- A facile one-pot synthesis of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, a key intermediate in the synthesis of oxicam anti-inflammatory agents
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4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (8) was synthesized by a one-pot procedure, starting from the readily available saccharine. The synthesis involves 4 transformations with an overall yield equivalent to that from the stepwise process.
- Manjarrez, Norberto,Perez, Herminia I.,Solis, Aida,Luna, Hector
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- Synthesis, monoamine oxidase inhibition activity and molecular docking studies of novel 4-hydroxy-N′-[benzylidene or 1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides
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Three series of 4-hydroxy-N′-[benzylidene/1-phenylethylidene]-2-H/methyl/benzyl-1,2-benzothiazine-3-carbohydrazide 1,1-dioxides (9–11)a-l were synthesized and unraveled to be highly potent dual inhibitors of monoamine oxidases (MAO-A and MAO-B). All the examined compounds demonstrated IC50 values in lower micro-molar range for both MAO-A as well as MAO-B. The most active MAO-A inhibitor was 4-hydroxy-N′-(1-phenylethylidene)-2H-benzo[e][1,2]thiazine-3-carbohydrazide 1,1-dioxide (9i) with an IC50 value of 0.11 ± 0.005 μM, whereas, methyl 4-hydroxy-2H-benzo[e][1,2]thiazine-3-carboxylate 1,1-dioxide (3) was the most active MAO-B inhibitor with an IC50 value of 0.21 ± 0.01 μM. Enzyme kinetics studies revealed that the most potent compounds inhibited both MAO enzymes (A & B) in a competitive fashion. Molecular docking studies were also performed to obtain an intuitive picture of inhibition potential for potent inhibitors. The high potency of these compounds is optimally combined with highly favorable ADME profile with predicted good oral bioavailability.
- Saddique, Furqan Ahmad,Zaib, Sumera,Jalil, Saquib,Aslam, Sana,Ahmad, Matloob,Sultan, Sadia,Naz, Humera,Iqbal, Mazhar,Iqbal, Jamshed
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p. 1373 - 1386
(2017/11/13)
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- Stereopure Functionalized Benzosultams via Ruthenium(II)-Catalyzed Dynamic Kinetic Resolution-Asymmetric Transfer Hydrogenation
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A highly diastereo- and enantioselective Ru(II)-catalyzed dynamic kinetic resolution-asymmetric transfer hydrogenation (DKR-ATH) of α-(N-sulfonylimino) and α-(N-sulfonylamino) aryl ketones to 4-hydroxy-benzo-δ- and 3-(α-hydroxy-arylmethyl)-benzo-γ-sultams is presented. By employing enantiopure ansa-Ru[PipSO2DPEN(CH2)4Ph] cat. II with S/C = 10 000 in a HCO2H/Et3N binary mix, up to >99.9% ee and dr >99:1 are obtained with 100% conversion under mild conditions. Application to access the stereopure "structurally simplified TsDPEN" N,N-ligand syn-3-(α-aminobenzyl)-benzo-γ-sultam ("syn-ULTAM") and its structural isomer trans-4-amino-3-phenyl-benzo-δ-sultam (trans-4) is demonstrated.
- Jeran, Marko,Cotman, Andrej Emanuel,Stephan, Michel,Mohar, Barbara
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supporting information
p. 2042 - 2045
(2017/04/28)
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- Microwave assisted synthesis and structure-activity relationship of 4-hydroxy-N′-[1-phenylethylidene]-2H/2-methyl-1,2-benzothiazine-3- carbohydrazide 1,1-dioxides as anti-microbial agents
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A series of 4-hydroxy-N′-[1-phenylethylidene]-2H/2-methyl, 1,2-benzothiazine-3-carbohydrazide 1,1-dioxides was synthesized from commercially available sodium saccharin. Base catalyzed ring expansion of methyl (1,1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)acetate followed by ultrasound mediated hydrazinolysis and subsequent reaction with 1-phenylethanones under the influence of microwaves yielded the title compounds. Besides, microwave assisted synthesis of 1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide and 4-methyl-1,4-dihydropyrazolo[4,3-c][1,2]benzothiazin-3-ol 5,5-dioxide is also discussed. Most of the synthesized compounds were found to possess moderate to significant anti-microbial (anti-bacterial and anti-fungal) activities. It is found that compounds with greater lipophilicity (N-methyl analogues) possessed higher anti-bacterial activities.
- Ahmad, Naveed,Zia-Ur-Rehman, Muhammad,Siddiqui, Hamid Latif,Ullah, Muhammad Fasih,Parvez, Masood
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experimental part
p. 2368 - 2377
(2011/06/21)
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- Process for the preparation of crystalline form-1 of 4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide
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The present invention is related to an improved process for preparing crystalline Form I of meloxicam, which produces the Form I in high yield.
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Page/Page column 1 - 3
(2010/02/15)
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- Synthesis of potential biologically active 1,2-benzothiazin-3-yl- quinazolin-4(3H)-ones
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A series of potential biologically active 2-(4-hydroxy-1,1-dioxido-2H-1,2- benzothiazin-3-yl)quinazolin-4(3H)-ones was synthesized in a straight forward manner by condensation of respective 4-hydroxy-1,2-benzothiazine-1,1-dioxides with anthranilamide followed by simple and high throughput cyclization of N-[2-(aminocarbonyl) phenyl]-4-hydroxy-1,2-benzothiazine-3-carboxamide-1,1- dioxides. All the synthesized compounds were subjected to preliminary evaluation for their biological activity against Gram positive and Gram negative bacteria. Some of the assayed compounds showed marked activity against Bacillus subtilis.
- Zia-Ur-Rehman, Muhammad,Choudary, Jamil Anwar,Ahmad, Saeed,Siddiqui, Hamid Latif
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p. 1175 - 1178
(2007/10/03)
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- New quaternary ammonium oxicam derivatives targeted toward cartilage: Synthesis, pharmacokinetic studies, and antiinflammatory potency
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Analogues of nonsteroidal antiinflammatory drugs (NSAIDs) oxicams, in which the active group was linked to a quaternary ammonium function [(4- hydroxy-2-methyl-2H-1,2-benzothiazine-1,1-dioxide-3-carboxamido)2- methylpyridinium iodide or piroxicam-N+ and [3-(4-hydroxy-2-methyl-2H-1,2- benzothiazine-1,1-dioxide-3-carboxamido)propyl]trimethylammonium iodide or propoxicam-N+] were synthesized. Compounds were labeled with tritium for piroxicam-N+ and carbon-14 for propoxicam-N+. Pharmacokinetic studies conducted on rats showed that these molecules were able to highly concentrate in joint cartilages but their bioavailability by the oral way was low. Only propoxicam-N+ exhibited a sufficient water solubility to be administered intravenously. This molecule was able to restore proteoglycans biosynthesis in cultured articular chondrocytes treated with Interleukin-1β with an efficiency identical to that of indomethacin. These results suggest that the functionalization of oxicam derivatives by a quaternary ammonium group greatly increases their affinity toward articular cartilage without eliminating their pharmacological activity. New drugs synthesized according to this scheme could be useful to obtain a significant decrease of the efficient administered dose and consequently an attenuation of adverse effects such as digestive toxicity.
- Nicolas, Colette,Verny, Michel,Giraud, Isabelle,Ollier, Monique,Rapp, Maryse,Maurizis, Jean-Claude,Madelmont, Jean-Claude
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p. 5235 - 5240
(2007/10/03)
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- Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity
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Meloxicam (5), an NSAID in the enol-carboxamide class, was developed on the basis of its antiinflammatory activity and relative safety in animal models. In subsequent screening in microsomal assays using human COX-1 and COX-2, we discovered that it possessed a selectivity profile for COX-2 superior to piroxicam and other marketed NSAIDs. We therefore embarked on a study of enol-carboxamide type compounds to determine if COX-2 selectivity and potency could be dramatically improved by structural modification. Substitution at the 6- and 7-positions of the 4-oxo-1,2-benzothiazine-3- carboxamide, alteration of the N-methyl substituent, and amide modification were all examined. In addition we explored several related systems including the isomeric 3-oxo-1,2-benzothiazine-4-carboxamides, thienothiazines, indolothiazines, benzothienothiazines, naphthothiazines, and 1,3- and 1,4- dioxoisoquinolines. While a few examples were found with greater potency in the COX-2 assay, no compound tested had a better COX-2/COX-1 selectivity profile than that of 5.
- Lazer, Edward S.,Miao, Clara K.,Cywin, Charles L.,Sorcek, Ronald,Wong, Hin-Chor,Meng, Zhaoxing,Potocki, Ian,Hoermann, MaryAnn,Snow, Roger J.,Tschantz, Matt A.,Kelly, Terence A.,McNeil, Daniel W.,Coutts, Simon J.,Churchill, Laurie,Graham, Anne G.,David, Eva,Grob, Peter M.,Engel, Wolfhard,Meier, Hans,Trummlitz, Günter
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p. 980 - 989
(2007/10/03)
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- A facile one-pot synthesis of 4-hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, a key intermediate in the synthesis of oxicam anti-inflammatory agents
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4-Hydroxy-3-methoxycarbonyl-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (8) was synthesized by a one-pot procedure, starting from the readily available saccharine. The synthesis involves 4 transformations with an overall yield equivalent to that from the stepwise process.
- Manjarrez,Perez,Solis,Luna
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p. 1405 - 1410
(2007/10/03)
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- TITANIUM-MEDIATED DIECKMANN CONDENSATION
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The Dieckmann condensation of alkyl 2-(N-methyl-N-(alkoxycarbonylmethyl)sulfamoyl)-benzoates Ia and Ib with titanium tetrachloride-tert-amine or butyltitanium ate complex III affords alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides IIa and IIb which are the piroxicam intermediates.
- Patek, Marcel
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p. 1223 - 1227
(2007/10/02)
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- CONDITIONS OF THE DIECKMANN CONDENSATION OF ALKYL 2-(N-METHYL-N-(ALKOXYCARBONYLMETHYL)SULFAMOYL-BENZOATES
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The Dieckmann condensation of alkyl 2-(N-methyl-N-(alkoxycarbonylmethyl)sulfamoyl)benzoates IIIa-IIIe with various bases affords alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides IVa-IVe which are intermediates in the synthesis of antiinflammatory drug piroxicam.The yields of benzothiazines IVa-IVe depend mostly on the nature of a base, reaction temperature and solvent used for these condensations.Hitherto undescribed esters IIIb-IIIe were sythesized and their structures were confirmed by 1H and 13C NMR, and mass spectra.
- Patek, Marcel,Hampl, Frantisek
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p. 3267 - 3277
(2007/10/02)
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- THE SYNTHESIS OF SUBSTITUTED 2H-1,2-BENZOTHIAZINES 1,1-DIOXIDES
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The base-catalyzed rearrangement of the esters of 2H-1,2-benzothiazolin-3-one-2-acetate 1,1-dioxide (IIa-IIc) afforded substituted 2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides IIIa-IIIc.After N-alkylation and aminolysis the antiinflammatory drugs piroxicam and isoxicam were obtained.
- Svoboda, Jiri,Palecek, Jaroslav,Dedek, Vaclav
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p. 1133 - 1139
(2007/10/02)
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- Processes for preparing piroxicam and intermediates leading thereto
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Processes for the preparation of the antiinflammatory agent piroxicam and intermediates leading thereto, the first of which comprises reacting N-methylsaccharin with (N-2-pyridyl)haloacetamides and alkyl haloacetates in the presence of an appropriate base to give, respectively, piroxicam and alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides, intermediates which can be converted into piroxicam; and the second of which comprises reacting a novel alkyl 2-(2-methyl-3-hydroxy-2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-haloacetate with a metal hydride to give alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides, intermediates leading to piroxicam.
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- 3-Hydroxy 2-methyl benzisothiazolines as intermediates in production of piroxicam
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Processes for the preparation of the antiinflammatory agent piroxicam and intermediates leading thereto, the first of which comprises reacting N-methylsaccharin with (N-2-pyridyl)haloacetamides and alkyl haloacetates in the presence of a metal hydride to give, respectively, piroxicam and alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides, intermediates which can be converted into piroxicam; and the second of which comprises reacting a novel alkyl 2-(2-methyl-3-hydroxy2,3-dihydro-1,2-benzisosulfonazol-3-yl)-2-haloacetate with a metal hydride to give alkyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxides, intermediates leading to piroxicam.
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- 3-Oxo-1,2-benzoisothiazoline-2-acetic Acid 1,1-Dioxide Derivatives. I. Reaction of Esters with Alkoxides
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Reaction of 3-oxo-1,2-benzoisothiazoline-2-acetic acid alkyl esters 1,1-dioxide (1a-d) with alkaline alkoxides was carried out under various conditions.Under mild conditions, o-(N-carboxymethylsulfamyl)benzoic acids dialkyl esters (2a-d) were obtained with good yields.Reaction of 1a-d or 2a-d with sodium alkoxide under drastic conditions afforded 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid alkyl esters 1,1-dioxide (3a-d).Transesterification was observed when esters 1b-d were treated with sodium methoxide in methanol.Esters 3a-d were hydrolyzed in concentrated aqueous sodium hydroxide affording the acid 6.Attempts to recrystallize 6 from water resulted in its decarboxylation to give 2H-1,2-benzothiazine-4-(3H)one 1,1-dioxide (7).Compound 6 could not be obtained by acid hydrolysis of esters 3a-d or by rearrangement of 3-oxo-1,2-benzoisothiazoline-2-acetic acid 1,1-dioxide (8).Different experimental evidence supports the suggestion that rearrangement took place by ethanolysis of the carboxamide linkage affording the open sulfonamides (fast step) followed by a Dieckmann cyclization (slow step).It was demonstrated that transesterification took place in the open sulfonamides 2.
- Schapira, Celia B.,Perillo, Isabel A.,Lamdan, Samuel
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p. 1281 - 1288
(2007/10/02)
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- Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide
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An improved process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (I), a known anti-inflammatory agent, is described. The process involves the reaction of a solution of alkyl 2,3-dihydro-3-oxo-1,2-benzisothiazole-2-acetate 1,1-dioxide (II) in dimethylformamide, with an alkali metal alkoxide using the specific portions of reactants and carefully controlled reaction conditions. Acidification of the reaction mixture precipitates out alkyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (III) in substantially pure form in high yields, without recrystallization. Product III is methylated on the sulfonamide nitrogen and reacted with 3-amino-5-methylisoxazole to obtain crude I. A further improvement in the process of the invention involves a more efficient method for purifying crude product I by solubilizing in dimethylformamide with heating to 125° C. to 148° C. The hot solution is filtered, and the filtrate is cooled to obtain crystalline product I.
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- Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide
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An improved process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (I), a known anti-inflammatory agent, requires the use of specific proportions of reactants and carefully controlled reaction conditions. An alkali metal alkoxide, suspended in dimethylformamide is combined, with stirring, as rapidly as possible with a solution of alkyl 2,3-dihydro-3-oxo-1,2-benzisothiazole-2-acetate 1,1-dioxide (II) in dimethylformamide, while maining the internal reaction temperature within 15°-30°C. More than two but less than six moles of the alkoxide are used per mole of the alkyl 2,3-dihydro-3-oxo-1,2-benzisothiazole-2-acetate 1,1-dioxide (II). After all reactants have been combined, stirring is continued for a specific period of time and then the reaction mixture is acidified. Total elapsed time from initial combination of reactants to acidification is from 30 to 50 minutes. Acidification of the reaction mixture precipitates out alkyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (III) in substantially pure form in high yields, without recrystallization. Product III is methylated on the sulfonamide nitrogen and reacted with 3-amino-5-methyl-isoxazole to obtain crude I. A further improvement in the process of the invention involves a more efficient method for purifying crude product I: the need for large quantities of dioxane solvent is obviated. After slurrying and washing, product I is solubilized in dilute alkali, and decolorized. After filtration and acidification pure product I in high yield is obtained. In addition to preparing the known anti-inflammatory agent (I), the initial reaction step of the invention wherein 2,3-dihydro-3-oxo-1,2-benzisothiazole-2-acetate, 1,1-dioxide (II) is rearranged to form alkyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (III), may be used with particular advantage for the preparation of other useful benzothiazine derivatives.
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