Showing papers on "Pyrazole published in 2007"

Discovery of 1-(4-Methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a Highly Potent, Selective, Efficacious, and Orally Bioavailable Inhibitor of Blood Coagulation Factor Xa.

Abstract: Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.

Pyrazole chemistry in crop protection

Abstract: An overview is given of the significance of pyrazole derivatives in crop protection chemistry. The main herbicidally, fungicidally and insecticidally active pyrazole classes are presented, together with their synthetic routes, their modes-of-action and their biological efficacies. Indazoles and other bicyclic pyrazole derivatives are also covered.

Highly Efficient Copper-Catalyzed N-Arylation of Nitrogen-Containing Heterocycles with Aryl and Heteroaryl Halides

Abstract: New (S)-pyrrolidinylmethylimidazole ligands (4a−c) have been readily synthesized in a straightforward fashion from least expensive starting materials in short steps in high yields. Relatively mild and highly efficient CuI-catalyzed N-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides have been developed in the presence of 4a and Cs2CO3. It is important to note that the protocol could tolerate functional groups such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on the aryl halide. The protocol could also be applicable to other π-electron-rich nitrogen heterocycles (pyrrole, pyrazole, indole, benzimidazole, and triazole), affording the N-arylazoles in good to excellent yields.

Synthetic pyrazole derivatives as growth inhibitors of some phytopathogenic fungi.

Abstract: The present study was carried out to investigate the antifungal activity of pyrazole/isoxazole-3-carboxamido-4-carboxylic acids, 4-oxo-5-substituted pyrazolo[3,4-d]pyrimidine-6-thiones, and N-alkyl/aryl-N′-(4-carbethoxy-3-pyrazolyl)thioureas against Pythium ultimum, Botrytis cinerea, and Magnaporthe grisea. The results on growth inhibition showed differences in the sensitivity of the three fungi to the tested substances, and in general P. ultimum was shown to be the most sensitive. On all phytopathogens the best results within the pyrazole/isoxazolecarboxamide series are given by the compounds with the carboxamide and carboxylic groups in positions 3 and 4; the presence of these groups seems to be critical for biological activity in this series of compounds. Among the pyrazolopyrimidines the derivative supplied with the benzylic group was the most active on the three fungi and in particular against P. ultimum. Several compounds belonging to the thiourea series are able to inhibit selectively M. grisea at ...

Inhibition of the heat shock protein 90 molecular chaperone in vitro and in vivo by novel, synthetic, potent resorcinylic pyrazole/isoxazole amide analogues

Abstract: Although the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) shows clinical promise, potential limitations encourage development of alternative chemotypes. We discovered the 3,4-diarylpyrazole resorcinol CCT018159 by high-throughput screening and used structure-based design to generate more potent pyrazole amide analogues, exemplified by VER-49009. Here, we describe the detailed biological properties of VER-49009 and the corresponding isoxazole VER-50589. X-ray crystallography showed a virtually identical HSP90 binding mode. However, the dissociation constant (K(d)) of VER-50589 was 4.5 +/- 2.2 nmol/L compared with 78.0 +/- 10.4 nmol/L for VER-49009, attributable to higher enthalpy for VER-50589 binding. A competitive binding assay gave a lower IC(50) of 21 +/- 4 nmol/L for VER-50589 compared with 47 +/- 9 nmol/L for VER-49009. Cellular uptake of VER-50589 was 4-fold greater than for VER-49009. Mean cellular antiproliferative GI(50) values for VER-50589 and VER-49009 for a human cancer cell line panel were 78 +/- 15 and 685 +/- 119 nmol/L, respectively, showing a 9-fold potency gain for the isoxazole. Unlike 17-AAG, but as with CCT018159, cellular potency of these analogues was independent of NAD(P)H:quinone oxidoreductase 1/DT-diaphorase and P-glycoprotein expression. Consistent with HSP90 inhibition, VER-50589 and VER-49009 caused induction of HSP72 and HSP27 alongside depletion of client proteins, including C-RAF, B-RAF, and survivin, and the protein arginine methyltransferase PRMT5. Both caused cell cycle arrest and apoptosis. Extent and duration of pharmacodynamic changes in an orthotopic human ovarian carcinoma model confirmed the superiority of VER-50589 over VER-49009. VER-50589 accumulated in HCT116 human colon cancer xenografts at levels above the cellular GI(50) for 24 h, resulting in 30% growth inhibition. The results indicate the therapeutic potential of the resorcinylic pyrazole/isoxazole amide analogues as HSP90 inhibitors.

In vitro biological characterization of a novel, synthetic diaryl pyrazole resorcinol class of heat shock protein 90 inhibitors

Abstract: The molecular chaperone heat shock protein 90 (HSP90) has emerged as an exciting molecular target. Derivatives of the natural product geldanamycin, such as 17-allylamino-17-demethoxy-geldanamycin (17-AAG), were the first HSP90 ATPase inhibitors to enter clinical trial. Synthetic small-molecule HSP90 inhibitors have potential advantages. Here, we describe the biological properties of the lead compound of a new class of 3,4-diaryl pyrazole resorcinol HSP90 inhibitor (CCT018159), which we identified by high-throughput screening. CCT018159 inhibited human HSP90beta with comparable potency to 17-AAG and with similar ATP-competitive kinetics. X-ray crystallographic structures of the NH(2)-terminal domain of yeast Hsp90 complexed with CCT018159 or its analogues showed binding properties similar to radicicol. The mean cellular GI(50) value of CCT018159 across a panel of human cancer cell lines, including melanoma, was 5.3 mumol/L. Unlike 17-AAG, the in vitro antitumor activity of the pyrazole resorcinol analogues is independent of NQO1/DT-diaphorase and P-glycoprotein expression. The molecular signature of HSP90 inhibition, comprising increased expression of HSP72 protein and depletion of ERBB2, CDK4, C-RAF, and mutant B-RAF, was shown by Western blotting and quantified by time-resolved fluorescent-Cellisa in human cancer cell lines treated with CCT018159. CCT018159 caused cell cytostasis associated with a G(1) arrest and induced apoptosis. CCT018159 also inhibited key endothelial and tumor cell functions implicated in invasion and angiogenesis. Overall, we have shown that diaryl pyrazole resorcinols exhibited similar cellular properties to 17-AAG with potential advantages (e.g., aqueous solubility, independence from NQO1 and P-glycoprotein). These compounds form the basis for further structure-based optimization to identify more potent inhibitors suitable for clinical development.

Heterobicyclic pyrazole compounds and methods of use

Abstract: Compounds of Formulas (Ia) and (Ib), and stereoisomers, geometric isomers, tautomers, solvates, metabolites and pharmaceutically acceptable salts thereof, are useful for inhibiting receptor tyrosine kinases and for treating disorders mediated thereby. Methods of using compounds of Formula Ia and Ib, and stereoisomers, geometric isomers, tautomers, solvates and pharmaceutically acceptable salts thereof, for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions are disclosed.

Pyrazole-based ligands for the [copper-TEMPO]-mediated oxidation of benzyl alcohol to benzaldehyde and structures of the cu coordination compounds

Abstract: New pyrazole-based ligands have been designed, and the catalytic performances of their copper(II) complexes for the [copper/TEMPO]-mediated oxidation of benzyl alcohol to benzaldehyde have been examined. The pyridine-pyrazole ligands give efficient catalysts, while the use of naphthol-pyrazole ligands results in inactive catalytic systems. Single-crystals of four Cu coordination compounds obtained from pyridine-pyrazole ligands and a free ligand have been isolated and were characterized by X-ray diffraction. Thus, the solid-state structures of three copper(II) complexes are described, together with a copper(I) coordination chain, exhibiting luminescent properties. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

(Arene)ruthenium(II) Complexes Containing Substituted Bis(pyrazolyl)methane Ligands – Catalytic Behaviour in Transfer Hydrogenation of Ketones

Abstract: A new and safer methodology has been developed for the synthesis of bis(pyrazol-1-yl)methane ligands (NN). Several ligands containing different phenyl groups on the central carbon atom have been obtained. Ruthenium derivatives of the type [Ru(arene)Cl(NN)]BPh4 (arene = benzene, p-cymene) have been synthesised using these ligands. One or two isomers that differ regarding the axial or equatorial disposition of the phenyl group on the metallacycle have been obtained. Their formation is rationalised by considering steric effects. The structures of five derivatives were determined by X-ray diffraction. In four complexes the phenyl substituent is in the axial disposition of the metallacycle and in one case in the equatorial orientation. The dihedral angle formed by the planes of the two pyrazole rings is always bigger for the complexes containing unsubstituted pyrazolyl heterocycles. The behaviour of the new derivatives in the transfer hydrogenation of benzophenone in the presence of KOH was studied. The benzene derivatives showed higher activity than the p-cymene complexes. A marked and positive effect of the methyl groups on the pyrazolyl rings was observed. The effect of the substituents on the benzyl carbon atom was also important. It has been observed that the benzophenone hydrogenation was possible without the addition of complexes. The effect of the KOH concentration was evaluated and a concentration that leads to negligible conversion in a base-only process was chosen. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)

Synthesis and antibacterial activity of some new fused chromenes

Abstract: A new class of pyrano(3,4-c)chromene, benzo(c)chromene, chromeno(3,4-c)pyridine and chromeno(4,3-c)pyrazole has been prepared from 3-benzoyl-2H-chromen-2-one 1. Most of the chromene derivatives showed moderate to high antibacterial activity as compared to the starting material 1.

Pyrazole and trispyrazolylmethane rhenium complexes as catalysts for ethane and cyclohexane oxidations

Abstract: The pyrazole complexes [ReCl2{N2C(O)Ph}(Hpz)(PPh3)2] 2 (Hpz = pyrazole), [ReCl2{N2C(O)Ph}(Hpz)2(PPh3)] 3 and [ReClF{N2C(O)Ph}(Hpz)2(PPh3)] 4, and the tris(pyrazolyl)methane compounds [ReCl2(HCpz3)(PPh3)][BF4] 5 (pz = pyrazolyl), [ReCl3{HC(pz)3}] 7, [ReOCl2{SO3C(pz)3}(PPh3)] 8 and [ReO3{SO3C(pz)3}] 9, and their precursors [ReCl2{η2-N,O-N2C(O)Ph}(PPh3)2] 1 and [ReOCl3(PPh3)2] 6, act as selective catalysts (or catalyst precursors), in a single-pot process, for the oxidation of ethane, in the presence of potassium peroxodisulfate K2S2O8, in trifluoroacetic acid (TFA), to give acetic acid, in a remarkable yield (up to ca. 40%) and under mild conditions (in some cases carboxylation can also occur to give propionic acid, but in a much lower yield). The catalytic peroxidative oxidation of ethane to acetaldehyde and of cyclohexane to cyclohexanone and cyclohexanol by an aqueous solution of H2O2 at room temperature is also achieved by using most of those catalyst precursors. The effects of a variety of factors were studied towards the optimization of the processes which are shown to proceed via both C-centered and O-centered radical mechanisms.

Monoamine Oxidase Isoform-Dependent Tautomeric Influence in the Recognition of 3,5-Diaryl Pyrazole Inhibitors

Abstract: A series of 3,5-diaryl pyrazoles were prepared and assayed for their ability to inhibit reversibly monoamine oxidase-A (MAO-A) and monoamine oxidase B (MAO-B). Several compounds show inhibitory activity with concentration values in the nanomolar range. A computational work was carried out on the two most selective inhibitors that have tautomeric pyrazole forms. The binding free energies of these compounds for each MAO isoform were influenced by the tautomeric equilibria.

Synthesis, Crystal Structure, and Activity of Pyrazole-Based Inhibitors of p38 Kinase

Abstract: A series of pyrazole inhibitors of p38 mitogen-activated protein (MAP) kinase were designed using a binding model based on the crystal structure of 1 (SC-102) bound to p38 enzyme New chemistry using dithietanes was developed to assemble nitrogen-linked substituents at the 5-position of pyrazoles Calculated log D was used in tandem with structure-based design to guide medicinal chemistry strategy and improve the in vivo activity of a series of molecules The crystal structure of an optimized inhibitor, 4 (SC-806), in complex with p38 enzyme was obtained to confirm the hypothesis that the addition of a basic nitrogen to the molecule induces an interaction with Asp112 of p38α A compound identified from this series was efficacious in an animal model of rheumatic disease

Pyrazole Derivatives as Corrosion Inhibitors for Steel in Hydrochloric Acid

Abstract: The effect of 1-{[benzyl-(2-cyano-ethyl)-amino]-methyl}-5-methyl-1H-pyrazole-3carboxylic acid methyl ester (P1) and 1-{[benzyl-(2-cyano-ethyl)-amino]-methyl}-5methyl-1H-pyrazole-3-carboxylic acid ethyl ester (P2) was evaluated as corrosion inhibitors of steel in molar hydrochloric using weight loss measurements and electrochemical polarisation. The results obtained reveal that those compounds reduce the corrosion rate. The inhibiting action increases with the concentration of pyrazole compounds to attain 98.5 % at the 10 -3 M of (P2). The increase in temperature leads to a decrease in the inhibition efficiency of the compounds in the temperature range 308 353 K. The adsorption isotherm of inhibitors on the steel has been determined. The thermodynamic data of activation and adsorption are determined.

Synthesis and Antimicrobial Evaluation of Some Chalcones and Their Derived Pyrazoles, Pyrazolines, Isoxazolines, and 5,6-Dihydropyrimidine-2-(1H)-thiones

Abstract: Chalcones were synthesized by a base catalyzed Claisen-Schmidt condensation reaction. Bromination of chalcones afforded the dibromo derivatives. Monobromo derivatives could be obtained by treating the corresponding dibromochalcones with dry benzene in the presence of triethylamine. Pyrazole derivatives were obtained by refluxing of dibromochalcones with phenylhydrazine or 2,4-dinitrophenylhydrazine in dry pyridine. Chalcones were treated with hydrazine hydrate or phenyl hydrazine in ethanol to afford Δ2-pyrazolines and N-phenyl-Δ2-pyrazolines. Condensation of chalcones with hydroxylamine hydrochloride or thiourea in ethanolic sodium hydroxide solution gave 4,5-dihydroisoxazoles and 5,6-dihydropyrimidine-2-(1H)-thiones. The prepared compounds were tested for antimicrobial activity against four different bacterial species displaying different degrees of antibacterial activities or inhibitory actions.