Showing papers on "Pyrazole published in 2003"

Synthesis and Activity of New Aryl- and Heteroaryl-Substituted Pyrazole Inhibitors of the Transforming Growth Factor-β Type I Receptor Kinase Domain

Abstract: Pyrazole-based inhibitors of the transforming growth factor-β type I receptor kinase domain (TβR-I) are described Examination of the SAR in both enzyme- and cell-based in vitro assays resulted in the emergence of two subseries featuring differing selectivity versus p38 MAP kinase A common binding mode at the active site has been established by successful cocrystallization and X-ray analysis of potent inhibitors with the TβR-I receptor kinase domain

Selective C-arylation of free (NH)-heteroarenes via catalytic C-H bond functionalization.

Abstract: A new system for palladium-catalyzed arylation of a broad spectrum of free (NH)-heteroarenes has been developed (indole, pyrrole, pyrazole, 2-phenylimidazole, imidazole, benzimidazole, and purine). Remarkable selectivity has been achieved in the presence of MgO base, providing single C-arylation products, while no N-arylation and no bis-arylation products have been detected. In the case of free imidazole, exclusive C-4 arylation may be switched to exclusive 2-arylation by the addition of CuI to the Pd/Ph3P/MgO system. When free aryl-(NH)-azoles are desired, direct arylation eliminates three steps in comparison to standard methods, including N-protection, stoichiometric metalation or halogenation, and N-deprotection.

Structure−Activity Relationships of the p38α MAP Kinase Inhibitor 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naph- thalen-1-yl]urea (BIRB 796)

Abstract: We report on the structure−activity relationships (SAR) of 1-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)naphthalen-1-yl]urea (BIRB 796), an inhibitor of p38α MAP kinase which has advanced into human clinical trials for the treatment of autoimmune diseases. Thermal denaturation was used to establish molecular binding affinities for this class of p38α inhibitors. The tert-butyl group remains a critical binding element by occupying a lipophilic domain in the kinase which is exposed upon rearrangement of the activation loop. An aromatic ring attached to N-2 of the pyrazole nucleus provides important π-CH2 interactions with the kinase. The role of groups attached through an ethoxy group to the 4-position of the naphthalene and directed into the ATP-binding domain is elucidated. Pharmacophores with good hydrogen bonding potential, such as morpholine, pyridine, and imidazole, shift the melting temperature of p38α by 16−17 °C translating into Kd values of 50−100 pM. Finally, we describ...

Blue phosphors of dinuclear and mononuclear copper(I) and silver(I) complexes of 3,5-bis(trifluoromethyl)pyrazolate and the related bis(pyrazolyl)borate.

Abstract: The synthesis, structure, and photoluminescence properties are described for the three-coordinate mononuclear and dinuclear complexes [H2B(3,5-(CF3)2Pz)2]M(2,4,6-collidine), M1, and {[3,5-(CF3)2Pz]M(2,4,6-collidine)}2, M2, respectively (M = Cu; Ag). The solids exhibit bright blue phosphorescence, at room temperature for the copper compounds and at 77 K for all compounds. Ag1, Cu1, and Cu2 exhibit blue pyrazole-based structured emissions with short phosphorescence lifetimes, 101−102 μs, due to an internal heavy-metal effect. Meanwhile, Ag2 exhibits curious multiple excitation-dependent emissions.

Regioselective synthesis of 1,3,5-substituted pyrazoles from acetylenic ketones and hydrazines.

Abstract: The synthesis of diversely substituted 1,3,5-substituted pyrazoles from the reaction of acetylenic ketones with substituted hydrazines is reported. The reactions were shown to be highly regioselective regardless of the nature of the substituents in the substrates and afforded essentially single pyrazole isomers in excellent yields.

Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors.

Abstract: In a previous paper, we reported the N-hydroxyformamidine derivative HET0016 as a potent and selective 20-HETE synthase inhibitor. Despite its attraction as a potential therapeutic agent for cerebral diseases, the preparation of an injectable formulation of HET0016 was limited by its poor solubility under neutral conditions and instability under acidic conditions. The instability of HET0016 in acidic conditions is due to the N-hydroxyformamidine moiety, which is considered to be essential for the potent and selective activity seen in our previous study. The activity was maintained when the N-hydroxyformamidine moiety was replaced by an imidazole ring (3a; IC(50) = 5.7 +/- 1.0 nM), but this was associated with a loss of selectivity for cytochrome p450s (CYPs). However, other azole derivatives such as isoxazole derivative 23 (IC(50) value 38 +/- 10 nM) and pyrazole derivative 24 (IC(50) value 23 +/- 12 nM) showed potent and selective activities with improved stability.

Synthesis, structure, and spectroscopic, photochemical, redox, and catalytic properties of ruthenium(II) isomeric complexes containing dimethyl sulfoxide, chloro, and the dinucleating bis(2-pyridyl)pyrazole ligands.

Abstract: Two isomeric Ru(II) complexes containing the dinucleating Hbpp (3,5-bis(2-pyridyl)pyrazole) ligand together with Cl and dmso ligands have been prepared and their structural, spectroscopic, electrochemical, photochemical, and catalytic properties studied. The crystal structures of trans,cis-[RuIICl2(Hbpp)(dmso)2], 2a, and cis(out),cis-[RuIICl2(Hbpp)(dmso)2], 2b, have been solved by means of single-crystal X-ray diffraction analysis showing a distorted octahedral geometry for the metal center where the dmso ligands coordinate through their S atom. 1D and 2D NMR spectroscopy corroborates a similar structure in solution for both isomers. Exposure of either 2a or 2b in acetonitrile solution under UV light produces a substitution of one dmso ligand by a solvent molecule generating the same product namely, cis(out)-[RuIICl2(Hbpp)(MeCN)(dmso)], 4. While the 1 e- oxidation of 2b or cis(out),cis-[RuIICl2(bpp)(dmso)2]+, 3b, generates a stable product, the same process for 2a or trans,cis-[RuIICl2(bpp)(dmso)2]+, 3a, ...

Tricyclic pyrazole derivatives, process for their preparation and their use as antitumor agents

Abstract: Compounds which are tricyclic pyrazole derivatives and analogues thereof, as set forth in the specification, or pharmaceutically acceptable salts thereof, together with pharmaceutical compositions comprising them are disclosed; these compounds or compositions are useful in the treatment of diseases caused by and/or associated with an altered protein kinase activity such as cancer, cell proliferative disorders, Alzheimer's disease, viral infections, auto-immune diseases and neurodegenerative disorders.

Ruthenium-catalyzed C-H/CO/Olefin coupling reaction of N-arylpyrazoles. Extraordinary reactivity of N-arylpyrazoles toward carbonylation at C-H bonds.

Abstract: The reaction of 1-arylpyrazoles with CO and ethylene in the presence of Ru3(CO)12 resulted in regioselective carbonylation at the ortho C−H bonds. While it is found that the pyrazole ring also func...

Pyrazole compositions useful as inhibitors of gsk-3

Abstract: The present invention provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof. These compounds are inhibitors of protein kinases, particularly inhibitors of GSK3 mammalian protein kinase. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of utilizing those compounds and compositions in the treatment of various protein kinase mediated disorders.

Beryllium Dichloride Coordination by Nitrogen Donor Molecules

Abstract: The reaction of anhydrous beryllium chloride with nitrogen donors L in diethylether as a solvent under mild conditions affords 1:2 complexes of the type L 2 BeCl 2 [L = benzonitrile (1), pyridine (2), 3,5-dimethylpyridine, pyrrolidine, piperidine (8), and diethylamine (10)]. Structural studies of compounds 1, 2, 8 (CHCl 3 ), and 10 have shown that the complexes have the beryllium centers N 2 Cl 2 -tetracoordinated with a distorted tetrahedral geometry of the core unit. In crystals of 8 and 10 these molecules are associated to form helical strings via distinct N-H-Cl hydrogen bonding. The reaction of the weak donor pyrazole (pyz) with (Et 2 O) 2 BeCl 2 at low temperature gives the mixed complex [(Et 2 O)(pyz)BeCl 2 ] (4), in which one diethylether molecule is retained in the inner coordination sphere of the metal. In tetrahydrofuran (thf) solution, no reaction is observed with pyrazole, indicating that tetrahydrofuran is the stronger donor as compared to pyrazole, and the (thf) 2 BeCl 2 solvate remains intact. By contrast, with the strong base pyrrolidine (pyrr) the same reaction leads to substitution of one chloride ligand to give the ionic product [(pyrr) 3 BeCl] + Cl - , (7). Both products (4, 7) have been structurally characterized. At room temperature the reactions with pyrazole or piperidine lead to ether cleavage as a side-reaction which may even become dominant at long reaction times and more forcing conditions. Dinuclear complexes of the type [LBeClμ 2 -OR)] 2 are formed, the structures of which have also been determined. The results suggest that hydrogen bonding may assist in the ether cleavage process, since this reaction is not observed for ligands devoid of N-H functions.

3-(2-hydroxy-phenyl)-1h-pyrazole-4-carboxylic acid amide derivatives as hsp90 inhibitors for the treatment of cancer

Abstract: Compounds of formula (IA) or (IB) or salts, N-oxides, hydrates or solvates thereof are Inhibitors of HSP90, and useful in the treatment of, for example, cancer: formula (IA), formula (IB) wherein Ar is an aryl or heteroaryl radical which is linked via a ring carbon, and which is substituted by a hydroxy group on a carbon in the 2-position, and which is otherwise either unsubstituted or optionally substituted; R1 is hydrogen or optionally substituted C1-C6 alkyl; R2 is hydrogen, optionally substituted cycloalkyl, cycloalkenyl, C1-C6 alkyl, C1-C6alkenyl, or C1-C6 alkynyl; or a carboxyl, carboxamide or carboxyl ester group; and R3 is a carboxamide group.

Substituted pyrrolo-pyrazole derivatives as kinase inhibitors

Abstract: Substituted pyrrolo-pyrazole derivatives of formula (I) and pharmaceutically acceptable salts thereof, as defined in the specification, process for their preparation and pharmaceutical compositions comprising them are disclosed; the compounds of the invention may be useful in therapy in the treatment of diseases associated with dysregulated protein kinase activity, like cancer

Stability and structure of mono- and dinuclear Cu(II), Ni(II) and Zn(II) complexes of pyrazole and triazole bridged bis-macrocycles

Abstract: The two ligands L1 and L2, consisting of two 1,4,7-triazacyclononane rings bridged by a pyrazole or a triazole group, form with Cu2+, Ni2+ and Zn2+ a series of mononuclear [MLHn](n + 2)+ (n = −3, −2, −1, 0, 1, 2) and dinuclear species [M2LHm](m + 4)+ (m = 0, −1, −2, −3), the stabilities of which have been determined by potentiometric titrations. The triazole bridged ligand L1 forms complexes which are more stable than those of the pyrazole bridged system L2. It also shows a higher tendency to form dinuclear species compared to L2. In addition two dinuclear species [Cu2(L2H−1)(μ-Ph2PO2)](ClO4)2·MeCN and [Cu4(L2H−1)2(μ4-PO4)](ClO4)3·MeCN·H2O have been isolated as solids and their X-ray structures have been determined. In the first complex we find a dinuclear Cu2+ species which is bridged by the pyrazolide group as well as by the exogenous diphenyl phosphinate. In the second case a μ4-phosphate ion bridges two dinuclear units, resulting in a tetranuclear species.

Synthesis of novel tricyclic heterocyclic compounds as potential anticancer agents using chromanone and thiochromanone as synthons

Abstract: The arylmethylene of benzopyrane or benzothiopyrane 3,4 have been synthesized and condensed with hydrazine, guanidine and thiourea to yield pyrazole 5-8, aminopyrimidine 9,10 and thioxopyrimidine derivatives 11,12, respectively. Compounds 3 or 4 on treatment with malononitrile in the presence of ammonium acetate/acetic acid or in the presence of piperidine/ methanol to yield benzopyrano- and benzothiopyranopyridine 13,14 and benzopyrano- and benzothiopyrane 15,16, respectively. The oxirane of compound 3 is prepared and condensed with CS 2 to yield the tricyclic system, thioxothienobenzopyrane 21. Ylidenemalononitrile for the ketone 1 and 2 are synthesized and condensed with aromatic aldehyde in presence of ammonium acetate/acetic acid to yield benzopyranopyridine and benzothiopyranopyridine derivatives 24,25, respectively, which are the isomer of compounds 13,14. Ylidenemalononitrile on condensation with phenylisothiocyanate yields benzo-pyrano- and benzothiopyranothioxopyridine 28,29, respectively.

Pyrazole compounds for treatment of neurodegenerative disorders

Abstract: The invention provides compounds of Formula (I): wherein R1,R2,R3, R4,R6,R7, R8 and A are as defined Compounds of formula (I) have activity inhibiting production of Abeta-peptide The invention also provides pharmaceutical compositions and methods for treating diseases, for example Alzheimer's disease, in mammals comprising compounds of Formula (I)

Immobilization of pyrazole compounds on silica gels and their preliminary use in metal ion extraction

Abstract: A series of acyclic pyrazole derivatives was prepared by condensation reactions. These compounds were covalently immobilized on silica gel through a flexible 3-glycidoxypropyltrimethoxysilane spacer arm. These materials were used as sorbents for the recovery of heavy and alkali metal ions from aqueous solutions. They exhibit good selectivity between heavy metal ions and alkali ions with an affinity especially high towards mercury. The comparison with liquid-liquid extraction shows that the capacity is not affected by the grafting of the pyrazole rings on the surface of silica. In addition, the solid-liquid process is more convenient in terms of facility of use.