- Vilsmeier reagent, NaHSe and diclofenac acid chloride: One-pot synthesis of a novel selenoindolinone with potent anticancer activity
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An effective and straightforward synthesis of 3-seleno functionalized indolinone (5) involving Vilsmeier reagent is presented. Likewise, a procedure to achieve lactamization of diclofenac with excellent yields by using hydrides is also ascertained. Compou
- Aydillo, Carlos,Plano, Daniel,Ruberte, Ana Carolina,Sanmartín, Carmen,Sharma, Arun K.
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- Synthesis, ex vivo and in vitro hydrolysis study of an indoline derivative designed as an anti-inflammatory with reduced gastric ulceration properties
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The compound 1-(2,6-dichlorophenyl)indolin-2-one (1), planned as a pro-drug of diclofenac (2), was easily synthesized in 94% yield by an intramolecular reaction in the presence of coupling agent (i.e., EDC). Compound 1 showed anti-inflammatory and analgesic activity without gastro-ulcerogenic effects. The chemical and enzymatic hydrolysis profile of the lactam derivative 1 does not indicate conversion to diclofenac (2).This compound is a new non-ulcerogenic prototype for treatment of chronic inflammatory diseases.
- Chung, Man Chin,Dos Santos, Jean Leandro,Oliveira, Ednir Vizioli,Blau, Lorena,Renato Farina Menegon,Peccinini, Rosangela Goncalves
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- Stability of diclofenac sodium in the inclusion complex with β-cyclodextrin in the solid state
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The aim of this study was to characterize the thermal stability of diclofenac sodium both alone and in the inclusion complex with β-cyclodextrin in the solid state, by determination of the number of the products of its decomposition, which were identified by GC-MS. The molar ratio of diclofenac sodium in the inclusion complex with β-cyclodextrin was 1:1. The decomposition of diclofenac sodium both alone and in inclusion complex with β-cyclodextrin occurred according to the first-order reaction. The HPLC of the samples thermostated at 80°C gave five products of decomposition, which were identified by GC-MS. Diclofenac sodium in the inclusion complex with β-cyclodextrin was more thermally stable. Thermal decomposition of diclofenac sodium leads to formation of five products, of which 4-chloro-10H-9-acridinone had not been reported previously in the literature.
- Cwiertnia, Barbara,Hladon, Teresa,Stobiecki, Maciej
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- Diclofenac sodium injection sterilized by autoclave and the occurrence of cyclic reaction producing a small amount of impurity
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A known impurity is formed in the production of a parenteral dosage form of diclofenac sodium if terminally sterilized by autoclave. This impurity has been detected as 1-(2,6-diclorophenyl) indolin-2-one, which is also an intermediate from which diclofenac sodium is generally synthesized. It is only the condition of the autoclave method (i.e., 123 ± 2°C) that enforces the intramolecular cyclic reaction of diclofenac sodium forming the indolinone derivative and sodium hydroxide. The formation of this impurity has been found to depend on the initial pH of the formulation. The reaction follows first-order kinetics, and the energy of activation is 5.34 kcal/mol. The other excipients in the formulation do not have a role in this reaction. The concentration of the impurity in the resultant product in the ampule goes beyond the limit of the raw materials in the pharmacopoeias. It is thus preferable to use an alternative sterilization method; that is, an aseptic filtration method in which the formation of this impurity can be avoided.
- Roy, Jiben,Islam, Mafizul,Khan, Anowar H.,Das, Subodh C.,Akhteruzzaman,Deb, Ajay K.,Mahbub Alam
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- Synthesis method of diclofenac sodium
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The invention discloses a synthesis method of diclofenac sodium, which comprises the following steps: (1) toluene. An oil layer is obtained by adding 2, 6 -dichlorophenol and sodium carbonate, keeping warm and refluxing, extracting the oil layer with water, and adding an alkali heat-preserving reaction in the oil layer to obtain 2, 6 -dichloroaniline. (2) 1, 2 Dichlorodimethylaniline prepared in step (6 -) is heated and melted, chloroacetyl chloride is added dropwise, and the heat is subjected to heat preservation reaction after being heated to crystallize to obtain N - (2, 6 - dichlorophenyl) - phenyl - chloroacetamide. (3) 2 (N - 2 Dichlorophenyl) 6 - phenyl - chloroacetamide prepared in step (-) is reacted with the aluminum trichloride to give a solid 1 - (2, 6 -dichlorophenyl) -2 -indolinone. (4) 3 (1 - 2-dichlorophenyl) 6 -indolinone prepared in step (-2 -) is added to alkali liquor, stirred and heated to reflux to obtain diclofenac sodium. The synthesis method is stable, easy to operate, low in cost, high in yield and suitable for industrial production.
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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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- Preparation method of 2-[(2, 6-dichlorophenyl) amino] sodium phenylacetate
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The invention belongs to the field of chemical pharmacy, and relates to a production process of a chemical bulk drug, in particular to a preparation method of 2-[(2, 6-dichlorophenyl) amino] sodium phenylacetate. The preparation method comprises the following steps: taking 2, 6-dichlorodiphenylamine and chloroacetyl chloride as initial raw materials; and completing acylation reaction, Lewis acidicionic liquid catalyzed Friedel-Crafts alkylation reaction and hydrolysis reaction by a one-pot method to finally obtain the 2-[(2, 6-dichlorophenyl) amino] sodium phenylacetate. The 2-[(2,6-dichlorophenyl) amino] sodium phenylacetate is synthesized by adopting a one-pot preparation scheme, has the advantages of short reaction time, simplicity in operation, mild conditions, high yield, good catalytic effect, high selectivity, recyclability and the like, and is beneficial to industrial production.
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Paragraph 0034-0034; 0038-0045
(2020/05/30)
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- Degradation kinetics and mechanism of diclofenac by UV/peracetic acid
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In this work, the degradation kinetics and mechanism of diclofenac (DCF) by UV/peracetic acid (PAA) was investigated. The effects of pH, PAA dose and common water components such as inorganic ions and dissolved organic matter (DOM) on DCF degradation by UV/PAA were also evaluated. It was observed that the addition of PAA promoted the photodegradation of DCF due to the generation of reactive radicals in the photolysis of PAA, which was also confirmed by the radical scavenging experiment. The best degradation efficiency of DCF was obtained at pH 8.5. The removal of DCF was enhanced gradually with increasing PAA dose. Since NO3- is a photosensitive substance which can generate HO under UV irradiation, its existence promoted the degradation of DCF. The presence of CO32- could slightly improve DCF degradation, which might be due to the role of generated carbonate radicals. Cl-, SO42- and Fe3+ had little effect on DCF removal, while Cu2+ could enhance DCF degradation because of its catalytic ability for PAA decomposition. An inhibition effect on DCF removal was observed in the presence of DOM, and it was more obvious in higher concentration of DOM. The elimination of total organic carbon (TOC) was low. According to the twelve reaction products detected in the UV/PAA system, the probable transformation mechanism of DCF was proposed exhibiting eight reaction pathways, i.e., hydroxylation, decarboxylation, formylation, dehydrogenation, dechlorination-hydrogenation, dechlorination-cyclization, dechlorination-hydroxylation and amidation. This study indicates that UV/PAA is a promising method for DCF removal from contaminated water.
- Fu, Yongsheng,Liu, Yiqing,Zhang, Li
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p. 9907 - 9916
(2020/03/23)
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- 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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p. 851 - 854
(2019/03/08)
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- 1 - Aryl -2 - indolinone derivatives preparation method
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The invention discloses a method for synthesis of 1-aryl-2-indolinone derivatives. The method comprises the following steps: dissolving N-aryl-substituted phenylacetamide (III) in an organic solvent, adding a chlorination reagent and carrying out a reaction so as to obtain N-chloro-N-aryl-substituted phenylacetamid (II); and subjecting N-chloro-N-aryl-substituted phenylacetamid to a reaction with a certain amount of Lewis acid and a proper amount of an organic solvent at a certain temperature so as to obtain 1-aryl-2-indolinone (I). The method provided by the invention has the advantages of simple operation, easily available reagents, a low price, mild conditions and capability of synthesizing a plurality of 1-aryl-2-indolinone (I) compounds.
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Paragraph 0053-0060
(2019/04/18)
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- A double-dispain preparation method
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The invention discloses a method for preparing diclofenac sodium. The method is characterized by comprising the following steps of: obtaining N-chloro-N-(2,6-dichlorophenyl)phenylacetamide (III) through reacting a chloride reagent with N-(2,6-dichlorophenyl)phenylacetamide (IV); obtaining 1-(2,6-dichlorophenyl)-2-indolinone (II) through reacting N-chloro-N-(2,6-dichlorophenyl)phenylacetamide (III) with a certain amount of Lewis acid in an organic solvent; and finally obtaining diclofenac sodium (I) through enabling the 1-(2,6-dichlorophenyl)-2-indolinone (II) to be subjected to hydrolysis reaction in a sodium hydroxide solution. The method disclosed by the invention has the characteristics of simplicity in operation, easily-available reagents, low cost, mild conditions and the like, and provides a novel processing route for the synthesis of diclofenac sodium.
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Paragraph 0033; 0034; 0035; 0071
(2018/09/08)
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- 1 - (2, 6 - Dichlorophenyl) - 2 - oxindole synthesis process
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The invention discloses a synthesis process of 1-(2,6-dichlorophenyl)-2-indolone. The synthesis process comprises the following steps: (1) a reaction step: taking diclofenac as a raw material, adding an organic mixed solvent to dissolve the diclofenac completely, adding thionyl chloride at room temperature, and carrying out a reaction at proper temperature for a proper time, so as to obtain a mixture containing a 1-(2,6-dichlorophenyl)-2-indolone crude product;(2) a post-treatment step: filtering the mixture obtained in the step (1) to obtain a solid, washing the obtained solid with water, and drying to obtain the 1-(2,6-dichlorophenyl)-2-indolone product. The synthesis process has the advantages that thionyl chloride is taken as a reaction reagent, and the product yield reaches up to 90 to 95 percent, so that on one hand, the reaction cost is reduced, and on the other hand, the purification process is simpler and more convenient.
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Paragraph 0028-0035
(2018/04/03)
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- A synthetic method for diclofenac zinc
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The invention relates to a synthetic method for diclofenac zinc, and belongs to the field of chemical synthesis of medicines. Aniline is adopted as a raw material and is reacted with 2,6-dichlorophenol under the action of acetyl chloride to obtain 2-(2,6-dichlorophenoxy)-N-phenylacetamide; the 2-(2,6-dichlorophenoxy)-N-phenylacetamide is adopted to prepare N-(2,6-dichlorophenyl)phenylamine under action of an inorganic alkali; the N-(2,6-dichlorophenyl)phenylamine is subjected to a cyclization reaction under the action of chloroacetyl chloride to prepare 1-(2,6-dichlorophenyl)-2-indolone; and the 1-(2,6-dichlorophenyl)-2-indolone is subjected to hydrolysis, and other reactions to synthesize the diclofenac zinc. According to the method, the cost is low, the yield is high, the total yield is 70%, reaction conditions are mild particularly, the method is environment-friendly, and waste gas generated in a reaction process, such as hydrogen chloride, is absorbed by an absorbing system, and therefore the method has a good industrialization prospect.
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- The Hydrolysis of Diclofenac Esters: Synthetic Prodrug Building Blocks for Biodegradable Drug-Polymer Conjugates
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Degradation reactions on diclofenac-monoglycerides (3a,b), diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c), diclofenac (1), and diclofenac lactam (4) were performed at 37°C in isotonic buffer solutions (apparent pH range 1-8) containing varying concentrations of acetonitrile (ACN). The concentration remaining of each analyte was measured versus time. Diclofenac-monoglycerides and diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c) were both found to undergo facile and complete hydrolysis in pH 7.4 isotonic phosphate buffer/10% ACN. Under mildly acidic, neutral or alkaline conditions, diclofenac-(p-hydroxybenzoate)-2-monoglyceride (3c) had the fastest hydrolysis rate (t1/2 = 3.23 h at pH 7.4), with simultaneous formation of diclofenac lactam (4) and diclofenac (1). Diclofenac-monoglycerides (3a,b) hydrolyzed more slowly under the same conditions, to again yield both diclofenac (1) and diclofenac lactam (4). There was also transesterification of diclofenac-2-monoglyceride (3b) to its regioisomer, diclofenac-1-monoglyceride (3a) across the pH range. Diclofenac was shown to be stable in neutral or alkaline conditions but cyclized to form the lactam (4) in acidic conditions. Conversely, the lactam (4) was stable under acidic conditions but was converted to an unknown species under alkaline or neutral conditions.
- Wang, Feng,Finnin, Joshua,Tait, Cassandra,Quirk, Stephen,Chekhtman, Igor,Donohue, Andrew C.,Ng, Sarah,D'Souza, Asha,Tait, Russell,Prankerd, Richard
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p. 773 - 785
(2016/05/09)
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- Simultaneous identification of Fenton degradation by-products of diclofenac, ibuprofen and ketoprofen in aquatic media by comprehensive two-dimensional gas chromatography coupled with mass spectrometry
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Diclofenac, ibuprofen and ketoprofen are anti-inflammatory drugs intensively used both in human and animal treatment. Due to their high stability these compounds are partially removed by wastewater treatment plants and from this reason the development of some alternative treatments such as advanced oxidative processes are necessary. The main problems in the optimization of an advanced oxidative process rise from the difficulties which appear in the identification of degradation by-products necessary for the establishment of degradation pathway. In this paper a developed method for the simultaneous identification of Fenton degradation by-products of the three above mentioned pharmaceuticals is presented. The obtained results show the comprehensive two-dimensional gas chromatography coupled with mass spectrometry as a proper method for the analysis of the complex mixture of compounds resulted from the Fenton degradation process. Moreover, some compounds never mentioned in the scientific literature were identified. (Chemical Equation Presented).
- Beldean-Galea, Mihail Simion,Coman, Virginia,Copaciu, Florina,Thiébaut, Didier,Vial, Jér?me
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p. 1021 - 1027
(2015/07/15)
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- In vitro cytotoxicity evaluation of diversely substituted N-aryl-2-oxindoles
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In continuation with our previous work, structurally diverse 2-indolinones bearing 2,6-dichloroaryl fragment at N 1 and (hetero)aryl benzylidene at C3 were evaluated for their antitumor activity on a panel of cancer cell lines such as MCF-7 (breast), MiapaCa2 (pancreas), KB (oral), HuTu80 (stomach), L132 (lung), B16F10 (melanoma), and Molt4 (leukemia) from various human organs. Among the screened compound library, molecules 4e, 4k, and 4r have shown excellent cytotoxicity on a stomach cancer cell line. Moreover, a significant number of compounds have also shown promising cytotoxicity on pancreas and oral cancer cell lines.
- Manvar, Atul,Bavishi, Abhay,Loriya, Rajesh,Jaggi, Manu,Shah, Anamik
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p. 3076 - 3084
(2013/07/11)
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- Synthesis of 1-(2,6-dichlorophenyl)-3-methylene-1,3-dihydro-indol-2-one derivatives and in vitro anticancer evaluation against SW620 colon cancer cell line
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A small library of 2-indolinone derivatives with the 2,6-dichlorophenyl ring at the N1 position and with varying substitutions including aryl groups at the 3-position were synthesized, and their structures were confirmed by spectral analysis. All molecules were screened for their in vitro cytotoxic activity on SW620 colon cancer cell lines. Among the designed series compounds 4c, 4f and 4j were found to be active at concentrations of 2-15 μg/ml. Some 3D-QSAR models were also built to understand the structure-activity relationship.
- Virsodia, Vijay,Manvar, Atul,Upadhyay, Kuldip,Loriya, Rajesh,Karia, Denish,Jaggi, Manu,Singh, Anu,Mukherjee, Rama,Shaikh, Mushtaque S.,Coutinho, Evans C.,Shah, Anamik
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experimental part
p. 1355 - 1362
(2009/09/27)
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- SUBSTITUTED ARYLSULFONYLAMINOMETHYLPHOSPHONIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR USE IN THE TREATMENT OF TYPE I AND II DIABETES MELLITUS
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The present invention relates to substituted arylsulphonylaminomethylphosphonic acid derivatives of general formula (I) wherein R, X, Y and Z are defined as in claim 1, the tautomers, enantiomers, diastereomers, mixtures thereof and salts thereof which have valuable pharmacological properties, particularly the suppression of the interaction of glycogen phosphorylase a with the GL subunit of glycogen-associated protein phosphatase 1 (PP1), and their use as pharmaceutical compositions.
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Page/Page column 40-41
(2009/03/07)
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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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- Nitrosothiol esters of diclofenac: Synthesis and pharmacological characterization as gastrointestinal-sparing prodrugs
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Despite its widespread use, diclofenac has gastrointestinal liabilities common to nonsteroidal antiinflammatory drugs (NSAIDs) that might be reduced by concomitant administration of a gastrointestinal cytoprotectant such as nitric oxide (NO). A series of novel diclofenac esters containing a nitrosothiol (-S-NO) moiety as a NO donor functionality has been synthesized and evaluated in vivo for bioavailability, pharmacological activity, and gastric irritation. All S-NO-diclofenac derivatives acted as orally bioavailable prodrugs, producing significant levels of diclofenac in plasma within 15 rain after oral administration to mice. At equimolar oral doses, S-NO-diclofenac derivatives (20a-21b) displayed rat antiinfiammatory and analgesic activities comparable to those of diclofenac in the carrageenan-induced paw edema test and the mouse phenylbenzoquinone-induced writhing test, respectively. All tested S-NO-diclofenac derivatives (20a-21b) were gastric-sparing in that they elicited markedly fewer stomach lesions as compared to the stomach lesions caused by a high equimolar dose of diclofenac in the rat. Nitrosothiol esters of diclofenac comprise a novel class of NO-donating compounds having therapeutic potential as nonsteroidal antiinflammatory agents with an enhanced gastric safety profile.
- Bandarage,Chen,Fang,Garvey,Glavin,Janero,Letts,Mercer,Saha,Schroeder,Shumway,Tam
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p. 4005 - 4016
(2007/10/03)
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- Cyclic acetal-like derivatives of diclofenac: Synthesis and in-vivo evaluation in rats
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Several cyclic acetal-like derivatives of diclofenac were selected for synthesis with the aim of reducing its gastrointestinal toxicity. 1H-2,5-Dihydro-(3,1)-benzoxazepine-4-one compounds were prepared by the reaction of diclofenac with aldehydes or ethylene ketals of ketones in the presence of p-toluenesulphonic acid. The test compounds showed activities comparable with the parent drug on formalin-induced rat paw oedema. One compound showed no gastric mucosal injury in an in-vivo ulcerogenicity test in rats.
- Khalaj,Amanlou,Jorjani
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p. 201 - 203
(2007/10/03)
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- The stability of diclofenac in acidic medium
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The effect of pH, temperature and solvent polarity on the stability of diclofenac has been studied by using a UV method. The apparent first-order rate constants of the reaction cyclization of diclofenac over the pH-range 0.5-2.0 and the thermodynamic parameters of the reaction: energy, entropy and enthalpy of activation and frequency factor for the specific rate constants, were determined. The rate of diclofenac cyclization increased with increasing of the solvent polarity.
- Zajac, Marianna,Stanisz, Beata,Musial, Wojciech
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p. 371 - 374
(2007/10/03)
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- SYNTHESIS AND PHARMACOLOGICAL ACTIVITY OF DERIVATIVES OF 3-AMINOMETHYLENE-1-(2',6'-DICHLOROPHENYL)OXINDOLE AND 2-AMINOMETHYLENEINDOXYL
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Derivatives of 3-aminomethylene-1-(2',6'-dichloro)phenyloxindole and 2-aminomethyleneindoxyl were synthesized.The 1H and 13C NMR spectra and pharmacology of the compounds were studied.
- Isakovich, I. P.,Azimov, V. A.,Ryabova, S. Yu.,Alekseeva, L. M.,Parshin, V. P.,et al.
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p. 100 - 105
(2007/10/03)
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- Synthesis and quantitative structure-activity relationships of diclofenac analogues
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The synthesis of a series of 2-anilinophenylacetic acid, close analogues of diclofenac, is described. These compounds were tested in two models used for evaluating the activity of nonsteroidal antiinflammatory drugs (NSAID's), inhibition of cyclooxygenase enzyme activity in vitro, and adjuvant-induced arthritis (AdA) in rats. Statistically significant correlations were found between the inhibitory activities of the compounds in these two models, indicating that cyclooxygenase inhibition seems to be the underlying mechanism for the antiinflammatory activity of these compounds. Quantitative structure-activity relationship (QSAR) analysis revealed that the crucial parameters for activity in both models were the lipophilicity and the angle of twist between the two phenyl rings. Optimal activities were associated with halogen or alkyl substituents in both ortho positions of the anilino ring. Compounds with OH groups in addition to two ortho substituents or compounds with only one or no ortho substituents were less active.
- Moser,Sallmann,Wiesenberg
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p. 2358 - 2368
(2007/10/02)
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