Synthesis of pyrazolo[3,4‐d]pyrimidine derivatives using ketene dithioacetals
TL;DR: The cyclization of 5-amino-3-methylthiopyrazole-4-carbonitriles or 4-carboxamides 3a-j, which were prepared by the reaction of ketene dithioacetals with formamide or carbon disulfide, was described in this article.
About: This article is published in Journal of Heterocyclic Chemistry.The article was published on 1990-03-01. It has received 93 citations till now. The article focuses on the topics: Ketene & Phenylhydrazine.
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TL;DR: Harmine has been identified as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro and the results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes.
Abstract: The specificities of 65 compounds reported to be relatively specific inhibitors of protein kinases have been profiled against a panel of 70-80 protein kinases. On the basis of this information, the effects of compounds that we have studied in cells and other data in the literature, we recommend the use of the following small-molecule inhibitors: SB 203580/SB202190 and BIRB 0796 to be used in parallel to assess the physiological roles of p38 MAPK (mitogen-activated protein kinase) isoforms, PI-103 and wortmannin to be used in parallel to inhibit phosphatidylinositol (phosphoinositide) 3-kinases, PP1 or PP2 to be used in parallel with Src-I1 (Src inhibitor-1) to inhibit Src family members; PD 184352 or PD 0325901 to inhibit MKK1 (MAPK kinase-1) or MKK1 plus MKK5, Akt-I-1/2 to inhibit the activation of PKB (protein kinase B/Akt), rapamycin to inhibit TORC1 [mTOR (mammalian target of rapamycin)-raptor (regulatory associated protein of mTOR) complex], CT 99021 to inhibit GSK3 (glycogen synthase kinase 3), BI-D1870 and SL0101 or FMK (fluoromethylketone) to be used in parallel to inhibit RSK (ribosomal S6 kinase), D4476 to inhibit CK1 (casein kinase 1), VX680 to inhibit Aurora kinases, and roscovitine as a pan-CDK (cyclin-dependent kinase) inhibitor. We have also identified harmine as a potent and specific inhibitor of DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) in vitro. The results have further emphasized the need for considerable caution in using small-molecule inhibitors of protein kinases to assess the physiological roles of these enzymes. Despite being used widely, many of the compounds that we analysed were too non-specific for useful conclusions to be made, other than to exclude the involvement of particular protein kinases in cellular processes.
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Patent•
04 Nov 2010TL;DR: In this paper, compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described to treat diseases and conditions, including diseases associated with activity of B-Raf V600E mutant protein kinase.
Abstract: Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on at least one Raf protein kinase. In certain aspects and embodiments, the described compounds are active in inhibiting proliferation of a Ras mutant cell line. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of B-Raf V600E mutant protein kinase, including melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, biliary tract cancer, and cholangiocarcinoma. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of c-Raf-1 protein kinase, including acute pain, chronic pain or polycystic kidney disease.
322 citations
TL;DR: Protein Kinase Inhibitors: An Old Scaffold As a New Tool for Medicinal Chemistry and Chemical Biology Studies
Abstract: Protein Kinase Inhibitors: An Old Scaffold As a New Tool for Medicinal Chemistry and Chemical Biology Studies Silvia Schenone,*,† Marco Radi,‡ Francesca Musumeci,† Chiara Brullo,† and Maurizio Botta †Dipartimento di Farmacia, Universita ̀ degli Studi di Genova Viale Benedetto XV, 3, 16132 Genova, Italy ‡Dipartimento di Farmacia, Universita ̀ degli Studi di Parma Viale delle Scienze, 27/A, 43124 Parma, Italy Dipartimento di Biotecnologie, Chimica e Farmacia, Universita ̀ degli Studi di Siena Via Aldo Moro, 2, 53100 Siena, Italy Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Building, Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania 19122, United States
105 citations
TL;DR: New 5-aminopyrazoles 2a-c were prepared in high yields from the reaction of known α,α-dicyanoketene-N,S-acetal with hydrazine hydrate under reflux in ethanol, and the antibacterial activity and cytotoxicity against Vero cells of several selected compounds are reported.
93 citations
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TL;DR: Substituierte Ketenmercaptale reagieren mit aromatischen und aliphatischen Aminen and Diaminen zu Keten-S.1.3.
Abstract: Substituierte Ketenmercaptale reagieren mit aromatischen und aliphatischen Aminen und Diaminen zu Keten-S.N-acetalen und Ketenaminalen; mit prim. heterocyclischen Aminen entstehen kondensierte Pyrimidine. Die Umsetzung mit β-Dicarbonylverbindungen fuhrt zu stark sauren 1.1.3.3-tetrasubstituierten 2-Alkylmercapto-propenen(1); mit 3-Amino-1-phenyl-pyrazolon-(5) erfolgt Ringschlus zu einem Pyrasolo[3.4-b]pyridin. Die N-Aryl-keten-S.N-acetale lassen sich zu Chinolinen cyclisieren.
96 citations
TL;DR: In this paper, les recents developpements dans la synthese heterocyclique a l'aide du dimethylacetal du nitrothiocetene (A), resultats des reactions de A avec les composes suivants: amines, composes a methylene actif, ylures d'azomethine, iminiums, enamines; reactions de derives substitues de A
82 citations