- Synthetic method of piroxicam
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The invention belongs to the field of chemical synthesis, and more specifically relates to a synthetic method of piroxicam. The synthetic method of piroxicam comprises following steps: 1, sodium saccharin and ethyl chloroacetate are taken as initial raw materials, and condensation reaction is carried out so as to obtain 3-oxo-1,2-benzoisothiazoline-2-methyl acetate-1,1-dioxide; 2, sodium methylateis added into the product in step 1, reaction is carried out under catalytic effect of potassium iodide, and 2-methyl-3,4- dioxo-4-oxo-2H-1,-2- benzothiazine-3-carboxylic acid methyl ester-1, 1-dioxide is obtained under the effect of DMSO; 3, the above product is reacted with 2-aminopyridine at 130 DEG C for 10h so as to obtain a high purity finished product. According to the synthetic method, potassium iodide is taken as a catalyst to increase the reaction conversion rate of step 2 obviously, impurity content is controlled effectively; and the total yield is increased to 69%.
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- Solid Pharmaceutical Preparations Containing Copolymers Based On Polyethers Combined With Poorly Water-Soluble Polymers
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The invention relates to dosage forms which contain preparations of poorly water-soluble substances in a polymer matrix of polyether copolymers, said polyether copolymers being obtained by the radically initiated polymerization of a mixture from 30 to 80% by weight of N-vinyl lactam, 10 to 50% by weight of vinyl acetate and 10 to 50% by weight of a polyether, and at least one poorly water-soluble polymer, the poorly water-soluble substance being present in the polymer matrix as an amorphous substance.
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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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- Topical and transdermal delivery system utilizing submicron oil spheres
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The present invention relates to a delivery system which includes a bioactive drug or cosmetic substance presented in the form of submicron oil spheres alone, or drugs or cosmetic substances in a combination with the oil spheres in an aqueous suspension or emulsion. Optionally, a skin penetration enhancer may be included in such formulations. Such preparations achieve improved bioavailability and exert larger pharmacological effects than an equivalent dose of the drug or cosmetic formulated in conventional creams, lotions or oleaginous bases.
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- Anti-inflammatory analgesic plaster
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An anti-inflammatory analgesic plaster carries thereon a base which comprises piroxicam and a polyoxyethylene nonionic surfactant having 5-15 moles of added ethylene oxide.
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- Process for obtaining 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide
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A process for obtaining 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, which may be used as a non-steroidal analgesic and anti-inflammatory drug. The process comprises reacting saccharin sodium with isopropyl chloroacetate in dimethylformamide, reacting the resultant isopropyl 3-oxo-1,2-benzoisothiazoline-2-acetate 1,1-dioxide with sodium isopropylate in isopropanol to produce an intermediate which, when methylated in an aqueous-alcoholic basic medium with dimethyl sulfate, gives an intermediate compound which when condensed with 2-aminopyridine in xylene, yields 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazone-3-carboxamide 1,1-dioxide.
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- Reactions of Piroxicam with Alkyl Iodides
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Alkylation of piroxicam with a homologous series of alkyl iodides gave reversibly formed O-alkyl products 1 as well as unexpected, irreversibly formed zwitterionic compounds 2, alkylated on the pyridine nitrogen, and O,N-bis-alkyl products 3.Proof of structure was accomplished by nmr and X-ray crystal analysis.Product distribution ratios were determined by hplc and are explained by the Hard-Soft Acid-Base principle.
- Hammen, Philip D.,Berke, Helen,Bordner, Jon,Braisted, Andrew C.,Lombardino, Joseph G.,Whipple, Earl B.
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- Process for the preparation of 3,4-dihydro-2-substituted-2H-1,2-thiazine-carboxylic acid 1,1-dioxide derivatives
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Process for the preparation of 3,4-dihydro-2-substituted-4(or 3)-oxo-2H-1,2-thiazine-3(or 4)-carboxylic acid 1,1,-dioxide magnesium chelate derivatives and its acids by reacting appropriately 3,4-dihydro-2-substituted-4(or 3)-oxo-2H-1,2-thiazine 1,1-dixoides with alkylmagnesiumcarbonate and then hydrolyzing and its use as intermediates for the preparation of N-substituted-2-substituted-2H-1,2-thiazine-3(or 4)-carboxamide-1,1-dioxide derivatives, effective antiinflammatory agents.
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- Pharmaceutical preparation for the therapeutic treatment of rheumatic diseases
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Pharmaceutical preparation containing phospholipids for the therapeutic treatment of rheumatic diseases which contain in addition to the antiphlogistically acting oxicam derivatives of the general formula STR1 special 1,2-diacyl-glycero-3-phosphocholines wherein 75-86% by weight of the acyl radicals are unsaturated fatty acid radicals, and the preparation thereof.
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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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- Process for preparing 2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide derivatives and intermediates therefor
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The process for the preparation of derivatives of 2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide of the formula STR1 wherein R represents hydroxy (Ia) or substituted hydroxy OR1 in which R1 is the cinnamoyl radical --CO--CH=CH--C6 H5 (Ib) consists in reacting a strong base salt of 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxide with an acyl chloride R1 Cl, in which R1 is the cinnamoyl radical, or R2 Cl, in which R2 is an aromatic or aliphatic C2 -C6 acyl radical to give the corresponding mixed anhydride, optionally esterified at position 4, which is then reacted with 2-aminopyridine to give the desired amide.
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- Process for preparing N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide
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A process for preparing N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide which comprises reacting an alkyl-4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate-1,1-dioxide with P-phenyl-N,N'-di-2-pyridylphosphonium diamide.
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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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- Process for the preparation of 4-hydroxy-3-(heterocyclocarbamoyl)-2H-1,2-benzothiazine-1,1-dioxides
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The present invention provides a process for the preparation of 4-hydroxy-3-(heterocyclocarbamoyl)-2H-1,2-benzothiazine-1,1-dioxides of the general formula: STR1 wherein R1 is a hydrogen atom or a methyl radical, R2 is a nitrogen-containing heterocyclic radical and R3 is a hydrogen or halogen atom or a methyl radical, and of the alkali metal, alkaline earth metal and amine salts thereof, by the reaction of an amine-substituted, nitrogen-containing heterocyclic compound with a halo-acetyl halide, reaction of the intermediate thus obtained with sodium benzoic acid sulphimide, ring expansion of the benzoisothiazole ring to give a benzothiazine ring and, in case R2 is to be an isoxazolyl radical, reverse rearrangement of the oxadiazole-ring formed by ring expansion to the isoxazolyl ring, wherein (in a one-pot reaction A) the reaction of an amine-substituted, nitrogen-containing heterocyclic compound with a halo-acetyl halide is carried out, without the addition of a base, in boiling ethyl acetate, the intermediate formed is, without isolation, reacted with sodium benzoic acid sulphimide and the reaction product isolated, whereafter, in a one-pot reaction B, the reaction product from the one-pot reaction A is reacted in a dipolar aprotonic solvent under an atmosphere of a protection gas with a strongly basic alkali-alkohole and thereafter with so much acid that about 2 equivalents of base remained unneutralized in the reaction solution and, if desired, the benzothiazine ring is N-methylated in the usual manner and the product obtained is, if desired, converted in known manner into an alkali metal, alkaline earth metal or amine salt.
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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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- Process for the preparation of 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides
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A novel process for preparing 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxides is disclosed. The process involves the base catalyzed rearrangement of a saccharinacetamide of structure I to give II, STR1 wherein R1 is hydrogen or lower alkyl and R2 is lower alkyl, aryl or a heterocyclic ring selected from the group consisting of pyridyl, substituted-pyridyl, and thiazolyl. Compounds of the formula II have useful anti-inflammatory properties. In addition, they can be used as intermediate in the preparation of known anti-inflammatory agents.
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