- Diversity-Oriented Synthesis of 1,2,4-Triazols, 1,3,4-Thiadiazols, and 1,3,4-Selenadiazoles from N-Tosylhydrazones
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The diversity-oriented synthesis of 1,2,4-triazols, 1,3,4-thiadiazols, and 1,3,4-selenadiazoles from N-tosylhydrazones was developed, and the reactions were general for a wide range of substrates, in which NH2CN, KOCN, KSCN, and KSeCN were used as odorless sources. Two different pathways were proposed, and N-tosylhydrazonoyl chlorides were formed in situ in the presence of NCS.
- Wei, Zeyang,Zhang, Qi,Tang, Meng,Zhang, Siyu,Zhang, Qian
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supporting information
p. 4436 - 4440
(2021/05/26)
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- NON BRAIN PENETRANT A2A INHIBITORS AND METHODS FOR USE IN THE TREATMENT OF CANCERS
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The present invention relates to compounds of Formula (I) or pharmaceutically acceptable salts thereof. The invention further relates to the use of the compounds of Formula (I) as A2A inhibitors. The invention also relates to the use of the compounds of F
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Paragraph 1688; 1690
(2020/04/24)
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- TRIAZOLOTRIAZINE DERIVATIVES AS A2A RECEPTOR ANTAGONISTS
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The present invention provides triazolotriazine derivatives of formula (1) as A2A receptor antagonists. Compounds of formula (1) and pharmaceutical compositions including the compounds can be used for the treatment of disorders related to A2A receptor hyp
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Page/Page column 16
(2020/01/24)
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- triAZOLOtriAZINE DERIVATIVES AS A2A RECEPTOR ANTAGONISTS
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The present invention provides triazolotriazine derivatives of formula (1) as A2A receptor antagonists. Compounds of formula (1) and pharmaceutical compositions including the compounds can be used for the treatment of disorders related to A2A receptor hyperfunctioning, such as certain types cancers. Compounds of formula (1) and methods of preparing the compounds are disclosed in the invention.
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Page/Page column 16
(2020/01/24)
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- A green one-pot synthesis of 3(5)-substituted 1,2,4-triazol-5(3)-amines as potential antimicrobial agents
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Abstract: An efficient procedure was proposed for the synthesis of 3(5)-substituted 1,2,4-triazol-5(3)-amines via a one-pot reaction of thiourea, dimethyl sulfate and various hydrazides. 1,2,4-Triazole derivatives were prepared in aqueous media under mild conditions while adhering to some principles of green chemistry. The products were easily isolated in 83–95% yields without any need for further purification. Inhibitory activities of all synthetic compounds were assessed against a variety of Gram-positive and Gram-negative pathogenic bacteria as well as some fungal pathogens. The best antibacterial effects were observed with 3(5)-phenyl-1H-1,2,4-triazol-5(3)-amine according to its MIC values (4–8?μg?mL?1). All compounds were successful in blocking the growth of fungi. Acceptable antioxidant properties were observed only with 3(5)-(4-nitrophenyl)-1H-1,2,4-triazol-5(3)-amine. Graphic abstract: 3(5)-Substituted 1,2,4-triazol-5(3)-amines were efficiently prepared via a one-pot reaction of thiourea, dimethyl sulfate and various hydrazides in water as the solvent. Inhibitory activity of all synthesized derivatives was proved according to their MIC, MBC and MFC values. It is found that they are potential antifungal agents.[Figure not available: see fulltext.].
- Beyzaei, Hamid,Khosravi, Zahra,Aryan, Reza,Ghasemi, Behzad
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p. 2565 - 2573
(2019/07/04)
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- 3-Aryl/Heteroaryl-5-amino-1-(3′,4′,5′-trimethoxybenzoyl)-1,2,4-triazoles as antimicrotubule agents. Design, synthesis, antiproliferative activity and inhibition of tubulin polymerization
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Many natural and synthetic substances are known to interfere with the dynamic assembly of tubulin, preventing the formation of microtubules. In our search for potent and selective antitumor agents, a novel series of 1-(3′,4′,5′-trimethoxybenzoyl)-5-amino-1,2,4-triazoles were synthesized. The compounds had different heterocycles, including thiophene, furan or the three isomeric pyridines, and they possessed a phenyl ring bearing electron-releasing or electron-withdrawing substituents at the 3-position of the 5-amino-1,2,4-triazole system. Most of the twenty-two tested compounds showed moderate to potent antiproliferative activities against a panel of solid tumor and leukemic cell lines, with four (5j, 5k, 5o and 5p) showing strong antiproliferative activity (IC50 50 values 2-100-fold lower for Jurkat and RS4;11 cells than those for the three lines derived from solid tumors (HeLa, HT-29 and MCF-7 cells). Compound 5k strongly inhibited tubulin assembly, with an IC50 value of 0.66 μM, half that obtained in simultaneous experiments with CA-4 (IC50 = 1.3 μM).
- Romagnoli, Romeo,Prencipe, Filippo,Oliva, Paola,Baraldi, Stefania,Baraldi, Pier Giovanni,Brancale, Andrea,Ferla, Salvatore,Hamel, Ernest,Bortolozzi, Roberta,Viola, Giampietro
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p. 361 - 374
(2018/07/13)
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- MULTISUBSTITUTED AROMATIC COMPOUNDS AS INHIBITORS OF THROMBIN
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There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.
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Paragraph 0319-0320
(2017/12/07)
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- KINASE INHIBITORS
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Compounds that inhibit kinase Lck or Btk, pharmaceutically acceptable salts, hydrides, stereoisomers and pharmaceutical compositions thereof are disclosed.
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Paragraph 083; 082
(2017/10/07)
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- Synthesis and structure activity relationship investigation of triazolo[1,5-a]pyrimidines as CB2 cannabinoid receptor inverse agonists
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CB2 cannabinoid receptor ligands are known to be therapeutically important for the treatment of numerous diseases. Recently, we have identified the heteroaryl-4-oxopyridine/7-oxopyrimidine derivatives as highly potent and selective CB2 receptor ligands, showing that the pharmakodynamics of the new compounds was controlled by the nature of the heterocycle core. In this paper we describe the synthesis and biological evaluation of 7-oxo-4-pentyl-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-6-carboxamide derivatives that led to the identification of novel CB2 receptor inverse agonists. Cyclic AMP experiments on CB2 receptors expressed in CHO cells revealed that introduction of structural modifications at position 2 of triazolopyrimidine template changes the functional activity from partial to inverse agonism. The molecular docking analysis of the novel structures is reported.
- Aghazadeh Tabrizi, Mojgan,Baraldi, Pier Giovanni,Ruggiero, Emanuela,Saponaro, Giulia,Baraldi, Stefania,Poli, Giulio,Tuccinardi, Tiziano,Ravani, Annalisa,Vincenzi, Fabrizio,Borea, Pier Andrea,Varani, Katia
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- An Fc–Small Molecule Conjugate for Targeted Inhibition of the Adenosine 2A Receptor
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The adenosine A2A receptor (A2AR) is expressed in immune cells, as well as brain and heart tissue, and has been intensively studied as a therapeutic target for multiple disease indications. Inhibitors of the A2AR have the
- Hsiao, Po-Yuan,Kalin, Jay H.,Sun, Im-Hong,Amin, Mohammed N.,Lo, Ying-Chun,Chiang, Meng-Jung,Giddens, John,Sysa-Shah, Polina,Gabrielson, Kathleen,Wang, Lai-Xi,Powell, Jonathan D.,Cole, Philip A.
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p. 1951 - 1960
(2016/10/24)
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- Binding kinetics of ZM241385 derivatives at the human adenosine A 2A receptor
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Classical drug design and development rely mostly on affinity- or potency-driven structure-activity relationships (SAR). Thus far, a given compound's binding kinetics have been largely ignored, the importance of which is now being increasingly recognized. In the present study, we performed an extensive structure-kinetics relationship (SKR) study in addition to a traditional SAR analysis at the adenosine A2A receptor (A 2AR). The ensemble of 24 A2AR compounds, all triazolotriazine derivatives resembling the prototypic antagonist ZM241385 (4-(2-((7-amino-2-(furan-2-yl)-[1,2,4]triazolo[1,5-a][1,3,5]triazin-5-yl)amino) ethyl)phenol), displayed only minor differences in affinity, although they varied substantially in their dissociation rates from the receptor. We believe that such a combination of SKR and SAR analyses, as we have done with the A 2AR, will have general importance for the superfamily of G protein-coupled receptors, as it can serve as a new strategy to tailor the interaction between ligand and receptor. Above and beyond: Insight into the binding kinetics of ZM241385 derivatives at the human adenosine A2A receptor has provided additional information beyond a traditional structure-activity relationship (SAR) analysis. The strategy, combining a structure-kinetics relationship investigation and SAR, can serve as an important tool for more directed medicinal chemistry efforts in the future.
- Guo, Dong,Xia, Lizi,Van Veldhoven, Jacobus P. D.,Hazeu, Marc,Mocking, Tamara,Brussee, Johannes,Ijzerman, Adriaan P.,Heitman, Laura H.
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p. 752 - 761
(2014/05/06)
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- Novel adenosine A2A receptor ligands: A synthetic, functional and computational investigation of selected literature adenosine A2A receptor antagonists for extending into extracellular space
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Growing evidence has suggested a role in targeting the adenosine A 2A receptor for the treatment of Parkinson's disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A2A receptor were synthesized and tested in a recombinant human adenosine A2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A2A receptor antagonists, and assessed their potential binding modes using molecular docking studies. The results suggest that linking from the phenolic oxygen of selected adenosine A2A receptor antagonists is relatively well tolerated due to the extension towards extracellular space, and leads to the potential of attaching further functionality from this position.
- J?rg, Manuela,Shonberg, Jeremy,Mak, Frankie S.,Miller, Neil D.,Yuriev, Elizabeth,Scammells, Peter J.,Capuano, Ben
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supporting information
p. 3427 - 3433
(2013/06/26)
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- Synthesis, molecular structure, NMR spectroscopic and computational analysis of a selective adenosine A2A antagonist, ZM 241385
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Herein, we describe the synthesis of the adenosine A2A antagonist ZM 241385 (9) starting from commercially available 2-furanhydrazide (1) and including a comprehensive structural characterization of all the intermediates and the final product.
- Joerg, Manuela,Agostino, Mark,Yuriev, Elizabeth,Mak, Frankie S.,Miller, Neil D.,White, Jonathan M.,Scammells, Peter J.,Capuano, Ben
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p. 1241 - 1251
(2013/08/23)
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- MULTISUBSTITUTED AROMATIC COMPOUNDS AS INHIBITORS OF THROMBIN
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There are provided inter alia multisubstituted aromatic compounds useful for the inhibition of thrombin, which compounds include substituted pyrazolyl or substituted triazolyl. There are additionally provided pharmaceutical compositions. There are additionally provided methods of treating and preventing a disease or disorder, which disease or disorder is amenable to treatment or prevention by the inhibition of thrombin.
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Page/Page column 83
(2011/10/31)
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- Synthesis of amino-1,2,4-triazoles by reductive ANRORC rearrangements of 1,2,4-oxadiazoles
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The reaction of various 1,2,4-oxadiazoles with an excess of hydrazine in DMF has been investigated. 3-Amino-1,2,4-triazoles are produced through a reductive ANRORC pathway consisting of the addition of hydrazine to the 1,2,4-oxadiazole followed by ring-opening, ring-closure, and final reduction of the 3-hydroxylamino-1,2,4-triazole intermediate. The general applicability of 1,2,4-oxadiazoles ANRORC reactivity is demonstrated also in the absence of C(5)-linked electron-withdrawing groups.
- Palumbo Piccionello, Antonio,Guarcello, Annalisa,Buscemi, Silvestre,Vivona, Nicolo,Pace, Andrea
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p. 8724 - 8727
(2011/03/19)
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- An aqueous medium synthesis and tautomerism study of 3(5)-amino-1,2,4-triazoles
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A catalyst-free highly efficient synthesis of 3(5)-amino-5(3)-(het)aryl-1,2,4-triazoles in aqueous medium was performed using conventional heating and microwave irradiation. The tautomerism in the products was investigated using NMR spectroscopy and X-ray crystallography. The effects of the substitution, temperature, solvents, and concentration on the tautomerism were studied. The triazoles were found to exist in 1H-forms, the 4H-form was not observed either in solid state or in solution. In general, 5-amino-1,2,4-triazoles were electronically preferred in the tautomeric equilibrium, but some exceptions from the established relationship were also identified.
- Dolzhenko, Anton V.,Pastorin, Giorgia,Dolzhenko, Anna V.,Chui, Wai Keung
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experimental part
p. 2124 - 2128
(2009/07/26)
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- Synthesis and pharmacological activity of triazolo[1,5-α]triazine derivatives inhibiting eosinophilia
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In continuation of our previous work on eosinophilia inhibitors, we synthesized an additional series of inhibitors, which consisted of 5-amino- 1-[(methylamino)thiocarbonyl]-1H-1,2,4-triazole derivatives and a newly developed series of 1,2,4-triazolo[1,5-
- Akahoshi, Fumihiko,Takeda, Shinji,Okada, Takehiro,Kajii, Masahiko,Nishimura, Hiroko,Sugiura, Masanori,Inoue, Yoshihisa,Fukaya, Chikara,Naito, Youichiro,Imagawa, Takashi,Nakamura, Norifumi
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p. 2985 - 2993
(2007/10/03)
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- Triazole derivative and pharmaceutical use thereof
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An agent for the prophylaxis and treatment of immune-related diseases, in particular, immunosuppressant, an agent for the prophylaxis and treatment of allergic diseases, an agent for the prophylaxis and treatment of eosinophil-related diseases and an eosinophilia inhibitor, comprising, as an active ingredient, a series of triazole derivatives of the following formula (I) STR1 or the following formula (III) STR2 wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof. A novel monocyclic or bicyclic triazole derivative. The agent for the prophylaxis and treatment of immune-related diseases, in particular, immunosuppressant, the agent for the prophylaxis and treatment of allergic diseases, the agent for the prophylaxis and treatment of eosinophil-related diseases, the eosinophilia inhibitor and the novel triazole derivative of the present invention all, have superior eosinophilia-inhibitory action and lymphocyte activation-inhibitory action. They are low toxic and persistent in action. They are particularly effective in the treatment of accumulation and activation of eosinophil and lymphocytes, inflammatory respiratory tract diseases, eosinophil-related diseases such as eosinophilia, and immune-related diseases.
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- Studies in antiparasitic agents: Part 24 - Synthesis of 5-(2-furyl)-2-substituted-amino-1,3,4-triazoles and substituted 1,3,4-triazolo-pyrimidines as potential antifilarial and leishmanicidal agents
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A series of 5-(2-furyl)-2-substituted-amino-1,3,4-triazoles (3-5) and 2-(2-furyl)-1,3,4-triazolopyrimidines (6, 9-19) have been synthesized as possible inhibitors of antioxidant enzymes in filariids and leishmanial parasites.All the compounds have been evaluated for their antifilarial and antileishmanial activities.The antifilarial activity has been evaluated against Litomosoides carinii infection in cotton rats while the in vitro leishmanicidal activity determined using macrophage amastigote culture isolated from cotton rats infected with Leishmania donovani.In both the tests none of the compounds exhibits any noteworthy antiparasitic activity.
- Srivastava, Ravi P.,Kumar, Versha V.,Bhatia, Sonika,Sharma, Satyavan
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p. 209 - 214
(2007/10/02)
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- 2-furyl-triazalo [1,5-a]-[1,3,5]triazines and pyrazolo [2,3-a][1,3,5]triazines
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Compounds of the formula I: STR1 wherein: X is O, S or NH;n is O or an integer of from 1 to 3;R 1 is hydrogen, (1-6C)alkyl, or (1-4C)alkanoyl;R 2 is CH 2 R 3, NHR 4, SO 2 NR 5 YNR 6 R 7 or R 8, in which R 3 is hydroxy, (1-4C)alkoxy or (1-4C)alkylsulphonyl
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- Adenine isosteres with bridgehead nitrogen. Part 1. Two independent syntheses of the triazolotriazine ring system leading to a range of substituents in the 2, 5 and 7 positions
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Condensation of a 3-substituted 5-amino-1,2,4-triazole with an N-cyanocarbonimidate (RX)2C=NCN, yields the title compounds, in most cases as a mixture of isomers; separation and elaboration then gives triazolotriazines bearing a range
- Caulkett, Peter W. R.,Jones, Geraint,McPartlin, Mary,Renshaw, Nigel D.,Stewart, Sarah K.,Wright, Brian
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p. 801 - 808
(2007/10/02)
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- Azole derivatives
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A compound of the formula I STR1 wherein: R 1 is hydrogen, (1-6C)alkyl, or (1-4C)alkanoyl;R 2 is phenyl, a C-linked aromatic 5- or 6-membered heterocyclic ring containing one of oxygen and sulphur and/or one or two nitrogen, or (1-8C)alkyl, alkenyl or alkynyl unsubstituted or substituted by a phenyl or a C-linked aromatic 5- or 6-membered heterocylic ring containing one of oxygen and sulphur and/or one or two nitrogen, any phenyl being unsubstituted or substituted by one, two or three of (1-4C)alkyl, (1-4C)alkoxy, halogen, trifluoromethyl, hydroxy, benzyloxy and (1-5C)alkanoyloxy;A is N or CT in which T is hydrogen or (1-4C)alkyl;or a pharmaceutically acceptable salt thereof, processes for the manufacture of the compounds, and pharmaceutical compositions containing them. The compounds are useful as adenosine antagonists.
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- [1,2,4]-Triazolo[1,5-a]and pyrazolo[2,3-a][1,3,5]triazine derivatives
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The invention concerns novel, pharmaceutically useful compounds of formula I in which Q is a 5-membered heteroaryl optionally bearing 1 or 2 substituents independently selected from (1-4C)alkyl and halogeno; R1 is hydrogen, (1-6C)alkyl, or (1-4
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- Heterocyclic compounds
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A compound of the formula I STR1 wherein: A 1 and A 2 are each independently N or CT in which T is hydrogen or (1-4C)alkyl;R 1 and R 2 are each independently hydrogen, (1-6C)alkyl, or (1-4C)alkanoyl;X 1 and X 2 are each independently O, S or NH; andL is a
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