Showing papers on "Pyrazole published in 2002"

7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists: a study on the importance of modifications at the side chain on the activity and solubility.

Abstract: It was demonstrated in the early 1990s that adenosine exerts many physiological functions through the interaction with four different receptors, named A1, A2A, A2B, and A3. In the past few years, our group has been involved in the development of A2A antagonists, which led to the synthesis of SCH 58261 (1), the first potent and selective adenosine A2A antagonist, which has been widely used as a reference compound. In this paper, we present an extended series of pyrazolotriazolopyrimidines synthesized with the aim to investigate the influence of the substitutions on the pyrazole ring. The choice of the substituents was based on their capability to improve water solubility while retaining high affinity and selectivity at the human A2A adenosine receptor subtype. In this series, some structural characteristics that are important for activity, i.e., tricyclic structure, free amino group at 5-position, furan ring, and substituent at 7-position on the pyrazole moiety, have been maintained. We focused our attenti...

Molecular interaction of the antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1- (2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide with the CB1 cannabinoid receptor.

Abstract: N-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 1) is a potent and selective antagonist for the CB 1 cannabinoid receptor. Using the AM1 molecular orbital method, conformational analysis of 1 around the pyrazole C3 substituent identified four distinct conformations designated Tg, Ts, Cg, and Cs. The energetic stability of these conformers followed the order Tg > Cg > Ts >Cs for the neutral (unprotonated) form of 1 and Ts > Tg > Cs > Cg for its piperidine N-protonated form. Unified pharmacophore models for the CB 1 receptor ligands were developed by incorporating the protonated form of 1 into the superimposition model for the cannabinoid agonists 4-[4-(1,1-dimethylheptyl)-2-hydroxyphenyl]perhydro-2α,6β-dihydroxynaphthalene (CP55244; 2) and the protonated form of (R)-[2,3-dihydro-5-methyl-3-[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl](1-naphthalenyl)methanone (WIN55212-2; 3) reported previously (Shim et al. In Rational Drug Design Symposium Series; Parrill, A. L., Reddy, M. R., Eds.; American Chemical Society: Washington, DC, 1999; pp 165-184). Values of K i for 1 and a series of 31 structural analogues were determined from radioligand binding analyses by competitive displacement of [ 3 H]CP55940 from cannabinoid receptors in a rat brain membrane preparation. Comparative molecular field analysis (CoMFA) was employed to construct three-dimensional (3D)-quantitative structure-activity relationship (QSAR) models for this data set as unprotonated species assuming the Tg, Cg, and Ts conformers and for the protonated species assuming the Ts, Tg, and Cs conformers. Values of the conventional r 2 and cross-validated r 2 (r cv 2 ) associated with these CoMFA models exceeded the threshold for statistical robustness (r 2 ≥ 0.90) and internal predictive ability (r cv 2 ≥ 0.50) in each of these six cases except for the protonated species assuming the Tg conformer (i.e., r 2 = 0.97; r cv 2 = 0.36). Results from conformational analyses, superimposition models, and 3D-QSAR models suggest that the N1 aromatic ring moiety of 1 dominates the steric binding interaction with the receptor in much the same way as does the C3 alkyl side chain of cannabinoid agonists and the C3 aroyl ring of the aminoalkylindole agonists. We also determined that several of the conformers considered in this study possess the proper spatial orientation and distinct electrostatic character to bind to the CB 1 receptor. We propose that the unique region in space occupied by the C5 aromatic ring of 1 might contribute to conferring antagonist activity. We further propose that the pyrazole C3 substituent of 1 might contribute to conferring either neutral antagonist or inverse agonist activity, depending upon the interaction with the receptor.

New flexible synthesis of pyrazoles with different, functionalized substituents at C3 and C5.

Abstract: Syntheses of pyrazoles featuring a functionalized side chain attached to carbon 3 and varying alkyl and aryl substituents attached to carbon 5 are presented. Installation of R = methyl, isopropyl, tert-butyl, adamantyl, or phenyl groups at C5 is reported here, starting by coupling protected alkynols with acid chlorides RCOCl, forming alkynyl ketones, which are reacted with hydrazine to form the pyrazole nucleus. Alcohol deprotection and conversion to a chloride gave 5-substituted 3-(chloromethyl)- or 3-(2-chloroethyl)pyrazoles. This sequence can be done within 2 d on a 30 g scale in excellent overall yield. Through nucleophilic substitution reactions, the chlorides are useful precursors to other polyfunctional pyrazoles. In the work here, derivatives with side chains LCH(2)- and LCH(2)CH(2)- at C3 (L = thioether or phosphine) were made as ligands. The significance of the ligands made here is that by placing a ligating side chain on a ring carbon (C3), rather than on a ring nitrogen, the ring nitrogen not bound to the metal and its attached proton will be available for hydrogen bonding, depending on the steric environment created by R at C5.

Synthesis and Structure−Activity Relationships of Amide and Hydrazide Analogues of the Cannabinoid CB1 Receptor Antagonist N-(Piperidinyl)- 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716)

Abstract: Analogues of the biaryl pyrazole N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 5) were synthesized to investigate the structure−activity relationship (SAR) of the aminopiperidine region. The structural modifications include the substitution of alkyl hydrazines, amines, and hydroxyalkylamines of varying lengths for the aminopiperidinyl moiety. Proximity and steric requirements at the aminopiperidine region were probed by the synthesis of analogues that substitute alkyl hydrazines of increasing chain length and branching. The corresponding amide analogues were compared to the hydrazides to determine the effect of the second nitrogen on receptor binding affinity. The N-cyclohexyl amide 14 represents a direct methine for nitrogen substitution for 5, reducing the potential for heteroatom interaction, while the morpholino analogue 15 adds the potential for an additional heteroatom interaction. The series of hydroxyalkyl amides of increasing chain length ...

New structural forms in molecular metal phosphonates: novel tri- and hexanuclear zinc(II) cages containing phosphonate and pyrazole ligands.

Abstract: The reaction of ZnCl2 with tert-butylphosphonic acid and 3,5-dimethylpyrazole in the presence of triethylamine as a hydrogen chloride scavenger affords a trinuclear molecular zinc phosphonate [Zn3Cl2(3,5-Me2Pz)4(t-BuPO3)2]. The structure of this compound contains a planar trizinc assembly containing two bicapping μ3 [t-BuPO3]2- ligands and terminal pyrazole and chloride ligands. In contrast an analogous reaction of ZnCl2 with phenylphosphonic acid and 3,5-dimethylpyrazole affords a hexanuclear zinc phosphonate [Zn6Cl4(3,5-Me2PzH)8(PhPO3)4]. The six zinc centers are arranged in a chairlike conformation. The four phosphonates in this complex also act as bridging tripodal μ3 [RPO3]2- ligands.

Density Functional Study on the Adsorption of Pyrazole onto Silver Colloidal Particles

Abstract: The adsorption of pyrazole onto silver colloids has been investigated by surface-enhanced Raman scattering (SERS) experiments for normal and deuterated ligand and by ab initio density functional theory (DFT) calculations performed for surface complex models. The best agreement between observed and calculated frequencies occurs when the pyrazolide anion is bound to two partially charged Ag atoms of the colloidal surface. The formation of the adsorbate is closely related to the presence of adsorbed hydroxide anions, which are able to promote the deprotonation of the organic ligand.

Novel pyrazole analogs acting on cannabinoid receptors

Abstract: One aspect of the invention is concerned with cannabimimetic pyrazole analogs. Another aspect of the invention is concerned with new and improved pyrazole analogs having high affinities and/or selectivities for the CB1 cannabinoid receptor. A further aspect of the invention is concerned with pharmaceutical preparations employing the inventive analogs and methods of administering therapeutically effective amounts of the inventive analogs to provide a physiological effect.

Large conductance calcium-activated k channel opener

Abstract: The present invention provides a large conductance calcium-activated K channel opener comprising a compound of the formula (I): wherein R1 and R3 are each sulfonamide, carbamoyl, acyl, amino, and the like, m and n are each 0 to 2, R2 and R4 are each cyano, nitro, hydroxyl, an alkoxy, a halogen, or an alkyl, Ring A is benzene or a heterocyclic ring, Ring B is benzene, a heterocyclic ring, a cycloalkane etc, and Ring Q is pyrazole or isoxazole, or a pharmaceutically acceptable salt thereof as an active ingredient.

Novel 4,5-dihydro-1h-pyrazole derivatives having cb1-antagonistic activity

Abstract: The present invention relates to a group of novel 4,5-dihydro-1H-pyrazole derivatives which are potent cannabinoid (CB1) receptor antagonists with utility for the treatment of diseases connected with disorders of the cannabinoid system. The compounds have the general formula (I) wherein the symbols have the meanings given in the specification. The invention also relates to methods for the preparation of these compounds, and to pharmaceutical compositions containing one or more of these compounds as an active component.

Carbonic anhydrase activators: design of high affinity isozymes I, II, and IV activators, incorporating tri-/tetrasubstituted-pyridinium-azole moieties.

Abstract: A series of tight binding carbonic anhydrase (CA) activators was obtained by reaction of amino-azoles (3-amino-pyrazole, 2-amino-imidazole, and 5-amino-tetrazole) with tri- or tetrasubstituted pyrylium salts. Many of the new pyridinium salts incorporating azole moieties reported here proved to be efficient in vitro activators of three CA isozymes, CA I, II, and IV. Very good activity was detected against hCA I and bCA IV (h = human; b = bovine isozymes), for which some of the new compounds showed affinities in the low nanomolar range, whereas against hCA II, their affinities were in the range of 95−150 nM. Substitution patterns of the pyridinium ring leading to best activity included 4-phenyl-2,6-dialkyl moieties or 2,4,6-tri- and 2,3,4,6-tetraalkyl groups. Ex vivo experiments showed some of the new activators to strongly enhance CA activity after incubation with human erythrocytes. Furthermore, due to their cationic nature, some of these compounds (the imidazole and pyrazole derivatives) are membrane-imp...

O-pyrazole glucoside sglt2 inhibitors and method of use

Abstract: A compound of formula (I), wherein A is CH2 or (CH2)2; R1 is hydrogen, arylalkyl, alkenyl, or alkyl; R2 is alkyl or perfluoroalkyl; and R?3 and R4? are as defined herein. Further provided are methods of using such compounds for the treatment of diabetes and related diseases, and to pharmaceutical compositions containing such compounds.

Substituted dihydro 3-halo-1h-pyrazole-5-carboxylates their preparation and use

Abstract: This invention relates to a compound of Formula I, a method for its preparation and its use in the preparation of a compound of Formula II wherein R1, R2, R3, X and n are as defined in the disclosure.This invention also discloses preparation of compounds of Formula III wherein R1, R2, R6, R7, R8 and n are as defined in the disclosure.Also disclosed are certain intermediates of Formula 4 for the preparation of compounds of Formula I wherein X is N and R2, R3 and n are as defined in the disclosure.

Design, synthesis and biological activity of rigid cannabinoid CB1 receptor antagonists.

Abstract: The design, synthesis and biological activities of potent pyrazole-based tricyclic CB1 receptor antagonists (2) are described. The key synthetic step involves the ring closure of the lithiated α, γ-keto ester adduct (4). The optimal nitroderivative (28) in this series exhibits a high CB1 receptor affinity (pKi=7.2) as well as very potent antagonistic activity (pA2=8.8) in vitro. The regioselectivity of the pyrazole ring closure is shown to depend strongly on the aromatic substitution pattern of the applied arylhydrazine.

Design, synthesis, and antiproliferative activity of some new pyrazole-fused amino derivatives of the pyranoxanthenone, pyranothioxanthenone, and pyranoacridone ring systems: a new class of cytotoxic agents.

Abstract: A series of novel pyranoxanthenones, pyranothioxanthenones, and pyranoacridones have been designed and synthesized as analogues of the acridone alkaloid acronycine, and their DNA binding and in vitro cytotoxicities have been investigated. The title compounds were derived by reaction of the corresponding 6-tosylates 5a-e with 2-hydroxyethylhydrazine, followed by conversion of the free hydroxyl of the substituted ethanols 6a-e to the corresponding mesylates, which were then treated with the suitably substituted secondary amines to provide the target derivatives 8-27. An alternative synthetic procedure for the preparation of these types of compounds is also developed, which resulted in an improvement of the overall yield. The new compounds exhibited interesting cytotoxic activity against the murine leukemia L1210 cell line, being more active than the parent compound, and a number of them possessed cytotoxicity against some human solid tumor cell lines. Especially in the case of a colon adenocarcinoma cell line, their IC(50) values were comparable to that of mitoxantrone. The results of this study indicate that the incorporation of an amino-substituted pyrazole ring into the acronycine chromophore, or into its isosteres, results in an improvement of the lead compound's activity, and therefore, it may be of use in the search of new anticancer agents derived from this natural product.

3-arylphenyl sulfide derivative and insecticide and miticide

Abstract: 3-Arylphenyl sulfide derivatives represented by general formula (I): (wherein R is a C2-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group or the like, B0 to B2 and B3 are hydrogen atoms, halogen atoms, cyano groups, C1-C4 haloalkyl groups or the like, n is 0, 1 or 2, and Ar is a phenyl ring, a pyridine ring, a thiophene ring, a pyrazole ring or the like), and insecticides and miticides containing the 3-arylphenyl sulfide derivatives as an active ingredient.

Benzamidoxime derivatives, intermediates and processes for their preparation, and their use as fungicides

Abstract: Benzamidoxime derivatives of the formula I: where R1 is difluoromethyl or trifluoromethyl R2 is hydrogen or fluorine R3 is C1-C4-alkyl which may be substituted by cyano, C1-C4-haloalkyl, C1-C4-alkoxy-C1-C4-alkyl, C3-C6-alkenyl, C3-C6-haloalkenyl, C3-C6-alkynyl, C3-C8-cycloalkyl-C1-C4-alkyl R4 is phenyl-C1-C6-alkyl which may carry one or more substitutents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy on the phenyl ring, or is thienyl-C1-C4-alkyl which may carry one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy on the thienyl ring, or is pyrazolyl-C1-C4-alkyl which may carry one or more substituents selected from the group consisting of halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy on the pyrazole ring, are prepared, and intermediates for their preparation and their use as fungicides are described.

Tuning and dissecting electronic and steric effects in ammonium receptors: Nonactin vs artificial receptors

Abstract: Ion selective electrodes (ISE) based on three different tripodal receptors (5, 6, and 7) have been investigated for sensing ammonium ion. Each receptor is based on three pyrazole groups that can accept three H-bonds from the bound ammonium ion. The receptor based on 4-bromo-3,5-dimethylpyrazole (6) is the most sensitive with a detection limit for ammonium ion of 2.5 x 10(-5) M at pH 8. The detection limits for the receptors based on 2,3-dimethylpyrazole (5) and unsubstitued pyrazole (7) are 1.0 x 10(-4) and 2.0 x 10(-4) M, respectively. The selectivities of the receptors 5, 6, and 7 for sensing ammonium ion over potassium ion (logK(NH)4+(/K)+) are -2.8, -2.3, and -1.7, respectively. In contrast, the detection limit and the selectivity of a nonactin-based ISE are 2.2 x 10(-5) M and -1.3, respectively. Crystallographic studies reveal that 6 accepts three H-bonds from the bound ammonium and singly protonated receptor 5 forms three H-bonds with the bound water molecule.