- A new efficient synthesis of 3-nitropyridine and substituted derivatives
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Pyridine and pyridine derivatives have been nitrated in the β-position by reaction with N2O5 or NO2·BF4 in MeNO2, THF or MeCN to form the N-nitropyridinium salt. This was then reacted with an aqueous solution of a nucleophile to give the β-nitro compound in moderate to good yield.
- Bakke, Jan M.,Ranes, Eli
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- ARYL LINKED IMIDAZOLE AND TRIAZOLE DERIVATIVES AND METHODS OF USE THEREOF FOR IMPROVING THE PHARMACOKINETICS OF A DRUG
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The present invention relates to aryl linked imidazole and triazole derivatives, compositions comprising said compounds, alone or in combination with other drugs, and methods of using the compounds for improving the pharmacokinetics of a drug. The compounds of the invention are useful in human and veterinary medicine for inhbiting CYP3A4 and for improving the pharmacokinetics of a therapeutic compound that is metabolized by CYP3A4.
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Page/Page column 95
(2015/06/03)
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- ARYL LINKED IMIDAZOLE AND TRIAZOLE DERIVATIVES AND METHODS OF USE THEREOF FOR IMPROVING THE PHARMACOKINETICS OF A DRUG
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The present invention relates to aryl linked imidazole and triazole derivatives, compositions comprising said compounds, alone or in combination with other drugs, and methods of using the compounds for improving the pharmacokinetics of a drug. The compounds of the invention are useful in human and veterinary medicine for inhbiting CYP3A4 and for improving the pharmacokinetics of a therapeutic compound that is metabolized by CYP3A4.
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Page/Page column 94
(2015/06/03)
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- Synthesis of novel 1,7-naphthyridines by Friedlaender condensation of pyridine substrates
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The general ability of appropriate pyridyl compounds (aldehyde or ketone) to undergo Friedlaender condensation to give different 1,7-naphthyridines has been demonstrated. 2,4-Disubstituted 1,7-naphthyridine 8 was prepared from 3-amino-4-acetylpyridine (6) and ketone 4 (82%). The Friedlaender self-condensation of pyridyl substrate 6 is reported, as well. The dimer product, 2-(3-aminopyridin-4-yl)-4-methyl-1,7-naphthyridine (7), was obtained in 97% yield. 2-Aryl-and 2,3-diaryl-1,7-naphthyridines (16-18) were prepared from 3-aminoisonicotinaldehyde (13) and arylketones 4, 14, and 15 (28-71%). The key substrates 6 and 13 are readily available via the improved pyridine nitration method. Copyright
- Stockmann, Vegar,Fiksdahl, Anne
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scheme or table
p. 1383 - 1387
(2012/01/05)
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- 7-Azacinnolin-4(1H)-one preparation and NMR studies of tautomery
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As part of our current investigations of nitropyridines, we hereby report the preparation of a new annulated heterocycle by C-azo coupling. Thus, the azacinnoline, pyrido[3,4-c]pyridazin-4(1H)-one (38%), was prepared from 4-acetyl-3-aminopyridine via diazotization. 1H, 13C, and 15N NMR spectroscopic investigations revealed that the azacinnoline exclusively exists in the NH-keto tautomeric form in DMSO-d6, CD 3OD, and D2O.
- Stockmann, Vegar,Primpke, Sebastian,Fiksdahl, Anne
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experimental part
p. 737 - 741
(2011/07/31)
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- 4-Pyridylanilinothiazoles that selectively target von Hippel - Lindau deficient renal cell carcinoma cells by inducing autophagic cell death
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Renal cell carcinomas (RCC) are refractory to standard therapy with advanced RCC having a poor prognosis; consequently treatment of advanced RCC represents an unmet clinical need. The von Hippel-Lindau (VHL) tumor suppressor gene is mutated or inactivated in a majority of RCCs. We recently identified a 4-pyridyl-2-anilinothiazole (PAT) with selective cytotoxicity against VHL-deficient renal cells mediated by induction of autophagy and increased acidification of autolysosomes. We report exploration of structure-activity relationships (SAR) around this PAT lead. Analogues with substituents on each of the three rings, and various linkers between rings, were synthesized and tested in vitro using paired RCC4 cell lines. A contour map describing the relative spatial contributions of different chemical features to potency illustrates a region, adjacent to the pyridyl ring, with potential for further development. Examples probing this domain validated this approach and may provide the opportunity to develop this novel chemotype as a targeted approach to the treatment of RCC. 2009 American Chemical Society.
- Hay, Michael P.,Turcotte, Sandra,Flanagan, Jack U.,Bonnet, Muriel,Chan, Denise A.,Sutphin, Patrick D.,Nguyen, Phuong,Giaccia, Amato J.,Denny, William A.
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supporting information; experimental part
p. 787 - 797
(2010/07/05)
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- Strategic studies in the syntheses of novel 6,7-substituted quinolones and 7- or 6-substituted 1,6- and 1,7-naphthyridones
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This paper describes the different strategies devised and applied to overcome the selectivity issues in the syntheses of 6,7-disubstituted-1H-quinolin-4-one, 7-substituted-1H-1,6-naphthyridin-4-one and 6-substituted-1H-1,7-naphthyridin-4-one derivatives. They allowed us to improve the overall yields and the scaling-up feasibility. Several examples illustrate these strategies with their advantages and drawbacks.
- Morgentin, Rémy,Pasquet, Georges,Boutron, Pascal,Jung, Frédéric,Lamorlette, Maryannick,Maudet, Micka?l,Plé, Patrick
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p. 2772 - 2782
(2008/09/19)
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- Preparation of nitropyridines by nitration of pyridines with nitric acid
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Preparation of nitropyridines by nitration of pyridines with nitric acid was discussed. Trifluoroacetic anhydride was chilled in an ice bath and the pyridine or substituted pyridines were slowly added and stirred at chilled conditions for 2 h. Relative amounts of the reactants were required for the nitration of pyridine were characterized by 1H and Nuclear magnetic resonance (NMR) spectroscopy and elemental analysis. It was observed that the yields of β-nitropyridines obtained using the standard protocol were generally higher than those obtained using N2O3.
- Katritzky, Alan R.,Scriven, Eric F. V.,Majumder, Suman,Akhmedova, Rena G.,Vakulenko, Anatoliy V.,Akhmedov, Novraz G.,Murugan, Ramiah,Abboud, Khalil A.
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p. 538 - 541
(2007/10/03)
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- The synthesis of β-nitropyridine compounds
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Pyridine and a number of substituted pyridines have been nitrated by reaction with N2O5 followed by reaction with an aqueous solution of SO2xH2O or NaHSO3. The dependence of the yields on the pH of the aqueous reaction medium, on the concentration of SO2xH2O-HSO3-, on addition of methanol to the aqueous phase, and on the reaction temperature were investigated. The yields obtained with NaHSO3 were: 3-nitropyridine 77%, 2-methyl-5-nitro-pyridine 36%, 3-methyl-5-nitropyridinc 24%, 3-acetyl-5-nitropyridine 18%, 5-nitropyridine-3-carboxylic acid 15%, 3-chloro-5-nitropyridine 11%, 4-methyl-3-nitropyridine 39%, 4-acetyl-3-nitropyridine 67%, 4-cyano-3-nitropyridine 45%, 4-phenyl-3-nitropyridine 68%, 4-formyl-3-nitropyridine 62% (from reaction in liquid SO2), 3-nitropyridine-4-carboxylic acid 48%, methyl 3-nitropyridine-4-carboxylate 75%, 2,3-dimethyl-5-nitropyridine 37%, 2,4-dimethyl-5-nitropyridine 64%, 3-nitroquinoline 10% and 4-nitroisoquinoline 42%.
- Bakke, Jan M.,Ranes, Eli,Riha, Jaroslav,Svensen, Harald
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p. 141 - 144
(2007/10/03)
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- Synthesis, Topoisomerase I Inhibitory Activity, and in Vivo Evaluation of 11-Azacamptothecin Analogs
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A series of analogs based on a novel template, 11-aza-(20S)-camptothecin, were obtained from total synthesis and tested as potential anticancer drugs in the topoisomerase I enzyme cleavable complex assay.The parent compound 11-aza-(20S)-camptothecin (8) was derived from a Friedlander condensation between the known aminopyridine derivative 3-(3-amino-4-picolylidene)-p-toluidyne and optically active tricyclic ketone 7.Compound 8 had activity approximately twice that of (20S)-camptothecin in the calf thymus topoisomerase I cleavable complex assay.Compounds were prepared wherein the 11-aza nitrogen atom was quaternized as either the corresponding N-oxide or methyl iodide.Compounds with quaternized N-11 showed improved water solubility and were equipotent to the clinically investigated camptothecin analog topotecan in the cleavable complex assay.These compounds were evaluated in vivo in nude mice bearing HT-29 human colon carcinoma xenografts.The analog 11-aza-(20S)-camptothecin 11-N-oxide was found to significantly retard tumor growth when compared to untreated controls.Finally 7,10-disubstituted 11-azacamptothecin analogs were synthesized using Pd(0) coupling reactions of 10-bromo-7-alkyl-11-aza-(20S)-camptothecins 19 and 20, which in turn were available from a Friedlander condensation of the novel bromopyridine derivatives 17a and 17b with 7.Among the 10-substituted series, a number of analogs displayed extremely high in vitro potency against topoisomerase I and improved aqueous solubility.A significant number of the compounds were found to be active in whole cell cytotoxicity assays and several were evaluated in nude mice bearing the HT-29 tumor xenografts.The most effective of these proved to be (S)-11-aza-7-ethyl-10-(aminohydroximinomethyl)camptothecin trifluoroacetic acid salt (27), a potent topoisomerase I inhibitor which demonstrated excellent efficacy in both short term and in extended in vivo assays.A comparison between in vitro enzyme data and in vivo data from nude mouse studies in other compounds in this series revealed a poor overall correlation between topoisomerase inhibition in vitro and antitumor efficacy in vivo.
- Uehling, David E.,Nanthakumar, Suganthini S.,Croom, Dallas,Emerson, David L.,Leitner, Peter P.,et al.
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p. 1106 - 1118
(2007/10/02)
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