cas 720-94-5, l-(4-Methylphenyl)-4,4,4-trifluorobutane-1,3-dione

Articles about 720-94-5Total 72 be found

Article title
Article abstract
Author
Journal number and time
Download

Simple synthesis method of celecoxib
The invention discloses a simple synthesis method of celecoxib. The method comprises the following steps: taking trifluoroacetoacetate and methylbenzene as starting raw materials, firstly synthesizing a compound I through Friedel-Crafts reaction under the catalysis of aluminum trichloride, and reacting the compound I with p-halobenzene sulfonamide in the presence of hydrazine hydrate under an alkaline condition to obtain celecoxib. The method not only avoids the preparation of the 4-hydrazinobenzenesulfonamide hydrochloride in the traditional method, but also avoids the diazotization reaction step in the production process of the 4-hydrazinobenzenesulfonamide hydrochloride, thereby reducing the risk of industrial production. The method has the advantages of short synthesis steps, one-pot method, simple and easily available raw materials and mild reaction conditions, and is suitable for amplification of chemical production.
-
Paragraph 0021; 0036-0037; 0040-0041; 0044-0045

(2022/03/27)

Further hit optimization of 6-(trifluoromethyl)pyrimidin-2-amine based TLR8 modulators: Synthesis, biological evaluation and structure–activity relationships
Toll-like receptor 8 (TLR8) is an endosomal TLR that has an important role in the innate human immune system, which is involved in numerous pathological conditions. Excessive activation of TLR8 can lead to inflammatory and autoimmune diseases, which highlights the need for development of TLR8 modulators. However, only a few small-molecule modulators that selectively target TLR8 have been developed. Here, we report the synthesis and systematic investigation of the structure–activity relationships of a series of novel TLR8 negative modulators based on previously reported 6-(trifluoromethyl)pyrimidin-2-amine derivatives. Four compounds showed low-micromolar concentration-dependent inhibition of TLR8-mediated signaling in HEK293 cells. These data confirm that the 6-trifluoromethyl group and two other substituents on positions 2 and 4 are important structural elements of pyrimidine-based TLR8 modulators. Substitution of the main scaffold at position 2 with a methylsulfonyl group or para hydroxy/hydroxymethyl substituted benzylamine is essential for potent negative modulation of TLR8. Our best-in-class TLR8-selective modulator 53 with IC50 value of 6.2 μM represents a promising small-molecule chemical probe for further optimization to a lead compound with potent immunomodulatory properties.
Dol?ak, Ana,?ribar, Dora,Scheffler, Alexander,Grabowski, Maria,?vajger, Urban,Gobec, Stanislav,Holze, Janine,Weindl, Günther,Wolber, Gerhard,Sova, Matej
(2021/09/06)

In Cellulo Generation of Fluorescent Probes for Live-Cell Imaging of Cylooxygenase-2
Live-cell imaging with fluorescent probes is an essential tool in chemical biology to visualize the dynamics of biological processes in real-time. Intracellular disease biomarker imaging remains a formidable challenge due to the intrinsic limitations of conventional fluorescent probes and the complex nature of cells. This work reports the in cellulo assembly of a fluorescent probe to image cyclooxygenase-2 (COX-2). We developed celecoxib-azide derivative 14, possessing favorable biophysical properties and excellent COX-2 selectivity profile. In cellulo strain-promoted fluorogenic click chemistry of COX-2-engaged compound 14 with non/weakly-fluorescent compounds 11 and 17 formed fluorescent probes 15 and 18 for the detection of COX-2 in living cells. Competitive binding studies, biophysical, and comprehensive computational analyses were used to describe protein-ligand interactions. The reported new chemical toolbox enables precise visualization and tracking of COX-2 in live cells with superior sensitivity in the visible range.
Kaur, Jatinder,Bhardwaj, Atul,Wuest, Frank
supporting information
p. 3326 - 3337
(2020/12/09)

Neuroprotective effect of novel celecoxib derivatives against spinal cord injury via attenuation of COX-2, oxidative stress, apoptosis and inflammation
A novel series of celecoxib derivatives were synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities for benefit in spinal cord injury (SCI). The title compounds were synthesized by conventional methods in good yields and subsequently tested for inhibitory activity against COX-1/COX-2. The most potent COX-2 inhibitor among the tested derivatives was further assayed for protective effect against experimental SCI of Sprague-Dawley rats. The designed compounds showed considerable inhibition of COX-2 as compared to COX-1 revealing compound 7m as most potent inhibitor of COX-2 isoenzyme (IC50 = 0.04 μM). The expression of mitochondrial apoptotic genes (Bcl-2 and Bax) together with COX-2 and iNOS was restored near to normal as evidenced by western blot analysis in SCI rats. Taken altogether, compound 7m was identified as most potent inhibitor of COX-2. It also showed protective action against SCI via attenuation of COX-2, oxidative stress and apoptosis and inflammation in Male Sprague-Dawley rats.
An, Yan,Fan, Mingxing,Li, Jianing,Liu, Yajun
(2020/07/07)

Synthesis, crystal structure and antitumor activity of 3-(2,4-dichlorophenyl)-2-phenyl-5-(p-tolyl)-7-(trifluoromethyl)pyrazolo[1,5-A]pyrimidine
The title compound, 3-(2,4-dichlorophenyl)-2-phenyl-5-(p-tolyl)- 7-(trifluoromethyl)pyrazolo[1,5-a] pyrimidine (C26H16C12F3N3, Mr = 498.32) has been synthesized by condensation of 4,4,4-trifluoro-1-(p-tolyl)butane- 1,3-dione with 4-(2,4-dichlorophenyl)-3-phenyl-1H-pyrazol-5-amine. The latter was prepared from 2,4-dichlorophenylaceton itrile and ethyl benzoate through Claisen condensation and then cyclization with hydrazine hydrate. The crystal structure of the title compound was determined. In addition, the title compound possesses marked inhibition against the proliferation of human lung adenocarcinoma cell line A549 and human gastric cancer cell line MKN45, displaying promising anticancer activities.
Liu, Jin,Zhao, Juan,Lu, Jiu-Fu
p. 591 - 596
(2021/02/26)

Development of celecoxib-derived antifungals for crop protection
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
(2020/02/27)

Preparation method of celecoxib
A preparation method of celecoxib comprises the following steps: preparing CEL-A completion liquid, preparing a crude dry celecoxib product, and purifying, drying and crushing the crude dry celecoxibproduct. The celecoxib product prepared by the method has the advantage of high purity.
-
Paragraph 0014; 0021

(2020/07/13)

Preparation method of high-purity celecoxib
The invention discloses a preparation method of high-purity celecoxib. According to the preparation method, a p-methylbenzoyl halide and trifluoroacetone are reacted under the action of an alkali to generate 4, 4, 4-trifluoro-1-(4-methylphenyl)-1, 3-butanedione, and then 4, 4, 4-trifluoro-1-(4-methylphenyl)-1, 3-butanedione is reacted with p-aminosulfonylphenylhydrazine/hydrochloride in an acidicaqueous solution to obtain high-purity celecoxib. According to the invention, the reaction time required for preparing celecoxib is greatly reduced, and the reaction period is only 20-30% of the original reaction period; reaction conditions are mild, and few isomer impurities are generated in the reaction; the output of three wastes is greatly reduced, and the generated wastewater is very easy totreat; and various impurities in the reaction can be effectively controlled without recrystallization.
-
Paragraph 0013; 0014; 0016; 0017; 0019; 0020

(2020/02/14)

CONTINUOUS PROCESSES FOR THE MANUFACTURE OF CELOCOXIB
A continuous process for the manufacture of celecoxib includes reacting a stream of a first solution of 4'-methylacetophenone in a first organic solvent and a stream of a second solution of ethyl trifluoroacetate in a second organic solvent in a first reactor in the presence of a base at a first reaction temperature of between 45°C and 90°C and at a first reaction pressure to form 4,4,4-Trifluoro-1-(4-methylphenyl)butane-1,3-dione. The first reaction pressure prevents boiling inside the first reactor. A stream of a first reactor product from the first reactor is continuously withdrawn, the first reactor product including a solution of 4,4,4-Trifluoro-1-(4-methylphenyl)butane-1,3-dione in the first organic solvent and the second organic solvent. A stream of the first reactor product and a stream of a third solution of (4-Sulfamoylphenyl)hydrazine hydrochloride in a third organic solvent are reacted in a second reactor at a second reaction temperature of between 80°C and 110°C and at a second reaction ressure to form celecoxib. The second reaction pressure prevents boiling inside the second reactor. A stream of a second reactor product is continuously withdrawn from the second reactor, the second reactor product including a solution of celecoxib in organic solvent.
-
Page/Page column 12-16

(2019/04/26)

Method for preparing Celecoxib dione intermediate
The invention provides a method for preparing a Celecoxib dione intermediate. The method comprises the steps: subjecting p-methylacetophenone and ethyl trifluoroacetate to a reaction in the presence of sodium methylate, wherein toluene serves as a solvent, and a reaction temperature is 20 DEG C to 40 DEG C; carrying out quenching with a hydrochloric solution after the reaction is complete, then, carrying out washing with purified water, and carrying out standing to separate out an aqueous phase; and subjecting an organic phase to cooling crystallization, thereby obtaining a yellowish solid product. According to the method provided by the invention, the safety of industrial production of the Celecoxib dione intermediate can be improved, the process is very convenient, and meanwhile, the purity and yield of the product are not lowered.
-
Paragraph 0019-0025

(2019/11/20)

An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors
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
supporting information
p. 1892 - 1899
(2019/10/11)

Preparation method of celecoxib impurity B
The invention discloses a preparation method of celecoxib impurity B. According to the method, the content of the impurity B is increased to be more than 25% through a synthetic method, and then the impurity is purified until the purity is more than 99% through the application of a supercritical fluid chromatography separation technology.
-
Paragraph 0033-0035

(2018/03/24)

Application of 1,5-diaryl-3-pyrazole compound in prevention and control of agricultural fungal diseases
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.
-
Paragraph 0018

(2018/12/13)

Design, synthesis and biological evaluation of novel hydroxamic acid based histone deacetylase 6 selective inhibitors bearing phenylpyrazol scaffold as surface recognition motif
In recent years, inhibition of HDAC6 became a promising therapeutic strategy for the treatment of cancer and HDAC6 inhibitors were considered to be potent anti-cancer agents. In this work, celecoxib showed moderate degree of HDAC6 inhibition activity and selectivity in preliminary enzyme inhibition activity assay. A series of hydroxamic acid derivatives bearing phenylpyrazol moiety were designed and synthesized as HDAC6 inhibitors. Most compounds showed potent HDAC6 inhibition activity. 11i was the most selective compound against HDAC6 with IC50 values of 0.020 μM and selective factor of 101.1. Structure-activity relationship analysis indicated that locating the linker group at 1′ of pyrazol gave the most selectivity. The most compounds 11i (GI50 = 3.63 μM) exhibited 6-fold more potent than vorinostat in HepG2 cells. Considering of the high selectivity against HDAC6 and anti-proliferation activity, such compounds have potential to be developed as anti-cancer agents.
Yang, Jinyu,Cheng, Gaoliang,Xu, Qihao,Luan, Shenglin,Wang, Shuxiang,Liu, Dan,Zhao, Linxiang
p. 1418 - 1425
(2018/03/07)

Design and synthesis of novel benzenesulfonamide containing 1,2,3-triazoles as potent human carbonic anhydrase isoforms I, II, IV and IX inhibitors
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.
p. 545 - 551
(2018/06/18)

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
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.
p. 3406 - 3413
(2018/05/24)

Method for preparing 1-p-methylphenyl-4,4,4-trifluoro-1,3-butanedione
The invention provides a method for preparing 1-p-methylphenyl-4,4,4-trifluoro-1,3-butanedione. The method comprises the step of reacting by virtue of trifluoroacetyl halide and p-methylacetophenone in an organic solvent under the action of a catalyst, so as to obtain 1-p-methylphenyl-4,4,4-trifluoro-1,3-butanedione and/or an enol formisomer of 1-p-methylphenyl-4,4,4-trifluoro-1,3-butanedione. The method provided by the invention has the advantages of low raw material cost, mild reaction conditions, low environmental pollution and suitability in industrial production.
-
Paragraph 0031; 0032; 0033; 0034; 0035; 0036; 0037; 0038

(2017/07/22)

Targeting DNA with anti-tumor activity of the naphthalene imide structure biodegradable derivatives, pharmaceutical composition and its preparation method and application
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.
-
Paragraph 0112

(2017/07/14)

With anti-tumor activity of phenyl hydroxamic acid compounds and use thereof (by machine translation)
The invention belongs to the field of medical technology, relates to a with anti-tumor activity of phenyl hydroxamic acid compounds, and in particular to the 3 (5) - substituted phenyl - 5 (3) - substituted pyrazole fragment phenyl hydroxamic acid compounds, and their pharmaceutically acceptable salt, hydrate, and the compound as the active ingredient of the pharmaceutical composition, and the preparation of histone deacetylase inhibitors and their use for the treatment and/or prevention of cancer. The compound of the following structure: wherein R1 Independently selected from one or more of the following substituents: halogen, (C1 - C4) alkyl, dioxo methylene; R2 Is independently selected from (C1 - C4) alkyl, halo (C1 - C4) alkyl, substituted or unsubstituted phenyl, said substituent is (C1 - C4) alkyl; n is 0 - 2 is an integer between. (by machine translation)
-
Paragraph 0049; 0050; 0051

(2018/04/01)

A new crystalline form fills the past cloth A and its preparation method
The invention provides a novel crystal form A of celecoxib and a preparation method thereof. The novel crystal form of celecoxib is prepared by using isopropanol as a solvent system, subjecting a reaction solution to rapid cooling and crystallization and carrying out filtering and drying. The X-ray powder diffraction spectrum of the crystal form has characteristic diffraction peaks at positions where 2theta (DEG, +/- 0.2) is 5.42, 10.80, 13.10, 14.92, 16.18, 19.73, 21.60, 22.28, 27.06 and 29.68. The crystal form A has the advantages of good stability, convenience in production, transportation and storage, capability of meeting requirements for a preparation raw material, etc.
-
Paragraph 0055

(2017/04/07)

A COX-2 enzyme inhibitor fills the past cloth method for synthesizing intermediate
The invention belongs to the technical field of clean synthesis and particularly relates to a synthetic method of a COX-2 enzyme inhibitor celecoxib intermediate. The method comprises the following steps: reacting initial raw materials (ethyl trifluoroacetate (II) and p-methylacetophenone (I)) in the presence of carbonate serving as alkali in an organic solvent and obtaining the celecoxib intermediate 4,4,4-trifluoro-(4-methylphenyl)-1,3-butanedione (III) with the yield of 83%-99%. In the whole process, the raw material consumption is low, alkali and a solvent can be recycled, and the generation of three wastes is low; and the method has good industrial prospect.
-
Paragraph 0008; 0027-0028

(2017/02/24)

Synthesis, fungicidal activity and mode of action of 4-phenyl-6-trifluoromethyl-2-aminopyrimidines against Botrytis cinerea
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
(2016/07/30)

A method for preparing fills the past cloth
The invention relates to a celecoxib preparation method. The method includes the following steps: 1, carrying out mixing dissolved clarification of celecoxib, an alcoholic solvent and ethyl acetate; and 2, adding the obtained dissolved clarified clear liquid into water, stirring for above 10min, filtering, washing with water, and drying. The invention also provides a synthesis method of celecoxib in step 1. Celecoxib prepared through the method in the invention overcomes the easy caking and large dissolution difference among capsules of celecoxib prepared in the prior art, and the obtained raw celecoxib has the advantages of difficult caking and small dissolution difference among capsules.
-
Paragraph 0065

(2017/01/09)

NO-RELEASING NONOATE (NITROGEN-BOUND) SULFONAMIDE-LINKED-COXIB ANTI-CANCER AGENTS
The present invention provides NO-releasing NONOate(nitrogen bound)sulfonamide- linked-coxib anti-cancer agents, having the structure of Formula (I): wherein R1, X, L, R2, R3, R4, and Z are as defined in the detailed description; pharmaceutical compositions comprising at least one compound of Formula (I); and methods useful for healing wounds, preventing and treating cancer, or treating actinic keratosis, cystic fibrosis or acne, using a compound of Formula (I).
-
Paragraph 00207; 00208

(2014/02/15)

TETRAHYDROPYRAZOLO [1,5-A] PYRIMIDINE AS ANTI-TUBERCULOSIS COMPOUNDS
A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein: R1 represents a group selected from: i) phenyl optionally substituted with one or two substituents independently selected from Me, OMe, CF3, F, Cl and NMe2;furanyl, thiophenyl, pyrrolyl, pyridyl, cyclohexyl or naphthyl, each of which is optionally substituted with one or two substituents independently selected from Me, OMe, CF3, F, Cl and NMe2; andiii) benzo[1,3]dioxo5-yl or 2,3-dihydrobenzo[1,4]dioxin-6-yl; R2 represents CF3, C1-4alkyl, or CHF2; when R1 represents optionally substituted furanyl, thiophenyl, pyrrolyl, pyridyl or naphthyl, R3 represents Et; when R1 represents optionally substituted cyclohexyl, R3 represents Et or Me; otherwise R3 represents Et, Me, Br or OMe, compositions containing them, their use in therapy, for example in the treatment of tuberculosis, and methods for the preparation of such compounds, are provided, together with certain novel compounds.
-
Paragraph 0255

(2014/02/16)

Novel one-pot synthesis of polysubstituted isocoumarins from arynes and trifluoroacetylated β-diketones
Polysubstituted isocoumarins such as thunberginol A were synthesized by the reaction of substituted 2-(trimethylsilyl)-phenyl triflate with trifluoromethylated β-diketones in the presence of CsF. The reaction proceeded via carboncarbon bond insertion of aryne followed by intramolecular cyclization and CF3 anion extrusion. The C(..O)CF3 unit has high potential for not only the nucleophilic moiety but also a useful leaving group of CF3.
Okuma, Kentaro,Hirano, Koki,Tanabe, Yukiko,Itoyama, Ryoichi,Miura, Atsumi,Nagahora, Noriyoshi,Shioji, Kosei
p. 492 - 494
(2014/04/17)

Synthesis of novel dansyl-labeled Celecoxib derivatives
Four novel dansyl-labeled derivatives of Celecoxib, a cyclooxygenase-2 (COX-2) selective inhibitor, were designed and synthesized. To realize the fluorophore-linker-approach divergent and convergent synthetic strategies were applied. Therefore Celecoxib p-benzoic acid, 8, was synthesized in a new and convenient way. The yield and the synthetic route to Celecoxib, 1, its pyrazolylic acid, 7, and its pyrazolylic methyl ester, 6, were improved. Through a convenient synthesis 1,11-diamino-3,6,9-trioxundecane, 19, was obtained in high yield and purity and used as a linker for the dansyl moiety.
Lill, Andreas,Scholich, Klaus,Stark, Holger
supporting information
p. 6682 - 6686
(2013/11/19)

Discovery of tetrahydropyrazolopyrimidine carboxamide derivatives as potent and orally active antitubercular agents
Tetrahydropyrazolo[1,5-a]pyrimidine scaffold was identified as a hit series from a Mycobacterium tuberculosis (Mtb) whole cell high through-put screening (HTS) campaign. A series of derivatives of this class were synthesized to evaluate their structure-activity relationship (SAR) and structure-property relationship (SPR). Compound 9 had a promising in vivo DMPK profile in mouse and exhibited potent in vivo activity in a mouse efficacy model, achieving a reduction of 3.5 log CFU of Mtb after oral administration to infected mice once a day at 100 mg/kg for 28 days. Thus, compound 9 is a potential candidate for inclusion in combination therapies for both drug-sensitive and drug-resistant TB.
Yokokawa, Fumiaki,Wang, Gang,Chan, Wai Ling,Ang, Shi Hua,Wong, Josephine,Ma, Ida,Rao, Srinivasa P. S.,Manjunatha, Ujjini,Lakshminarayana, Suresh B.,Herve, Maxime,Kounde, Cyrille,Tan, Bee Huat,Thayalan, Pamela,Ng, Seow Hwee,Nanjundappa, Mahesh,Ravindran, Sindhu,Gee, Peck,Tan, Maria,Wei, Liu,Goh, Anne,Chen, Pei-Yu,Lee, Kok Sin,Zhong, Chen,Wagner, Trixie,Dix, Ina,Chatterjee, Arnab K.,Pethe, Kevin,Kuhen, Kelli,Glynne, Richard,Smith, Paul,Bifani, Pablo,Jiricek, Jan
supporting information
p. 451 - 455
(2013/07/11)

TETRAHYDROPYRAZOLO [1,5 -A] PYRIMIDINE AS ANTI -TUBERCULOSIS COMPOUNDS
A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 represents a group selected from: i) phenyl optionally substituted with one or two substituents independently selected from Me, OMe, CF3, F, CI and NMe2; ii) furanyl, thiophenyl, pyrrolyl, pyridyl, cyclohexyl or naphthyl, each of which is optionally substituted with one or two substituents independently selected from Me, OMe, CF3, F, CI and NMe2; and iii) benzo[1,3]dioxo5-yl or 2,3-dihydrobenzo[1,4]dioxin-6-yl; R2 represents CF3, C1-4alkyl, or CHF2; When R1 represents optionally substituted furanyl, thiophenyl, pyrrolyl, pyridyl or naphthyl, R3 represents Et; When R1 represents optionally substituted cyclohexyl, R3 represents Et or Me; Otherwise R3 represents Et, Me, Br or OMe, compositions containing them, their use in therapy, for example in the treatment of tuberculosis, and methods for the preparation of such compounds, are provided, together with certain novel compounds
-
Page/Page column 27-28

(2012/11/07)

Development of novel antibacterial agents against methicillin-resistant Staphylococcus aureus
Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to public health because of its resistance to multiple antibiotics most commonly used to treat infection. In this study, we report the unique ability of the cyclooxygenase-2 (COX-2) inhibitor celecoxib to kill Staphylococcus aureus and MRSA with modest potency. We hypothesize that the anti-Staphylococcus activity of celecoxib could be pharmacologically exploited to develop novel anti-MRSA agents with a distinct mechanism. Examination of an in-house, celecoxib-based focused compound library in conjunction with structural modifications led to the identification of compound 46 as the lead agent with high antibacterial potency against a panel of Staphylococcus pathogens and different strains of MRSA. Moreover, this killing effect is bacteria-specific, as human cancer cells are resistant to 46. In addition, a single intraperitoneal administration of compound 46 at 30 mg/kg improved the survival of MRSA-infected C57BL/6 mice. In light of its high potency in eradicating MRSA in vitro and its in vivo activity, compound 46 and its analogues warrant continued preclinical development as a potential therapeutic intervention against MRSA.
Chiu, Hao-Chieh,Lee, Su-Lin,Kapuriya, Naval,Wang, Dasheng,Chen, Yi-Ru,Yu, Sung-Liang,Kulp, Samuel K.,Teng, Lee-Jene,Chen, Ching-Shih
experimental part
p. 4653 - 4660
(2012/08/29)

Comparative study of the regioselectivity and reaction media for the synthesis of 1-tert-butyl-3(5)-trifluoromethyl-1H-pyrazoles
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.
p. 7112 - 7119
(2013/02/21)

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
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
experimental part
p. 4760 - 4767
(2011/11/04)

AN IMPROVED PROCESS FOR THE PREPARATION OF CELECOXIB
The present invention relates to an improved process for the preparation of 4-[5-(4- methy lphenyl)-3-(trifluoromethyl)-1H-pyrazol- 1-yl]benzenesulfonamide of Formula (I), by condensing 1-(4-methylphenyl)-4,4,4-trifluorobutane-1,3-dione (IV), Formula (IV) with 4-hydrazinophenylsulfonamide (V) or its acid addition salt Formula (V) in a solvent selected from water and in presence of acid. The present invention also relates to the process for the purification of Celecoxib in a solvent mixture.
-
Page/Page column 8-9

(2010/09/17)

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
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
experimental part
p. 2124 - 2135
(2009/07/18)

Nitrooxymethyl-substituted analogues of celecoxib: Synthesis and pharmacological characterization
Nitrooxymethyl-substituted analogues of celecoxib were synthesized and tested for their cyclooxygenase (COX)-inhibiting, vasodilator, and anti-aggregatory activities, as well as for their metabolic stability in human serum and whole blood. The results showed their potency and selectivity in inhibiting the COX isoforms, evaluated in whole human blood, as well as their anti-aggregatory activity to depend closely on the position at which the NO-donor moiety is introduced. All products dilated rat aorta strips precontracted with phenylephrine in a dose-dependent manner through a cGMP-dependent mechanism. They were stable in human serum while, in blood, they were metabolically transformed, principally to the related alcohols.
Boschi, Donatella,Lazzarato, Loretta,Rolando, Barbara,Filieri, Andrea,Cena, Clara,Di Stilo, Antonella,Fruttero, Roberta,Gasco, Alberto
scheme or table
p. 369 - 379
(2010/04/23)

PROCESS FOR PREPARATION OF CELECOXIB
There is provided a process for preparation of celecoxib by reacting 4,4,4-trifluoro-1-[4-(methyl)phenyl]butane-1,3-dione with 4-sulphonamidophenylhydrazine or its salt in a solvent medium that contains an alkyl ester. There is also provided a process for the purification of celecoxib using aromatic hydrocarbon solvents.
-
Page/Page column 4

(2008/12/07)

New celecoxib derivatives as anti-inflammatory agents
A series of 1,5-diarylpyrazoles with a substituted benzenesulfonamide moiety was synthesized and evaluated for cyclooxygenase (COX-1/COX-2) inhibitory activities. Some compounds, for example, (±)-2-[4-(5-p-tolyl-3- trifluoromethyl-pyrazole-1-yl)-benzenesulfonylaminooxy]-propionic acid 16 and its disodium salt 21, had a higher in vivo anti-inflammatory activity compared to celecoxib, despite having no in vitro COX-1 or COX-2 inhibitory activity. Their gastrointestinal side effect profile is essentially more favorable than that of celecoxib.
Szabó, Gy?rgy,Fischer, János,Kis-Varga, ágnes,Gyires, Klára
p. 142 - 147
(2008/09/19)

Interactions of aroyl- and heteroaroyltrifluoroacetones with thiobenzoylhydrazine
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
p. 606 - 614
(2013/07/25)

NEW 1 , 2 -DIARYL PYRAZOLES USEFUL AS ANALGETIC AND ANTI-INFLAMMATORY AGENTS
The present invention relates to new compounds of formula (I), (I) wherein the meaning of R1 is hydrogen atom, C1-C5 acyl group, benzoyl group or R2- COOR3 group, Y is hydrogen atom or alkali ion, R2 is C1-C4 straight or branched alkylidene group and R3 is hydrogen atom, C1-C4 alkyl group or alkali ion, and/or stereoisomers and/or diastereomers and/or pharmaceutically acceptable salts and/or hydrates and/or solvates thereof, which are suitable for the treatment of pain of acute and chronic inflammation origin as well as postoperative pain and dysmenorrhea. The invention also relates to the process of the synthesis of compounds of formula (I) as well as the pharmaceutical composition containing the same and the use for treatment of pain, inflammation and disorders associated with inflammation.
-
Page/Page column 15

(2008/06/13)

CYP2C9 structure-metabolism relationships: Optimizing the metabolic stability of COX-2 inhibitors
The cytochrome P450 (CYP) family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. CYP2C9, one of the major isoforms of the CYP family, is responsible for the phase I metabolism of a variety of drugs. The aim of the present investigation is to use rational design together with MetaSite, a metabolism site prediction program, to synthesize compounds that retain their pharmacological effects but that are metabolically more stable in the presence of CYP2C9. The model compound for the study is the nonsteroidal anti-inflammatory drug celecoxib, a COX-2 selective inhibitor and known CYP2C9 substrate. Thirteen analogs of celecoxib were designed, synthesized, and evaluated with regard to their metabolic properties and pharmacologic effects. The docking solutions and the predictions from MetaSite gave useful information leading to the design of new compounds with improved metabolic properties.
Ahlstr?m, Marie M.,Ridderstr?m, Marianne,Zamora, Ismael,Luthman, Kristina
p. 4444 - 4452
(2008/02/13)

Reaction of aroyl- and hetaroyltrifluoroacetones with acylhydrazines: Regioselectivity and tautomerism of the condensation products
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
p. 1732 - 1741
(2008/04/05)

Keto-enol and enol-enol tautomerism in trifluoromethyl-β-diketones
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.
p. 780 - 786
(2008/03/27)

PYRAZOLO AND IMIDAZO-PYRIMIDINE DERIVATIVES
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.
-
Page/Page column 18

(2008/06/13)

COX-2 INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES-RELATED OCULAR DISORDERS
A method is described for the prevention or treatment of diabetes--related ocular disorders in a subject, the method comprising administering to the subject a Cox-2 inhibitor alone or in combination with a conventional anti-diabetic agent. Also described are therapeutic and pharmaceutical compositions and kits that are useful in the present invention.
-
Page/Page column 137

(2008/06/13)

COMBINATIONS OF COX AND VASOPRESSIN INHIBITORS FOR THE TREATMENT OF DISMENORRHEA
The use of a combination of (A) a vasopressin receptor family antagonist or a pharmaceutically acceptable derivative thereof, and (B) a COX inhibitor or a pharmaceutically acceptable derivative thereof, is described for the treatment or prophylaxis of dysmenorrhoea.
-
Page/Page column 45

(2008/06/13)

Method for the treatment or prevention of dermatological disorders with a cyclooxygenase-2 inhibitor alone and in combination with a dermatological treatment agent and compositions therewith
A method for preventing or treating dermatological disorders and dermatological disorder-related complications in a subject involves a monotherapy with a Cox-2 inhibitor or a combination therapy with a Cox-2 inhibitor and a dermatological treatment agent. Also described are therapeutic compositions comprising a Cox-2 inhibitor and a dermatological treatment agent. Pharmaceutical compositions and kits for implementing the present method are also described.
-
Page 64

(2010/02/10)

Combination of a Cox-2 inhibitor and a DNA topoisomerase I inhibitor for treatment of neoplasia
The present invention provides combinations of a Cox-2 inhibitor and a DNA topoisomerase inhibitor and methods of use thereof for preventing and/or treating neoplasia or or a neoplasia-related disorder in a subject.
-
Page/Page column 62

(2010/02/13)

METHODS AND COMPOSITIONS FOR TREATING OR PREVENTING PSYCHIATRIC DISORDERS WITH COX-2 INHIBITORS ALONE AND IN COMBINATION WITH ANTIDEPRESSANT AGENTS
The present invention relates to a novel method of treating and/or preventing psychiatric disorders in a subject by administering to the subject at last one Cox-2 inhibitor alone or in combination with one or more antidepressant agents. Compositions, pharmaceutical compositions and kits are also described.
-
Page/Page column 183-184

(2010/02/14)

METHOD FOR THE TREATMENT OR PREVENTION OF BONE DISORDERS WITH A CYCLOOXYGENASE-2 INHIBITOR ALONE AND IN COMBINATION WITH A BONE DISORDER TREATMENT AGENT AND COMPOSITIONS THEREWITH
The present invention describes a novel method for preventing or treating bone disorders and bone disorder-related complications in a subject involving a monotherapy with a Cox-2 inhibitor or a combination therapy with a Cox-2 inhibitor and a bone disorder treatment agent. Also described are therapeutic compositions comprising a Cox-2 inhibitor and a bone disorder treatment agent. Pharmaceutical compositions and kits for implementing the present method are also described.
-
Page/Page column 90-91

(2008/06/13)

METHOD FOR PREVENTING OR TREATING AN OPTIC NEUROPATHY
The present invention provides methods and compositions for the prevention and/or treatment of an optic neuropathy, comprising a Cox-2 inhibitor and an intraocular pressure reducing agent.
-
Page/Page column 57

(2008/06/13)