- 3,4,5-Trinitropyrazole-based energetic salts
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High-density energetic salts that are comprised of nitrogen-rich cations and the 3,4,5-trinitropyrazolate anion were synthesized in high yield by neutralization or metathesis reactions. The resulting salts were fully characterized by 1H, 13C NMR, and IR spectroscopy; differential scanning calorimetry; and elemental analysis. Additionally, the structures of the 3,5-diaminotriazolium and triaminoguanidinium 3,4,5-trinitropyrazolates were confirmed by single-crystal X-ray diffraction. Based on the measured densities and calculated heats of formation, the detonation performances (pressure: 23.74-31.89 GPa; velocity: 7586-8543 ms -1; Cheetah 5.0) of the 3,4,5-trinitropyrazolate salts are comparable with 1,3,5triamino-2,4,6-trinitrobenzene (TATB; 31.15GPa and 8114 ms -1). Impact sensitivities were determined to be no less than 35 J by hammer tests, which places these salts in the insensitive class.
- Zhang, Yanqiang,Guo, Yong,Joo, Young-Hyuk,Parrish, Damon A.,Shreeve, Jean'ne M.
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- Experimental and theoretical studies on the structure and vibrational properties of nitropyrazoles
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We report a theoretical and experimental study on the structure and vibrational properties of pyrazole and its mononitropyrazoles. The infrared (IR) and Raman spectra of pyrazole, N-nitropyrazole, 3-nitropyrazole and 4-nitropyrazole have been recorded in the solid state. To interpret the experimental data, ab initio computations of the vibrational frequencies were carried out using the Gaussian 03 program following the full optimizations at the HF/6-311++G(d,p), B3P86/6-311++G(d,p), B3LYP/6-311++G(d,p) and B3LYP/aug-cc-pVDZ levels. The combined use of experiments and computations allowed a firm assignment of the majority of observed bands for all compounds. The calculated stretching frequencies have been found to be in good agreement with the experimental frequencies. However, the fundamental vibrational frequencies of nitropyrazoles calculated at the B3LYP/aug-cc-pVDZ level are superior compared with those values that are obtained at the HF/311++G(d,p), B3P86/311++G(d,p) and B3LYP/311++G(d,p) levels of theory. The differences in the bond distances and bond angles are confined to the twist of the nitro group that present the greatest deviation from planarity in molecules.
- Nageswara Rao,Ravi,Tewari, Surya P.,Venugopal Rao
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- Solubility, thermodynamic modeling and Hansen solubility parameter of a new type of explosive in four binary solvents (benzene + ethanol, n-propanol, n-butanol and isoamyl alcohol) from 283.15 K to 323.15 K
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The solubility of 3,4-dinitropyrazole (DNP) in four binary solvents (benzene + ethanol, n-propanol, n-butanol and isoamyl alcohol) was measured by a dynamic laser monitoring at the temperature from 283.15 K to 323.15 K at pressure of 0.1 MPa. The solubility of DNP increased positively with increasing temperature, while increased with decreasing molar fraction of benzene in each binary system. Moreover, the experimental solubility values of DNP in this work were correlated well with four thermodynamic models namely “the modified Apelblat equation, Jouyban-Acree model, NRTL model and Wilson model” obtaining average root-mean-square deviation (104RMSD) lower than 98.93 for correlative studies. In addition, Hansen solubility parameters were used to explain and predict the solubility behavior. Finally, mixing thermodynamic properties were estimated and analyzed based on solubility data and the Wilson model, and it's easy to understand that the dissolution was a spontaneous process from the results.
- Guo, Hao-qi,Li, Yong-xiang,Yang, Yu-lin,Li, Zi-yang
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- Solubility determination and correlation for 3-nitropyrazole in four binary solvents (water?+?methanol, ethanol, 1-propanol and acetone) from 283.15?K to 323.15?K
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The solubility of 3-nitropyrazole in four binary solvents (water + methanol, ethanol, 1-propanol and acetone) was measured by a dynamic laser monitoring over the temperature range of 283.15 K, 288.15 K, 293.15 K, 298.15 K, 303.15 K, 308.15 K, 313.15 K, 318.15 K and 323.15 K at pressure of 0.1 MPa. The solubility of 3-nitropyrazole increased positively with increasing temperature, while increased with decreasing mass-fraction of water in each binary system. Moreover, the experimental solubility values of 3-nitropyrazole in this work were correlated well with four thermodynamic models namely “the modified Apelblat equation, λh equation, Jouyban-Acree model and CNIBS/R-K model” obtaining average relative deviations (104RMSD) lower than 4.79 for correlative studies, which shows that all the four models have a good correlation. Through the comparison of R2 and 104RMSD, it was found that the modified Apelblat equation can get more satisfactory results. In addition, Hansen solubility parameters were used to explain and predict the solubility behavior. Solute-solvent interaction was calculated by molecular simulation to investigate the solubility behavior deeply. Finally, the thermodynamic parameters (ΔdisGo, ΔdisHo, ΔdisSo) of 3-nitropyrazole dissolution processes in investigated four binary solvents were evaluated utilizing the van't Hoff equation. The positive ΔdisHo and ΔdisSo, indicate that the dissolution processes of 3-nitropyrazole are endothermic and entropy-driven in all chosen binary solvents. And the main contributor of ΔdisGo is positive enthalpy. The solubility of 3-nitropyrazole in mixed solvents (water + methanol, water + ethanol, water + 1-propanol and water + acetone) will provide essential support for the further researches of crystallization and spheroidization of 3-nitropyrazole.
- Liu, Wen-Dong,Li, Yong-Xiang,Cao, Duan-Lin,Guo, Heng-Jie,Li, Zi-Yang
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- Crystal structure of 3,4-dinitropyrazole in water
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3,4-dinitropyrazole (DNP) was synthesized by N-nitration, thermal rearrangement and C-nitration with pyrazole as the raw material. A pure DNP single crystal was obtained by solvent evaporation using water as a solvent, and its structure was characterized by X-ray single crystal diffraction. The results showed that the single crystal structure of DNP contained water, and the molar ratio of DNP/water was 4:1. The DNP molecules existed stably due to the presence of intermolecular and intramolecular hydrogen bonding, as well as π-π stacking between DNP molecules. This study was valuable to the production and application of DNP.
- Guo, Haoqi,Yu, Siyuan,Li, Yongxiang,Wang, Jianlong,Cao, Duanlin,Qin, Zexin
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- Metal salts of dinitro-, trinitropyrazole, and trinitroimidazole
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The syntheses of alkali and earth alkaline dinitropyrazolate (DNP), trinitropyrazolate (TNP), and trinitroimidazolate (TNI) salts are reported. Additionally, copper trinitroimidazolate was synthesized. Their characterization by NMR spectroscopy, mass spectrometry, elemental analysis, and vibrational spectroscopy is reported as well. Crystal structures of compound Ba(DNP)2 (9), which crystallizes with one molecule of methanol and ethyl ether as well as of compounds Sr(TNP)2·3H2O (12), Ba(TNP)2·3H2O (13), and LiTNI·3H2O (14) were determined. The energetic and thermal properties were measured as well. Green- and red-burning pyrotechnic formulations containing barium salts 9 and 13 as well as strontium salts 8 and 12 serving as colorants are tested. Additionally, formulations using Sr(TNP)2·3H2O (12) and Ba(TNP)2·3H2O (13) as the oxidizer and colorant at the same time were examined. The formulations were investigated with regard to their combustion behavior and performances such as burn time, dominant wavelength, spectral purity, luminous intensity, and luminous efficiency. The sensitivities towards ignition stimuli and the decomposition temperatures were determined as well.
- Drukenmüller, Ines E.,Klap?tke, Thomas M.,Morgenstern, Yvonne,Rusan, Magdalena,Stierstorfer, J?rg
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- Comparison of Functionalized Lithium Dihydrobis(azolyl)borates with Their Corresponding Azolates as Environmentally Friendly Red Pyrotechnic Coloring Agents
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The recent awareness of the impact of strontium on health has stimulated research efforts on lithium-based red pyrotechnic colorants. We have previously shown lithium dihydrobis(azolyl)borates to be promising candidates due to their favorable adjustment to a reductive and low-temperature flame atmosphere. These compounds are assumed to be sufficiently stable only if the pKa values of the heterocycles are between 5 and 20. Apart from their acidities, functionalization of 1H-tetrazole and 1H-pyrazole with nitro or amino groups, respectively, tailors the oxygen balances of the resulting Lewis acid base adducts to enhance the fuel-rich flame environment or to make them oxidizing agents. This work determines whether the lithium salts of dihydrobis(3-nitropyrazol-1-yl)borate and dihydrobis(5-aminotetrazol-1-yl)borate are suitable replacements for strontium-containing color imparters. Furthermore, the influence of potentially green-light-producing boron is evaluated by comparing the emissions of the lithium borates and the corresponding lithium azolates.
- Dufter, Alicia M. W.,Klap?tke, Thomas M.,Rusan, Magdalena,Schweiger, Alexander,Stierstorfer, J?rg
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- Isomers of Dinitropyrazoles: Synthesis, Comparison and Tuning of their Physicochemical Properties
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Three isomeric dinitropyrazoles (DNPs) were synthesized starting from readily available 1H-pyrazole by slightly improved methods than described in the literature. 3,4-Dinitropyrazole (3), 1,3-dinitropyrazole (4), and 3,5-dinitropyrazole (5) were obtained and compared to each other with respect to thermal stability, crystallography, sensitivity and energetic performance. Two isomers (3 and 4) show high densities (1.79 and 1.76 g cm–3) and interesting thermal behavior as melt-castable materials (3: Tmelt.=71 °C, Tdec.=285 °C; 5: Tmelt. = 68 °C, Tdec.=171 °C). Furthermore, eight salts (sodium, potassium, ammonium, hydrazinium, hydroxylammonium, guanidinium, aminoguanidinium and 3,6,7-triamino-[1,2,4]triazolo[4,3-b][1,2,4]triazole (TATOT) of 3 and 5 were synthesized in order to tune performance and sensitivity values. These compounds were characterized using 1H, 13C, 14N, 15N NMR and IR spectroscopy as well as mass spectrometry, elemental analysis and thermal analysis through differential scanning calorimetry. Crystal structures of 14 compounds were obtained (3–7, 10–12 and 15–20) by low-temperature single crystal X-ray diffraction. Impact, friction and electrostatic discharge (ESD) values were also determined by standard methods. The sensitivity values range between 8.5 and 40 J for impact and 240 N and 360 N for friction and show mainly insensitive character. The energetic performances were determined using recalculated X-ray densities, heats of formation and the EXPLO5 code and support the energetic character of the title compounds. The calculated energetic performances (VD: 6245–8610 m s?1; pCJ: 14.1–30.8 GPa) were compared to RDX ((O2NNCH2)3).
- B?lter, Marc F.,Harter, Alexander,Klap?tke, Thomas M.,Stierstorfer, J?rg
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- Lithium Nitropyrazolates as Potential Red Pyrotechnic Colorants
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Strontium-based red pyrotechnic colorants have fallen into disrepute due to the harmful influence of this alkaline earth metal on adolescents. In this context, the energetic character, safety, and combustion to benign nitrogen gas of nitropyrazoles are used for the design of the corresponding lithiated materials, which are investigated as potential replacements in the current work. For this purpose, the lithium salts of 3,4-dinitro-1H-pyrazole, 3,5-dinitro-1H-pyrazole, 4-amino-3,5-dinitro-1H-pyrazole, 3,4,5-trinitro-1H-pyrazole, and 4-hydroxy-3,5-dinitro-1H-pyrazole were extensively characterized by standard analytical methods, low-temperature single-crystal X-ray diffraction, studies of the thermo-chemical behavior, and sensitivity assessments. Our assumption that the high nitrogen contents and the low oxygen balances of these compounds would adjust a cool, reductive flame atmosphere essential for red emissions by lithium was put to the test.
- Dufter-Münster, Alicia M. W.,Harter, Alexander G.,Klap?tke, Thomas M.,Reinhardt, Elena,R?mer, Julia,Stierstorfer, J?rg
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- METHOD FOR PREPARING NITROPYRAZOLES
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A process for the sigmatropic rearrangement of the compound of formula in which R3 is an NO2 group and R4 is either a hydrogen or an NO2 group, includes heat treating the compound by microwave.
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Paragraph 0020-0027; 0034-0041; 0043-0046
(2021/07/02)
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- PYRROLO(PYRAZOLO)PYRIMIDINE DERIVATIVE AS LRRK2 INHIBITOR
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The present invention relates to a pyrrolo(pyrazolo)pyrimidine derivative having efficacy as an LRRK2 inhibitor, a preparation method therefor, and a pharmaceutical composition for preventing or treating degenerative brain diseases, containing the same.
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Paragraph 0088
(2020/11/23)
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- Method for synthesizing 3,4-dinitropyrazole by using micro-channel reactor
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The invention discloses a method for synthesizing 3,4-dinitropyrazole by using a micro-channel reactor. The method comprises the following steps: with pyrazole as a raw material, subjecting pyrazole and a nitric-acetic anhydride system to nitration in the micro-channel reactor so as to synthesize N-nitropyrazole; then with N-nitropyrazole as a raw material, carrying out thermal rearrangement so asto synthesize 3-nitropyrazole; and finally, with 3-nitropyrazole as a raw material, synthesizing 3,4-dinitropyrazole in virtue of a nitric acid-sulfur acid mixed acid system in the micro-channel reactor. According to the invention, the micro-channel reactor is employed, so the adverse outcomes of hardly controllable process, proneness to local overheating which leads to dangers, easy generation of side reactions and the like of convetional tank reactors are avoided, rapid reaction is realized, and direct enlargement can be realized through increase of the number of parallel micro-channel reactors. With the method, the yield of the synthesized 3,4-dinitropyrazole reaches 87.5%, and the purity of the synthesized 3,4-dinitropyrazole reaches 99.8%.
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Paragraph 0057; 0064; 0071
(2018/10/11)
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- Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7
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A series of acidic diaryl ether heterocyclic sulfonamides that are potent and subtype selective NaV1.7 inhibitors is described. Optimization of early lead matter focused on removal of structural alerts, improving metabolic stability and reducing cytochrome P450 inhibition driven drug-drug interaction concerns to deliver the desired balance of preclinical in vitro properties. Concerns over nonmetabolic routes of clearance, variable clearance in preclinical species, and subsequent low confidence human pharmacokinetic predictions led to the decision to conduct a human microdose study to determine clinical pharmacokinetics. The design strategies and results from preclinical PK and clinical human microdose PK data are described leading to the discovery of the first subtype selective NaV1.7 inhibitor clinical candidate PF-05089771 (34) which binds to a site in the voltage sensing domain.
- Swain, Nigel. A.,Batchelor, Dave,Beaudoin, Serge,Bechle, Bruce M.,Bradley, Paul A.,Brown, Alan D.,Brown, Bruce,Butcher, Ken J.,Butt, Richard P.,Chapman, Mark L.,Denton, Stephen,Ellis, David,Galan, Sebastien R. G.,Gaulier, Steven M.,Greener, Ben S.,De Groot, Marcel J.,Glossop, Mel S.,Gurrell, Ian K.,Hannam, Jo,Johnson, Matthew S.,Lin, Zhixin,Markworth, Christopher J.,Marron, Brian E.,Millan, David S.,Nakagawa, Shoko,Pike, Andy,Printzenhoff, David,Rawson, David J.,Ransley, Sarah J.,Reister, Steven M.,Sasaki, Kosuke,Storer, R. Ian,Stupple, Paul A.,West, Christopher W.
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supporting information
p. 7029 - 7042
(2017/09/07)
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- High-selectivity and high-yield non-solvent preparation method of 1-methyl-3,4,5-trinitropyrazole (MTNP) intermediate 3,5-dinitropyrazole
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The invention provides a high-selectivity and high-yield non-solvent preparation method of a high-energy insensitive explosive 1-methyl-3,4,5-trinitropyrazole (MTNP) intermediate 3,5-dinitropyrazole. The synthesis method comprises the steps: with pyrazole as a starting material, carrying out nitrification to introduce N-NO2 to a 1 site, and carrying out non-solvent rearrangement reaction translocation to a 3 site to generate C-NO2; then introducing N-NO2 into the 1 site, carrying out non-solvent rearrangement reaction translocation to a 5 site to generate C-NO2, to obtain the intermediate 3,5-dinitropyrazole, and carrying out nitration and methylation to obtain MTNP which is an ideal candidate for substitution of TNT. The synthesis method is simple, high in selectivity and high in yield, the used non-solvent rearrangement method is an important way for solving environmental pollution, the use of some high-toxic organic solvents is avoided, the cost is reduced, the problem of tedious post-processing is solved, and the requirements of green chemistry are met.
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Paragraph 0020; 0021; 0022; 0023; 0024; 0025; 0026
(2016/10/10)
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- From N-Nitro to N-Nitroamino: Preparation of High-Performance Energetic Materials by Introducing Nitrogen-Containing Ions
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In the design of energetic materials, high energetic performance and good molecular stability are two main goals. Energetic functionalization which strives for maximum energy often results in unstable chemical bonds and causes safety problems in practical production and storage operations. In this work, N-nitro- and N-nitroamino-functionalized mono- and bis(1,2,4-triazoles) were synthesized and characterized by infrared, and multinuclear NMR spectra, and elemental analyses. The N-nitroamino-functionalization strategy was employed for bis(imidazole), leading to high density compound 14 (2.007 g cm-3 at 100 K; 1.94 g cm-3 at room temperature) and energetic salt 15. While N-nitro-functionalized products are thermally unstable and highly moisture sensitive, N-nitroamino-functionalized energetic salts, which are comprised of additional nitrogen-containing ions, exhibit good density, moderate to excellent structural stabilities, and high performance.
- Yin, Ping,Shreeve, Jean'Ne M.
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supporting information
p. 14513 - 14517
(2016/01/25)
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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 simple and environmentally benign nitration of pyrazoles by impregnated bismuth nitrate
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We report herein a facile, rapid, and environmentally friendly synthesis of nitropyrazoles in good yields using silica-bismuth nitrate and silica-sulfuric acid-bismuth nitrate at room temperature for the first time. The relatively non-toxic nature, ease o
- Ravi,Gore, Girish M.,Tewari, Surya P.,Sikder, Arun K.
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p. 1322 - 1327
(2014/01/06)
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- Coupling of C-nitro-NH-azoles with arylboronic acids. A route to N-aryl-C-nitroazoles
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A method for the synthesis of N-aryl-C-nitroazoles is presented. A coupling reaction between variously substituted arylboronic acids and 3(5)-nitro-1H-pyrazole catalyzed by copper salt has been carried out in methanol in the presence of sodium hydroxide t
- Kurpet, Marta K.,Dabrowska, Aleksandra,Jarosz, Malgorzata M.,Kajewska-Kania, Katarzyna,Kuznik, Nikodem,Suwinski, Jerzy W.
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supporting information
p. 1517 - 1525
(2013/10/22)
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- QUINOLINE AND ISOQUINOLINE COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are compounds for treatment of JAK kinase mediated diseases, including JAK2 kinase-, JAK3 kinase- or TYK2 kinase-mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds a
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Page/Page column 97
(2012/03/26)
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- QUINAZOLINE COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are quinazoline compounds for treatment of JAK kinase mediated diseases, including JAK2 kinase-, JAK3 kinase- or TYK2 kinase-mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
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Page/Page column 45
(2012/03/12)
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- AZOLOPYRIDINE AND AZOLOPYRIMIDINE COMPOUNDS AND METHODS OF USE THEREOF
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Provided herein are azolopyridine and azolopyrimidine compounds for treatment of JAK kinase mediated diseases, including JAK2 kinase-, JAK3 kinase- or TYK2 kinase-mediated diseases. Also provided are pharmaceutical compositions comprising the compounds and methods of using the compounds and compositions.
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Page/Page column 124
(2012/03/26)
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- Facile and environmentally friendly synthesis of nitropyrazoles using montmorillonite K-10 impregnated with bismuth nitrate
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Nitropyrazoles in higher yields were synthesized using montmorillonite K-10 impregnated with bismuth nitrate and the present procedure may be applied for the nitration of a wide variety of azoles in the drug and pharmaceutical industries.
- Ravi,Tewari, Surya P.
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experimental part
p. 37 - 41
(2012/04/10)
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- HETEROARYLS AMIDE DERIVATIVES AND THEIR USE AS GLUCOKINASE ACTIVATORS
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The present invention provides Formula (1A) compounds that act as glucokinase activators; pharmaceutical compositions thereof; and methods of treating diseases, disorders, or conditions mediated by glucokinase. X, Y, Z, R1, R2, R3, and R4 are as described herein.
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Page/Page column 63-64
(2010/04/06)
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- Synthesis, reduction potentials, and antitubercular activity of ring A/B analogues of the bioreductive drug (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl] oxy}- 6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (PA-824)
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The nitroimidazooxazine S-1 (PA-824) is a new class of bioreductive drug for tuberculosis. A series of related bicyclic nitroheterocycles was synthesized, designed to have a wide range of one-electron reduction potentials E(1) (from -570 to -338 mV, compared with -534 mV for S-1). The observed E(1) values closely correlated with the om values of the heteroatom at the 4/8-position of the adjacent six-membered ring. Although the compounds spanned a range of E(1) values around that of S-1, only the nitroimidazothiazines showed significant antitubercular activity (at a similar level of potency), suggesting that E(1) is not the main driver of efficacy. Furthermore, there was a correlation between activity and the formation of imidazole ring-reduced products at the two-electron level, pointing to the potential importance of this reduction pathway, which is determined by the nature of the substituent at the 2-position of the 4-nitroimidazole ring.
- Thompson, Andrew M.,Blaser, Adrian,Anderson, Robert F.,Shinde, Sujata S.,Franzblau, Scott G.,Ma, Zhenkun,Denny, William A.,Palmer, Brian D.
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supporting information; experimental part
p. 637 - 645
(2009/12/01)
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- PYRROLIDINONE GLUCOKINASE ACTIVATORS
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.
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Page/Page column 26
(2009/10/30)
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- PYRIDAZINONE GLUCOKINASE ACTIVATORS
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Provided herein are compounds of the formula (I): as well as pharmaceutically acceptable salts thereof, wherein the substituents are as those disclosed in the specification. These compounds, and the pharmaceutical compositions containing them, are useful for the treatment of metabolic diseases and disorders such as, for example, type II diabetes mellitus.
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Page/Page column 26; 41
(2009/10/30)
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- Pyrazole glucokinase activators
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Disclosed herein are pyrazole glucokinase activators of the formula (I) useful for the treatment of metabolic diseases and disorders, preferably diabetes mellitus.
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Page/Page column 26
(2008/06/13)
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- Oxime glucokinase activators
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Disclosed herein are pyrazole glucokinase activators of the formula (I): that are useful for the treatment of metabolic diseases and disorders.
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Page/Page column 13
(2008/12/06)
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- INDAZOLE COMPOUNDS FOR ACTIVATING GLUCOKINASE
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The present invention aims to provide a glucokinase activator useful as a pharmaceutical agent such as an agent for the prophylaxis or treatment of diabetes, obesity and the like. A compound represented by the formula (I): wherein R1, R2, R3, R4 are as defined herein; or a salt thereof.
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Page/Page column 232
(2009/01/23)
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- N-benzoylpyrazoles are novel small-molecule inhibitors of human neutrophil elastase
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Human neutrophil elastase (NE) plays an important role in the pathogenesis of pulmonary disease. Using high-throughput chemolibrary screening, we identified 10 N-benzoylpyrazole derivatives that were potent NE inhibitors. Nine additional NE inhibitors were identified through further screening of N-benzoylpyrazole analogues. Evaluation of inhibitory activity against a range of proteases showed high specificity for NE, although several derivatives were also potent inhibitors of chymotrypsin. Analysis of reaction kinetics and inhibitor stability revealed that N-benzoylpyrazoles were pseudoirreversible competitive inhibitors of NE. Structure-activity relationship (SAR) analysis demonstrated that modification of N-benzoylpyrazole ring substituents modulated enzyme selectivity and potency. Furthermore, molecular modeling of the binding of selected active and inactive compounds to the NE active site revealed that active compounds fit well into the catalytic site, whereas inactive derivatives contained substituents or conformations that hindered binding or accessibility to the catalytic residues. Thus, N-benzoylpyrazole derivatives represent novel structural templates that can be utilized for further development of efficacious NE inhibitors.
- Schepetkin, Igor A.,Khlebnikov, Andrei I.,Quinn, Mark T.
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p. 4928 - 4938
(2008/03/13)
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- ARYL-AMINO SUBSTITUTED PYRROLOPYRIMIDINE MULTI-KINASE INHIBITING COMPOUNDS
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Compounds represented by Formula (I): or stereoisomers or pharmaceutically acceptable salts thereof, are inhibitors of least two of the Abl, Aurora-A, Blk, c-Raf, cSRC, Src, PRK2, FGFR3, Flt3, Lck, Mekl, PDK-1, GSK3?, EGFR, p70S6K, BMX, SGK, CaMKII, Tie-2
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Page/Page column 124-125
(2008/06/13)
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- Synthesis and histamine H2-receptor antagonist activity of 4-(1-pyrazolyl)butanamides, guanidinopyrazoles, and related compounds
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A series of 4-(1-pyrazolyl)butanamides, pyrazolylalkyl cyanoguanidines, and related compounds with diverse functional groups (e.g. nitro, amino, guanidino groups) in the 3-position of the pyrazole ring was prepared via 4-(3-nitro-1-pyrazolyl)butanenitrile (5) and the corresponding carboxylic acid 7 as central intermediates. The amides 9a-d were prepared from the primary amines 8a-d which represent partial structures of the H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine. The roxatidine-derived 4-(3-nitro-1-pyrazolyl)butanamide (9a) proved to be the compound with the highest H2-receptor antagonist activity of 23 compounds tested at the isolated guinea pig right atrium preparation, achieving about 6 times famotidine's or 160 times cimetidine's potency. By contrast, in Ghosh-Schild rats 9a did not inhibit histamine-stimulated gastric acid secretion at a dosage of 0.1 μmol/kg i.v. Compounds 20a (the 3-(trifluoroethylguanidino)pyrazole analogue of 9a, 12a (the cyanoguanidine analogue) and N-{4-[3-(trifluoroethylguanidino)-1-pyrazolyl]butyl}cyanoguanidine (29), which are about as active as famotidine in the atrium, turned out to be very potent inhibitors of gastric acid secretion as well (e.g., 29: 74% inhibition at 0.025 μmol/kg). These compounds are comparable to famotidine in the rat stomach and by far superior to cimetidine and ranitidine in this test system.
- Buschauer,Mohr,Schunack
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p. 349 - 358
(2007/10/02)
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- The metabolism of a series of ester pro-drugs by NCTC 2544 cells, skin homogenate and LDE testskin
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The metabolism of a series of substituted pyrazolopyridine ester pro-drugs was investigated using NCTC 2544 cells, human skin homogenate and LDE Testskin as model systems. The compounds were incubated in each system and the disappearance of drug and the production of the major hydrolysis product was observed with time and quantitated using HPLC. The toxicity of the ester pro-drugs and the metabolites was examined in NCTC 2544 cells using a cell viability assay procedure. Hydrolytic activity was slightly higher in the cell culture model than in skin homogenate solution but the rank order of activity for each pro-drug was similar. The metabolic activity of LDE Testskin was much reduced compared with the other systems, but again the overall pattern of metabolism was not dissimilar. These findings indicate that NCTC 2544 cells provide a reasonable model for human skin ester hydrolysis both in terms of rate and in terms of substrate specificity.
- Lamb,Denyer,Sanderson,Shaw
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p. 965 - 973
(2007/10/02)
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- Mass Spectrometry of Nitroazoles. 3-Ortho Effects: The loss of OH. and H2O from Methyl Substituted Nitrodiazoles
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Methyl substituted nitrodiazoles which have the substituents at adjacent positions in the ring are subject to several ortho effects.Deuterium labelling of the methyl group and the mobile N-bonded hydrogen show that the loss of OH. originates from the substituents.In some cases the N-bonded hydrogen atom participates also in the loss of OH. and of H2O.
- Luijten, W. C. M. M.,Thuijl, J. van
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p. 299 - 303
(2007/10/02)
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