Pyridazine Research Articles

The organization of pyridazine adsorbed on Au(1 1 1) electrode in sulfuric and perchloric acids – As probed by in situ STM

The adsorption of pyridazine (PD) on a gold electrode served as a model to study the orientation and arrangement of an organic adsorbate bearing a heterocyclic molecular structure at an electrified interface. Because the two N-ends of PD could interact with a Au electrode, the acid-base equilibrium of PD at an electrified interface can be different from that in a solution phase. Unprotonated and protonated PD interacted with the Au electrode differently, leading to dissimilar spatial structures on the Au(111) electrode. Moreover, having a large dipole moment of 4.22 D, PD adopted different adsorption configurations, as the Au potential was modulated. The indispensable anion present in the supporting electrolyte can compete with PD for surface sites on the Au electrode. Since the potential of a charged conductor is established by the physical contact with an electrolyte, the study of the adsorption of PD on a Au(111) electrode calls for the use of an in situ tool, such as a scanning tunneling microscope (STM), which provides sub-nanometer information of the interface in real-time and real-space. Different phases of adsorbed PD molecules on an ordered Au(111) electrode were revealed as a function of potential, pH and anion. The most notable event for PD adsorbed on Au(111) is attributed to the sharp transition from a disordered state to highly organized structures in 0.1 M H2SO4 and HClO4. The obtained STM images enabled a direct measurement of the spacing between PD admolecules, from which the molecular reorientations on the Au electrode were inferred. PD admolecules flipped from the horizontal to the upright configuration, tethered to Au substrate via the two N-ends, at positive potentials. Different ordered PD structures seen in H2SO4 and HClO4 imply anions were coadsorbed with PD molecule on the Au electrode. The acid-base equilibrium of PD at the Au electrode was examined with STM in pH 1 and 3 media.

Comparison of 18F-Flurpiridaz and 13N-NH3·H2O PET/CT myocardial perfusion imaging in animal experiments

Objective To explore the biodistribution and quantitative value of 18F-Flurpiridaz in mini-swine, and compare with 13N-NH3·H2O. Methods Ten Bama mini-swine were divided into normal group and myocardial infarction group (n=5 in each group). Normal group was not treated and myocardial infarction group was modeled by thoracotomy and coronary artery ligation. Both groups were preceded by 13N-NH3·H2O imaging, followed by 18F-Flurpiridaz imaging (time interval >40 min). Injection dosage of 2 tracers was the same (185-370 MBq). 18F-Flurpiridaz whole-body PET/CT imaging was also performed in normal group. Biological distribution of 18F-Flurpiridaz was observed, and the ratio of radioactive uptake of 18F-Flurpiridaz between myocardium and adjacent tissues or organs was calculated. Image quality score and rest myocardial blood flow (rMBF) of 2 imaging tracers in normal group were measured and compared. MPI image quality score, cardiac function parameters such as summed rest score (SRS), myocardial infarction area percentage, total perfusion defect (TPD), and left ventricular ejection fraction (LVEF) of 2 imaging tracers were compared in myocardial infarction group. Data was analyzed by paired t test. Results In normal group, 18F-Flurpiridaz in the myocardium was clearly observed, with high radioactive uptake maintaining within 2 h postinjection. The radioactivity count ratios of left ventricular myocardium to cardiac pool, the lungs and liver were high (5.19-12.87, 4.17-50.51, 2.08-6.92). The quality of 18F-Flurpiridaz MPI images in both groups was excellent (10/10). The rMBF (ml·g-1·min-1) in different regions of left ventricle measured by 18F-Flurpiridaz and 13N-NH3·H2O imaging were not significantly different (left anterior descending: 0.98±0.06 vs 0.92±0.13; left circumflex: 0.98±0.05 vs 0.88±0.12; right coronary artery: 0.95±0.07 vs 0.88±0.15; left ventricle: 0.96±0.07 vs 0.90±0.13; t values: from -1.70 to -0.90, all P>0.05). There was no significant difference in SRS, myocardial infarction area percentage, TPD, rMBF or LVEF between 18F-Flurpiridaz and 13N-NH3·H2O (SRS: 10.6±4.1 vs 9.2±4.6; myocardial infarction area percentage: (15.2±9.0)% vs (12.6±6.6)%; TPD: (11.6±6.3)% vs (9.6±3.9)%; LVEF: (68.6±11.1)% vs (71.4±11.3)%; t values: -2.33-2.75, all P>0.05). Conclusions Comparing with 13N-NH3·H2O, 18F-Flurpiridaz has the advantages of good MPI image quality, accurate measurement of cardiac function parameters and quantitative potential of myocardial blood flow, which make it as a promising positron myocardial perfusion imaging agent. Key words: Myocardial perfusion imaging; Pyridazines; Fluorine radioisotopes; Ammonia; Positron-emission tomography; Tomography, X-ray computed; Swine

The coordinative flexibility of rigid phenanthroline-analogous di(NHC)-ligands

Abstract In 2010 we have introduced a new N-N connected 1,4-dicarbene ligand named ‘vegi’ based on an imidazo-anellated pyridazine (Kunz et al., 2010) [1]. Although the tricyclic ligand resembles 1,10-phenanthroline, the dicarbene ligand turned out to be much more flexible. It can serve as a chelating as well as a bridging ligand. In addition, the electronic properties (strongly electron-donating) are distinct from 1,10-phenanthroline or 2,2′-bipyridine. This review comprises the synthesis, electronic properties, the coordination chemistry as well as the reactivity of this remarkable ligand and its complexes.

Synthesis of Novel Polyazinyl-Substituted Triazolopyridines from [1,2,3]Triazolo[1,5-a]pyridines

A series of 7-azinyl-substituted triazolopyridines and 3-(6-azi­nyl-substituted 2-pyridyl)triazolopyridines were synthesized by addition of the corresponding 3-substituted 7-lithiotriazolopyridine to pyrimidine, pyrazine, pyridazine, and 1,3,5-triazine respectively, followed by hydrolysis and oxidation.

Synthesis, chemical behavior, structure elucidation and iNOS inhibitory activity of 1-substituted 3-methylsulfanyl-5,6,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazines.

Novel slim and shapely sp3-rich nitrogen containing heterocyclic ring systems are sought-after platforms for the expansion of molecular diversity in lead discovery. The present work describes the synthesis and characterization of a series of derivatives of hitherto unknown 3-methylsulfanyl-5,6,7,8-tetrahydro-1H-[1,2,4]triazolo[1,2-a]pyridazines 2. This approach was guided by a computational study, aiming at an optimization of previously reported [1,2,4]triazolo[1,2-a]pyridazine-1-thiones 1 known to inhibit the inducible nitric oxide synthase (iNOS). The title compounds are accessible by methylation of compounds 1 under mild conditions. The products were biologically evaluated by the same cell-based assay as applied for previous products of type 1 using RINm5F cells, which were stimulated to produce NO on the influence of proinflammatory cytokines IL-1β and IFN-γ. Compounds 2 did not display the anticipated improved iNOS inhibitory activity in the selected assay but contribute to SAR in the field. In addition, an unprecedented formation of side-products 3 via oxidation has been investigated. The novel scaffolds represent attractive starting points for the construction of diverse molecules which differ considerably from known compounds based on flat and lipophilic aromatic scaffolds.

Synthesis of Some Pyridazine Based Pyrazolines

Synthesis of Some Pyridazine Based Pyrazolines

A novel method for the synthesis of imidazo[1,5- b ]pyridazines

Condensation of 4-phenylimidazole-1,2-diamine with 1-aryl-3-(dimethylamino)-2-propen-1-ones leads to the formation of 4-aryl-5phenylimidazo[1,5- b ]pyridazin-7-amines, which smoothly react at the exocyclic amino group with acetic anhydride, phenyl isocyanate, and para-tolualdehyde. How to Cite Vandyshev, D. Yu.; Shikhaliyev, Kh. S.; Potapov, A. Yu.; Krysin, M. Yu. Chem. Heterocycl. Compd. 201 5 , 51 , 573. [ Khim. Geterotsikl. Soedin. 2015 , 51 , 573.] For this article in the English edition see DOI 10.1007/s10593-015-1738-x

Relationship between CaMK II and levosimendan against arrhythmia induced by myocardial ischemia-reperfusion in rats in vitro

Objective To evaluate the relationship between calmodulin protein kinase Ⅱ (CaMK Ⅱ) and levosimendan against arrhythmias induced by myocardial ischemia-reperfusion (I/R) in rats in vitro.Methods Thirty male Wistar rats,weighing 250-300 g,were randomly divided into 3 groups (n =10 each) using a random number table:control group (group C),I/R group and levosimendan group (group L).Their hearts were rapidly excised and perfused in a langendorff apparatus with K-H solution saturated with 95％ O2-5％ CO2 at 36.5-37.5 ℃.At 20 min of equilibration,the hearts were perfused with K-H solution for 60 min in group C.The hearts were subjected to 30 min of ischemia followed by 30 min reperfusion with K-H solution in group I/R.The hearts were subjected to 30 min of ischemia followed by 30 min reperfusion with K-H solution containing 300 nmol/L levosimendan in group L.Left ventricle developed pressure (LVDP),left ventricle end-diastolic pressure (LVEDP),+ dP/dt-dP/dtmax and heart rate (HR) were recorded immediately before ischemia and at 15 and 30 min of reperfusion.Arrhythmia was recorded during reperfusion and scored.Specimens were obtained from the apex of heart at 30 min of reperfusion for determination of the intracellular calcium concentration ([Ca2 +] i).Myocardial specimens were obtained from the left ventricle at 30 min of reperfusion to detect CaMK Ⅱ activity.Results Compared with group C,arrhythmia score,[Ca2+]i and CaMK [Ⅱ activity were significantly increased,and LVDP,+ dP/dtmax,-dP/dtmax and HR were decreased,and LVEDP was increased at 15 and 30 min of reperfusion in group I/R.Compared with group I/R,the number of ventricular premature beat,arrhythmia score,[Ca2+] i and CaMK Ⅱ activity were significantly decreased,and LVDP,+ dP/dtmax,-dP/dtmax and HR were increased,and LVEDP was decreased at 15 and 30 min of reperfusion in group L.Conclusion Inhibition of CaMK Ⅱ activity is involved in the mechanism by which levosimendan decreases the development of arrhythmias induced by myocardial I/R in rats. Key words: Calcium-calmodulin-dependent protein kinase type 2; Pyridazines; Myocardial reperfusion injury; Arrhythmias, cardiac

N,N-Bond Formation in Intramolecular Cobalt-Catalyzed [2+2+2] Cyclizations of Alkynyl-Linked Bisnitriles, and the Preparation of Annulated Pyridazines

N,N-Bond Formation in Intramolecular Cobalt-Catalyzed [2+2+2] Cyclizations of Alkynyl-Linked Bisnitriles, and the Preparation of Annulated Pyridazines

Pyridazine and its Related Compounds. 151 Photolysis of 3-Azido-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine in Different Solvents

The photochemistry of 3-azidopyrazolopyridazine has been investigated. The irradiation of 3-azido-4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazine 1 in various solvents brings to a photolytic nitrene intermediate, which involve into a ring- opening to give 3-substituted pyridazine derivatives. While the photolysis in toluene and/or anisole the photo attacks reaction of nitrene is faster than the ring opining to give the corresponding 3-anilinopyrazolopyridazine derivatives. The photolysis in the presence of diethyl malonate led to a mixture of three pyridazine derivatives.

Effect of levosimendan on pulmonary artery pressure in patients with pulmonary hypertension undergoing mitral valve replacement

Objective To investigate the effect of levosimendan on pulmonary artery pressure in patients with pulmonary hypertension undergoing mitral valve replacement.Methods Twenty-four ASA Ⅱ or Ⅲ and NY-HA class Ⅱ or Ⅲ patients,aged 35-60 yr,with mean pulmonary artery pressure (MPAP) ＞ 30 mm Hg,undergoing mitral valve replacement were randomly divided into 2 groups (n =12 each):control group (group C) and levosimendan group (group L).In group L,a loading dose of levosimendan 24 μg/kg was injected intravenously after aortic unclamping,followed by infusion of levosimendan at a rate of 0.2 μg· kg-1 · min-1 until 1 d after operation.Group C received the equal volume of normal saline.HR,MAP,MPAP,pulmonary capillary wedge pressure (PCWP),cardiac index (CI) were recorded at 5 min after induction (T0),at the end of CPB (T1) and at 1 h after operation (T2),and the pulmonary vascular resistance (PVR) and rate-pressure product (RPP) were calculated.The improvement in pulmonary hypertension was recorded.Results PCWP was significantly lower and CI higher at T1,2 in both groups,and HR was significantly higher at T1,2 and MPAP lower at T2 in group C,and MPAP and PVR were significantly lower at T1,2 in group L than at T0 (P ＜ 0.05).HR,MPAP and PVR were significantly lower and CI was significantly higher at T1,2,RPP was significantly lower at T2 and the improvement in pulmonary hypertension was higher in group L than in group C (P ＜ 0.05).Conclusion Levosimendan can improve pulmonary hypertension without increasing the myocardial oxygen consumption and with a significant increase in myocardial contractility in patients with pulmonary hypertension undergoing mitral valve replacement. Key words: Cardiotonic agents; Pyridazines; Heart valve prosthesis implantation; Mitral valve; Hypertension, pulmonary

ChemInform Abstract: Synthesis and Reactions of Some New Selenolo[2,3‐c]pyridazines.

AbstractA new series of selenopyridazine and pyrimidoselenopyridazine derivatives are synthesized as possible biodegradable agrochemicals starting from selenolo[2,3‐c]pyridazines (I), (XI) or (XXII).

Optimizing Scale Up Yield to Pyridazines and Fused Pyridazines

Optimizing Scale Up Yield to Pyridazines and Fused Pyridazines

ChemInform Abstract: Synthesis, Characterization, and Structure of Some New Substituted 5,6‐Fused Ring Pyridazines.

AbstractCompounds (I) are prepared from freshly cracked cyclopentadiene.

Monitoring the 1160 cm−1 band of pyridazine to investigate complexes with formamide

Hydrogen bonding between pyridazine (PRD) and formamide (FA) molecules has been investigated both experimentally by Raman spectroscopy on their binary mixtures and theoretically by DFT calculations on various gas-phase PRD:FA clusters. The band at 1160cm−1 of PRD was used for the first time as a marker for monitoring the degree of complexation. Upon dilution with FA, a new band at 1169cm−1 is observed and attributed to hydrogen-bonded PRD. The Raman experiments were complemented by DFT calculations and the corresponding structures, vibrational spectra and binding energies were determined. The most stable species were found to be the 1:2 PRD:FA complexes and such stoichiometry is in excellent agreement with the experimental determination. The shift to higher frequency observed to the prominent modes of PRD may be related to a shortening of the NC and CC bonds, upon complexation, which causes a decrease in the electron delocalization in PRD ring.

General study of pyridazine compounds against cyclooxygenase enzyme and their relation with analgesic, anti-inflammatory and anti-arthritic activities

There is increased focus on developed non-steroidal anti-inflammatory drugs (NSAIDs) containing a pyridazine nucleus. The NSAIDs are one of the most commonly used medications worldwide to inhibit cyclooxygenase (COX-1 and COX-2) enzyme in varying extent by inhibiting prostaglandin (PGEs) synthesis for the treatment of pain, inflammation, arthritis and edema. Their routine and long-term use causes gastrointestinal (GIT) and renal toxicities. In order to minimize these side-effects, selective COX-2 inhibitors are prepared with an improved GIT and renal safety profile relative to other NSAIDs. The recent development toward the effective NSAIDs agents causes dual COX and lipooxygenase inhibitory effects because COX-2 inhibitors cause cardiovascular problems. The literature stimulated these above findings. Our attention has been focused on the series of pyridazine or other derivatives that were reported or will be reported in the future as anti-inflammatory, analgesic, anti-arthritic as well as anti-edemic agent.

Effect of STH-2 cardioplegic solution containing levosimendan on ischemia-reperfusion injury in isolated rat hearts

Objective To investigate the effect of STH-2 cardioplegic solution containing levosimendan on ischemia-reperfusion (I/R) injury in isolated rat hearts. Methods Thirty-two male Wistar rats weighing 250-300 gwere anesthetized with intraperitoneal 3% pentobarbital 30 mg/kg. The hearts were rapidly excised and perfused with oxygenated (95% O2-5% CO2) K-H solution for 30 min in a Langendorff apparatus and then divided into 4groups (n = 8 each) according to the composition of cardioplegic solution: group Ⅰ control (group C) was perfused with STH-2 cardioplegic solution; group Ⅱ , Ⅲ and Ⅳ were peffused with STH-2 cardioplegic solution containing levosimendan 0.03 μmol/L (L1), 0.3 μmol/L (L2) and levosimendan 0.3 μmol/L + glibenclamide 10 μmol/L (L2+ G) respectively. The isolated hearts were first perfused with different cardioplegic solutions for 2 h and then with K-H solution for 30 min. The coronary effluent was collected before ischemia (baseline) and at 10, 20 and 30 min of reperfusion for measurement of creatine kinase (CK) and lactate dehydrogenase (LDH)activities. Myocardial specimens were obtained from apex at 30 min of reperfusion for determination of myocardial ATP and MDA contents and SOD activity. Results Perfusion with STH-2 cardioplegic solution significantly increased CK and LDH activities and MDA content, and significantly decreased SOD activity. Levosinendan 0.03or 0.3 μmol/L significantly attenuated the cardioplegia-induced increase in LDH,CK and SOD activities and MDA content. The protective effects of levosimendan on myocardium against I/R injury were reversed by glibenclamide to some extent. Conclusion Levosimendan can protect myocardium from I/R injury in a dose-dependent manner by opening KATP channel. Key words: Pyridazines; Cardioplegic solutions; Myocardial reperfusion injury

ChemInform Abstract: Synthesis of Some 3,6-Disubstituted Pyridazines.

Some novel 3-halo-6-(4-substituted-phenoxy)pyridazines and 3,6-di-(4-substituted-phenoxy)pyridazines were synthesized from 3,6-dichloropyridazine or 3,6-diiodopyridazine. 3,6-Diiodopyridazine was prepared from 3,6-dichloropyridazine using hydriodic acid/iodine monochloride.

Solid State Structure of 6,7-Dihydro-1,4-Di(2′-Pyridyl)-5H-Cyclopenta[d]Pyridazine

The X-ray structure of 6,7-dihydro-1,4-di(2′-pyridyl)-5H-cyclopenta[d]pyridazine ligand (5-dppn) shows the existence of a trans/trans conformation. The 5-dppn crystallizes in a triclinic space group P-1 with a = 7.1048(15) A; b = 9.008(2) A; c = 10.986(3) A; α = 88.279(16)°; β = 85.454(15)°; γ = 69.104(12)°; V = 654.7(3) A3 and Z = 2. The analysis of 5-dppn crystal structure demonstrates the presence of edge-edge Ar–H···N and face-face Aliph-H···N centrosymmetric dimer interactions. The unit cell packing arrangement confirmed the presence of two molecules opposite to each other. The X-ray structure of 6,7-dihydro-1,4-di(2′-pyridyl)-5H-cyclopenta[d]pyridazine ligand (5-dppn) shows the existence of a trans/trans conformation.

Raman and DFT study of static, dynamic interactions and isotope effect in pyridazine + H 2O/D 2O systems

Polarized Raman and density functional theory (DFT) approach have been applied to study the static and dynamic properties of pyridazine (PRD) in H 2O(W) and D 2O(D) environment. The possible hydrogen bonded (HB) complexes of PRD with H 2O in gas phase and in the water solvation (using IEF-PCM and Onsager models) have been calculated using a B3LYP functional and 6-31+G(d,p)/6-311++G(d,p) basis sets. The static interaction in the PRD + H 2O complex leads to a blue shift in all the Raman modes of PRD and red shift in the O–H modes of water. The IEF-PCM solvation model gives the Raman wavenumbers closest to the experimental values. Raman spectra of ∼962 and 1061 cm −1 mode of PRD in the mixture of PRD + H 2O and PRD + D 2O at different mole fractions of PRD ( x) have been measured. A difference in the wavenumber shift of the two modes of PRD is observed experimentally when PRD is diluted with H 2O and D 2O. The wavenumber shift at maximum dilution ( x = 0.1), however, takes the same value in both H 2O and D 2O. In view of the similar chemical properties of H 2O and D 2O, the difference in the trend of the wavenumber shift is not trivial. It has been explained on the basis of relative values of dipole moments of H 2O, D 2O, and conjugated molecules of PRD with H 2O/D 2O calculated theoretically and the role of larger diffusive property of H 2O compared to D 2O. The dynamical process in the mixture of PRD+ H 2O/D 2O is discussed by studying the variation of the linewidth with concentration. A theoretical model, which is based on the fact that the concentration in microscopic volume fluctuates, fits the experimental results nicely.