119-39-1Relevant articles and documents
Identification of the decomposition products of hydralazine hydrazones with three endogenous ketones and kinetic study of the formation of 3-methyl-8-triazolo[3,4-a]phthalazine from hydralazine and pyruvic acid
Nakano,Tomitsuka,Juni
, p. 3407 - 3411 (1980)
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Hirsch,Orphanos
, p. 1551,1554 (1966)
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Inhibitory effects of drugs on the metabolic activity of mouse and human aldehyde oxidases and influence on drug–drug interactions
Takaoka, Naoki,Sanoh, Seigo,Okuda, Katsuhiro,Kotake, Yaichiro,Sugahara, Go,Yanagi, Ami,Ishida, Yuji,Tateno, Chise,Tayama, Yoshitaka,Sugihara, Kazumi,Kitamura, Shigeyuki,Kurosaki, Mami,Terao, Mineko,Garattini, Enrico,Ohta, Shigeru
, p. 28 - 38 (2018)
As aldehyde oxidase (AOX) plays an emerging role in drug metabolism, understanding its significance for drug–drug interactions (DDI) is important. Therefore, we tested 10 compounds for species-specific and substrate-dependent differences in the inhibitory effect of AOX activity using genetically engineered HEK293 cells over-expressing human AOX1, mouse AOX1 or mouse AOX3. The IC50 values of 10 potential inhibitors of the three AOX enzymes were determined using phthalazine and O6-benzylguanine as substrates. 17β-Estradiol, menadione, norharmane and raloxifene exhibited marked differences in inhibitory effects between the human and mouse AOX isoforms when the phthalazine substrate was used. Some of the compounds tested exhibited substrate-dependent differences in their inhibitory effects. Docking simulations with human AOX1 and mouse AOX3 were conducted for six representative inhibitors. The rank order of the minimum binding energy reflected the order of the corresponding IC50 values. We also evaluated the potential DDI between an AOX substrate (O6-benzylguanine) and an inhibitor (hydralazine) using chimeric mice with humanized livers. Pretreatment of hydralazine increased the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0–24) of O6-benzylguanine compared to single administration. Our in vitro data indicate species-specific and substrate-dependent differences in the inhibitory effects on AOX activity. Our in vivo data demonstrate the existence of a DDI which may be of relevance in the clinical context.
Synthesis of 4-Substituted Phthalazin-1(2H)-ones from 2-Acylbenzoic Acids: Controlling Hydrazine in a Pharmaceutical Intermediate through PAT-Guided Process Development
Mennen, Steven M.,Mak-Jurkauskas, Melody L.,Bio, Matthew M.,Hollis, L. Steven,Nadeau, Kelly A.,Clausen, Andrew M.,Hansen, Karl B.
, p. 884 - 891 (2015)
A simple one-pot, two-step process for the conversion of 2-acylbenzoic acids to phthalazin-1(2H)-ones was developed. A robust process was required that delivered the final isolated solid with consistently low levels of residual hydrazine, for further processing to the final drug substance. An in situ formed intermediate was critical to control reactivity and allowed for the controlled crystallization that prevented entrainment of hydrazine. Leveraging Process Analytical Technology (PAT), we investigated the reaction profile with in situ IR and Power Compensation Calorimetry (PCC) to aid development prior to a successful scale-up.
Antituberclous compounds. XXVII. Synthesis of 7,8-dihydropyrido-[2.3-d]pyridazin-(6H)-one.
Kakimoto,Tonooka
, p. 2996 - 2997 (1969)
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Synthesis and Investigation of Phthalazinones as Antitubercular Agents
Santoso, Kristiana T.,Cheung, Chen-Yi,Hards, Kiel,Cook, Gregory M.,Stocker, Bridget L.,Timmer, Mattie S. M.
supporting information, p. 1278 - 1285 (2019/02/24)
A series of 2- and 7-substituted phthalazinones was synthesised and their potential as anti-tubercular drugs assessed via Mycobacterium tuberculosis (mc26230) growth inhibition assays. All phthalazinones tested showed growth inhibitory activity (MIC 100 μm), and those compounds containing lipophilic and electron-withdrawing groups generally exhibited better anti-tubercular activity. Several lead compounds were identified, including 7-((2-amino-6-(4-fluorophenyl)pyrimidin-4-yl)amino)-2-heptylphthalazin-1(2H)-one (MIC=1.6 μm), 4-tertbutylphthalazin-2(1H)-one (MIC=3 μm), and 7-nitro-phthalazin-1(2H)-one (MIC=3 μm). Mode of action studies indicated that selected pyrimidinyl-phthalazinones may interfere with NADH oxidation, however, the mode of action of the lead compound is independent of this enzyme. MIC=minimum inhibitory concentration.
Design and synthesis of phthalazine-based compounds as potent anticancer agents with potential antiangiogenic activity via VEGFR-2 inhibition
Elmeligie, Salwa,Aboul-Magd, Asmaa M.,Lasheen, Deena S.,Ibrahim, Tamer M.,Abdelghany, Tamer M.,Khojah, Sohair M.,Abouzid, Khaled A. M.
, p. 1347 - 1367 (2019/07/29)
In the designed compounds, either a biarylamide or biarylurea moiety or an N-substituted piperazine motif was linked to position 1 of the phthalazine core. The anti-proliferative activity of the synthesised compounds revealed that eight compounds (6b, 6e, 7b, 13a, 13c, 16a, 16d and 17a) exhibited excellent broad spectrum cytotoxic activity in NCI 5-log dose assays against the full 60 cell panel with GI50 values ranging from 0.15 to 8.41 μM. Moreover, the enzymatic assessment of the synthesised compounds against VEGFR-2 tyrosine kinase showed the significant inhibitory activities of the biarylureas (12b, 12c and 13c) with IC50s of 4.4, 2.7 and 2.5 μM, respectively, and with 79.83, 72.58 and 71.6% inhibition of HUVEC at 10 μM, respectively. Additionally, compounds (7b, 13c and 16a) were found to induce cell cycle arrest at S phase boundary. Compound 7b triggered a concurrent increase in cleaved caspase-3 expression level, indicating the apoptotic-induced cell death.
A paclitaxel and to phenyl phthalazine ketone BTK inhibitor combination pharmaceutical composition and its application
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, (2019/03/23)
The present invention provides a kind of paclitaxel and to phenyl phthalazine ketone BTK inhibitor combination pharmaceutical composition comprising an active ingredient and a pharmaceutically acceptable auxiliary material, wherein the active ingredient by the taxol of formula (I) of a BTK inhibitors shown, the active ingredient of taxol in the formula (I) indicated by the molar ratio of BTK inhibitors (0.14 - 0.20): 1. The pharmaceutical composition can be used for preparing the prevention and/or treating the Bruton tyrosine kinase-related disease drug, the treatment effect is good.