34552-84-6

Basic information

• Product Name: ISOXICAM
• Synonyms: )-,1,1-dioxide;2h-1,2-benzothiazine-3-carboxamide,4-hydroxy-2-methyl-n-(5-methyl-3-isoxazolyl;pacyl(antiinflammatory);ISOXICAM;4-Hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide;Pacyl;Vectren;W 8495
• CAS NO: 34552-84-6
• Molecular Formula: C₁₄H₁₃N₃O₅S
• Molecular Weight: 335.34
• EINECS: 252-084-5
• Product Categories: OCTOPIROX
• Mol File: 34552-84-6.mol

Chemical Properties

• Melting Point: 265-271℃
• Boiling Point: 518.8°Cat760mmHg
• Flash Point: 267.5°C
• Appearance: /
• Density: 1.588
• Refractive Index: 1.686
• Storage Temp.: -20°C Freezer
• Solubility: Chloroform (Slightly, Heated), DMSO (Slightly), Methanol (Slightly, Heated, Soni
• PKA: 4.50±1.00(Predicted)
• CAS DataBase Reference: ISOXICAM(CAS DataBase Reference)
• NIST Chemistry Reference: ISOXICAM(34552-84-6)
• EPA Substance Registry System: ISOXICAM(34552-84-6)

Safety Data

• WGK Germany: 2
• RTECS: DL0703000
• Hazardous Substances Data: 34552-84-6(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
ISOXICAM is used as an anti-inflammatory agent for the treatment of various forms of rheumatoid arthritis, osteoarthritis, and musculoskeletal disorders. Its potent anti-inflammatory action and once-daily dosing make it a suitable choice for managing these conditions.
Used in Antiseborrheic Applications:
ISOXICAM is also used for treating seborrheic dermatitis, a common skin condition that causes redness, itching, and flaking of the skin. Its anti-inflammatory properties help alleviate the symptoms and improve skin health.

Originator

Warner-Lambert (USA)

Manufacturing Process

A mixture of 40.5 g (0.15 mol) of 3-carbethoxy-4-hydroxy-2-methyl-2H-1,2- benzothiazine 1,1-dioxide, 20.6 g (0.21 mol) of 3-amino-5-methylisoxazole, and 2,500 ml of xylene was refluxed for 24 hours in a Soxhlet apparatus, the thimble of which contained 60 g of Linde type 4A molecular sieve. The mixture was cooled to 25°C and the resulting crystalline precipitate was collected and washed with ether to give 44 g of crude product. Recrystallization from 1,600 ml of 1,4-dioxan gave 34.7 g of material, MP 265°C to 271°C dec.

Therapeutic Function

Antiinflammatory

World Health Organization (WHO)

Isoxicam, a nonsteroidal anti-inflammatory agent, was introduced in 1983 for the treatment of rheumatic disorders. By 1985 its use had been associated with serious adverse effects, including four deaths from rare skin reactions. This led to its withdrawal in France followed immediately by the voluntary suspension of marketing worldwide by the major manufacturer.

Synthesis

Isoxicam, 1,1-dioxide 4-hydroxy-2-methyl-N-(5-methyl-3-isoxazolyl)-2H-1,2- benzothiazine-3-carboxamide (3.2.80), is synthesized analogous to piroxicam, using amidation of 1,1-dioxide 3-methoxycarbonyl-3,4-dihydro-2-H-1,2-benzothiazine-4-one (3.2.78) in the last stage with 3-amino-5-methylisoxazole, instead of 2-aminopyridine [127–130].

InChI:InChI=1/C14H13N3O5S/c1-8-7-11(16-22-8)15-14(19)12-13(18)9-5-3-4-6-10(9)23(20,21)17(12)2/h3-7,18H,1-2H3,(H,15,16,19)

Upstream product

• 1072-67-9 5-methylisoxazol-3-ylamine 
• 35511-15-0 methyl 2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide 
• 59826-56-1 1-{[5-(4-Hydroxy-2-methyl-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone S,S,-dioxide 
• 80201-72-5 (1,1,3-Trioxo-1,3-dihydro-1λ⁶-benzo[d]isothiazol-2-yl)-acetic acid 2-methoxy-ethyl ester 
• 107124-72-1 Bis(2-methoxyethyl) 2-(N-carboxymethylsulfamoyl)benzoate 
• 80201-73-6 2-methoxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide 
• 61680-15-7 methyl 2-<<<2-<(5-methyl-3-isoxazolyl)amino>-2-oxoethyl>amino>sulfonyl>benzoate 
• 5510-10-1 2-methyl-2H-1,2-benzothiazine-4-(3H)-one-1,1-dioxyde 
• 24683-21-4 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid ethyl ester 1,1-dioxide 
• 40713-75-5 2-methyl-4-(1-pyrrolidinyl)-2H-1,2-benzothiazine 1,1-dioxide 
• 55387-64-9 2-Methyl-1,1-dioxo-4-pyrrolidin-1-yl-1,2-dihydro-1λ⁶-benzo[e][1,2]thiazine-3-carbonyl chloride 
• 128-44-9 saccharin sodium salt 
• 59826-55-0 1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone S,S-dioxide 
• 59826-54-9 N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2(3H)-acetamide 1,1-dioxide 

Relevant articles and documents

Effect of structural modification of enol-carboxamide-type nonsteroidal antiinflammatory drugs on COX-2/COX-1 selectivity

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.

Process for the preparation of 3,4-dihydro-2-substituted-2H-1,2-thiazine-carboxylic acid 1,1-dioxide derivatives

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.

Pharmaceutical preparation for the therapeutic treatment of rheumatic diseases

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.

THE SYNTHESIS OF SUBSTITUTED 2H-1,2-BENZOTHIAZINES 1,1-DIOXIDES

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.

Process for the preparation of 4-hydroxy-3-(heterocyclocarbamoyl)-2H-1,2-benzothiazine-1,1-dioxides

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.

Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide

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.

Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide

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.

Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide

A novel process for preparing 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide (I), starting with 3-amino-5-methylisoxazole (II) is disclosed. Compound I exhibits anti-inflammatory properties and is useful for treating inflammation. In the process of the invention an intermediate obtained, 2,3-dihydro-N-(5-methyl-3-isoxazolyl)-3-oxo-1,2-benzisothiazole-2-acetamide 1,1-dioxide (IV) undergoes rearrangement to provide 1-{[5-(4-hydroxy-2H-1,2-benzothiazin-3-yl)-1,2,4-oxadiazol-3-yl]methyl}ethanone S,S-dioxide (V), which is methylated, according to conventional procedures. The methylated intermediate VI, upon further treatment, undergoes a second rearrangement to obtain the desired anti-inflammatory compound I.