to rationalize its profile of selectivity.
- Galli, Ubaldina,Ciraolo, Elisa,Massarotti, Alberto,Margaria, Jean Piero,Sorba, Giovanni,Hirsch, Emilio,Tron, Gian Cesare
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supporting information
p. 17275 - 17287
(2015/12/01)
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- Structure-based design of novel class II c-Met inhibitors: 2. SAR and kinase selectivity profiles of the pyrazolone series
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As part of our effort toward developing an effective therapeutic agent for c-Met-dependent tumors, a pyrazolone-based class II c-Met inhibitor, N-(4-((6,7-dimethoxyquinolin-4-yl)oxy)-3-fluorophenyl)-1,5-dimethyl-3-oxo-2- phenyl-2,3-dihydro-1H-pyrazole-4-c
- Liu, Longbin,Norman, Mark H.,Lee, Matthew,Xi, Ning,Siegmund, Aaron,Boezio, Alessandro A.,Booker, Shon,Choquette, Debbie,D'Angelo, Noel D.,Germain, Julie,Yang, Kevin,Yang, Yajing,Zhang, Yihong,Bellon, Steven F.,Whittington, Douglas A.,Harmange, Jean-Christophe,Dominguez, Celia,Kim, Tae-Seong,Dussault, Isabelle
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scheme or table
p. 1868 - 1897
(2012/05/04)
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- Preparation and evaluation of trisubstituted pyrimidines as phosphatidylinositol 3-kinase inhibitors. 3-Hydroxyphenol analogues and bioisosteric replacements
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Two classes of trisubstituted pyrimidines related to PI-103 1 have been prepared and their inhibitory activities against phosphatidylinositol 3-kinase (PI3K) p110α were determined. From those with direct 6-aryl substitution compound 11a was the most potent inhibitor with an IC50 value of 62 nM, and showed similar activity against other class 1a PI3K isoforms tested, p110β and p110γ. When a linking chain was introduced, as in the second exemplified class, compound 15f inhibited p110α with IC 50 142 nM, and showed greater selectivity towards p110α. Compounds of both classes showed promising inhibition of cellular proliferation in IGROV-1 ovarian cancer cells. Among compounds designed to replace the 3-phenolic motif with structural isosteres, analogues incorporating a 4-indazolyl group possessed enzyme and cellular activities comparable to the parent phenols.
- Large, Jonathan M.,Torr, Jane E.,Raynaud, Florence I.,Clarke, Paul A.,Hayes, Angela,Stefano, Francesca Di,Urban, Frederique,Shuttleworth, Stephen J.,Saghir, Nahid,Sheldrake, Peter,Workman, Paul,McDonald, Edward
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scheme or table
p. 836 - 851
(2011/03/19)
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- Highly enantioselective synthesis of β-amino acid derivatives by the lewis base catalyzed hydrosilylation of β-enamino esters
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A study was conducted to demonstrate highly enantioselective synthesis of β-amino acid derivatives by the Lewis base catalyzed hydrosilylation of βenamino esters. It was found that these catalyst and its analogue displayed excellent activities and enantioselectivities in promoting hydrosilylation of N-aryl β-enamino esters. N-picolinoylpyrrolidine derivatives and N-picolioylephedrine were also evaluated in hydrosilylation of (Z)-methyl 3-phenyl-3-(phenylamino)acrylate. The generality of the Lewis base organocatalyzed hydrosilylation of various β-enamino esters were examined under the optimized conditions. It was observed that the catalytic system exhibited a high sensitivity to the N-substituents, while all the N-aryl β-enamino esters underwent the hydrosilylation smoothly to give corresponding β-amino esters.
- Zheng, Hong-Jie,Chen, Wen-Bing,Wu, Zhi-Jun,Deng, Jin-Gen,Lin, Wen-Qing,Yuan, Wei-Cheng,Zhang, Xiao-Mei
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supporting information; experimental part
p. 9864 - 9867
(2009/10/02)
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- FUSED AZOLE-PYRIMIDINE DERIVATIVES
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The present invention relates to hovel fused azolepyrimidine derivatives, processes for preparing them and pharmaceutical preparations containing them. The fused azolepyrimidine derivatives of the present invention exhibit enhanced potency for phosphotidy
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- Synthesis and muscarinic activities of 3-(pyrazolyl)-1,2,5,6-tetrahydropyridine derivatives
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A series of 3-(pyrazolyl)-1,2,5,6-tetrahydropyridine derivatives (B) was synthesized and tested for muscarinic activity in receptor binding assays using [3H]-oxotremorine-M (3H-OXO-M) and [3H]-pirenzepine (3H-PZ) as ligands. Potential muscarinic agonistic or antagonistic properties of the compounds were determined using binding studies measuring their potencies to inhibit the binding of 3H-OXO-M and 3H-PZ. Preferential inhibition of 3H-OXO-M binding was used as an indicator for potential muscarinic agonistic properties; this potential was confirmed in functional studies on isolated organs. All compounds with agonistic properties showed 3H-PZ/3H-OXO-M potency ratios in excess of 20. In contrast, for antagonists this ratio was found to be close to unity. Mono-halogenation resulted in compounds (4b and 4d) with M3 agonistic properties as shown by their atropine sensitive stimulant properties in the guinea pig ileum, but with very little or no M1 activity. Some minor in vivo effects were observed for both these compounds, with the iodinated compound 4d inducing salivation. Compound 4d also showed some positive mnemonic properties in rats where spatial short-term memory had been compromised by temporary cholinergic depletion. These data indicate that some M3 agonism may be desired in therapeutic agents aimed at the treatment of the cognitive deficits of Alzheimer's disease patients.
- Plate, Ralf,Plaum, Marc J. M.,De Boer, Thijs,Andrews, John S.,Rae, Duncan R.,Gibson, Sam
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p. 227 - 237
(2007/10/03)
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- Dual-Acting Thromboxane Receptor Antagonist/Synthase Inhibitors: Synthesis and Biological Properties of alkenoic Acids
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The design, synthesis, and pharmacology of a new class of compounds possessing bith thromboxane receptor antagonist and thromboxane synthase inhibitory properties are described.Replacement of the phenol group of the known thromboxane antagonist series 4(Z)-6-hex-4-enoic acid by a 3-pyridyl group led to a series of compounds, 5, which were potent thromboxane synthase inhibitors and weak thromboxane antagonists.Further modifications at the dioxane C2 position led to compounds, 7, which were potent dual-acting agents.In the case of compound 7w, the dual activity was shown to reside almost exclusively in the (-)-enantiomer, 7x.Following oral dosing to rats and dogs, 7x (3 mg/kg) displayed significant dual activity over a period of at least 8 h.
- Faull, Alan W.,Brewster, Andrew G.,Brown, George R.,Smithers, Michael J.,Jackson, Ruth
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p. 686 - 694
(2007/10/02)
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- Acidity and tautomerism of β-keto esters and amides in aqueous solution
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The pH-rate profiles for the keto-enol tautomerization of 17 β-keto esters and amides (RCOCH2COX: R = methyl; phenyl; 2-, 3-, and 4-pyridyl; 3(and 4)-(N-methylpyridinio); X = OCH3, OC2H5, NH2, or N(CH3)2) have been measured by stopped-flow spectrophotometry in aqueous solution (ionic strength 0.1, 25 °C) over the range pH = 2-12. Analysis of these profiles gives the microscopic rate constants for ketonization and enolization of each of these species in these aqueous solutions. Analysis of the pH dependence of the buffer catalysis for the general-acid-catalyzed protonation of these enolate conjugate bases allowed the evaluation of paE for the deprotonation of each enol species. In combination with pKaeq, these data in turn allow the calculation of the acidities of the keto tautomers (pKaK) and the equilibrium constants for enolization (KE = [enol]/[keto] ). In all cases, both the keto and enol tautomers of the amides are more acidic than the corresponding ester derivatives. The equilibrium enol/keto ratios (KE) were found to decrease in the order: 2-pyridyl > 4-pyridyl > 3-pyridyl > 4-(N-methylpyridinio) > 3-(N-methylpyridinio) > methyl ≈ phenyl for both β-keto esters and amides. A simple linear correlation between pKaE and pKaKwas observed for these series of β-keto esters and amides. Bronsted plots of second-order rate constants for deprotonation of the keto tautomer as a function of keto tautomer acidity were found to be linear, with a values in the range 0.37-0.54 for hydroxide ion, acetate ion, and several amine bases. However, the "water-catalyzed" reaction is unusual with Br?nsted α = -0.17. This α value is only readily explicable in terms of a combined general acid + general base catalysis involving two water molecules for the equilibration of the keto tautomer and the neutral enol species.
- Bunting, John W.,Kanter, James P.
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p. 11705 - 11715
(2007/10/02)
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- TAUTOMERISM OF AZINE DERIVATIVES. 4. KETO-ENOL TAUTOMERISM OF β-KETO ESTERS OF THE AZINE SERIES
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The structures of pyrazinoyl-, 3-pyridazinoyl-, 4-pyrimidoyl-, and 2-, 3-, and 4-pyridoylacetic esters were studied by means of IR, NMR, and 1H and 13C NMR spectroscopy and quantum-chemical calculations (Pariser-Parr-Pople and CNDO/2).The effect of solvents (including strongly and weakly basic solvents) on the position of the tautomeric equilibria of these β-keto esters was studied.The ?+ constants for the keto and enol fragments were estimated by means of quantum-chemical calculations and 13C NMR spectroscopy.
- Stekhova, S. A.,Zagulyaeva, O. A.,Lapachev, V. V.,Mamaeva, V. P.
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p. 640 - 644
(2007/10/02)
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