Pyrazole Carboxylic Acid Research Articles

Synthesis and Some Reactions of Pyrazole-3-carboxylic acid Having Trifluoromethyl Unit

4-Benzoil-5-fenil-2,3-furandion 1 ve (4-(triflorometil)fenil) benzaldehit-fenil hidrazonun 1a reaksiyonundan 4-benzoil-5-fenil-1-(4-(triflorometil)fenil)-1 H -karboksilik asit 2 elde edildi. Elde edilen yeni pirazol karboksilik asit ( 2 ) turevi, asit klorurune donusturuldu ve cesitli nukleofillerle asit klorur arasinda yeni turevlerin reaksiyonlari gerceklestirildi. Esterler ( 4a-c ), ilgili alkoller ve asit klorur ( 3 ) ile Schotten Baumann metodu kullanilarak elde edildi. Pirazolopiridazinon turevleri ( 8 , 9 , 10 ), pirazol karboksilik asit ve cesitli hidrazinler arasindaki halkalanma reaksiyonlari sonucunda elde edildi. Ek olarak, amidleri ( 5a , 5b-5f ) ve karbon-ure turevlerini ( 6a-c ) elde etmek icin asit klorur ile cesitli aminler ve urelerle reaksiyonlar gerceklestirildi. Nitril bilesigi ( 7 ), SOCl 2 ve DMF kullanilarak amin bilesiginden suyun uzaklastirilmasi ile elde edildi. Sentezlenen tum molekuller, potansiyel aktivitelerinden dolayi antimikrobiyal aktiviteye tabi tutuldu. Molekullerden 6-nitro-3,4-difenil-2-(4-(triflorometil)fenil)-2,6-dihidro-7 H -pirazolo[3,4-d]piridazin-7-on bilesiginin ( 10 ) sadece Gram-pozitif bakterilere karsi antibakteriyal aktivite gosterdi. Bacillus cereus ve Micrococcus luteus , A MIC degerleri 32 ve 128 µg/mL aktif oldugu bulundu. Yapisinda nitro grubu bulunduran ve aktivite gosteren 10 nolu molekulden dolayi fonksiyonel grubun aktivite uzerinde onemli bir etkisi oldugu soylenebilir. Ayrica 10 nolu molekulun pozitif kontrol olan streptomycin antibiyotiginden daha etkili bir zon olusturdugu da gozlendi. Bu durumda etkisini gosterdigi bakteriler icin ileri calismalar konusunda iyi bir antibiyotik adayi olabilir.

Related Acoustical Parameters and Ultrasonic Velocity of substituted Pyrazole Carboxylic Acid derivatives at 305K in 80% (DMF+Water) Mixture at Different Concentrations

Related Acoustical Parameters and Ultrasonic Velocity of substituted Pyrazole Carboxylic Acid derivatives at 305K in 80% (DMF+Water) Mixture at Different Concentrations

Structure analysis of a phenylpyrazole carboxylic acid derivative crystallizing with three molecules in the asymmetric unit (Z′ = 3) using X-ray powder diffraction

Crystal structure analysis of a pyrazole carboxylic acid derivative, 5-(trifluoromethyl)-1-phenyl-1H-pyrazole-4-carboxylic acid (1) has been carried out from laboratory powder X-ray diffraction data. The crystal packing in the pyrazole carboxylic acid derivative exhibits an interplay of strong O–H…O, C–H…N and C–H…F hydrogen bonds to generate a three-dimensional molecular packing via the formation ofR22(8) andR22(9) rings. Molecular electrostatic potential calculations indicated that carbonyl oxygen, pyrazole nitrogen and fluorine atoms to be the strongest acceptors. The relative contribution of different interactions to the Hirshfeld surface of pyrazole carboxylic acid and a few related structures retrieved from CSD indicates that H…H, N…H and O…H interactions can account for almost 70% of the Hirsfeld surface area in these compounds.

Structural Elucidation and Supercapacitive Performance in a 1D Cadmium(II) Polymer Based on Pyrazole Carboxylic Acid

One pyrazole carboxylic complex, namely, {[Cd(Hpzca)2(H2O)3]·H2O}n (1), where H2pzca is 1H-pyrazole-4-carboxylic acid, has been synthesized under solvothermal condition, and the crystal structure was determined by single crystal X-ray diffraction. The X-ray study reveals that complex 1 is a 1D polymer. While it was used as the electrode material for a supercapacitor, exhibited large specific capacitance, high rate capability and good cycling stability. Capacitances of 106 F g−1 could be achieved at a rate of 0.5 mVs−1 and the retention was maintained at about 93% even after 1000 cycles.

Enantioselective synthesis of GNE-6688, a potent and selective inhibitor of interleukin-2 inducible T-cell kinase (ITK)

An enantioselective synthesis of the previously-disclosed ITK inhibitor GNE-6688 is described. Synthesis of the nitropyrazole fragment is highlighted by a Ru-catalyzed transfer hydrogenation using the Wills tethered ligand system. Synthesis of the pyrazole carboxylic acid fragment features an allylboration catalyzed by a chiral diol-SnCl4 complex, followed by a highly diastereoselective directed cyclopropanation.

Brightly luminescent lanthanide pyrazolecarboxylates: Synthesis, luminescent properties and influence of ligand isomerism

The complexes of the formula Ln(carb)3(H2O)2 (where Ln = Eu, Tb, Gd, La, Yb; carb = various pyrazolecarboxylic acids) were synthesized and thoroughly characterized. It was shown that the quantum yields of terbium complexes depend mainly on the type of substituents of the ligand, while the quantum yields of europium complexes are influenced by the ligand isomerism due to the presence or absence of the ligand-to-metal charge transfer (LMCT) state. These compounds were successfully tested as bioimaging probes as well as OLED emitting layers due to their high photo- and electroluminescent performance.

Computing Eccentricity Based Topological Indices of Octagonal Grid O n m

Graph theory is successfully applied in developing a relationship between chemical structure and biological activity. The relationship of two graph invariants, the eccentric connectivity index and the eccentric Zagreb index are investigated with regard to anti-inflammatory activity, for a dataset consisting of 76 pyrazole carboxylic acid hydrazide analogs. The eccentricity ε v of vertex v in a graph G is the distance between v and the vertex furthermost from v in a graph G. The distance between two vertices is the length of a shortest path between those vertices in a graph G. In this paper, we consider the Octagonal Grid O n m . We compute Connective Eccentric index C ξ ( G ) = ∑ v ∈ V ( G ) d v / ε v , Eccentric Connective Index ξ ( G ) = ∑ v ∈ V ( G ) d v ε v and eccentric Zagreb index of Octagonal Grid O n m , where d v represents the degree of the vertex v in G.

Crystal engineering of a series of complexes and coordination polymers based on pyrazole-carboxylic acid ligands

Three new complexes and two coordination polymers have been synthesized.

Sedaxane, Isopyrazam and Solatenol™: Novel Broad-spectrum Fungicides Inhibiting Succinate Dehydrogenase (SDH) - Synthesis Challenges and Biological Aspects.

Sedaxane (SDX) 1, isopyrazam (IZM) 2 and Solatenol™ (STL) 3 are broad-spectrum pyrazole carboxamides, which originate from novel chemical classes of fungicides. Their mode of action (MoA) is inhibition of succinate dehydrogenase (SDH), which was recognized for a long time to deliver only compounds with a narrow biological spectrum. This view changed with the market introduction of BASF's boscalid in 2003. All major agro-companies subsequently worked in parallel on this MoA successfully and recently introduced new compounds to the market. Syngenta entered the SDHI area in 1998 and was able to introduce three complementary compounds to the market between 2010 and 2012. In this short review some synthesis challenges and biological effects of SDX 1, IZM 2 and STL 3 will be covered. New cost-efficient synthesis strategies for the preparation of o-biscyclopropyl-aniline, new benzonorbornene intermediates and the key pyrazole carboxylic acid intermediate which is essential for all three Syngenta SDHIs, will be in the focus of this review.

Ligand concentration-dependent supramolecular complexes with uncoordinated carbonyl groups based on a new pyrazole carboxylic acid ligand

One new pyrazole-based ligand, 1-carboxymethyl-3,5-dimethyl-1H-pyrazole-4-carboxylic acid (H2cmdpca), has been synthesized and characterized. Structural analysis reveals that H2cmdpca crystallizes in the monoclinic system and adopts a 3-D supramolecular network via the interaction of intermolecular hydrogen bonds. The reactions of Cd(II) ions with H2cmdpca and 4,4′-bipyridine (4,4′-bpy) afforded three metal complexes, [Cd(4,4′-bpy)(Hcmdpca)2(H2O)3]·H2O (1), [Cd(4,4′-bpy)(Hcmdpca)2(H2O)]·3H2O (2), and [Cd(4,4′-bpy)(Hcmdpca)2(H2O)] (3). Structural analyses reveal that these complexes are all monoclinic and 1, 2, and 3 exhibit mononuclear, 1-D chain, and 1-D with binuclear loop structures, respectively, which are further assembled into 3-D supramolecular frameworks through non-covalent interactions. 1 and 2 are true supramolecular isomers, while 2 and 3 are “pseudo-supramolecular” isomers. In addition, the thermal stability and luminescent properties of the complexes are also investigated.

Ordered vacancies and their chemistry in metal-organic frameworks.

Vacancies are common in solid materials, but it remains a challenge to introduce them at specific locations with controlled distributions. Here we report the creation of ordered metal vacancies and linker vacancies in a cubic metal-organic framework (MOF) based on Zn(II) and pyrazolecarboxylic acid by removing a quarter of the metal ions and half of the linkers. The MOF with ordered vacancies shows increased pore size, thus allowing large dye molecules to fit in the pores. Furthermore, by filling the vacancies with new metals and new linkers, eight new single-crystalline MOFs with multicomponents in absolute order are introduced. The capability of performing stepwise elimination and addition reactions systematically in extended solids without destroying the structural integrity has generated complex MOF structures which otherwise cannot be made.

Pyrazole derivatives as potent inhibitors of c-Jun N-terminal kinase: Synthesis and SAR studies

Mitogen activated protein kinases including c-Jun N-terminal kinase play an indispensable role in inflammatory diseases. Investigation of reported JNK-1 inhibitors indicated that diverse heterocyclic compounds bearing an amide group rendered potent JNK-1 inhibitory activity which prompted us to synthesize new JNK-1 inhibitors containing a pyrazole heterocyclic group. A DABCO mediated 1,3-dipolar cycloaddition reaction in neat resulted in pyrazole carboxylic acid which was converted to desired amides. Upon confirmation of the structures, all the compounds were screened for JNK-1 inhibitory activity and in vivo anti-inflammatory activity. Several synthesized analogues have exhibited JNK-1 inhibitory activity less than 10μM, in particular compounds 9c, 10a and 10d were found to be potent among all the compounds.

Synthesis, structure–activity relationships, and in vitro antibacterial and antifungal activity evaluations of novel pyrazole carboxylic and dicarboxylic acid derivatives

A series of pyrazole-3-carboxylic acid and pyrazole-3,4-dicarboxylic acid derivatives were synthesized, the structures were confirmed by their NMR (1H and 13C) and FT-IR spectra, and elemental analyses. The antibacterial and antifungal activities of the compounds against five bacterial and five fungal pathogens were screened using modified agar well diffusion assay. Most of the molecules have inhibitory effects on both standard and clinical Candida albicans strains. However, only the molecules 8, 10, 21, and 22 demonstrate some inhibitory effects on Candida parapsilosis, Candida tropicalis, and Candida glabrata strains. The structure–antifungal activity relationships of the compounds on the C. albicans strains were investigated by electron-conformational method. The pharmacophores and antipharmacophores responsible for the inhibition and non-inhibition of the C. albicans strains were obtained by electronic and geometrical characteristics of the reactive fragments of the molecules. These fragments along with the associated parameters can be used in designing the future more potent antifungal agents. It has been shown that both the positions of electronegative atoms like F and O in the pyrazole substituents and the amount of the associated charges on such atoms are crucial in regulating the strength of antifungal activity for the C. albicans strain.

ChemInform Abstract: Convergent and Streamlined Synthesis of 6‐Etherified Imidazo[1,2‐b]pyridazine‐2‐amine Derivatives Possessing VEGFR‐2 Kinase Inhibitory Activity.

Abstract A convergent and streamlined synthesis of selective vascular endothelial growth factor receptor (VEGFR) 2 kinase inhibitors has been achieved using a synthetic strategy based on an SNAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in the final step. For the synthesis of 6-chloroimidazo[1,2-b]pyridazine, a one-pot reaction using 3-amino-6-chloropyridazine, cyclopropanecarboxamide, and bromoacetyl bromide was developed. The phenols were easily prepared by chemoselective acylation of 3-aminophenols with pyrazole carboxylic acids, and an efficient and high-yielding synthesis of N-ethylpyrazole was also developed. The SNAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in DMSO in the presence of cesium carbonate successfully proceeded at 100–110 °C to give the target products in good yields. This new chromatography-free process will be not only useful for the further bulk supply of these compounds but also applicable to the synthesis of other compounds containing the 6-etherified imidazo[1,2-b]pyridazin-2-amine core.

MODIFIED METHOD FOR THE SYNTHESIS OF ISOMERIC N -SUBSTITUTED (1 H -PYRAZOLYL)PROPANE-1,3-DIONES

The condensation reaction of isomeric N -substituted (1 H -pyrazol-4-yl)ethanones with the ethyl esters of pyrazole carboxylic acids and fluoroacetic acids has been studied using NaH as the base. Under optimized conditions, it proved to be a convenient and preparative method for the synthesis of N -substituted (1 H -pyrazolyl)propane-1,3-diones and (1 H -pyrazolyl)-4-polyfluorobutane-1,3-diones. Authors: I. V. Taydakov and S. S. Krasnoselsky English translation in Chemistry of Heterocyclic Compounds , 2011, 47 (6), pp 695-699 http://link.springer.com/article/10.1007/s10593-011-0821-1

Design, Synthesis, and Bioactivity of Pyrazole Acid Derivatives as Endothelin Receptor Antagonists

A series of novel pyrazole carboxylic acid derivatives was designed and synthesized, and their antagonism effect on endothelin (ET)-1-induced contraction in the rat thoracic aortic ring was screened. The radio receptor assay was used to examine the potency of the compounds on ET receptor. Some target compounds demonstrated significant inhibitory activity, especially 7m, which showed a potent inhibition percentage higher than the contrast compound BQ123. Further assays on the binding and selectivity for ET showed that 7m had highly potent binding activity on ETA at the nanomole level, and the ratio of ETA/ETB was 36. Therefore, we inferred that 7m was a non-selective antagonist of ETA and ETB and had potential for further development in cardiovascular diseases.

Convergent and streamlined synthesis of 6-etherified imidazo[1,2-b]pyridazine-2-amine derivatives possessing VEGFR-2 kinase inhibitory activity

A convergent and streamlined synthesis of selective vascular endothelial growth factor receptor (VEGFR) 2 kinase inhibitors has been achieved using a synthetic strategy based on an SNAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in the final step. For the synthesis of 6-chloroimidazo[1,2-b]pyridazine, a one-pot reaction using 3-amino-6-chloropyridazine, cyclopropanecarboxamide, and bromoacetyl bromide was developed. The phenols were easily prepared by chemoselective acylation of 3-aminophenols with pyrazole carboxylic acids, and an efficient and high-yielding synthesis of N-ethylpyrazole was also developed. The SNAr reaction of 6-chloroimidazo[1,2-b]pyridazine with phenols in DMSO in the presence of cesium carbonate successfully proceeded at 100–110 °C to give the target products in good yields. This new chromatography-free process will be not only useful for the further bulk supply of these compounds but also applicable to the synthesis of other compounds containing the 6-etherified imidazo[1,2-b]pyridazin-2-amine core.

Selective non-lipid modulator of LPA5 activity in human platelets

Lysophosphatidic acid (LPA) is a potent activator of human platelets in vitro. Recently, the G protein-coupled receptor LPA5/GPR92 has been identified to be the relevant LPA receptor responsible for the activation of human platelets by LPA. In a high-throughput screening campaign we identified a diphenyl pyrazole carboxylic acid as a small-molecule inhibitor for LPA5. Confirmation for the specificity of this small molecule was achieved in human platelets as the relevant cellular in vitro model. We could confirm using antagonists for alternative LPA receptors that we identified in our work the first non-lipid, small-molecule inhibitor for LPA5/GPR92 specifically inhibiting LPA-mediated platelet activation in vitro.

Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain l-2-hydroxy acid oxidase

Long chain l-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.

(1aR,5aR)1a,3,5,5a-Tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic Acid (MK-1903): A Potent GPR109a Agonist that Lowers Free Fatty Acids in Humans

G-protein coupled receptor (GPCR) GPR109a is a molecular target for nicotinic acid and is expressed in adipocytes, spleen, and immune cells. Nicotinic acid has long been used for the treatment of dyslipidemia due to its capacity to positively affect serum lipids to a greater extent than other currently marketed drugs. We report a series of tricyclic pyrazole carboxylic acids that are potent and selective agonists of GPR109a. Compound R,R-19a (MK-1903) was advanced through preclinical studies, was well tolerated, and presented no apparent safety concerns. Compound R,R-19a was advanced into a phase 1 clinical trial and produced a robust decrease in plasma free fatty acids. On the basis of these results, R,R-19a was evaluated in a phase 2 study in humans. Because R,R-19a produced only a weak effect on serum lipids as compared with niacin, we conclude that the beneficial effects of niacin are most likely the result of an undefined GPR109a independent pathway.