- Synthesis, characterization and cell viability test of six vanadyl complexes with acetylacetonate derivatives
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Vanadium compounds are known to display a number of therapeutic effects, namely insulin-mimetic and cardiovascular effects. Evidence of the antiproliferative and proapoptotic activity of a number of vanadyl complexes, together with their low toxicity, establishes these metal compounds as promising antitumoral therapeutic agents. In the present work, we describe the synthesis and full characterization of six new vanadyl complexes with acetylacetonate derivatives bearing asymmetric substitutions on the β-dicarbonyl moiety: the complexes were characterized in the solid state as well as in solution. Our results show that all complexes are in square pyramidal geometry; cis isomers in the equatorial plane are favored in the presence of strongly coordinating solvents. EPR evidence suggests that all complexes are in the bis-chelate form, although in two cases the mono-chelated complex seems to be present as well. Preliminary tests carried out on non-tumor and tumor cell lines show that these complexes are effective in suppressing cell viability and elicit a distinct response of tumor and non-tumor cells.
- Sgarbossa, Speranza,Diana, Eliano,Marabello, Domenica,Deagostino, Annamaria,Cadamuro, Silvano,Barge, Alessandro,Laurenti, Enzo,Gallicchio, Margherita,Boscaro, Valentina,Ghibaudi, Elena
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- A convenient and regioselective synthesis of 4-trifluoromethylpyridines
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Trifluoromethyl-substituted β-diketones regioselectively react with primary enamines such as β-aminocrotononitrile and ethyl β-aminocrotonate, providing moderate to good yields of 4-trifluoromethylpyridines.
- Katsuyama,Ogawa,Yamaguchi,Funabiki,Matsui,Muramatsu,Shibata
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- Synthesis and photoluminescent properties of Eu (III) complexes with fluorinated β-diketone and nitrogen heterocyclic ligands
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Two fluorinated β-diketones and their six europium (III) complexes using 2,2-dipyridine, 1,10-phenanthroline or 4′-phenyl-terpyridine as the secondary ligand were synthesized and characterized. The photoluminescence behavior for these complexes was investigated in solid state in detail. Based on the emission spectra and luminescence decay curves of these complexes in solid state, the Judd-Ofelt intensity parameters (Ωt), lifetime (τ) and luminescence quantum efficiency (η) were determined. The Ω2 values indicate that the europium (III) ion is in a highly polarizable chemical environment in these complexes. Europium (III) complexes with the secondary ligands 2,2-dipyridine or 1,10-phenanthroline exhibited much better photoluminescence properties than complexes with the secondary ligand 4′-phenyl-terpyridine. Especially, europium (III) complexes of 4,4,4-trifluoro-1-(4-fluorophenyl)-butane-1,3-dione containing the secondary ligands 2,2-dipyridine or 1,10-phenanthroline showed a longer lifetime (τ = 0.799 and 0.826 ms, respectively) and a higher luminescence quantum efficiency (η = 56.5 and 56.1, respectively) among these complexes.
- Wang, Dan,Luo, Zheng,Liu, Zhao,Wang, Dunjia,Fan, Ling,Yin, Guodong
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- Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products
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Acylhydrazines react with 1,3-diketones of the general formula CF 3COCH2COR (where R is an aryl or hetaryl group) at both carbonyl groups. The reaction at the trifluoroacetyl group is favored by donor substituents in the aromatic ring of the 1,3-diketone or by the 2-furyl and, especially, 2-thienyl group as a hetaryl substituent, as well as by elevated temperature. The condensation products at the carbonyl group contiguous to the aryl or hetaryl ring have the structure of 5-hydroxy-4,5-dihydropyrazoles and do not undergo tautomeric transformations in solution. The condensation products at the trifluoroacetyl group have either 5-hydroxy-4,5-dihydropyrazole or hydrazone structure and give rise to ring-chain tautomeric equilibrium in solution. Electron-withdrawing substituents in the aromatic ring of the 1,3-dicarbonyl fragment and CDCl3 as solvent favor formation of the cyclic tautomer. The state of the tautomeric equilibrium is weakly sensitive to structural variations in the hydrazine component.
- Pakal'nis,Zerova,Yakimovich
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Read Online
- Development of celecoxib-derived antifungals for crop protection
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Selective COX-2 inhibitor celecoxib was found directly inhibiting the growth of tested phytopathogenic fungi with the inhibitory rate ranging from 30 to 40% at 100 μg/ml. Lead optimization of celecoxib led to the identification of compound 12 among its derivatives as the most active antifungal candidate. The antifungal effect of compound 12 was supposed to be independent of COX-2 inhibition. Transcriptome profiling analysis of Fusarium graminearium (PH-1) treated with compound 12 brought about 406 up-regulated and 572 down-regulated differentially express genes (DEGs) respectively.
- Liu, Xiuxiu,Ma, Yihui,Sun, Xianglong,Yang, Jun,Yang, Lirong
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- An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors
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Integrated continuous manufacturing has emerged as a promising device for the rapid manufacturing of active pharmaceutical ingredients (APIs). We herein report a newly designed continuous flow micro-total process system platform for the rapid manufacturing of celecoxib, a selective nonsteroidal anti-inflammatory drug. This approach has been proven generally for the synthesis of several alkyl and aryl substituted pyrazoles. In order to minimize the tedious work-up process of potential reaction intermediates/products, we have developed a continuous flow extraction and separation platform to carry out the entire reaction sequence resulting in a short residence time with good yield. The present process was further extended to gram-scale synthesis of the COX-2-related API, viz. celecoxib, in the continuous flow process.
- Sthalam, Vinay Kumar,Singh, Ajay K.,Pabbaraja, Srihari
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supporting information
p. 1892 - 1899
(2019/10/11)
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- Application of 1,5-diaryl-3-pyrazole compound in prevention and control of agricultural fungal diseases
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The invention belongs to the technical field of pesticides, and particularly relates to application of 1,5-diaryl-3-pyrazole compound in prevention and control of agricultural fungal diseases. The general structural formula of the 1,5-diaryl-3-pyrazole compound is as shown in the description, wherein R1 is selected from fluorine, methoxyl or methyl; and R2 is selected from -CHOOH, -SO2NH2, -NO2, -F,-C1 or -Br. Compared with a traditional agricultural fungicide, the 1,5-diaryl-3-pyrazole compound provided by the invention is unique in structure, adopts an action mechanism different from that ofa traditional fungicide, and has no cross resistance risks on resistance strains generated by an existing fungicide.
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Paragraph 0020
(2018/12/13)
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- Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
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In a quest to discover new biologically active compounds, a series of twenty novel heterocyclic derivatives substituted at position 5 with -H (7a-7j) or -CF3 (8a-8j), bearing benzenesulfonamide at N-1 position and various aroyl groups at position 4 of the 1,2,3-triazole ring was synthesized and screened for their carbonic anhydrase (CA, EC 4.2.1.1) inhibition potential against four human (h) isoforms hCA I, II, IV and IX. All the compounds (7a-7j and 8a-8j) were synthesized via [3+2] cycloaddition reaction from 4-azidobenzenesulfonamide. Interestingly, compounds 7a-7j were prepared in one pot manner via enaminone intermediate using novel methodology. All the newly synthesized compounds (7a-7j & 8a-8j) were found to be excellent inhibitors of edema related isoform hCA I with their inhibition constant (Ki) ranging from 30.1 to 86.8 nM as compared to standard drug acetazolamide (AAZ) with Ki = 250 nM. Further it was found that most of tested compounds were weaker inhibitors of isoform, hCA II although compounds 7b, 7d-7e, 8a, 8d-8f, 8i (mostly with electron withdrawing substituents) have shown better inhibition potential (Ki i = 52.4 nM) than AAZ (Ki = 74 nM) while against tumor associated hCA IX, all the compounds have shown moderate inhibition potential. Present study have added one more step in exploring the 1,2,3-triazlole moiety in the medicinal field.
- Kumar, Rajiv,Vats, Lalit,Bua, Silvia,Supuran, Claudiu T.,Sharma, Pawan K.
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p. 545 - 551
(2018/06/18)
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- An SAR study of hydroxy-trifluoromethylpyrazolines as inhibitors of Orai1-mediated store operated Ca2+ entry in MDA-MB-231 breast cancer cells using a convenient Fluorescence Imaging Plate Reader assay
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The proteins Orai1 and STIM1 control store-operated Ca2+ entry (SOCE) into cells. SOCE is important for migration, invasion and metastasis of MDA-MB-231 human triple negative breast cancer (TNBC) cells and has been proposed as a target for cancer drug discovery. Two hit compounds from a medium throughput screen, displayed encouraging inhibition of SOCE in MDA-MB-231 cells, as measured by a Fluorescence Imaging Plate Reader (FLIPR) Ca2+ assay. Following NMR spectroscopic analysis of these hits and reassignment of their structures as 5-hydroxy-5-trifluoromethylpyrazolines, a series of analogues was prepared via thermal condensation reactions between substituted acylhydrazones and trifluoromethyl 1,3-dicarbonyl arenes. Structure-activity relationship (SAR) studies showed that small lipophilic substituents at the 2- and 3-positions of the RHS and 2-, 3- and 4-postions of the LHS terminal benzene rings improved activity, resulting in a novel class of potent and selective inhibitors of SOCE.
- Stevenson, Ralph J.,Azimi, Iman,Flanagan, Jack U.,Inserra, Marco,Vetter, Irina,Monteith, Gregory R.,Denny, William A.
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p. 3406 - 3413
(2018/05/24)
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- Targeting DNA with anti-tumor activity of the naphthalene imide structure biodegradable derivatives, pharmaceutical composition and its preparation method and application
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The invention discloses targeted DNA (deoxyribonucleic acid) naphthyldiimide-structure-containing celecoxib derivatives with antitumor activity, of which the structure is disclosed as Formula (I), wherein R is hydrogen, alkyl group or alkoxy group. The invention also discloses a preparation method of the derivatives and application of the derivatives in preparing drugs for resisting mammary cancer, cervical carcinoma and lung adenocarcinoma. The celecoxib structure is modified, and the naphthyldiimide group is used instead of sulfaphenyl group in the celecoxib, thereby designing and synthesizing a series of celecoxib derivatives containing the naphthyldiimide structure unit. The synthesized compounds 5a-5t have certain inhibiting actions on human mammary cancer cells, Hela cells and human lung adenocarcinoma cells. Part of the compounds have excellent antitumor activity, wherein the compounds 5o and 5h have very high selectivity for Hela cells, and the compound 5i has high selectivity for MCF-7 cells. The IC50 value is greatly lower than that of amonafide and higher than that of cis-platinum and celecoxib.
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Paragraph 0123
(2017/07/14)
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- A Sequential Route to Cyclopentenes from 1,6-Enynes and Diazo Ketones through Gold and Rhodium Catalysis
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This work reports the construction of cyclopentene cores from 1,6-enynes and aryl diazo ketones through two new reaction sequences involving initial gold-catalyzed cyclization of 1,6-enynes with diazo species, followed by rhodium-catalyzed skeletal rearrangement of the resulting 3-cyclopropyl-2-en-1-ones. In most instances the rhodium-catalyzed reactions afforded cyclopentene derivatives whereas several n-alkyl- or ortho-substituted phenyl ketones delivered seven-membered oxacycles. A plausible mechanism provides rationales for these two distinct products. (Figure presented.).
- Kale, Balaji S.,Lee, Hsin-Fu,Liu, Rai-Shung
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supporting information
p. 402 - 409
(2017/02/10)
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- Stereoarrayed CF3-Substituted 1,3-Diols by Dynamic Kinetic Resolution: Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation
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CF3-substituted 1,3-diols were stereoselectively prepared in excellent enantiopurity and high yield from CF3-substituted diketones by using an ansa-ruthenium(II)-catalyzed asymmetric transfer hydrogenation in formic acid/triethylamine. The intermediate mono-reduced alcohol was also obtained in very high enantiopurity by applying milder reaction conditions. In particular, CF3C(O)-substituted benzofused cyclic ketones underwent either a single or a double dynamic kinetic resolution during their reduction. Doubling up: A double dynamic kinetic resolution is described for the ansa-ruthenium(II)-catalyzed asymmetric transfer hydrogenation of diketones in formic acid/triethylamine to yield the title compounds, displaying a stereotriad, in excellent stereopurity. The intermediate mono-reduced alcohols were isolated in very high enantiopurity by using milder reaction conditions.
- Cotman, Andrej Emanuel,Cahard, Dominique,Mohar, Barbara
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supporting information
p. 5294 - 5298
(2016/04/26)
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- Synthesis, fungicidal activity and mode of action of 4-phenyl-6-trifluoromethyl-2-aminopyrimidines against Botrytis cinerea
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Anilinopyrimidines are the main chemical agents for management of Botrytis cinerea. However, the drug resistance in fungi against this kind of compounds is very serious. To explore new potential fungicides against B. cinerea, a series of 4-phenyl-6-trifluoromethyl-2-amino-pyrimidine compounds (compounds III-1 to III-22) were synthesized, and their structures were confirmed by 1H-NMR, IR and MS. Most of these compounds possessed excellent fungicidal activity. The compounds III-3 and III-13 showed higher fungicidal activity than the positive control pyrimethanil on fructose gelatin agar (FGA), and compound III-3 on potato dextrose agar (PDA) indicated high activity compared to the positive control cyprodinil. In vivo greenhouse results indicated that the activity of compounds III-3, III-8, and III-11 was significantly higher than that of the fungicide pyrimethanil. Scanning electron micrography (SEM) and transmission electron micrography (TEM) were applied to illustrate the mechanism of title compounds against B. cinerea. The title compounds, especially those containing a fluorine atom at the ortho-position on the benzene ring, could maintain the antifungal activity against B. cinerea, but their mechanism of action is different from that of cyprodinil. The present study lays a good foundation for us to find more efficient reagents against B. cinerea.
- Liu, Chunhui,Cui, Zining,Yan, Xiaojing,Qi, Zhiqiu,Ji, Mingshan,Li, Xinghai
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- 1,5-Diketones Synthesis via Three-Component Cascade Reaction
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A mild and efficient cascade synthesis of 1,5-diketones from readily available N,N-dicyclohexylmethylamine, 1,3-dicarbonyl compounds, and trifluoromethyl β-diketones has been developed. This cascade reaction occurs via an oxidation/Mannich reaction/Cope elimination/Michael addition/retro-Claisen reaction sequence, and provides multiple C-C bond formations in one pot. In addition, exquisite chemoselectivity is achieved in the reaction between 1,3-dicarbonyl compounds and trifluoromethyl β-diketones.
- Xing, Li-Juan,Lu, Tao,Fu, Wei-Li,Lou, Mei-Mei,Chen, Bo,Wang, Zhi-Shen,Jin, Yang,Li, Dan,Wang, Bin
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supporting information
p. 3076 - 3080
(2015/11/03)
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- Discovery and structure-activity relationships study of novel thieno[2,3-b]pyridine analogues as hepatitis C virus inhibitors
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Current treatment for hepatitis C is barely satisfactory, there is an urgent need to develop novel agents for combating hepatitis C virus infection. This study discovered a new class of thieno[2,3-b]pyridine derivatives as HCV inhibitors. First, a hit compound characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. And then, structure activity relationship study of the hit compound led to the discovery of several potent compounds without obvious cytotoxicity in vitro (12c, EC50 = 3.3 μM, SI >30.3, 12b, EC50 = 3.5 μM, SI >28.6, 10l, EC50 = 3.9 μM, SI >25.6, 12o, EC 50 = 4.5 μM, SI >22.2, respectively). Although the mechanism of them had not been clearly elucidated, our preliminary optimization of this class of compounds had provided us a start point to develop new anti-HCV agents.
- Wang, Ning-Yu,Zuo, Wei-Qiong,Xu, Ying,Gao, Chao,Zeng, Xiu-Xiu,Zhang, Li-Dan,You, Xin-Yu,Peng, Cui-Ting,Shen, Yang,Yang, Sheng-Yong,Wei, Yu-Quan,Yu, Luo-Ting
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supporting information
p. 1581 - 1588
(2014/03/21)
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- Synthesis of 1,5-diarylpyrazoles as potential cox-2 inhibitors with nitric oxide releasing ability
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A few celecosib like 1,5-diarylpyrazoles conjugated with nitric oxide (NO) donating nitrate ester group were synthesized and evaluated for their selective COX-2 inhibitory activity along with NO releasing ability of corresponding nitrate esters. Most of the synthesized compounds exhibited improved COX-2 inhibition when compared with the reference drug celecoxib. The nitrate ester derivatives (coxib prodrugs) 7 (nitrate ester of 1,5-diarylpyrazole with 2 carbon linker), and 9 (nitrate ester of 1,5-diarylpyrazole with 3 carbon linker), upon incubation in human whole blood were partly transformed into the corresponding alcohols 6, and 8 respectively. Molecular docking studies were performed on alcohol derivatives and revealed additional H-bond interactions compared to celecoxib.
- Rao, Bolla Narasimha,Muthuppalaniappan, Meyyappan,Dinavahi, Saketh Sriram,Viswanadha, Srikant,Bagul, Chandrakant,Srinivas, Kolupula,Vakkalanka, Swaroop Kumar V. S.,Atcha, Krishnam Raju,Kamal, Ahmed
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p. 594 - 603
(2013/08/23)
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- Comparative study of the regioselectivity and reaction media for the synthesis of 1-tert-butyl-3(5)-trifluoromethyl-1H-pyrazoles
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A study is presented for the synthesis of a series of 1-tert-butyl-3(5)- (trifluoromethyl)-1H-pyrazoles from the reaction of 4-alkoxy-1,1,1-trifluoro-3- alken-2-ones [CF3C(O)CH=C(R1)(OR), where R = Et and R 1 = H or R = Me and R1 = Me, Ph, 4-Me-C6H 4, 4-MeO-C6H4, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-I-C 6H4, fur-2-yl, thien-2-yl, or naphth-2-yl] with tert-butylhydrazine hydrochloride. When [BMIM][BF4] (1-butyl-3-methylimidazolium tetrafluoroborate) and pyridine were used as the reaction media, we obtained a mixture of 1-tert-butyl-3(5)- trifluoromethylpyrazoles. The formation of 5-trifluoromethyl-1-tert-butyl-1H- pyrazoles with high regioselectivity occurred when the reaction was carried out with NaOH in EtOH. The formation of 1-tert-butyl-3-trifluoromethyl-1H-pyrazoles occurred, after hydrolysis of the 4-alkoxy-1,1,1-trifluoro-3-alken-2-ones in H2O and H2SO4, followed by cyclization in [BMIM][BF4] and pyridine.
- Martins, Marcos A. P.,Marzari, Mara R. B.,Frizzo, Clarissa P.,Zanatta, Marcileia,Buriol, Lilian,Andrade, Valquiria P.,Zanatta, Nilo,Bonacorso, Helio G.
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p. 7112 - 7119
(2013/02/21)
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- Synthesis and preliminary in vitro biological evaluation of new carbon-11-labeled celecoxib derivatives as candidate PET tracers for imaging of COX-2 expression in cancer
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The enzyme cyclooxygenase-2 (COX-2) is overexpressed in a variety of malignant tumors. This study was designed to develop new radiotracers for imaging of COX-2 in cancer using biomedical imaging technique positron emission tomography (PET). Carbon-11-labeled celecoxib derivatives, [11C]4a-c and [11C]8a-d, were prepared by O-[11C] methylation of their corresponding precursors using [11C]CH3OTf under basic conditions and isolated by a simplified solid-phase extraction (SPE) method in 52 ± 2% (n = 5) and 57 ± 3% (n = 5) radiochemical yields based on [11C]CO2 and decay corrected to end of bombardment (EOB). The overall synthesis time from EOB was 23 min, the radiochemical purity was >99%, and the specific activity at end of synthesis (EOS) was 277.5 ± 92.5 GBq/μmol (n = 5). The IC50 values to block COX-2 for known compounds celecoxib (4d), 4a and 4c were 40, 290 and 8 nM, respectively, and preliminary findings from in vitro biological assay indicated that the synthesized new compounds 4b and 8a-d display similar strong inhibitory effectiveness in the MDA-MB-435 human cancer cell line in comparison with the parent compound 4d. These results encourage further in vivo evaluation of carbon-11-labeled celecoxib derivatives as new potential PET radiotracers for imaging of COX-2 expression in cancer.
- Gao, Mingzhang,Wang, Min,Miller, Kathy D.,Zheng, Qi-Huang
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experimental part
p. 4760 - 4767
(2011/11/04)
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- Synthesis and anti-microbial activity of some new fluorinated 1H-pyrazoles
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Several new trifluoromethyl-1H-pyrazoles were prepared by reaction of hydrazine monohydrate with 1,3-diketones. Their structures were confirmed by elemental analysis, IR, 1H NMR and EI-MS spectroscopy. The anti-microbial activities of the newly synthesized compounds were examined by disc diffusion method against Escherichia coli, Staphylococcus aureus, Pyricularia oryzae and Rhizoctnia solani. All the trifluoromethyl-1H-pyrazoles exhibited a certain degree of anti-bacterial and anti-fungal activities.
- Wang, Dun-Jia,Fan, Ling,Zheng, Chun-Yang,Fang, Zheng-Dong
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experimental part
p. 584 - 586
(2010/06/13)
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- Synthesis and characterization of the titanium complexes bearing two β-enaminoketonato ligands with electron withdrawing groups/modified phenyls and their behaviors for ethylene (co-)polymerization
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A series of new titanium complexes with two asymmetric bidentate β-enaminoketonato [N,O] ligands (2b-t), [PhNC(CF3)CHC(Ar)O] 2TiCl2 (2b, Ar = -C6H4F(o); 2c, Ar = -C6H4F(m); 2d, Ar = -C6H4F(p); 2e, Ar = -C6H4Cl(p); 2f, Ar = -C6H 4OMe(p); 2g, Ar = -C6H4CF3(p); 2h, Ar = -C6H4CF3(m); 2i, Ar = -C6H 4CF3(o); 2j, Ar = -C6H4Cl(o); 2k, Ar = -C6H4Br(o); 2l, Ar = -C6H4I(o); 2m, Ar = -C6H3F2(2,4); 2n, Ar = -C 6H3F2(2,6); 2o, Ar = -C6H 3F2(3,4); 2p, Ar = -C6H3F 2(3,5); 2q, Ar = -C6F5; 2r, Ar = C 6F4OMe; 2s, Ar = -C6H3Cl 2(2,6); 2t, Ar = -C6H3Cl2(2,5)), have been synthesized based on substituted acetophenones. X-Ray analyses reveal that complexes 2h, 2k, 2m, and 2n adopt distorted octahedral geometry around the titanium center, in which the two chloride ligands are situated in the cis-orientation. 2s also adopts distorted octahedral geometry, but the two chloride ligands in it are situated in the trans-orientation due to the increase of the steric effect of the phenyl derived from the acetophenone. The influence of the substituent effects on catalyst performance, including catalytic activities and the molecular weight distribution of the polymers obtained, was investigated in detail. With modified methylaluminoxane (MMAO) as a cocatalyst, complexes 2b-r and 2t are active catalysts for ethylene polymerization at room temperature, and produce high molecular weight polymers. It is observed that the catalytic activities are significantly enhanced by introducing some electron-withdrawing groups, such as -F, -Cl and -CF3, into the suitable positions of the phenyl ring close to the oxygen donor. It should be noted that complexes 2c-i, 2p, 2n and 2t are also capable of promoting the living copolymerization of ethylene with norbornene at room temperature, yielding high molecular weight copolymers with narrow molecular weight distributions (PDI = 1.05-1.30). The Royal Society of Chemistry 2010.
- Ye, Wei-Ping,Shi, Xin-Cui,Li, Bai-Xiang,Liu, Jing-Yu,Li, Yue-Sheng,Cheng, Yan-Xiang,Hu, Ning-Hai
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experimental part
p. 9000 - 9007
(2011/01/11)
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- First synthesis of functionalized 5-aryl-3-(trifluoromethyl)phenols by regioselective [3+3] cyclocondensations of 1,3-bis(silyloxy)-1,3-butadienes with 3-aryl-3-silyloxy-1-trifluoromethyl-2-en-1-ones
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A variety of functionalized 5-aryl-3-(trifluoromethyl)phenols were prepared by the first TiCl4-mediated [3+3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-aryl-3-trimethylsilyloxy-1-trifluoromethyl-2-en-1-ones.
- Büttner, Stefan,Riahi, Abdolmajid,Hussain, Ibrar,Yawer, Mirza A.,Lubbe, Mathias,Villinger, Alexander,Reinke, Helmut,Fischer, Christine,Langer, Peter
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experimental part
p. 2124 - 2135
(2009/07/18)
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- Interactions of aroyl- and heteroaroyltrifluoroacetones with thiobenzoylhydrazine
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The interaction of aroyl(heteroaroyl)trifluoroacetones with thiobenzoylhydrazine may occur at both carbonyl groups. Reaction at the trifluoroacetyl group is facilitated by terminal substituents in the 1,3-dicarbonyl part, which leads can effectively conjugate with the adjacent carbonyl group. The products of condensation at the trifluoroacetyl group are 2-[2-aryl(heteroaroyl)-2-oxoethyl]-5-phenyl-2-trifluoromethyl-2,3-dihydro-1,3, 4-thiadiazoles, while condensation at the aroyl(heteroaroyl)group gave 3-aryl(heteroaryl)-5-hydroxy-1-thiobenzoyl-5-trifluoromethyl-4, 5-dihydro-1H-pyrazoles, which are not prone to tautomeric transformations in solution. 2008 Springer Science+Business Media, Inc.
- Pakalnis,Zerova,Yakimovitch,Alekseyev
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p. 606 - 614
(2013/07/25)
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- ALPHA-UNSUBSTITUTED ARYLMETHYL PIPERAZINE PYRAZOLO[1,5-A] PYRIMIDINE AMIDE DERIVATIVES
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Methods of preventing, treating or delaying the onset of HIV in a subject by administering to the subject novel pharmaceutically active arylmethyl pyrazolo[1,5-α ]pyrimidine amide derivatives, or pharmaceutical compositions containing the same are described. Additionally, compounds of novel pharmaceutically active arylmethyl piperazine pyrazolo[l,5-α]pyrimidine amide derivatives and their use for the manufacture of specific medicaments are described.
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Page/Page column 128
(2008/12/08)
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- Keto-enol and enol-enol tautomerism in trifluoromethyl-β-diketones
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The keto-enol (K?E) and enol-enol (E?E) equilibria of a variety of trifluoromethyl-β-diketones were investigated using 1H, 13C, 19F NMR spectroscopy, infrared spectroscopy and ultraviolet-visible spectrophotometry in nonpolar solvents. In general, NMR, IR and UV spectral evidence indicates that trifluoromethyl-β-diketones exist as mixtures of two chelated cis-enol forms in nonpolar media. Infrared spectroscopy and ultraviolet spectrophotometry show the E?E equilibrium lies in the direction of the enol form which maximizes conjugation in most cases. Exceptions are noted and discussed.
- Sloop, Joseph C.,Bumgardner, Carl L.,Washington, Gary,Loehle, W. David,Sankar, Sabapathy S.,Lewis, Adam B.
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p. 780 - 786
(2008/03/27)
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- Synthesis and SAR/3D-QSAR studies on the COX-2 inhibitory activity of 1,5-diarylpyrazoles to validate the modified pharmacophore
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Diverse analogs of 1,5-diarylpyrazoles having 3-hydroxymethyl-4-sulfamoyl (SO2NH2)/methyl sulfonyl (SO2Me)-pheny group at N1 were synthesized and evaluated for their in vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The SAR study mainly involved the variations at positions C-3, C-5 and N1 of the pyrazole ring. Several small hydrophobic groups at/around position-4 of C-5 phenyl, viz. 3,4-dimethylphenyl analog 9, 3-methyl-4-methylsulfanylphenyl analog 14 and 2,3-dihydrobenzo[b] thiophenyl analog 17, exhibited impressive COX-2 inhibitory potency. In general, the sulfonamide analogues with a CHF2 at C-3 were found to be more potent than those having a CF3 group. The three dimensional quantitative structure activity relationship comprising comparative molecular field analysis (3D-QSAR-CoMFA) afforded the models with high predictivity which further validated the acceptance of hydroxymethyl (CH2OH) group in the hydrophilic pocket of the COX-2 enzyme.
- Singh, Sunil K.,Saibaba,Rao, K. Srinivasa,Reddy, P. Ganapati,Daga, Pankaj R.,Rajjak, S. Abdul,Misra, Parimal,Rao, Y. Koteswar
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p. 977 - 990
(2007/10/03)
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- PYRAZOLO AND IMIDAZO-PYRIMIDINE DERIVATIVES
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The present invention relates to novel pyrazolo- and imidazo-pyrimidine derivatives of formula (I) wherein A, D, E, L, M, Q, R1, R2 and R3 are as defined in the description and claims and to processes for their preparation, pharmaceutical compositions containing said derivatives and their use in the prevention and treatment of diseases.
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Page/Page column 18-19
(2008/06/13)
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- Polar substitutions in the benzenesulfonamide ring of celecoxib afford a potent 1,5-diarylpyrazole class of COX-2 inhibitors
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Several chemical modifications in the N1-benzenesulfonamide ring of celecoxib are presented. The series with a hydroxymethyl group adjacent to the sulfonamide was found to be the most potent modification that yielded many compounds selectively active against COX-2 enzyme in vitro.
- Singh, Sunil K.,Reddy, P. Ganapati,Rao, K. Srinivasa,Lohray, Braj B.,Misra,Rajjak, Shaikh A.,Rao, Yeleswarapu K.,Venkateswarlu
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p. 499 - 504
(2007/10/03)
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- Discovery of a potent, selective and orally active canine COX-2 inhibitor, 2-(3-difluoromethyl-5-phenyl-pyrazol-1-yl)-5-methanesulfonyl-pyridine
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Structure-activity relationship (SAR) studies of 2-[3-di(and tri)fluoromethyl-5-arylpyrazol-1-yl]-5-methanesulfonylpyridine derivatives for canine COX enzymes are described. This led to the identification of 12a as a lead candidate for further progression. The in vitro and in vivo activity of 12a for the canine COX-2 enzyme as well as its in vivo efficacy and pharmacokinetic properties in dog are highlighted.
- Li, Jin,Lundy DeMello, Kristin M.,Cheng, Henry,Sakya, Subas M.,Bronk, Brian S.,Rafka, Robert J.,Jaynes, Burton H.,Ziegler, Carl B.,Kilroy, Carolyn,Mann, Donald W.,Nimz, Eric L.,Lynch, Michael P.,Haven, Michelle L.,Kolosko, Nicole L.,Minich, Martha L.,Li, Chao,Dutra, Jason K.,Rast, Bryson,Crosson, Rhonda M.,Morton, Barry J.,Kirk, Glen W.,Callaghan, Kathleen M.,Koss, David A.,Shavnya, Andrei,Lund, Lisa A.,Seibel, Scott B.,Petras, Carol F.,Silvia, Annette
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- Synthesis of fluorinated heterocycles
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Selected 1,3-diketones having a trifluoromethyl group and/or a fluorine in the 2-position were condensed with aromatic hydrazines, hydroxylamine, urea, thiourea, guanidine, and substituted anilines producing pyrazoles, isoxazoles, pyrimidines, and quinolines, respectively, in yields ranging from 27 to 87%.
- Sloop, Joseph C.,Bumgardner, Carl L.,Loehle, W. David
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p. 135 - 147
(2007/10/03)
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- New Heterocyclic compounds for therapeutic use
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A class of compounds particularly diaryl pyrazole of general formulas 1 and 2 where R and R′ represents alkyl, hydrogen, halogens, haloalkyl, cyano, nitro, formyl, carboxyl, alkoxycarbonyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, alkylthio, alkylsulfinyl, alkylsulphonyl, N- alkylsulfamyl, N-arylsulfamyl, cyanoamido, amino, amidino, N-monoalkylamido, N-monoarylamido, N,N-dialkylamido, N-alkyl-N-arylamido, N, N-dialkylsulfamyl with the alkyl, or alkyl part of each such group containing 1-3 carbon atoms or mixtures thereof optionally their salts when they exist, and preparation thereof. The compounds of the present invention are antiinflammatory, antipyretic, antirheumatic, antiosteoarthritic agents with antibacterial activity. The particular class of compounds is given below (Formula 1 and Formula 2).
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- Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)- 3(trifluoromethyl)-1h-pyrazol-1-yl]benzenesulfonamide (sc-58635, celecoxib)
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A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC- 236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-y1]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
- Penning, Thomas D.,Talley, John J.,Bertenshaw, Stephen R.,Carter, Jeffery S.,Collins, Paul W.,Docter, Stephen,Graneto, Matthew J.,Lee, Len F.,Malecha, James W.,Miyashiro, Julie M.,Rogers, Roland S.,Rogier,Yu, Stella S.,Anderson, Gary D.,Burton, Earl G.,Cogburn, J. Nita,Gregory, Susan A.,Koboldt, Carol M.,Perkins, William E.,Seibert, Karen,Veenhuizen, Amy W.,Zhang, Yan Y.,Isakson, Peter C.
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p. 1347 - 1365
(2007/10/03)
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