1601-20-3Relevant articles and documents
Chemical synthesis of an indomethacin ester prodrug and its metabolic activation by human carboxylesterase 1
Takahashi, Masato,Ogawa, Tomohiro,Kashiwagi, Hiroshi,Fukushima, Fumiya,Yoshitsugu, Misaki,Haba, Masami,Hosokawa, Masakiyo
, p. 997 - 1000 (2018)
It is necessary to consider the affinity of prodrugs for metabolic enzymes for efficient activation of the prodrugs in the body. Although many prodrugs have been synthesized with consideration of these chemical properties, there has been little study on the design of a structure with consideration of biological properties such as substrate recognition ability of metabolic enzymes. In this report, chemical synthesis and evaluation of indomethacin prodrugs metabolically activated by human carboxylesterase 1 (hCES1) are described. The synthesized prodrugs were subjected to hydrolysis reactions in solutions of human liver microsomes (HLM), human intestine microsomes (HIM) and hCES1, and the hydrolytic parameters were investigated to evaluate the hydrolytic rates of these prodrugs and to elucidate the substrate recognition ability of hCES1. It was found that the hydrolytic rates greatly change depending on the steric hindrance and stereochemistry of the ester in HLM, HIM and hCES1 solutions. Furthermore, in a hydrolysis reaction catalyzed by hCES1, the Vmax value of n-butyl thioester with chemically high reactivity was significantly lower than that of n-butyl ester.
Synthesis method of indometacin and analogues thereof
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, (2020/04/29)
The invention belongs to the technical field of indometacin synthesis, and discloses a synthesis method of indometacin and analogues thereof. The synthesis method of indometacin and analogues thereofcomprises the following steps: directly introducing alkyl, aromatic ring or heteroaromatic ring to the C2 position of indole through palladium catalyzed reaction; introducing a carboxylic acid fragment to the C3 position of the indole; and introducing an aroyl group to the N1 position of the indole. The method solves the problems that most of existing indometacin synthesis methods carry out modification by constructing an indole ring, simple structure change of indometacin molecules based on the synthesis strategy often needs de novo synthesis and synthesis steps for later modification and structure-activity relationship research of the indometacin molecules are tedious.
Preparation method for acemetacin
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Paragraph 0007, (2017/06/21)
The invention relates to a preparation method for an anti-inflammatory and anti-phlogistic analgesic medicament, in particular to a preparation method for acemetacin, and belongs to the technical field of chemical pharmacy. The method comprises the following steps: introducing hydrogen chloride into acetic acid to prepare acetic acid and hydrogen chloride acidolysis solution, adding acemetacin tert-butyl ester into the acidolysis solution, stirring at a constant temperature, performing an acid hydrolysis reaction, cooling after the reaction is ended, standing, crystallizing, filtering, performing top washing, and refining to obtain the finished product acemetacin.
Ortho-Carbaborane derivatives of indomethacin as cyclooxygenase (COX)-2 selective inhibitors
Scholz, Matthias,Blobaum, Anna L.,Marnett, Lawrence J.,Hey-Hawkins, Evamarie
supporting information; experimental part, p. 4830 - 4837 (2012/09/22)
A series of novel indomethacin analogues with carbaboranes as three-dimensional substitutes for the chlorophenyl ring have been prepared. Their cyclooxygenase (COX) inhibition and enzyme selectivity has been tested and compared to the corresponding adamantyl analogues. Surprisingly, only the ortho-carbaborane derivatives were active compounds. Preliminary biological studies gave an interesting insight into the validity of employing carbaboranes as pharmacophores.
Profiling indomethacin impurities using high-performance liquid chromatography and nuclear magnetic resonance
Hess,Teubert,Ortwein,Eger
, p. 301 - 311 (2007/10/03)
The anti-inflammatory drug indomethacin was investigated regarding new related impurities. Therefore, related substances 2-9 were prepared by independent synthesis and physicochemically characterized. To determine indomethacin and its related substances, a new HPLC-UV method was developed and validated. Indomethacin and its impurities were eluted on a C18 column with a mobile phase consisting of methanol and an aqueous solution of 0.2% phosphoric acid at a flow rate of 1.5 ml/min and were quantified by UV detection at 320 nm. Overall, the HPLC-UV method was simple and reliable for the detection of eight impurities in indomethacin. In addition to the HPLC-UV method, 1H nuclear magnetic resonance (NMR) was used to investigate indomethacin regarding impurities. For that purpose, related substances 2-9 were systematically added to indomethacin and investigated. The NMR method was found to be very useful for the identification of impurities in bulk substance without prior separation. Both HPLC-UV and NMR were used to analyze 38 batches of indomethacin available on the European market. The outcome was that 42% of the batches did not meet the compendial requirements although they met the specifications of current compendial methods. Some batches contained the previously undescribed impurity 8, while other batches contained by-products from two distinct synthetic routes. The methods presented herein are important contributions to the ongoing efforts to reduce impurities and therefore the risk of adverse side-effects in drugs that are no longer under patent protection.
Lactone compounds for treating patient with precancerous lesions
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, (2008/06/13)
Substituted lactone compounds are useful in the treatment of precancerous lesions and neoplasms.
