- Synthesis and benzodiazepine receptor affinity of pyrazolo[1,5-a]pyrimidine derivatives. 3. New 6-(3-thienyl) series as α1 selective ligands
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New 3-aryl-6-(3-thienyl)pyrazolo[1,5-a]pyrimidin-7-ones (2a-j) are synthesized and evaluated in vitro on Bz/GABAA receptors and on recombinant benzodiazepine receptors (αxβ2/3γ2; x = 1-3, 5) expressed in HEK293 cells. SAR studies on the new com
- Selleri, Silvia,Bruni, Fabrizio,Costagli, Camilla,Costanzo, Annarella,Guerrini, Gabriella,Ciciani, Giovanna,Gratteri, Paola,Bonaccini, Claudia,Malmberg Aiello, Petra,Besnard, Fran?ois,Renard, Stephane,Costa, Barbara,Martini, Claudia
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- Synthesis and biological evaluation of novel pyrazolo[1,5-a]pyrimidines: Discovery of a selective inhibitor of JAK1 JH2 pseudokinase and VPS34
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A series of novel 3,6-di-substituted or 3-substituted pyrazolo[1,5-a]pyrimidines were prepared via a microwave-assisted approach that generated a broad array of derivatives in good yields (20–93%, ave. = 59%). The straightforward synthesis involved sequential treatment of commercially-available acetonitrile derivatives with DMF-dimethylacetal (120 °C, 20 min), followed by treatment with NH2NH2·HBr (120 °C, 20 min), and 1,1,3,3-tetramethoxypropane or 2-aryl-substituted malondialdehdyes (120 °C, 20 min). Compounds were screened for antimitotic activities against MCF7 breast cancer and/or A2780 ovarian cancer cell lines in vitro. The most active compounds exhibited EC50 values ranging from 0.5 to 4.3 μM, with the 3-(4-(trifluoromethyl)phenyl)-6-[4-(2-(piperidin-1-yl)ethoxy]phenyl analogue (34e) and the 3-(2-fluorophenyl)-6-[4-(2-(4-methylpiperizin-1-yl)ethoxy]phenyl analogue (35a) being two to three fold more active than Compound C (Dorsomorphin) in A2780 and MCF7 assays, respectively. Importantly, a monosubstituted 3-(benzothiazol-2-yl) derivative (13) was equipotent with the more synthetically challenging 3,6-disubstituted derivatives (34a–e and 35a–e), and exhibited a promising and unique selectivity profile when screened against a panel consisting of 403 protein kinases (Kinomescan selectivity score = 0.005, Kd = 0.55 ± 0.055 μM and 0.410 ± 0.20 μM for JAK1 JH2 pseudokinase and VPS34, respectively).
- Singleton, Justin D.,Dass, Reuben,Neubert, Nathaniel R.,Smith, Rachel M.,Webber, Zak,Hansen, Marc D.H.,Peterson, Matt A.
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supporting information
(2019/12/24)
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- A oxazolidinone antibacterial compound of intermediate and its preparation method
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The invention provides a new intermediate compound 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazole-3(5)-amino-4-yl)pyridine represented by formula 4 in the production process of a compound (S)-N-{[3-(3-fluoro-4-(4-(2-pyridyl)pyrazolyl)phenyl)-2-oxazolidine-5-yl]methyl}acetamide, and a preparation method thereof. The new intermediate guarantees the abundant source of synthesis raw materials, reduces the cost of the raw materials, omits a complicated column chromatography purifying technology, makes the operation simple, and makes the amplified production of the target compound possible.
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Paragraph 0072-0074
(2017/11/16)
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- Oxazolidinones compound and application thereof
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The invention provides an oxazolidinones compound shown as the formula VI, or salt, an aquo-complex, or a crystal form of the oxazolidinones compound, which are pharmaceutically acceptable. The invention also provides a preparation method of the compound. In the current field of a chemical drug, activity of most compounds with changed structures becomes better, while toxicity is obviously enhanced, so that the compounds cannot be used as drugs. Compared with a compound in the prior art, the oxazolidinones compound provided in the invention has excellent anti-drug-resistance and antimicrobial activity. What is unexpected is that the oxazolidinones compound has better safety and benefits safe drug use and therapy of a patient.
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Paragraph 0162; 0166-0167
(2016/10/10)
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- Exploratory process development and kilogram-scale synthesis of a novel oxazolidinone antibacterial candidate
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A concise, environmentally benign, and cost-effective route was developed for the large-scale preparation of 1, a novel oxazolidinone antibacterial candidate. The key intermediate 2-(1-(2-fluoro-4-nitrophenyl)-1H-pyrazol-4-yl) pyridine 7 was prepared with high purity by mild deamination of the regioisomeric mixture 21. The mixture was prepared from a nucleophilic SNAr reaction by selective C-N coupling of the secondary amine functionality of 4-(pyridin-2-yl)-1H-pyrazol-3-amine 14 with 1,2-difluoro-4-nitrobenzene 10 in optimized conditions with the primary amine group remaining intact. The gaseous nitrogen release rate and reaction mixture temperature of the deamination step can be well controlled by altering the feeding manner, thereby providing safety guarantees. The optimized synthetic strategy of 1 with an overall yield of 27.6%, including seven sequential transformations by only five solid-liquid isolations, significantly improved the product separation workup. The strategy bypassed time-consuming and laborious procedures for any intermediate involved as well as for the final API. This study presents a process enabling the rapid delivery of a multikilogram quantity of API with high purity.
- Yang, Tao,Chen, Jia-Xiang,Fu, Yiwei,Chen, Kaixiao,He, Jinyun,Ye, Weiwei,Sang, Zitai,Luo, Youfu
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p. 511 - 519
(2014/05/06)
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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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Page/Page column 21
(2012/11/08)
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- Studies with azinylacetonitriles: 2-Pyridylacetonitrile as a precursor to functionally substituted pyridines
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2-Pyridylacetonitrile (1) couples with aromatic diazonium salts to yield arylhydrazones 2a-c, that were shown to exist in the syn-form 2 rather than the anti-form 4. Compounds 2a,c reacted with hydroxylamine in refluxing DMF to yield the interesting 1,2,3-triazolylpyridines 6. Attempts to cyclize 2 to give the corresponding fused pyrazolopyridines 9 failed. On the other hand, compound 1 condensed with dimethylformamide dimethyl acetal to yield enaminonitrile 10 that could be converted into pyrazolylpyridine 11.
- Al-Sheikh, Mariam Abdullah,Elnagdi, Mohamed Hilmy
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experimental part
p. 4406 - 4413
(2010/04/24)
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- Microwave-assisted protocols for the expedited synthesis of pyrazolo[1,5-a] and [3,4-d]pyrimidines
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General, high-yielding MAOS protocols for the expedited synthesis of functionalized pyrazolo[1,5-a]pyrimidines and pyrazolo[3,4-b]pyrimidines, as well as their pyrazole precursors, are described amenable to an iterative analogue library synthesis strategy for lead optimization.
- Daniels, R. Nathan,Kim, Kwangho,Lebois, Evan P.,Muchalski, Hubert,Hughes, Mary,Lindsley, Craig W.
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p. 305 - 310
(2008/09/17)
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- PYRAZOLO AND IMIDAZO-PYRIMIDINE DERIVATIVES
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The present invention relates to novel pyrazolo- and imidazo-pyrimidine derivatives of formula (I) wherein A, D, E, L, M, Q, R1, R2 and R3 are as defined in the description and claims and to processes for their preparation, pharmaceutical compositions containing said derivatives and their use in the prevention and treatment of diseases.
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Page/Page column 20-21
(2008/06/13)
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- Pyrazolopyrimidines
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The invention relates to prazolopyrimidines of the formula in which R1, R2, R3, R4, R5, and X are as defined in the disclosure, to a process for preparing these compounds, and to their use for control
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Page/Page column 34
(2008/06/13)
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- Synthesis and initial SAR studies of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines: A new class of KDR kinase inhibitors
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We have synthesized and evaluated the activity of 3,6-disubstituted pyrazolo[1,5-a]pyrimidines as a new class of KDR kinase inhibitors. Starting with screening lead 1, potency against isolated KDR was fully optimized with 3-thienyl and 4-methoxyphenyl substituents at the 6- and 3-positions (3g, KDR IC50=19 nM), respectively. The synthesis and SAR of these compounds are described.
- Fraley, Mark E.,Hoffman, William F.,Rubino, Robert S.,Hungate, Randall W.,Tebben, Andrew J.,Rutledge, Ruth Z.,McFall, Rosemary C.,Huckle, William R.,Kendall, Richard L.,Coll, Kathleen E.,Thomas, Kenneth A.
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p. 2767 - 2770
(2007/10/03)
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