Derivatives benzothiazine


(57) Abstract:

Usage: new derivatives of benzothiazine are used as intermediates in the synthesis of occasionalcocaineuse drugs have anti-inflammatory activity. The inventive compounds produced by interaction of 1, 1-dioxide-N-(2-pyridyl)-4-hydroxy-2-methyl-2 N-1, 2-benzothiazine-3-carboxamide with table 1.

The invention relates to new chemical compounds derived benzothiazine responsible of General formula I

where R1lower alkyl WITH1-C4.

Known 6,6-dioxide-ocsinventory General formula II, where R2radical heteroaryl as anti-inflammatory and painkillers, in particular Droxicam (R2=2-pyridyl),

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Studies have been conducted to obtain a simple and effective intermediates which would synthesize Droxicam in conditions, making it easy to obtain on an industrial scale.

You know getting Droxicam based on the ester of the formula III

where R3radical alkoxyl. In addition, the patent FR-2 597103 describes obtaining Droxicam based on compounds voiceskin compounds responsible of General formula 1 in which R1the radical is a lower alkyl (1-4 carbon atoms), can simplify the synthesis of Droxicam.

The compounds of formula I are obtained by reaction of compound III in which R3radical 2-pyridylamine, with the compound of General formula IV

Cl--O-R1where R1has the meaning given in relation to the General formula I, in the presence of a base.

The reaction between the compounds of General formulas III and IV occurs at a temperature of from -5 to 30aboutC for 1-5 hours Exact amounts of reactants entering the reaction are not critical, but it is however preferable to use at least 2 molar parts of a compound of formula IV per mole of the compounds of formula III for a more complete the reaction, as well as good yield.

The reaction is carried out in a medium of an organic solvent, selected from a number of pyridine, triethylamine, substituted pyridine, such as 4-dimethylaminopyridine, monomethyltin, dimethylpyridin; dimethylsulfoxide, dichloromethane, 1,2-dichloroethane, dimethylformamide, 1-2-dimethoxyethane, dioxane, tetrahydrofuran. In case of using a solvent which is not a base, it is necessary to add at the very the P CLASS="ptx2">

Alternative it is possible to conduct the reaction between the compounds of formulas III and IV in the presence of alkali metal hydride, for example sodium hydride, in organic solvents, such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane, toluene, xylene, or dipolar aprotic solvents such as dimethylsulfoxide, dimethylformamide, hexamethylphosphoramide.

The reaction is carried out at the same temperature for the same time, as described for the case when we are talking about organic base.

In addition, new chemical compounds of General formula I, in which R1has values that can be transformed into Proximal formula II in which R2the radical is 2-pyridyl, heated in the organic solvent, such as pyridine, at 25-60aboutFor 5-24 h

These compounds of General formula 1 are thus used for the preparation of Droxicam. Furthermore, the new compounds exhibit anti-inflammatory activity.

The reaction leading to the formation of compounds of General formula 1 apparently occurs with the formation of the original organic salt or alkali metal salt, the anion which reacts with chloroform is the education connection, subject of the invention of General formula I. the Claim of the applicant but is not limited to this interpretation.

The reaction can be schematically represented as follows

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The following examples of the preparation of derivatives of General formula 1 and obtain Droxicam, the General formula II (R2= 2-pyridine) based on derivatives of the General formula I.

P R I m e R 1. Obtaining 1,1-dioxide-N-etoxycarbonyl-N-(2-pyridyl)-4-ethoxycarbonyl-2-methyl-2H-12 - benzothiazin-3-carboxamide.

90 ml (0,945 mole) of ethylchloride added slowly to a suspension containing 75 g (0,226 mole) of 1,1-dioxide-N-(2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid Yes in 225 ml of anhydrous pyridine at 0aboutAnd keep the temperature below 10aboutC. Stirring for 1 h, the temperature of the reaction medium reaches room temperature (approximately 20 theaboutC). Pour the suspension into 200 ml of ice water, stirred for 1 h at 0-5aboutC, filtered and washed with 200 ml of cold water.

The resulting product when active mixing is mixed with 200 ml of cold acetone, get 96.4 g (yield: 90%) of a white product with so pl. 144-146aboutC. By recrystallization with ethyl acetate floor is 6]

of 1.10(t, 3H), of 1.30 (t, 3H), 3,30 (s, 3H), 4,24 (g, 2H), 4,35 (g, 2H), 7,42 (m, 2H): 7,60 (m, 1H), 7,80 (m, 2H), of 7.96 (m, 2H), 8,53 (d, 1H)

IR (EHF): 1755, 1748, 1690, 1335, 1245, 1015, 715 cm-1.

P R I m m e R 2. Obtaining 1,1-dioxide-N-etoxycarbonyl-N-(2-pyridyl)-4-ethoxycarbonyl-2-methyl - 2H-1,2-benzothiazin-3-carboxamide.

2,62 g of 55% sodium hydride, suspended in mineral oil, washed with n-pentane to separate the oil by decantation. In the resulting sodium hydride (1.44 g to 0.06 mole) was added 100 ml of tetrahydrofuran in an ice bath with a temperature of 5aboutWith added 6.3 g (0,025 mol) of 1,1-dioxide-N-(2-pyridyl)-4-hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamid Yes. Stirred for 1 h, keeping the temperature between 0 and 5aboutWith and add to 6.7 ml of 0.07 mole) of ethylchloride. Mix 1-2 hours before until the temperature reaches room temperature (20aboutWith), filtered, evaporated to the dry filter, washed with cold water to give 11.2 g (yield 94%). By recrystallization with ethyl acetate to obtain the product with so pl. 148-149aboutWith the spectroscopic characteristics of the same characteristics as specified in example 1.

P R I m e R 3. In conditions similar to those described in examples 1, 2, can be mentioned the following compounds using cootie-2-me-til-2H-1,2 benzothiazine-3-carboxamide, 1,1-dioxide-N-benzyloxycarbonyl-N-(2 - pyridyl)-4-benzyloxycarbonyl hydroxy-2-methyl-2H-1,2-benzothiazin-3-carboxamide 1,1-Dioxide-N-methoxycarbonyl-N-(2-pyridyl)-4-methoxycarbonylamino-2-methyl-2H-1,2-benzothiazin-3-carboxamide

P R I m e R 4. Getting 6,6-dioxide-5-methyl-3-(2-pyridyl)-2H,5H-1,3-oxazin [5,6-c][1,2]-benzothiazin-2,4-(3H)-dione to Droxicam.

Suspended 90 g (0,189 mol) of 1,1-dioxide, N-etoxycarbonyl-N-(2-pyridyl)-4-ethoxycarbonyl-2-methyl-2H-1,2-benzo - thiazin - 3-carboxamide in 150 ml of anhydrous pyridine. Heat the mixture to 35aboutC and maintained at this temperature for 15 hours Cooled to room temperature (20aboutC) and pour 750 ml of water. The precipitate is filtered, washed first with water, then acetone. So, get 64 g of product (yield: 95%). By recrystallization from 1,2-dichloromethane get a solid crystalline substance with a melting point 261-263aboutC.

Spectroscopic data: 1H-NMR, , [DMSO-d6]

to 3.02 ( 3H), 7,52 (m, 2H), 7,92 (m, 5H), charged 8.52 (d, 1H).

IR(EHF): 1185, 1355, 1410, 1640, 1710, 1790 cm-1.

Anti-inflammatory activity (inhibitor of runoff caused by carrageenan).

Was studied anti-inflammatory activity of the compounds obtained by the regional activity of phenylbutazone. Used the method described by Winter, with employees Proc. soc. (Exp. Biol. Med. 1982, 111, 544-547).

Calculated DA on the basis of the results obtained after 3 h after oral administration of the substance, and 2 h after injection carragenine in each paw with 0.1 ml of 2% aqueous solution carragenine subcutaneous route).

The results are shown in the table.

Below as examples of the three galouye form new compounds

An example of the composition of the capsules 1,1-Dioxide-N-etoxycarbonyl - N-(2-pyridyl)-4 - ethoxycarbonyl-2 - methyl - 2H-1,2 - benzothiazin-3 - carboxamide 0,020 g Lactose 0,136 g Talc 0,0016 g magnesium Stearate 0,0016 g Aerosil-200 0.0008 grams Weight capsules 0,160 g

An example of the composition of the tablets 1,1-Dioxide-N-atomichron - N-(2-pyridyl)-4-ethoxy - carbonyloxy-2-methyl - 2H-1,2-benzothiazin-3 - carboxamide 0,020 g Avicel pH 102 0,046 g Lactose to 0.055 g Primogel 0.003 g Polyvinylpyrrolidone 0.005 g magnesium Stearate to 0.011 g Mass of tablets 0,100 g Sample composition candles 1,1-Dioxide-N-ethoxy - carbonyl-N-(2-pyridyl)-4 - ethoxycarbonyl-2 - methyl - 2H-1,2-benzothiazin - 3-carboxamide 0,050 g Monolin 1,950 g Mass of candles 2,000 g


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where R1lower C1C4-alkyl, as a sub who enoy activity.


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EFFECT: improved preparing method, valuable properties of compounds.

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