170569-91-2

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Relevant academic research and scientific papers

A CONTINUOUS FLOW MICRO-TOTAL PROCESS SYSTEM FOR PREPARATION OF CELECOXIB AND ANALOGS THEREOF

The present invention relates to preparation of pyrazoles. This invention further relates to a continuous flow micro-total process system for preparation of celecoxib, a COX-2 selective non-steroidal anti-inflammatory drug, and analogs thereof.

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.

Synthesis of 1,5-diarylpyrazoles as potential cox-2 inhibitors with nitric oxide releasing ability

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.

Isomeric acetoxy analogs of celecoxib and their evaluation as cyclooxygenase inhibitors

A group of celecoxib analogs having a SO2NH2 (9a-f), or SO2Me (12a-f), COX-2 pharmacophore at the para-position of the N-1 phenyl ring in conjunction with a C-5 phenyl ring having a variety of substituents (4-, 3-, 2-OAc;

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.

Highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles

A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of 1,3-diketones with arylhydrazines is described. The reaction proceeds at room temperature in N,N-dimethylacetamide and furnishes pyrazoles in 59-98% yield

Cyclodehydration reaction in water medium leads to library/multigram synthesis of 1,5-diarylpyrazoles

The cyclodehydration reaction leading to 1,5-diarylpyrazoles in water medium has been observed for the first time. The method has been used in generating library of compounds for drug discovery program under microwave condition and tried for a multigram synthesis of celecoxib, a premier COX-2 inhibitor, under normal laboratory condition.

Method of using cyclooxygenase-2 inhibitors in maintaining the fetal ductus ateriosus during treatment and prevention of preterm labor

This invention relates to the use of a tocolytic agent or agents in combination with selective cyclooxygenase-2 inhibitors of Formula (II) or a pharmaceutically-acceptable salt or derivative thereof for preparing a medicament for maintaining circulation through fetal ductus arteriosus during treatment or prevention of preterm labor in a subject in need of such treatment or prevention.

METHOD OF USING CYCLOOXYGENASE-2 INHIBITORS IN THE TREATMENT AND PREVENTION OF NEOPLASIA

This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating neoplasia. In particular, the invention describes the method of preventing and treating epithelial cell neoplasia in a subject, said method comprising treating the subject with a therapeutically-effective amount of a compound of Formula (I) wherein A, R and R are as described in the specification.

COMBINATION OF A SELECTIVE NMDA NR2B ANTAGONIST AND A COX-2 INHIBITOR

The present invention provides a combination of a selective NMDA NR2B antagonist and a COX-2 inhibitor for the treatment or prevention of pain or nociception.