65813-55-0Relevant articles and documents
Enrichment of Relevant Oxidative Degradation Products in Pharmaceuticals With Targeted Chemoselective Oxidation
Nanda, Kausik K.,Mozziconacci, Olivier,Small, James,Allain, Leonardo R.,Helmy, Roy,Wuelfing, W. Peter
, p. 1466 - 1475 (2019/01/22)
The ability to produce and isolate relatively pure amounts of relevant degradation products is key to several aspects of drug product development: (a) aid in the unambiguous structural identification of such degradation products, fulfilling regulatory requirements to develop safe formulations (International Conference on Harmonization Q3B and M7); (b) pursue as appropriate safety evaluations with such material, such as chronic toxicology or Ames testing; (c) for a specified degradation product in a late-stage regulatory filing, use pure and well-characterized material as the analytical standard. Producing such materials is often a resource- and time-intensive activity, either relying on the isolation of slowly formed degradation products from stressed drug product or by re-purposing the drug substance synthetic route. This problem is exacerbated if the material of interest is an oxidative degradation product, because typical oxidative stressing (H2O2 and radical initiators) tends to produce a myriad of irrelevant species beyond a certain stress threshold, greatly complicating attempts for isolating the relevant degradation product. In this article, we present reagents and methods that may allow the rapid and selective enrichment of active pharmaceutical ingredient with the desired oxidative degradation product, which can then be isolated and used for purposes described above.
Abiotic degradation and environmental toxicity of ibuprofen: Roles of mineral particles and solar radiation
Rubasinghege, Gayan,Gurung, Rubi,Rijal, Hom,Maldonado-Torres, Sabino,Chan, Andrew,Acharya, Shishir,Rogelj, Snezna,Piyasena, Menake
, p. 22 - 32 (2017/12/26)
The growing medical and personal needs of human populations have escalated release of pharmaceuticals and personal care products into our natural environment. This work investigates abiotic degradation pathways of a particular PPCP, ibuprofen, in the presence of a major mineral component of soil (kaolinite clay), as well as the health effects of the primary compound and its degradation products. Results from these studies showed that the rate and extent of ibuprofen degradation is greatly influenced by the presence of clay particles and solar radiation. In the absence of solar radiation, the dominant reaction mechanism was observed to be the adsorption of ibuprofen onto clay surface where surface silanol groups play a key role. In contrast, under solar radiation and in the presence of clay particles, ibuprofen breaks down to several fractions. The decay rates were at least 6-fold higher for irradiated samples compared to those of dark conditions. Toxicity of primary ibuprofen and its secondary residues were tested on three microorganisms: Bacillus megaterium, Pseudoaltermonas atlantica; and algae from the Chlorella genus. The results from the biological assays show that primary PPCP is more toxic than the mixture of secondary products. Overall, however, biological assays carried out using only 4-acetylbenzoic acid, the most abundant secondary product, show a higher toxic effect on algae compared to its parent compound.
Manganese terpyridine artificial metalloenzymes for benzylic oxygenation and olefin epoxidation
Zhang, Chen,Srivastava, Poonam,Ellis-Guardiola, Ken,Lewis, Jared C.
supporting information, p. 4245 - 4249 (2014/06/09)
New catalysts for non-directed hydrocarbon functionalization have great potential in organic synthesis. We hypothesized that incorporating a Mn-terpyridine cofactor into a protein scaffold would lead to artificial metalloenzymes (ArMs) in which the selectivity of the Mn cofactor could be controlled by the protein scaffold. We designed and synthesized a maleimide-substituted Mn-terpyridine cofactor and demonstrated that this cofactor could be incorporated into two different scaffold proteins to generate the desired ArMs. The structure and reactivity of one of these ArMs was explored, and the broad oxygenation capability of the Mn-terpyridine catalyst was maintained, providing a robust platform for optimization of ArMs for selective hydrocarbon functionalization.
High turnover remote catalytic oxygenation of alkyl groups: How steric exclusion of unbound substrate contributes to high molecular recognition selectivity
Das, Siddhartha,Brudvig, Gary W.,Crabtree, Robert H.
, p. 1628 - 1637 (2008/09/18)
H-bonding mediated molecular recognition between substrate and ligand -COOH groups orients the substrate so that remote, catalyzed oxygenation of an alkyl C-H bond by a Mn-oxo active site can occur with very high (>98%) regio- and stereoselectivity. This paper identifies steric exclusion - exclusion of non H-bonded substrate molecules from the active site - as one requirement for high selectivity, along with the entropic advantage of intramolecularity. If unbound substrate molecules were able to reach the active site, they would react unselectively, degrading the observed selectivity. Both of the faces of the catalyst are blocked by two ligand molecules each with a -COOH group. The acid p-tBuC6H4COOH binds to the ligand -COOH recognition site but is not oxidized and merely blocks approach of the substrate therefore acting as an effective inhibitor for ibuprofen oxidation in both free acid and ibuprofen ester form. Dixon plots show that inhibition is competitive for the free acid ibuprofen substrate, no doubt because this substrate can compete with the inhibitor for binding to the recognition site. In contrast, inhibition is uncompetitive for the ibuprofen-ester substrate, consistent with this ester substrate no longer being able to bind to the recognition site. Inhibition can be reversed with MeCOOH, an acid that can competitively bind to the recognition site but, being sterically small, no longer blocks access to the active site.
C-nitroso compounds and use thereof
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Page column 61, (2010/11/29)
A C-nitroso compound having a molecular weight ranging from about 225 to about 1,000 (from about 225 to about 600 for oral administration) on a monomeric basis wherein a nitroso group is attached to a tertiary carbon, which is obtained by nitrosylation of a carbon acid having a pKa less than about 25, is useful as an NO donor. When the compound is obtained from a carbon acid with a pKa less than about 10, it provides vascular relaxing effect when used at micromolar concentrations and this activity is potentiated by glutathione to be obtained at nanomolar concentrations. When the compound is obtained from a carbon acid with a pKa ranging from about 15 to about 20, vascular relaxing effect is obtained at nanomolar concentrations without glutathione. The compound is preferably water-soluble and preferably contains a carbon alpha to the nitrosylated carbon which is part of a ketone group. In one embodiment, the C-nitroso compound is obtained by nitrosylation of a conventional drug or such drug modified to modify the carbon acid pKa thereof When such drug is a nonsteroidal anti-inflammatory drug, the resulting C-nitroso compound functions as a COX-1 and COX-2 inhibitor without the deleterious effects associated with COX-1 inhibition but with the advantageous effects associated with COX-1 and COX-2 inhibition. One such C-nitroso compound is a nitrosoketoibuprofen. A specific example of this kind of compound is isolated as dimeric 2-[4′-(α-nitroso)isobutyrylphenyl] propionic acid. In another case, the C-nitroso compound contains the moiety where X is S, O or NR One embodiment is directed to COX-2 inhibitors where a tertiary carbon atom and/or an oxygen atom and/or a sulfur atom is nitrosylated.
Regiocontrolled Photooxygenation of Ibuprofen by Pyrimidopteridinetetrone- and Anthraquinone-Oxygen Systems
Sako, Magoichi,Oyabu, Iwao,Hirota, Kosaku,Maki, Yoshifumi
, p. 601 - 602 (2007/10/02)
Ibuprofen 4 underwent regiocontrolled photooxygenation on the propionic acid and isobutyl moieties in the presence of pyrimidopteridinetetrone 1- and anthraquinone 3- oxygen systems.
Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof
-
, (2008/06/13)
Novel esters of the general formula STR1 in which STR2 is the acyl residue of a non-steroidal anti-inflammatory compound containing a carboxylic acid function. The novel esters are prepared by reacting an acide R--COOH when R is as above, with 1-haloethyl ethyl carbonate. There are also provided pharmaceutical compositions containing any of the said novel esters.
Alkanoic acid derivatives
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, (2008/06/13)
An alkanoic acid compound is disclosed of formula: STR1 and certain of its physiologically acceptable salts and esters. The alkanoic acid compound and its salts and esters have an unexpectedly greater anti-inflammatory activity than representative members
