- Synthesis of monosubstituted 1,2,4,5-tetrazines –3-amino-1,2,4,5-tetrazines
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The substitution of pyrazolyl moiety in 3-(3,5-dimethyl-1H-pyrazol-1-yl)-1,2,4,5-tetrazine with N-nucleophiles provided a series of highnitrogen tetrazine derivatives, including 2-nitro-1-(1,2,4,5-tetrazin-3-yl)guanidine, N-(1H-tetrazol-5-yl)-1,2,4,5-tetrazin-3-amine, N-(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazin-3-amine, N,N'-di(1,2,4,5-tetrazin-3-yl)-1,2,4,5-tetrazine-3,6-diamine, N-(1,2,4,5-tetrazin-3-yl)- [1,2,4]triazolo[4,3-b][1,2,4,5]tetrazin-6-amine, and tritetrazinylamine. The thermal stability of these new compounds was evaluated by differential scanning calorimetry and their energetic characteristics were calculated.
- Rudakov, Gennady F.,Moiseenko, Yurii A.,Spesivtseva, Natal'ya А.
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- The 'inverse electron-demand' Diels-Alder reaction in polymer synthesis. Part 4.1 the preparation and crystal structures of some bis(1,2,4,5-tetrazines)
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Reaction of 3,6-bis(3,5-dimethylpyrazolyl)-1,2,4,5-tetrazine with mono- and di-amines gives rise to nucleophilic substitution of one or both of the pyrazolyl substituents, and reaction with diamines under appropriate conditions can lead to bis(3-amino-1,2
- Glidewell, Christopher,Lightfoot, Philip,Royles, Brodyck J. L.,Smith, David M.
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- Improved Synthesis and Thermochemical Properties of Amino- and Hydrazino-1,2,4,5-Tetrazines
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[Figure not available: see fulltext.] Improved protocols for the synthesis of 3,6-diamino- and 3,6-dihydrazino-1,2,4,5-tetrazines as well as 6-amino[1,2,4]triazolo[4,3-b]-[1,2,4,5]tetrazine were developed. Combustion energies were determined by the bomb calorimetry and the enthalpies of formation in the standard state were calculated for the compounds of this study. Based on the obtained data, the contribution of the 1,2,4,5-tetrazine moiety to the enthalpy of combustion of its derivatives was estimated.
- Kon’kova, Tat’yana S.,Matyushin, Yurii N.,Miroshnichenko, Evgeniy А.,Palysaeva, Nadezhda V.,Sheremetev, Aleksei B.
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- COMPOSITIONS AND METHODS FOR DELIVERING A SUBSTANCE TO A BIOLOGICAL TARGET
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The present application provides compositions and methods using bioorthogonal inverse electron demand Diels-Alder cycloaddition reaction for rapid and specific covalent delivery of a payload to a ligand bound to a biological target.
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Paragraph 0105
(2020/03/26)
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- Selective N1/N4 1,4-Cycloaddition of 1,2,4,5-Tetrazines Enabled by Solvent Hydrogen Bonding
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An unprecedented 1,4-cycloaddition (vs 3,6-cycloaddition) of 1,2,4,5-tetrazines is described with preformed or in situ generated aryl-conjugated enamines promoted by the solvent hydrogen bonding of hexafluoroisopropanol (HFIP) that is conducted under mild reaction conditions (0.1 M HFIP, 25 °C, 12 h). The reaction constitutes a formal [4 + 2] cycloaddition across the two nitrogen atoms (N1/N4) of the 1,2,4,5-tetrazine followed by a formal retro [4 + 2] cycloaddition loss of a nitrile and aromatization to generate a 1,2,4-triazine derivative. The factors that impact the remarkable change in the reaction mode, optimization of reaction parameters, the scope and simplification of its implementation through in situ enamine generation from aldehydes and ketones, the reaction scope for 3,6-bis(thiomethyl)-1,2,4,5-tetrazine, a survey of participating 1,2,4,5-tetrazines, and key mechanistic insights into this reaction are detailed. Given its simplicity and breath, the study establishes a novel method for the simple and efficient one-step synthesis of 1,2,4-triazines under mild conditions from readily accessible starting materials. Whereas alternative protic solvents (e.g., MeOH vs HFIP) provide products of the conventional 3,6-cycoladdition, the enhanced hydrogen bonding capability of HFIP uniquely results in promotion of the unprecedented formal 1,4-cycloaddition. As such, the studies represent an example of not just an enhancement in the rate or efficiency of a heterocyclic azadiene cycloaddition by hydrogen bonding catalysis but also the first to alter the mode (N1/N4 vs C3/C6) of cycloaddition.
- Zhu, Zixi,Glinkerman, Christopher M.,Boger, Dale L.
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supporting information
p. 20778 - 20787
(2020/12/22)
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- HETEROARYL DERIVATIVES OF FORMULA (I) AS ATF4 INHIBITORS
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The invention is directed to substituted heteroaryl derivatives. Specifically, the invention is directed to compounds according to Formula (I) wherein A, C, D, L2, L3, R1, R2, R3, R4, R 5, R6, z2, z4, z5, and z6 are as defined herein; or salts thereof. The compounds of the invention are inhibitors of the ATF4 pathway and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
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Page/Page column 107-108
(2019/10/29)
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- An Improved Synthesis of 3,6-Diamino-1,2,4,5-tetrazine. II. From Triaminoquanidine and 2,4-Pentanedione
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A new synthesis for the title compound that gives an 80percent overall yield was developed.Treatment of triaminoguanidine monohydrochloride (1) with 2,4-pentanedione (2) gave 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2-dihydro-1,2,4,5-tetrazine (3) in 80-85percent yield.Oxidation of 3 with nitric oxide or nitrogen dioxide to 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (4) followed by ammonolysis of 4 gave 3,6-diamino-1,2,4,5-tetrazine (5) in quantitatively yields
- Coburn, M.D.,Buntain, G.A.,Harris, B.W.,Hiskey, M.A.,Lee, K.-Y.,Ott, D.G.
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p. 2049 - 2050
(2007/10/02)
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- An Improved Synthesis of 3,6-Diamino-1,2,4,5-tetrazine. I
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Treatment of 1,3-diaminoguanidine monohydrochloride (1) with 2,4-pentanedione (2) in alcohols under carefully controlled conditions gave 3,6-diamino-1,2-dihydro-1,2,4,5-tetrazine monohydrochloride (3) in 45-50percent yields along with 3,5-dimethyl-1H-pyrazole (4) and its hydrochloride 5.Oxidation of 3 with sodium perborate produced 3,6-diamino-1,2,4,5-tetrazine (6) in quantitative yield.
- Coburn, Michael D.,Ott, Donald G.
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p. 1941 - 1945
(2007/10/02)
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- Radical Cations and Anions of 1,2,4,5-Tetrazines: an Electron Spin Resonance and Cyclic Voltammetric Study
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Exposure to (60)Co γ-ray of dilute solutions of a range of s-tetrazines in fluorotrichloromethane at 77 K gave the corresponding radical cations, identified by their e.s.r. spectra.Two distinct types of spectra were obtained, one showing large hyperfine coupling to four equivalent (14)N nuclei is assigned to n(?)-radical cations, and the other, only found for -NR2 substituents, with strong coupling to two nitrogen nuclei, is assigned to ?-radical cations.The former include the parent s-tetrazine and the 3,6-dimethyl, -diphenyl, dichloro, dimethoxy, bis(methylthio), and di(aziridin-1-yl) derivatives.The latter were also prepared in fluid solution, and showed reversible behaviour in their cyclic voltammograms, in contrast with the former group.The corresponding radical anions have been studied in both fluid and solid solution, all derivatives showing major hyperfine coupling to the four ring (14)N nuclei.Total spin densities have been estimated for both types of radical cations and for the radical anions, and in all cases the total is in the 1.05-1.2 range.This deviation from unity is interpreted in terms of spin polarisation giving rise to considerable negative spin densities.
- Fischer, Hans,Mueller, Thomas,Umminger, Irmgard,Neugebauer, Franz A.,Chandra, Harish,Symons, Martyn C. R.
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p. 413 - 422
(2007/10/02)
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