- A novel copper-catalyzed, hydrazine-free synthesis of N-1 unsubstituted 1H-indazoles using stable guanylhydrazone salts as substrates
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A CuI-catalyzed, hydrazine-free transformation of 2-(2-bromoarylidene)guanylhydrazone hydrochlorides using Cs2CO3 as a base and DMEDA as a ligand at 120 °C for 5 h delivers substituted 1H-indazoles with yields up to 75%. The C,N double bond configuration of the substrates was determined by NMR experiments and quantum chemical calculations. The reaction mechanism was studied using quantum chemical calculations.
- Rekowski, Szymon P.,Kroener, Bettina K.,Kathuria, Deepika,Wani, Aabid A.,Chourasiya, Sumit S.,Conrad, Jürgen,Bharatam, Prasad V.,Frey, Wolfgang,Beifuss, Uwe
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- A NaH-promoted N-detosylation reaction of diverse p-toluenesulfonamides
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A NaH-mediated detosylation reaction of various Ts-protected indoles, azaheterocycles, anilines and dibenzylamine was reported. The method features cheap reagent, convenient operations, mild reaction conditions and broad substrate scope. Moreover, this study revealed that the loading of NaH in tosylation reactions of nitrogen-containing compounds with NaH as a base in DMA or DMF should be controlled due to the possibility of adverse detosylation.
- Sun, Wanwan,Chen, Xiaobei,Hu, Ying,Geng, Huihui,Jiang, Yuanrui,Zhou, Yuxin,Zhu, Wenjing,Hu, Min,Hu, Haohua,Wang, Xingyi,Wang, Xinli,Zhang, Shilei,Hu, Yanwei
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supporting information
(2020/10/05)
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- THERAPEUTIC INDAZOLES
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The invention provides compounds of formula (I): and salts thereof wherein R1-R5 have any of the meanings described in the specification. The compounds are useful for treating bacterial infections (e.g. tuberculosis).
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Page/Page column 37-38
(2019/03/17)
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- Design, synthesis, biological evaluation and dynamics simulation of indazole derivatives with antiangiogenic and antiproliferative anticancer activity
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VEGFR-2 has a pivotal role in promoting cancer angiogenesis. Herein, two series of novel indazole-based derivatives were designed, synthesized and evaluated for their in vitro inhibitory action against VEGFR-2 kinase enzyme. The second series 11a-e exhibited better potency than the first one 7a-d and 8a-f. Compounds 11b, 11c and 11e exhibited the most potent action, with IC50 of 5.4 nM, 5.6 nM and 7 nM, respectively. As a measure of cellular VEGFR-2 inhibition, compounds 11b and 11c showed strong inhibition of human umbilical vein endothelial cells (HUVEC) proliferation with 80% and 99.6% inhibition at 10 μM concentration, respectively. Attempting to interpret SAR of the synthesized compounds, and provide a basis for further optimization; a comprehensive modeling study was implemented. Molecular docking, dynamics simulation and free energy calculation of the synthesized compounds along with known VEGFR-2 inhibitors were applied. The study illustrated the effect of several factors on VEGFR-2 inhibition, such as the interaction with solvent accessible region of the enzyme, the presence of NH linker and the degree of conformational restriction. Finally, our compounds were evaluated for their in vitro anti-proliferative effect against the full NCI panel of cancer cell lines, where compounds 11a and 11c displayed mean GI% of 93 and 130%, respectively, and showed partly a better behavior than the FDA approved drug sorafenib, with respect to activity (GI50) and safety (LC50) against several cell lines. Thus, compound 11c represents a promising candidate for cancer treatment through antiangiogenic dependent and antiangiogenic independent modes of action.
- Elsayed, Nevine M.Y.,Serya, Rabah A.T.,Tolba, Mai F.,Ahmed, Marawan,Barakat, Khaled,Abou El Ella, Dalal A.,Abouzid, Khaled A.M.
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p. 340 - 359
(2018/11/23)
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- New nitroindazolylacetonitriles: Efficient synthetic access: Via vicarious nucleophilic substitution and tautomeric switching mediated by anions
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New N-Alkyl-nitroindazolylacetonitriles were efficiently obtained via vicarious nucleophilic substitution of N-methyl-nitroindazoles with 4-chlorophenoxyacetonitrile. All compounds were fully characterized by NMR and mass spectroscopy techniques and the structures of some of them were additionally confirmed by X-ray diffraction analysis data. Tautomeric switching was observed in this series of nitroindazolylacetonitriles upon addition of basic anions followed by UV-Vis spectrophotometric and 1H-NMR titrations. The formation of tautomeric species induced by anionic species was endorsed by Density Functional Theory calculations.
- Eddahmi, Mohammed,Moura, Nuno M. M.,Bouissane, Latifa,Gamouh, Ahmed,Faustino, Maria A. F.,Cavaleiro, José A. S.,Paz, Filipe A. A.,Mendes, Ricardo F.,Lodeiro, Carlos,Santos, Sérgio M.,Neves, Maria G. P. M. S.,Rakib, El Mostapha
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p. 14355 - 14367
(2019/09/30)
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- Syntheses of 1-aryl-5-nitro-1h-indazoles and a general one-pot route to 1-aryl-1h-indazoles
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An efficient route to substituted 1-aryl-1H-indazoles has been developed and optimized. The method involved the preparation of arylhydrazones from acetophenone or benzaldehyde substituted by fluorine at C2 and nitro at C5, followed by deprotonation and nucleophilic aromatic substitution (SNAr) ring closure in 45–90%. Modification of this procedure to a one-pot domino process was successful in the acetophenone series (73–96%), while the benzaldehyde series (63–73%) required a step-wise addition of reagents. A general one-pot protocol for 1-aryl-1H-indazole formation without the limiting substitution patterns required for the SNAr cyclization has also been achieved in 62–78% yields. A selection of 1-aryl-1H-indazoles was prepared in high yield by a procedure that requires only a single laboratory operation.
- Annor-Gyamfi, Joel K.,Gnanasekaran, Krishna Kumar,Bunce, Richard A.
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- Synthesis, antifungal activity and qsar of novel pyrazole amides as succinate dehydrogenase inhibitors
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We design and synthesize a series of novel pyrazole amides based on the commercialized fungicides and our previous work. The antifungal activity was tested in vitro by mycelial growth inhibition assay. The results show that all the compounds are of antifungal activities against the tested fungi at different levels. Among them, N-(2-(7-bromo-5-chloro-1H-indazol-1-yl)phenyl)-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide (Vk) exhibited higher antifungal activity than boscalid against two fungi. Molecular docking study revealed that the carbonyl oxygen atom of Vk forms two hydrogen bonds toward the hydroxyl hydrogens of TYR58 and TRP173.
- Du, Shijie,Li, Zhonghao,Tian, Zaimin,Xu, Lu
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- Preparation method of indazole and application of indazole in medicine synthesis
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The invention belongs to the field of chemicals, and relates to a preparation method of indazole and an application of the indazole in medicine synthesis. The invention discloses a preparation method of indazole and an application of the indazole in synthesizing 1H-indazole-3-carboxylic acid, lonidamine, a compound 8, a compound 9, a compound 10, axitinib, YD-3, YC-1 and similar substances thereof.
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Paragraph 0082; 0083; 0084; 0085
(2017/04/21)
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- Copper(I) Oxide-Mediated Cyclization of o-Haloaryl N-Tosylhydrazones: Efficient Synthesis of Indazoles
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An efficient synthesis of indazoles from readily accessible E/Z mixtures of o-haloaryl N-tosylhydrazones has been developed. The thermo-induced isomerization of N-tosylhydrazones is discussed. A series of valuable indazole derivatives are prepared in good yields, and the method has been successfully applied to the synthesis of the bioactive compounds, lonidamine, AF-2785, axitinib, YC-1 and YD-3.
- Tang, Meng,Kong, Yuanfang,Chu, Bingjie,Feng, Dan
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p. 926 - 939
(2016/04/05)
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- N-indazole substituted thiourea derivatives and preparation method and application thereof
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The invention discloses N-indazole substituted thiourea derivatives and a preparation method and application thereof and belongs to the technical field of chemical medicine.The thiourea derivatives are a series of compounds simultaneously containing the 1H-indazole ring structure and the asymmetrical thiourea structure, and the compounds are not reported in the literature.The bioactivity test result analysis of the thiourea derivatives show that the compounds are good in antioxidant activity, the average scavenging rate is above 80%, the scavenging rate of the compound 12b, the compound 12c, and the compound 12d and the compound 12h is higher than 90%, the scavenging activity IC50 of the compound 12h on DPPH is 0.14mg/mL; part of the target compounds has certain inhibition activity on herpes viruses, vaccinia viruses, reoviruses, Coxsackie viruses, Feline coronary herpes viruses, HIV viruses and the like, and the compound 12c and the compound 12n are high in antivirus activity; the synthesized compounds hopefully have new bioactivity which is not expounded, and a certain material basis is provided for the development of new medicine.
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Paragraph 0074; 0075; 0076; 0080; 0081; 0082
(2016/10/09)
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- Design, synthesis and biological evaluation of indazole-pyrimidine based derivatives as anticancer agents with anti-angiogenic and antiproliferative activities
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Three series of novel indazole-pyrimidine based compounds were designed, synthesized and biologically evaluated as VEGFR-2 kinase inhibitors. The most active compound 6i (IC50 = 24.5 nM) was further evaluated against a HUVEC cell line showing an IC50 of 1.37 μM. Moreover, it showed an indirect anti-angiogenic effect through the suppression of secretion of VEGF and TGF-b1 from prostate cancer cells. Five compounds were selected by the NCI for evaluation of their in vitro anticancer activity against the full NCI panel of cell lines at 10 μM. Compounds 6e and 6f were further selected for 5-dose testing. Compound 6e exerted nanomolar GI50 values against several cell lines: CCRF-CEM (901 nM), MOLT-4 (525 nM) and CAKI-1 (992 nM) and one digit micromolar activity against the rest of the cell lines ranging from 1.05 μM to 2.41 μM. Compound 6f showed one digit micromolar activity against the whole panel of cell lines ranging from 1.55 μM to 7.4 μM. A molecular docking study was employed to investigate the predicted binding mode of the target compounds with VEGFR-2, using Autodock software. Furthermore, MD simulation was implemented for compounds 6i and 10c for further validation and rationalization of their binding mode.
- Elsayed, Nevine M. Y.,Abou El Ella, Dalal A.,Serya, Rabah A. T.,Tolba, Mai F.,Shalaby, Raed,Abouzid, Khaled A. M.
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p. 881 - 899
(2016/06/09)
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- A green and facile approach for synthesis of nitro heteroaromatics in water
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A convenient and green method for the oxidation of nitrogen-rich heterocyclic amines to nitro-substituted heteroaromatics using potassium peroxymonosulfate (2KHSO5·KHSO4·K 2SO4, Oxone) in water was developed. This method has several advantages over previous methods: operational simplicity, safety, inexpensive reagents, the use of H2O as the sole solvent, and mild conditions. The utility of the present oxidative system was demonstrated by the synthesis of the important energetic compounds 3,4,5-trinitro-1H-pyrazole (TNP) and 5-amino-3-nitro-1H-1,2,4-triazole (ANTA).
- Zhao, Xiu X.,Zhang, Ji C.,Li, Sheng H.,Yang, Qing P.,Li, Yu C.,Pang, Si P.
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p. 886 - 890
(2014/08/05)
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- A general, one-step synthesis of substituted indazoles using a flow reactor
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Flow chemistry is a rapidly emerging technology within the pharmaceutical industry, both within medicinal and development chemistry groups. The advantages of flow chemistry, increased safety, improved reproducibility, enhanced scalability, are readily apparent, and we aimed to exploit this technology in order to provide small amounts of pharmaceutically interesting fragments via a safe and scalable route, which would enable the rapid synthesis of multigram quantities on demand. Here we report a general and versatile route which utilises flow chemistry to deliver a range of known and novel indazoles, including 3-amino and 3-hydroxy analogues.
- Wheeler, Rob C.,Baxter, Emma,Campbell, Ian B.,MacDonald, Simon J. F.
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experimental part
p. 565 - 569
(2011/12/02)
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- Microwave-assisted N-Boc deprotection under mild basic conditions using K3PO4·H2O in MeOH
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A simple and efficient method for the deprotection of secondary Boc-protected amino compounds under mild basic conditions using K3PO4·H2O in MeOH assisted by microwave irradiation has been presented.
- Dandepally, Srinivasa Reddy,Williams, Alfred L.
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scheme or table
p. 1071 - 1074
(2009/05/11)
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- An efficient synthesis of 1-H indazoles
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The reaction of substituted salicyaldehydes with hydrazine hydrochloride under different conditions gave the corresponding 1-H indazoles. However, the reaction of benzaldehydes with hydrazine hydrate under the same conditions yielded only hydrazones.
- Lokhande,Raheem, Abdul,Sabale,Chabukswar,Jagdale
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p. 6890 - 6892
(2008/02/12)
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- Mild deprotection of tert-butyl carbamates of NH-heteroarenes under basic conditions
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Aqueous methanolic potassium carbonate under reflux has been demonstrated to be a highly effective deprotective agent for the tert -butyl carbamates of indoles, indazoles, carbazole, thiazoloindole, and pyrrole. The method is a mild one and is particularly expeditious for NH-heteroarenes bearing electron-withdrawing groups. Copyright Taylor & Francis Group, LLC.
- Chakrabarty, Manas,Kundu, Taraknath,Harigaya, Yoshihiro
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p. 2069 - 2077
(2007/10/03)
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- Screening for cardiovascular safety: A structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists
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An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 μM) and brain (>20 μg/g) with 15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.
- Kym, Philip R.,Souers, Andrew J.,Campbell, Thomas J.,Lynch, John K.,Judd, Andrew S.,Iyengar, Rajesh,Vasudevan, Anil,Gao, Ju,Freeman, Jennifer C.,Wodka, Dariusz,Mulhern, Mathew,Zhao, Gang,Wagaw, Seble H.,Napier, James J.,Brodjian, Sevan,Dayton, Brian D.,Reilly, Regina M.,Segreti, Jason A.,Fryer, Ryan M.,Preusser, Lee C.,Reinhart, Glenn A.,Hernandez, Lisa,Marsh, Kennan C.,Sham, Hing L.,Collins, Christine A.,Polakowski, James S.
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p. 2339 - 2352
(2007/10/03)
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- A Novel Approach to 1H-Indazoles via Arylazosulfides
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Treatment of variously substituted (o-alkylaryl)azosulfides 1a-n with potassium tert-butoxide in DMSO at room temperature smoothly furnishes 1H-indazoles 2a-n.
- Dell'Erba, Carlo,Novi, Marino,Petrillo, Giovanni,Tavani, Cinzia
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p. 3529 - 3536
(2007/10/02)
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- Phenylmercaptotetrazolo- and nitroindazolo masked development/image modifiers
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Novel nitrobenzyl compounds are incorporated into a photographic emulsion or developer for controlled release of development/image modifier compounds. This occurs imagewise only after developer oxidation products have been formed in the course of the development process. For example, nitrobenzyl-masked phenylmercaptotetrazole (PMT), incorporated into a silver halide emulsion, reacts with developer oxidation products via an electron transfer mechanism to release the potent development restrainer PMT.
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- Phase Transfer Catalyzed Synthesis of Indazoles from o-Alkylbenzenediazonium Tetrafluoroborates
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Reaction of o-methyl- and o-ethylbenzenediazonium tetrafluoroborates with two equivalents of potassium acetate and five mole percent of 18-crown-6 in ethanol-free chloroform produce indazoles in good to excellent yields.Indazoles bearing either electron-withdrawing or electron-donating substituents may be prepared.
- Bartsch, Richard A.,Yang, Il-Woo
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p. 1063 - 1064
(2007/10/02)
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