- Isolation and structural characterization of degradation products of aceclofenac by HPLC, HRMS and 2D NMR
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The stability of aceclofenac under stress conditions was assessed to identify the degradation products. So, it was subjected to stress conditions like acid, base and oxidation, according to ICH guideline Q1A (R2). One degradation product formed when the drug was subjected to acid stress. Three degradation products were formed during the basic stress condition. The drug substance was found to be stable to oxidative stress. The degradants formed during the stress were separated on a C-18 column using gradient preparative HPLC elution. The only product (DP-2) formed during the acid stress and this one is same as of one of the three degradation products (DP-1, DP-2, DP-3) were formed during base stress. 1D and 2D NMR spectra and mass spectral analysis supported the proposed structures for the products. The products DP-2 and DP-3 have been reported earlier but this is the first report of product DP-1 as a degradation product of aceclofenac.
- Guduru, Santhosh,Anji Karun Mutha,Vijayabhaskar,Kaliyaperumal, Muralidharan,Korupolu, Raghu Babu,Bonige, Kishore Babu,Rumalla, Chidananda Swamy
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- Two monoclinic forms of diclofenac acid
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Diclofenac acid, [2-(2,6-dichlorophenylamino)phenyl]acetic acid, C14H11Cl2NO2, crystallizes in two polymorphic forms in the monoclinic system. In both forms, molecules are linked to each other through the carboxyl groups giving rise to centrosymmetric dimers. No interaction among different dimers has been found.
- Castellari, Carlo,Ottani, Stefano
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- Morpholinoalkyl ester prodrugs of diclofenac: Synthesis, in vitro and in vivo evaluation
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Morpholinoalkyl esters (HCl salts) of diclofenac (1) were synthesized and evaluated in vitro and in vivo for their potential use as prodrugs for oral delivery. Prodrugs were freely soluble in simulated gastric fluid (SGF) and pH 7.4 phosphate buffer and showed a minimum of a 2000-fold increase in solubility over the parent drug. All prodrugs were more lipophilic than 1 as indicated by n-octanol/pH 7.4 buffer partition coefficients, but less lipophilic than 1 in terms of n-octanol/SGF partition coefficients. Potentiometrically determined ionization constants (pK(a)s) were in the range of 7.52 to 8.40 at 25 °C. The chemical and enzymatic hydrolyses of prodrugs were evaluated in SGF/pH 7.4 phosphate buffer and rat plasma, respectively, at 37 °C. All prodrugs were quantitatively hydrolyzed to 1 by either chemical and/or enzymatic means. An increase in carbon chain length rendered the prodrugs more stable at pH 7.4, but less stable in SGF. In general, the esters were hydrolyzed rapidly in rat plasma at 37 °C, the half-lives of hydrolysis being in the range of 4.85 to 23.49 min. Based on in vitro results, prodrug 2 was chosen to evaluate solid-state stability, bioavailability, and in vivo ulcerogenicity. At elevated temperatures, the solid-state decomposition of 2 followed biphasic kinetics, with rapid decomposition occurring initially. The extent, but not the rate, of absorption was significantly greater in rats for prodrug 2 than 1 following single dose oral administration. Prodrug 2 was significantly less irritating to gastric mucosa than 1 following single and chronic oral administration in rats.
- Tammara,Narurkar,Crider,Khan
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- Cleavage of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates
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The hydrolysis of tertiary amidomethyl ester prodrugs of carboxylic acids by rat liver homogenates is reported. Amidomethyl esters are rapidly and quantitatively converted to the corresponding acid and secondary amide. Reactivity is inversely dependent upon the molar refractivity and lipophilicity of the ester, as well as with steric bulk in the carboxylic acid moiety. In contrast to chemical and plasma hydrolyses, no dependence upon the pK(a) of the carboxylate leaving group was observed, nor was there any dependence upon the amide N-substituent. The rate of decomposition was inhibited by the carboxylesterase inhibitor eserine but not by the cytochrome P450 inhibitor SKF-525A, indicating the involvement of esterases in the hydrolysis reaction. These results indicate that amidomethyl esters may be expected to be readily cleaved in vivo. Copyright (C) 1999 Elsevier Science B.V.
- Iley, Jim,Mendes, Eduarda,Moreira, Rui,Souza, Sofia
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- Synthesis and spectroscopic/DFT structural characterization of coordination compounds of Nb(V) and Ti(IV) with bioactive carboxylic acids
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The reactions are reported of NbX5 (X = Cl, Br), TiCl4 and Ti(OiPr)4 with a selection of carboxylic acids exhibiting a known biological role, in a chlorinated solvent. The reactions of NbX5 with acetylsalicylic acid (aspirin) proceeded with selective deacetylation of the organic reactant and formation of the salicylate complexes NbX4(C7H5O3) (1a, X = Cl; 1b, X = Br) in 60–65% yields. NbCl5 reacted with diclofenac and ethacrynic acid (EA-CO2H) to give NbCl3[κ3O,O,N-O2CCH2(C6H4)NC6H3Cl2], 2 (80% yield), and NbCl4(O2C-EA), 3 (72% yield), respectively. Ti(OiPr)4 reacted with ethacrynic acid giving Ti(OiPr)2(O2C-EA)2, 4, in 74% yield, as a mixture of two isomers. All the products were characterized by means of analytical and spectroscopic methods, moreover DFT studies were carried out to give insight into structural features.
- De Palo, Alice,Biancalana, Lorenzo,Bortoluzzi, Marco,Alessandra Martini, Maria,Marchetti, Fabio,Pampaloni, Guido
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- Mass spectrometric characterization of circulating covalent protein adducts derived from a drug Acyl glucuronide metabolite: Multiple albumin adductions in diclofenac patients
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Covalent protein modifications by electrophilic acyl glucuronide (AG) metabolites are hypothetical causes of hypersensitivity reactions associated with certain carboxylate drugs. The complex rearrangements and reactivities of drug AG have been defined in great detail, and protein adducts of carboxylate drugs, such as diclofenac, have been found in liver and plasma of experimental animals and humans. However, in the absence of definitive molecular characterization, and specifically, identification of signature glycation conjugates retaining the glucuronyl and carboxyl residues, it cannot be assumed any of these adducts is derived uniquely or even fractionally from AG metabolites. We have therefore undertaken targeted mass spectrometric analyses of human serum albumin (HSA) isolated from diclofenac patients to characterize drug-derived structures and, thereby, for the first time, have deconstructed conclusively the pathways of adduct formation from a drug AG and its isomeric rearrangement products in vivo. These analyses were informed by a thorough understanding of the reactions of HSA with diclofenac AG in vitro. HSA from six patients without drug-related hypersensitivities had either a single drug-derived adduct or one of five combinations of 2-8 adducts from among seven diclofenac N-acylations and three AG glycations on seven of the protein's 59 lysines. Only acylations were found in every patient. We present evidence that HSA modifications by diclofenac in vivo are complicated and variable, that at least a fraction of these modifications are derived from the drug's AG metabolite, and that albumin adduction is not inevitably a causation of hypersensitivity to carboxylate drugs or a coincidental association. Copyright
- Hammond, Thomas G.,Meng, Xiaoli,Jenkins, Rosalind E.,Maggs, James L.,Castelazo, Anahi Santoyo,Regan, Sophie L.,Bennett, Stuart N.L.,Earnshaw, Caroline J.,Aithal, Guruprasad P.,Pande, Ira,Kenna, J. Gerry,Stachulski, Andrew V.,Park, B. Kevin,Williams, Dominic P.
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- Stability indicating methods for the determination of aceclofenac
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Five new selective, precise and accurate methods for the determination of aceclofenac in the presence of its degradation product; diclofenac are described. Method A utilizes third derivative spectrophotometry at 242 nm. Method B is RSD1 spectrophotometric method based on the simultaneous use of the first derivative of ratio spectra and measurement at 245 nm. Method C is a pH-induced difference (ΔA) spectrophotometry using UV measurement at 273 nm. Method D is a spectrodensitometric one, which depends on the quantitative densitometric evaluation of thin layer chromatogram of aceclofenac at 275 nm. Method E is RP-HPLC that depends on using methanol: water (60:40 v/v) as mobile phase at a flow rate of 1 ml/min and UV detection at 275 nm. Regression analysis of a beer's plot showed good correlation in the concentration ranges 5-40, 10-40, 15-50, 50-200, 1-50 μg/ml for methods A, B, C, D and E, respectively. These methods are suitable as stability indicating methods for the determination of aceclofenac in presence of its main degradation product, diclofenac. The proposed methods were applied for the analysis of the drug in its pharmaceutical formulation and the results obtained were compared with those obtained with the official B.P. method.
- Hasan,Abdel-Elkawy,Elzeany,Wagieh
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- Diclofenac n-derivatives as therapeutic agents with anti-inflammatory and anti-cancer effect
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A series of diclofenac N-derivatives (2, 4, 6, 8c, 9c, 10a-c) were synthesized in order to test their anti-cancer and anti-inflammatory effects. The anticarcinogen activity has been assayed against three cancer cell lines: HT29, human colon cancer cells; Hep-G2, human hepatic cells; and B16-F10, murine melanoma cells. First, we determined the cytotoxicity of the different compounds, finding that the most effective compound was compound 8c against all cell lines and both compounds 4 and 6 in human Hep-G2 and HT29 cell lines. Compounds 4 and 8c were selected for the percentage of apoptosis determination, cell cycle distribution, and mitochondrial membrane potential measure because these products presented the lowest IC50 values in two of the three cancer cell lines assayed (B16-F10 and HepG2), and were two of the three products with lowest IC50 in HT29 cell line. Moreover, the percentages of apoptosis induction were determined for compounds 4 and 8c, showing that the highest values were between 30 to 60%. Next, the effects of these two compounds were observed on the cellular cycle, resulting in an increase in the cell population in G2/M cell cycle phase after treatment with product 8c, whereas compound 4 increased the cells in phase G0/G1, by possible differentiation process induction. Finally, to determine the possible apoptosis mechanism triggered by these compounds, mitochondrial potential was evaluated, indicating the possible activation of extrinsic apoptotic mechanism. On the other hand, we studied the anti-inflammatory effects of these diclofenac (DCF) derivatives on lipopolysaccharide (LPS) activated RAW 264.7 macrophages-monocytes murine cells by inhibition of nitric oxide (NO) production. As a first step, we determined the cytotoxicity of the synthesized compounds, as well as DCF, against these cells. Then, sub-cytotoxic concentrations were used to determine NO release at different incubation times. The greatest anti-inflammatory effect was observed for products 2, 4, 8c, 10a, 10b, and 9c at 20 μg·mL?1 concentration after 48 h of treatment, with inhibition of produced NO between 60 to 75%, and a concentration that reduces to the 50% the production of NO (IC50 NO) between 2.5 to 25 times lower than that of DCF. In this work, we synthesized and determined for the first time the anti-cancer and anti-inflammatory potential of eight diclofenac N-derivatives. In agreement with the recent evidences suggesting that inflammation may contribute to all states of tumorigenesis, the development of these new derivatives capable of inducing apoptosis and anti-inflammatory effects at very low concentrations represent new effective therapeutic strategies against these diseases.
- Galisteo, Alberto,Jannus, Fatin,García-García, Amalia,Aheget, Houssam,Rojas, Sara,Lupia?ez, José A.,Rodríguez-Diéguez, Antonio,Reyes-Zurita, Fernando J.,Quílez Del Moral, José F.
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- Pd(OH)2/C, a Practical and Efficient Catalyst for the Carboxylation of Benzylic Bromides with Carbon Monoxide
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A simple, efficient, cheap, and broadly applicable system for the carboxylation of benzylic bromides with carbon monoxide and water is reported. Upon simple reaction with only 2.5 wt % of Pearlman's catalyst and 10 mol % of tetrabutylammonium bromide in tetrahydrofuran at 110 °C for 4 h, a range of benzylic bromides can be smoothly converted to the corresponding arylacetic acids in good to excellent yields after simple extraction and acid-base wash. The reaction was found to be broadly applicable, scalable, and could be successfully extended to the use of ex situ-generated carbon monoxide and applied to the synthesis of the nonsteroidal anti-inflammatory drug diclofenac.
- Wakuluk-Machado, Anne-Marie,Dewez, Damien F.,Baguia, Hajar,Imbratta, Miguel,Echeverria, Pierre-Georges,Evano, Gwilherm
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p. 713 - 723
(2020/02/04)
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- A diclofenac - glycine - [...], preparation method and application
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The invention discloses a diclofenac - glycine - [...], preparation method and application. The conjugate is to glycine as the connecting arm, respectively with the diclofenac and [...]; diclofenac is connected with glycine through amide linkage; diclofenac - glycine conjugate with resveratrol through connected [...] site. Because of the introduction of the glycine, to increase the solubility of the conjugate, diclofenac and resveratrol introduced into the coupling anti- arthritis significantly enhanced, the bad reaction is reduced, the safety is higher; the conjugate synthesis method is simple, and is suitable for industrial production.
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Paragraph 0029; 0030
(2019/06/30)
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- Copper(ii)-catalyzed c-n coupling of aryl halides and n-nucleophiles promoted by quebrachitol or diethylene glycol
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Herein, we report the natural ligand quebrachitol (QCT) as a promoter for a Cu(II) catalyst, which is highly effective for N-Arylation of various amines and related aryl halides. A series of diarylamine derivatives were obtained in high yields by using diethylene glycol (DEG) as both ligand and solvent. The C-N coupling reactions proceed under mild conditions and exhibit good functional group tolerance.
- Chen, Guoliang,Chen, Yuanguang,Du, Fangyu,Fu, Yang,Wu, Ying,Zhou, Qifan
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supporting information
p. 2161 - 2168
(2019/11/25)
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- A synthesis method of diclofenac (by machine translation)
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The present invention provides a diclofenac synthetic method, which belongs to the technical field of drug synthesis; synthetic method of this invention the specific reaction steps are as follows: step 1): compound (a) in the presence of sodium methoxide/methanol reaction, to obtain compound (b); step 2): compound (b) with a compound (c) in the presence of an alkali reaction, to obtain compound (d); step 3): compound (d) with a compound (e) in the organic solvent, under the action of catalyst reaction, to obtain compound (f); the method of raw materials are easy, simple operation, high yield, low cost, less wastes, high safety, is suitable for industrial production. (by machine translation)
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Paragraph 0063-0070
(2019/10/23)
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- “On Water” promoted N-arylation reactions using Cu (0)/myo-inositol catalytic system
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Myo-inositol is originally applied as a cardiovascular medicine in clinic, which can be multi-ton manufactured via extraction from the byproducts in agricultural product processing such as defatted rice bran and corn-soaking water. Herein, the application of myo-inositol (MI) as a novel versatile tridentate O-donor ligand has been first described for promoting Cu-catalyzed amination reaction in aqueous medium.
- Zhou, Qifan,Du, Fangyu,Chen, Yuanguang,Fu, Yang,Chen, Guoliang
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supporting information
p. 1938 - 1941
(2019/06/24)
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- Preparation method of diclofenac
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The invention belongs to the technical field of chemical drug synthesis, and particularly relates to a preparation method of diclofenac. The preparation method comprises the following steps: (1) adding 2-chlorophenylacetic acid or 2-chlorophenylacetate and a polar aprotic solvent into a reaction bottle, performing dissolution under stirring, adding 2,6-dichloroaniline, an alkali, a catalyst and areaction accelerator, performing heating under stirring to 120-160 DEG C, and performing heat preservation for a reaction for 2-24 h, wherein the catalyst is nano copper oxide or nano cuprous iodide;and (2) cooling the reaction mixture obtained in the step (1) to 70-90 DEG C, performing filtration, performing reduced-pressure distillation on the filtrate to obtain a crude product, performing purification on the crude product, and performing drying to obtain the diclofenac. According to the method provided by the invention, the catalyst has high catalytic efficiency and a small usage amount, areaction solvent is easy to recover, the production costs are low, the prepared product has a high yield, high purity and high quality, and the industrial production application is easy to realize.
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Paragraph 0027-0124
(2019/09/13)
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- Diclofenac 1,3,4-oxadiazole derivatives; biology-oriented drug synthesis (BIODS) in search of better non-steroidal, non-acid antiinflammatory agents
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Background: Inflammation is defined as the response of immune system cells to damaged or injured tissues. The major symptoms of inflammation include increased blood flow, cellular influx, edema, elevated cellular metabolism, reactive oxygen species (ROS) nitric oxide (NO) and vasodilation. This normally protective mechanism against harmful agents when this normal mechanism becomes dysregulated that can cause serious illnesses including ulcerative colitis, Crohn’s disease, rheumatoid arthritis, osteoarthritis, sepsis, and chronic pulmonary inflammation. Method: In this study synthetic transformations on diclofenac were carried out in search of better non-steroidal antiinflammatory drugs (NSAIDs), non-acidic, antiinflammatory agents. For this purpose diclofenac derivatives (2-20) were synthesized from diclofenac (1). All derivatives (2-20) and parent diclofenac (1) were evaluated for their antiinflammatory effect using different parameters including suppression of intracellular reactive oxygen species (ROS), produced by whole blood phagocytes, produced by neutrophils, and inhibition of nitric oxide (NO) production from J774.2 macrophages. The most active compound also evaluated for cytotoxicity activity. Results: Diclofenac (1) inhibited the ROS with an IC of 3.9 ± 2.8, 1.2 ± 0.0 μg/mL respectively 50 and inhibited NO with an IC50 of 30.01 ± 0.01 μg/mL. Among its derivatives 4, 5, 11, 16, and 20, showed better antiinflammatory potential. The compound 5 was found to be the most potent inhibitor of intracellular ROS as well as NO with IC50 values of 1.9 ± 0.9, 1.7 ± 0.4 μg/mL respectively and 7.13 ± 1.0 μg/mL, respectively, and showed good inhibitory activity than parent diclofenac. The most active compounds were tested for their toxic effect on NIH-3T3 cells where all compounds were found to be non-toxic compared to the standard cytotoxic drug cyclohexamide. Conclusion: Five derivatives were found to be active. Compound 5 was found to be the most potent inhibitor of ROS and NO compared to parent diclofenac 1 and standard drugs ibuprofen and L-NMMA, respectively. The most active compounds 1, 4, 5, 11 and 20 were found to be non-toxic on NIH-3T3 cells. Compound 4, 5, and 20 also showed good antiinflammatory potential, compound 11 and 16 showed moderate and low level of inhibition, respectively.
- Shah, Shazia,Arshia,Kazmi, Nida Siraj,Jabeen, Almas,Khan, Khalid Mohammed,Raza, Abeer,Faheem, Aisha,Dastagir, Nida,Ahmed, Tariq,Ahmed, Shakil,Perveen, Shahnaz
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p. 674 - 687
(2018/11/21)
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- Selective ortho C?H Cyanoalkylation of (Diacetoxyiodo)arenes through [3,3]-Sigmatropic Rearrangement
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We herein report a robust catalyst-free cross-coupling between ArI(OAc)2 and α-stannyl nitriles, aided by TMSOTf. The transformation introduces a cyanoalkyl group to the ortho position of ArI(OAc)2 and simultaneously reduces the aryl iodine(III) to iodide, thus providing α-(2-iodoaryl) nitrile as the product. This transformation could be completed within 5 min at ?78 °C and features superb functional-group tolerance and efficient scalability. DFT calculations indicate that the formation of a ketenimine(aryl)iodonium intermediate and subsequent [3,3]-sigmatropic rearrangement are involved as key steps.
- Tian, Junsong,Luo, Fan,Zhang, Chaoshen,Huang, Xin,Zhang, Yage,Zhang, Lei,Kong, Lichun,Hu, Xiaochun,Wang, Zhi-Xiang,Peng, Bo
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supporting information
p. 9078 - 9082
(2018/07/25)
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- Design and Synthesis of Novel Nonsteroidal Anti-Inflammatory Drugs and Carbonic Anhydrase Inhibitors Hybrids (NSAIDs-CAIs) for the Treatment of Rheumatoid Arthritis
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We report the synthesis of a series of hybrid compounds incorporating 6- and 7-substituted coumarins (carbonic anhydrase, CA inhibitors) derivatized with clinically used NSAIDs (indomethacin, sulindac, ketoprofen, ibuprofen, diclofenac, ketorolac, etc., cyclooxygenase inhibitors) as agents for the management of rheumatoid arthritis (RA). Most compounds were effective in inhibiting the RA overexpressed hCA IX and XII, with KI values in the low nanomolar-subnanomolar ranges. The antihyperalgesic activity of such compounds was assessed by means of the paw-pressure and incapacitance tests using an in vivo RA model. Among all tested compounds, the 7-coumarine hybrid with ibuprofen showed potent and persistent antihyperalgesic effect up to 60 min after administration.
- Bua, Silvia,Di Cesare Mannelli, Lorenzo,Vullo, Daniela,Ghelardini, Carla,Bartolucci, Gianluca,Scozzafava, Andrea,Supuran, Claudiu T.,Carta, Fabrizio
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p. 1159 - 1170
(2017/02/19)
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- A segmented flow platform for on-demand medicinal chemistry and compound synthesis in oscillating droplets
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We report an automated flow chemistry platform that can efficiently perform a wide range of chemistries, including single/multi-phase and single/multi-step, with a reaction volume of just 14 μL. The breadth of compatible chemistries is successfully demonstrated and the desired products are characterized, isolated, and collected online by preparative HPLC/MS/ELSD.
- Hwang, Ye-Jin,Coley, Connor W.,Abolhasani, Milad,Marzinzik, Andreas L.,Koch, Guido,Spanka, Carsten,Lehmann, Hansjoerg,Jensen, Klavs F.
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supporting information
p. 6649 - 6652
(2017/07/10)
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- Preparation process of diclofenac diethylamine
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The present invention discloses a preparation process of diclofenac diethylamine. The process comprise the steps of: (1) dissolving a raw material of diclofenac sodium in a mixed aqueous solution comprising water and a water-miscible organic solvent, reacting with hydrochloric acid, precipitating a diclofenac solid after the reaction, and conducting solid-liquid separation to obtain diclofenac; and (2) heating diclofenac to dissolve by using acetone as a solvent and dropwise adding diethylamine to conduct a salt-forming reaction, precipitating a diclofenac diethylamine solid after the reaction, and conducting solid-liquid separation to obtain diclofenac diethylamine. The preparation process has the characteristics of high yield, good quality and stability, which are suitable for practical industrial mass production, and is conducive to maintaining the product stability.
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Paragraph 0039; 0040
(2016/12/16)
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- Compositions and methods for the treatment of moderate to severe pain
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The invention relates to the compounds of formula I or its pharmaceutical acceptable salts, as well as polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I; and methods for treating or preventing moderate to severe pain, may be formulated for oral, buccal, rectal, topical, transdermal, transmucosal, intravenous, parenteral administration, syrup, or injection. Such compositions may be used to treatment of muscle pain, spasticity, neuropathic pain, fibromyalgia, post-operative pain, muscle spasticity, headache, chronic pain, sub-chronic pain and local pain.
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- An algorithm to determine the mechanism of drug distribution in lipid-core nanocapsule formulations
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Aqueous solutions of lipid-core nanocapsules are interesting drug delivery systems for passive drug targeting. In this study, we hypothesized that the drug distribution mechanisms in lipid-core nanocapsule formulations could be categorized into six different types. To experimentally determine the type of drug distribution in these formulations, we proposed the use of an algorithm as an innovative strategy. The approach is shown to be a valuable tool to optimize and select formulations intended for drug delivery. The best physico-chemical parameter in terms of predicting the type of distribution was the log D value. In conclusion, the use of the algorithm developed in this study represents a simple and rapid approach through which it was possible to experimentally determine the drug distribution in colloidal formulations for eight drug models.
- Oliveira, Catiuscia P.,Venturini, Cristina G.,Donida, Bruna,Poletto, Fernanda S.,Guterres, Silvia S.,Pohlmann, Adriana R.
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p. 1141 - 1150
(2013/03/28)
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- Synthesis of oligo(ethylene glycol) substituted phosphatidylcholines: Secretory PLA2-targeted precursors of NSAID prodrugs
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A series of new phosphatidylcholine analogues with structurally modified sn-2-substituents have been prepared. The synthetic compounds include oligo(ethylene glycol) derivatives with chain-terminal pharmacophores that upon catalytic hydrolysis by phospholipase A2 yielded a series of oligo(ethylene glycol)-conjugates of the respective drugs. The approach here outlined may open a new way to employ OEG derivatives of phospholipids for therapeutic applications as secretory PLA2-targeted precursors of prodrugs.
- Rosseto, Renato,Hajdu, Joseph
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experimental part
p. 110 - 116
(2010/06/16)
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- PROCESS FOR THE PREPARATION OF DICLOFENAC EPOLAMINE
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The present invention concerns a process for the preparation of the salt diclofenac epolamine comprising the following steps: a) reacting 1 -(2,6-dichlorophenyl)-2-indolinone with a base selected from sodium hydroxide or potassium hydroxide in an aqueous solvent, thus obtaining sodium or potassium diclofenac salt; b) dissolving the so obtained sodium or potassium diclofenac salt in a solvent- mixture comprising water and an organic solvent selected from the group consisting of ethyl acetate, methyl isobutyl ketone, toluene, isobutyl acetate, n-butyl acetate, n-propyl acetate, isopropyl acetate; c) adding a strong acid to give diclofenac acid and removing the water phase; d) anhydrifying the remaining organic solvent phase; and e) adding 1-(2-hydroxyethyl)-pyrrolidine.
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Page/Page column 8-9
(2010/08/05)
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- Expedient drug synthesis and diversification via ortho-C-H iodination using recyclable PdI2 as the precatalyst
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(Figure Presented) Pd(II)-catalyzed ortho-C-H iodination reactions of phenylacetic acid substrates have been achieved using recyclable PdI2 as the precatalyst. This class of substrates is incompatible with the classic amide formation/ortho-lithiation/iodination sequence. The power of this new technology is demonstrated by facile drug functionalization and drastically shortened syntheses of the drugs diclofenac and lumiracoxib.
- Mei, Tian-Sheng,Wang, Dong-Hui,Yu, Jin-Quan
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supporting information; experimental part
p. 3140 - 3143
(2010/09/03)
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- UNIQUE DUAL-ACTION THERAPEUTICS
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A new family of therapeutics which provides a controlled-release delivery platform for non-steroidal anti-inflammatory agents on an ester or an ester-carbonate backbone is disclosed herein. These agents are reversible inhibitors of acetylcholinesterase and are thus useful for clinical conditions benefiting from inflammation suppression and cholinergic intervention. These compounds are of the general formula wherein n = 0, 1; X = C, Si, and N+ and NSAID = ibuprofen, naproxen, indomethacin and diclofenac. Other embodiments are also disclosed
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Page/Page column 46; 47; 49
(2010/05/14)
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- Combination Therapies for Treating Metabolic Disorders
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This invention is directed to pharmaceutical combinations comprising an antioxidant agent, an anti-inflammatory agent, and optionally at least one other anti-diabetic agent useful for treating metabolic disorders. This invention also encompasses pharmaceutically acceptable compositions comprising an antioxidant agent, an anti-inflammatory agent, optionally at least one other anti-diabetic agent, and at least one pharmaceutically acceptable carrier. The combinations and compositions of this invention are useful as methods for treating metabolic disorders including diabetes, particularly Type I and Type II diabetes, as well as diseases and disorders associated with diabetes, including but not limited to atherosclerosis, cardiovascular disease, inflammatory disorders, nephropathy, neuropathy, retinopathy, β-cell dysfunction, dyslipidemia, LADA, metabolic syndrome, hyperglycemia, insulin resistance, and/or chronic obstructive pulmonary disease in a mammal, particularly a diabetic mammal, and specifically a human patient. This invention is particularly directed to pharmaceutical compositions comprising an lipoic acid, one or more anti-inflammatories selected from the group consisting of diflunisal, diclofenac, dexibuprofen, dexketoprofen, naproxen, and salicylate, and optionally one or more pharmaceutically acceptable carriers. The compositions of this invention are useful as methods for treating metabolic disorders including type II diabetes, insulin resistance, beta-cell dysfunction, and hyperglycemia in a patient, particularly a diabetic patient.
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- Multifunctional Forms of Polyoxazoline Copolymers and Drug Compositions Comprising the Same
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The present disclosure provides copolymers of 2-substituted-2-oxazolines possessing two or three reactive functional groups which are also chemically orthogonal. The copolymers described may be random copolymers, block copolymers or a mixture of random and block copolymer configurations. Furthermore, the present disclosure provides novel methods for synthesizing the above polymers and for conjugating to molecules such as targeting, diagnostic and therapeutic agents.
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- Controlled-Delivery System of Pharmacologically Active Substances, Preparation Process and Medical Use Thereof
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The invention concerns a system for biocompatible drug release comprising: (i) a polymer matrix; (ii) an inorganic component located inside said matrix and characterized by a lamellar structure with a net positive or negative charge able to intercalate (iii) a pharmacologically active principle into said lamellar structure, by establishing an ionic type of bond with it and thereby obtaining an intercalation compound. The preparation process for the release system comprises the stages of: treating the lamellar solid in such a way as to give it a net positive or negative charge, then combining it with the chosen active principle, also in an ionic form, to obtain an intercalation compound which is then mixed with the polymer matrix. The release system can be employed in making medical devices, like sutures, membranes, osteosynthesis plaques, multilayered devices, gels and drug delivery systems.
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- Aminocarbonyloxymethyl ester prodrugs of flufenamic acid and diclofenac: Suppressing the rearrangement pathway in aqueous media
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Aminocarbonyloxymethyl ester prodrugs are known to undergo rearrangement in aqueous solutions to form the corresponding N-acylamine side product via an O → N intramolecular acyl transfer from the carbamate conjugate base. Novel aminocarbonyloxymethyl esters of diclofenac and flufenamic acid containing amino acid amide carriers were synthesized and evaluated as potential prodrugs displaying less ability to undergo rearrangement. These compounds were prepared in reasonable yield by a four-step synthetic method that uses the appropriate N-Boc-protected amino acid N-hydroxysuccinimide ester and secondary amine and chloromethyl chloroformate as key reactants. Their reactivity in pH 7.4 buffer and 80% human plasma at 37°C was assessed by RP-HPLC. The aminocarbonyloxymethyl esters containing a secondary carbamate group derived from amino acids such as glycine or phenylalanine were hydrolyzed quantitatively to the parent drug both in non-enzymatic and enzymatic conditions, with no rearrangement product being detected. The oral bioavailability in rats was determined for selected diclofenac derivatives. These derivatives displayed a bioavailability of 25 to 68% relative to that of diclofenac, probably due to their poor aqueous solubility and lipophilicity. These results suggest that further optimization of aminocarbonyloxymethyl esters as potential prodrugs for non-steroidal anti-inflammatory drugs require the use of amino acid carriers with ionizable groups to improve aqueous solubility.
- Ribeiro, Lina,Silva, Nuno,Iley, Jim,Rautio, Jarkko,Jaervinen, Tomi,Mota-Filipe, Helder,Moreira, Rui,Mendes, Eduarda
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- Quinazolin-4(3H)-ones of 2-[(2′,6′-dichlorophenyl)amino]phenyl acetic acid with substituted aryl acetamide and their microbial studies
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Synthesis and antimicrobial activity of quinazolinones III1-48 have been reported from 2-[(2′,6′-dichlorophenyl)amino]phenyl acetic acid and various substituted aryl acetamides at position two and three of quinazolinone nucleus respectively via benzoxazine intermediate I. All the compounds have been established on the basis of spectral data (IR, 1H NMR) and elemental analysis.
- Patel,Chaudhari
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p. 838 - 841
(2007/10/03)
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- Oral administration forms for administering a fixed tramadol and diclofenac combination
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An oral administration unit containing the active substances Tramadol and Diclofenac and/or physiologically acceptable salts thereof, in which both active substances are contained in the same administration unit as two separately formulated subunits.
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- Kinetics of degradation of diclofenac sodium in aqueous solution determined by a calorimetric method
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An isothermal heat conduction microcalorimeter has been used to study the stability of diclofenac sodium both alone and its inclusion complex with β-cyclodextrin in aqueous solution. The rates of heat evolved during degradation of diclofenac sodium have been measured by a highly sensitive microcalorimetric technique as function of concentration, pH and temperature. The calorimetric accessible data have been incorporated in the equations for determination of rate constants, change in enthalpy and order of reaction. The decomposition of diclofenac sodium both alone and its inclusion complex with β-cyclodextrin in solution corresponds to a pseudo-first order reaction. The values of rate constants, k's at 338.15 K, (calculated from the variation of heat evolution with the time) for the degradation of diclofenac sodium at pH 5, 6, 7, 8 and its inclusion complex with β-cyclodextrin at pH 7 are found to be 4.71 × 10-4, 5.69 × 10-4, 6.12 × 10-4, 6.57 × 10-4 and 4.26 × 10-4 h-1 respectively. There is good agreement between calorimetric determined t0.5 and literature values. It has been found that β-cyclodextrin retards the degradation of diclofenac sodium. The kinetic parameters have been calculated for the reaction. The negative entropy of activation suggests the formation of an ordered transition state.
- Chadha, Renu,Kashid,Jain
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p. 631 - 635
(2007/10/03)
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- PACKAGING BAG FOR PLASTER AND PACKAGED PLASTER
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Packaged patch (10) according to the invention comprises patch (2) situated in space (4) inside patch package (3) composed of laminated packaging material (1), and its edges are sealed. Laminated packaging material (1) comprises hygroscopic material layer (13) made of LDPE containing 20-40 wt% of an inorganic filler, situated between moisture-permeable material layer (14) made of LDPE and having a moisture permeability of 40-120 g/m2/day and a screen material layer which blocks penetration of moisture, etc. and is composed of HDPE layer (12) and aluminum foil (11). The saturation hygroscopicity of laminated packaging material (1) is 2-30 g/m2under atmosphere conditions with a temperature of 25°C and a relative humidity of 75%. This construction sufficiently reduces the effect of moisture on a drug in patch (2) and allows patch (2) to be held in a stable state for prolonged periods, while also improving the economy and handleability of patch package (3).
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- Oral administration forms for administering a fixed tramadol and diclofenac combination
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An oral administration unit containing the active substances Tramadol and Diclofenac and/or physiologically acceptable salts thereof, in which both active substances are contained in the same administration unit as two separately formulated subunits.
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- Agents for intravitreal administration to treat or prevent disorders of the eye
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Methods and preparations for treating disorders of the eye and/or causing posterior vitreous disconnection or disinsertion. Preparations containing a) urea, b) urea derivatives (e.g., hydroxyurea, thiourea), c) a non-steroidal anti-inflamatory agents, d) antmetabolites, e) urea, urea derivatives, non-enzymatic proteins, nucleosides, nucleotides and their derivatives (e.g., adenine, adenosine, cytosine, cytadine, guanine, guanitadine, guanidinium, thymidine, thimitadine, uradine, uracil, cystine), uric acid, calcium acetal salicylate, ammonium sulfate or other compound capable of causing non-enzymatic dissolution of the hyaloid membrane or e) any of the possible combinations thereof, are administered to the eye in therapeutically effective amounts.
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- Sol-controlled thermocolloid matrix based on gelatin for oral sustained-release form
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A peroral depot medicament with controlled active substance release is composed of a gelatine matrix that continuously dissolves in an aqueous medium above 37° C., and a medicament distributed therein. The release of the medicament, that may be easily or scarcely soluble, lipophilic or hydrophilic, is variable in time and may be adjusted according to the medicament.
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- Liquid oral formulation of diclofenac
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The invention relates to an aqueous oral pharmaceutical preparation of diclofenac which can be used for treating pain and inflammatory processes, and to the preparation of a preparation of this type.
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- Ethoxycarbonyloxy ethyl esters of non-steroidal anti-inflammatory carboxylic acids and pharmaceutical compositions thereof
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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.
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- Process for preparation of o-(2,6-dichloroanilino)phenylacetic acid and novel intermediate for use in preparation of the same
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Disclosed is a process for the preparation of o-(2,6-dichloroanilino)phenylacetic acid (Diclofenac) or its pharmacologically acceptable acid addition salt, which comprises hydrolyzing an N,N-disubstituted-o-(2,6-dichloroanilino)phenylacetamide derivative with an alkali. Also a novel intermediate for use in the preparation of Diclofenac, that is, an N,N-disubstituted-o-halogenophenylacetamide in which the halogen is iodine or bromine, is disclosed.
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- Process for the synthesis of isatin derivatives
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Process for the preparation of the 2-(2,6-dichloroanilino)-phenylacetic acid which comprises, as a basic step, the heating of a mixture containing a pyridic base, an organic or inorganic acid and 4,5,6,7-tetrahydro-N-(2,6-dichlorophenyl)-isatin or its O-acyl or O-alkyl derivatives.
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- O-(N-Allyl-2,6-dichloroanilino)phenylacetic acid derivative and a process for preparing the same
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An o-(N-allyl-2,6-dichloroanilino)phenylacetic acid derivative represented by the formula: STR1 wherein R1, R2 and R3, which may be the same or different, individually represent a hydrogen atom, a halogen atom or an alkyl group; Y represents a hydroxyl group, an alkoxyl group, a --OM1 group in which M1 is an alkali metal atom, a --OM1/22 group in which M2 is an alkaline earth metal atom, an amino group having the formula --NR5 R6 in which R5 and R6, which may be the same or different, individually represent a hydrogen atom or an alkyl group, or a hydroxylamino group, and processes for preparing the same.
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- [N-benzyl-o-(2,6-dichloroanilino)phenyl]acetic acid derivatives
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Novel compounds of [N-benzyl-o-(2,6-dichloroanilino)phenyl]acetic acid derivatives having the formula STR1 wherein X represents H, Cl, Br or a C1 -C4 alkyl group and Y is OH, OR or SR and R represents a C1 -C4 alkyl group.
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