SU1122225A3 - Method of obtaining crystalline water-soluble nonhygroscopic ethylenediamine monoethanolamine or diethanolamino salt of h-(2-pyridyl)-2-methyl-4-oxy-2h-1,2-benzthiazine-3-carboxamide-1,1-dioxide - Google Patents

Abstract

1. METHOD FOR OBTAINING CRYSTALLINE WATER-SOLUBLE NON-HYGROSCOPIC ETHYLENEDIAMINE, MONOETHANOLAMINE OR DIETHANOLAMINE SALT OF H -

Description

1 1

The invention relates to a method for producing new chemical compounds, namely to a method for producing a crystalline water-soluble non-hygroscopic ethylenediamine, monoethanolamine or diethanolamine salt of N-(2-pyrimidine)-2-methyl4-OXY-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide.

The indicated salts of K|-(2-pyridyl)-2methyl-4-oxy-2H-,2-benzothiazine-3carboxamide-t,I-dioxide have an anti-inflammatory effect and can be used as non-steroidal therapeutic agents for the relief of painful inflammatory conditions caused by rheumatoid arthritis.

N-(2-pyridyl)-2-methyl4-OXY-2H-1,2-benzothiazine-3-carboxamide-f,1-dioxide (piroxicam) is known to have anti-inflammatory activity. Piroxicam is obtained by reacting methyl ester of 1,1-dioxide-2-methyl-4-oxy-2H-1,2-benzothiazine-3-carboxylic acid with 2-aminopyridene in a dry xylene medium at the boiling point of the reaction mass in a nitrogen atmosphere. Piroxicam is the closest analogue in structure and action of new salts of N-(2-pyridyl)-2-methyl4-OXY-2H-1,2-benzothiazine-3-carboxamide-f,1-dioxide Q.

However, Piroxicam is very poorly soluble in water.

The aim of the invention is to obtain new salts of N-(2-pyridyl)-2methyl-4-oxy-2H-,2-benzothiazine-3carboxamide-1,1-dioxide, which have increased solubility in water.

The stated objective is achieved in that, according to the method for obtaining the crystalline water-soluble non-hygroscopic ethylenediamine, monoethanolamine or diethanolamine salt of }{-(2-pyridyl)-2-methyl-4-OXY-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, I molar equivalent of N -(2-pyridyl)-,2-methyl-4-oxy2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is reacted with 1-2 molar equivalents of ethylenediamine, or monoethanolamine, or diethanolamine at 20-120 C in a polar protic solvent or a halohydrocarbon solvent.

Water is used as a polar protic solvent.

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Methylene chloride is used as a halogenated hydrocarbon solvent.

The target product is isolated by evaporation of the solvent from the reaction mixture, followed by trituration of the resulting solid residue or crude concentrated product with a solvent such as a mixture

10 ethyl acetate - chloroform, etc.

The target product can be isolated by crystallization.

Example: In a 250 ml Erlenmeyer reaction flask with a magnetic

15 Using a stirrer, stir 500 mg (0.0015 mol) of N-(2-pyridyl)-2-methyl-4-oxo)-2H-, 1,2-benzothiazine-3-carboxamide-1,1-dioxide and 75 ml of water. Stirring is started and 180 mg of

(0.003 mol) of ethylenediamine (0.2 ml). The resulting reaction mixture is heated on a steam bath for 3 min and a yellow solution is obtained.

25 colors. By evaporating this solution almost to dryness under reduced pressure a yellow resin is obtained, which is then ground into powder with 200 ml of chloroform and 30 ml of ethyl acetate by stirring the mixture.

30 for 1 h. The resulting light yellow solid is isolated by suction filtration and washed on a filter funnel with a fresh portion of ethyl acetate.

35 Thus, a clean

ethylenediamine salt of N -(2-pyridyl) 2-methyl-4-oxy-2H-1,2-benzothiazine-3carboxamic acid -1,1-dioxide with m.p. 151-154 C. The pure product was further characterized by IR absorption spectrum and elemental analysis.

Calculated,%: C 52.16; H 5.40; N 17.89. 5CisH NjO S

CgHtNa Found,%: C 51.81; I 5.41;

17.77.

Example 2. To a suspension of 2.0 g (0.00604 mol) of N-(2-pyridyl)-2-methyl-4-OXY-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 300 ml of water are added 388 mg (0.00634 mol) of 2-aminoethanol (0.383 vai) and the resulting mixture is heated on a steam bath for approximately 3 min. Then the resulting yellow solution is filtered to remove

a very small amount of water-insoluble substances, after which the resulting filtrate is concentrated in a vacuum, obtaining a yellow oil as a residual liquid. Trituration of this substance with 200 ml of a mixed solvent of ethyl acetate and chloroform (3:2 by volume) followed by stirring at room temperature (25 C) overnight (6 h) under dry nitrogen affords a solid precipitate which is successively isolated by suction filtration. After thoroughly washing the isolated solid with ethyl acetate and drying in vacuo to constant weight, 2.07 g (87% yield) of pure monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-oxy-2H-1 ,2-benzothiazine-3-carboxamide-1 ,1-dioxide with m.p. 174-177 C are finally obtained. The pure product is further characterized by IR absorption spectrum and elemental analysis. Calcd. D: C 52.03; H 5.14;

N 14.28.

C,, Found,%: C 51.72; H 5.14;

1 13.93.

Example 3. A filtered solution consisting of 65.0 g (0.166 mol) of H-(2-pyridyl)2-methyl-4-oxy-2H-1 ,2-benzothiazine-3-carboxamide-1 ,1-dioxide dissolved in 660 ml of methylene chloride is placed in a 2-liter round-bottomed reaction flask equipped with a magnetic stirrer, a dropping funnel (250 ml), and a thermometer. A solution containing 0.1 g of monoethanolamine -(2-pyridyl)2-methyl-4-oxy-2H-1 ,2-benzothiazine-. 3-carboxamide-1,i-dioxide as a seed crystal, prepared in advance by dissolving the solid in 610 ml of methylene chloride contained in an Erlenmeyer flask at 25°C, with gentle stirring using a magnetic stirrer. An additional 50 ml of methylene chloride is then used as a wash when transferring the solution

into the specified reaction flask. At this point in time, the last of the specified flasks and its contents are heated to using a steam bath, and then the entire system is subjected to constant and thorough mixing.

while a solution consisting of 10.7 g (0.175 mol) of ethanolamine dissolved in 110 ml of fresh methylene chloride is slowly added to this system over 50 min. At the end of this stage, the spent reaction mixture is stirred (i.e. granulated) at

27 C for 1 h and then filtered on a Buchner funnel to give a crystalline salt. The latter product is dried in a vacuum oven at 35 C to constant weight to give 63.1 g of pure monoethanolamine S salt of N-(2-pyridyl 1)-2-methyl-4-hydroxy2H-1,2-benzothiazine-3-carboxamide-1,1 dioxide with m.p. 171-174 °C. The net yield of purified product is 63.0 g (96.8%). The purified product is further characterized by nuclear magnetic resonance spectrum and elemental analysis and is identical in all respects with the product of Example 2. 5 Calculated, %: C 52.03; H 5.14; N 14.28.

Found,%: C 52.09; H 5.15; N 14.30.

Q Example 4. To a suspension of 2.0 g (0.00604 mol) N - (2-pyridyl) 2-methyl-4-hydroxy-2H-1,2-benzothiazine3-carboxamide-1,1-dioxide in 30 ml of water are added 687.00634 mol) diethanolamine and the resulting mixture is heated on a steam bath for 3 min. The resulting yellow solution is then filtered, removing a very small amount of white solids, and then concentrated

The resulting filtrate was removed under vacuum to give a yellow oil as the residual liquid. Treatment of the latter material with 200 ml of a mixed solvent of ethyl acetate and chloroform (3:2 by volume) followed by stirring at room temperature (25°C) overnight (18 h) under dry nitrogen afforded a yellow gum which was subsequently isolated by decanting the solvent. The gum was triturated with 100 ml of chloroform and heated on a steam bath for 2 min (just until boiling) followed by scratching to induce crystallization. The mixture was cooled to room temperature and then stirred for 2.5 h under dry nitrogen. $i After removal of the solid crystalline material by suction filtration and its washing with fresh solvent - chloroform, followed by drying in vacuum to constant weight, 2.11% (yield 80%) of pure diethanolamine salt of K - 2-pyridyl-2-methyl-4-hydroxy-2H-1,-benzthiazine-3carboxamide-1,1-dioxide with mp 143 IAG C is finally obtained. The purified product is further characterized by IR absorption spectrum and elemental analysis. Calculated, %: C 52.28; H 5.54; « 12.84. C|q H,,. S, Found, %: C 52.04; H 5.40; N 12.55, Example 5. A dry pharmaceutical composition is prepared by mixing the following materials in weight ratios: Ethylenediamine salt VI - (2-pyridyl) -2-methyl- . 4-OXY-2H-1,2-benzothiazine-3-carboxamide-1 ,1-dioxide 5.88 Microcrystalline cellulose 34.00 Corn starch (US Pharmacopoeia) - 9.08 Magnesium stearate 1.04 After thoroughly mixing the dry composition, tablets are stamped from the resulting mixture, each tablet containing 5 mg of the active component. Other tablets, prepared in a similar manner, contain 0.25 and 50 mg of the active component. Example 6. A dry solid pharmaceutical composition is prepared by mixing the following materials in weight ratios: N-(2-pyridin)-2-methyl4-OXY-2H-1,2-benzothiazine monoethanolamine salt, 3-carboxamide-1,1 dioxide, 59.21; Dicalcium phosphate anhydrous, 230.10; Corn starch (US Pharmacopoeia), 32.50; Sodium lauryl sulfate, 0.32; Magnesium stearate, 2.87. The prepared mixture is thoroughly mixed to obtain a homogeneous powder product. Hard gelatin capsules (No. 2) are then prepared containing 50 mg of the active ingredient each. Example. An aqueous solution of propylene glycol containing the diethanolamine salt of N-(2-:pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamium-1,1-dioxide is prepared by dissolving this compound in a propylene glycol-water mixture (1:4, by weight) containing 1 wt.% trisodium phosphate and having a pH of 8.0. Such an amount of the compound is used that the resulting solution contains 5 mg of the active ingredient per 1 ml. The solution is then sterilized by filtration through a porous cellulose membrane with a pore size of 0.2 μm. A sterile aqueous propylene glycol solution suitable for intramuscular administration to animals. Example 8. An aqueous solution for injections are prepared by mixing 1 part by weight of the monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-oxy-2H1,2-benzothiazine-3-carboxamide-1,1-dioxide with 2.5 parts by weight of disodium phosphate using a mortar and pestle. The resulting crushed dry mixture is sterilized with ethylene oxide and then aseptically transferred to ampoules and sealed. For intravenous administration, such an amount of distilled water is added to each of the filled ampoules before use as to obtain a solution containing 10 mg of the active substance in 1 ml of solution. EXAMPLE 9. The formulation for tablets is prepared by mixing the following materials in weight ratios: Monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-oxy-2H-1, 2-Benzthiazine-3-carboxamide-1 ,1-dioxide 23.92 Microcrystalline cellulose 31.1.03 Modified pregelatinized starch, N.F. 84.00 Magnesium stearate 0.945 Sodium lauryl sulfate 0.105 After thorough mixing of the dry composition, tablets are stamped from the resulting mixture, each tablet containing 20 mg of the active ingredient. Other tablets prepared in a similar manner. 71 contain 5, 10 and 50 mg of the active ingredient. EXAMPLE 10 A formulation for tablets is prepared by mixing the following materials in weight ratios: Conoethanolamine salt of H-(2-cyridyl)-2-methyl4-oxy-2H-1 ,2-benzothiazine-3-carboxamide-1 ,1-dioxide ...23.69 Anhydrous dicalcium phosphate 113.37 Polyvinylpyrrolidone 50.00 Modified, pregelatinized starch, NF 10.0 Magnesium stearate 2.65 Magnesium lauryl sulfate 0.294 After thorough mixing of the dry composition, tablets are stamped from the resulting mixture, each tablet containing 20 mg of the active component. Other tablets prepared in a similar manner contain 5.10 and 50 mg of the active component. The new ethylenediamine, monoethanolamine and diethanolamine salts of benzthiazine dioxide are crystalline, non-hygroscopic, fast-dissolving solids with high solubility in water and stable chemical and physical properties. They can be used as non-steroidal therapeutic agents for the treatment of painful inflammatory conditions caused by rheumatoid arthritis, in various pharmaceutical dosage forms for oral, topical or parenteral administration. Salts of N-(2-pyridyl)-2-methyl-4-OXY-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide are used for therapeutic treatment as antiarthritic agents. For example, the monoethanolamine salt of N-2-pyridyl)-2-methyl-4-OXY-2H1,2-benzothiazine-3-carboxamide-1,1-dioxide exhibits anti-inflammatory activity in a standard test on carrageenan-induced tumor on the rat paw. It was found to cause significant tumor inhibition at a dosage level of 33 mg/kg administered orally. Anti-inflammatory activity is defined as the percentage inhibition of NIN tumor formation on the hind paw of female albino rats. (weighing 150-190 g) in response to subplantar injection of carrageenan. Carrageenan is administered as a 1% aqueous suspension (0.05 ml) 1 hour after oral administration of the drug, which is usually given as an aqueous solution. Tumor formation is determined by measuring the volume of the injected paw, initially and also 3 hours after carrageenan injection. The increase in volume 3 hours after carrageenan injection represents the individual response. Compounds are considered active if the difference in response between animals given the drug (group of 6 rats) and the control group, which received only the vehicle, is significant compared with the results obtained with standard compounds such as acetylsalicylic acid at a dose of 100 mg/ml or phenylbutazone at a dose of 33 mg/kg, when both drugs are administered orally. I The described dioxide salts benzthiazine over its analogue in structure and action - piroxicam have additional advantages. For example, if N-(2-pyridyl)-2-methyl-4-oxy-2H I ,2-benzothiazine-3-carboxamide-1 ,1-dioxide (piroxicam) is very poorly soluble in water, the monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-oxy-2H-1,2-benzothiazine-3-carboxamide-1 ,1-dioxide immediately dissolves in the specified solvent and is therefore more rapidly absorbed by the blood stream when administered orally than the corresponding less soluble calcium salt or anhydrous sodium salt of N-(2-pyridyl)-2-methyl-4-oxyn-1,2-benzoxazine-3-carboxamide-1 ,1-dioxide. In addition, this salt gives a transparent , stable aqueous solution even at very high concentrations (more than 100 mg/ml). Other new salts also show similar results. It is known that the trimethylamine salt of N-(2-pyridyl)-2-methyl-1-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide and the corresponding triethylamine salt are poorly soluble in water. The simple ammonium salt is very unstable when subjected to drying in a vacuum. The new salts of benzthiazine dioxide are crystalline, non-hygroscopic solids, which are easily isolated in pure form. This facilitates bulk processing of the said salts into finished pharmaceutical dosage forms, which are suitable for use either orally, locally, or parenterally, etc. The advantage of the proposed salts before the known anti-inflammatory drug (piroxicam) is the improvement of solubility in water (determined by the equilibrium solubility of compounds at 25 C in water), which is essential for the resorption of tablets when taking them and the release of the active ingredient. Equilibrium solubility in water at , mgA / ml: for piroxicam 0.01, for the monoethanolamine salt of piroxicam 100, i.e. when using the new monoethanolamine salt of piroxicam, a 10,000-fold improvement in solubility in water is observed. Dissolution in the case of constant surface area at in water for piroxicam is 0.0032 mgA / ml / cm2 / min, and for the new ethylenediamine salt 1.3 mgA / ml / cm / / min, i.e. explosive solubility of the new salt is observed. In addition, determination of the dissolution profile for a 5 mg/L tablet containing the monoethanolamine salt of piroxicam as the active ingredient (according to Example 10), which was carried out using the rotating paddle method (provided for by the US Pharmacopoeia) (rotation speed 50 rpm, dissolution medium pH 2 at), showed rapid release of the active ingredient from the tablet (in 5 min). The described salts can be prescribed as antiarthritic agents in doses varying from about 5 to 100 mg per day depending on the weight and condition of the patient. The preferred dosage is in the range from 0.08 mg to 16 mg per kg of body weight per day, (depending on the individual response to the specified drug, as well as on the type of pharmaceutical formulation and the duration of the treatment period. In some cases, a dosage less than the lower or more than the upper limits of the specified range is prescribed, which are divided into several smaller doses for administration during the day. Benzthiazine dioxide salts can also be prescribed in combination with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, soft and hard lozenges, solid suppositories, powders, sprays, creams, ointments, suppositories, jellies, pastes, lotions, ointments, aqueous solutions and suspensions, injectable solutions, elixirs, syrups and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Oral pharmaceutical compositions may be sweetened and/or flavored. The said salts are present in such dosage forms at concentration levels varying from about 0.5 to 90% by weight. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be used, along with various disintegrating agents such as starch, preferably corn, potato or tapioca, alginic acid and certain complex silicates together with granular binders such as polyvinylpyrrolidone. gelatin and acacia. In addition, lubricating materials such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may be employed as fillers in hard gelatin capsules; preferred materials also include lactose or milk sugar, as well as high molecular weight polyethylene glycol. For oral administration of aqueous solutions and suspensions and/or elixirs, the active component may be combined with various sweetening or flavoring agents, coloring materials or dyes, and further emulsifying and/or suspending agents.

II112222512

means in combination with diluents, buffers pH greater than 8, and liquid,

such as water, ethanol, propylene - the diluent initially converts glycol, glycerin and their various into isotonic. Aqueous solutions

combinations are suitable for intravenous administration

For parenteral administration 5 injections, oily solutions - for

amine solutions can be used for intra-articular and intramuscular injections

salts in sesame oil or groundnut and subcutaneous injections. In addition,

nut or aqueous propylene glycol, local administration may be indicated, aqueous ethanol, as well as sterile additive salts of amines when

distilled aqueous solutions in the treatment of inflammatory conditions

water. Water paicTBopM shouldskin or eyes with creams,

contain the proper amount of jellies, pastes, ointments, solutions.

Claims (3)

1. METHOD FOR PRODUCING CRYSTALLINE WATER-SOLUBLE NON-HYGROSCOPIC ETHYLENEDIAMINE, MONOETHANOLAMINE OR DIETHANOLAMINE SALT N -(2-PYRIDYL)-2-METHYL-4-OXY-2H-1, 2-BENZTHIAZINE-Z-CARBOXAMIDE-!,1-DIOC- SIDA, characterized in that _λ . that I is the molar equivalent of M~(2-pyridyl) 2-methyl-4-oxy-2H-1,2-benzothiazine- 3-Carboxamide-1,1-dioxide is reacted with 1-2 molar equivalents of ethylenediamine, or monoethanolamine, or diethanolamine at 20-120°C in a polar protic solvent or a halide-hydrocarbon solvent. 2. The method according to π. I, differing in that water is used as a polar protic solvent. 3. The method according to π.,1, characterized in that methylene chloride is used as the halogen-hydrocarbon solvent. Λ and 1 1122225