CS228930B2 - Method of preparing crystalline,non-hygroscopic,water-soluble salts of n/2-pyridyl/-2-methyl-4-hydroxy-2h-1,2-benzothiazine-3-carboxamide-1,1-dioxide - Google Patents

Description

The invention discloses novel useful salts of benzothiazine dioxide, in particular certain novel crystalline, non-hygroscopic, water-soluble salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide , which are particularly valuable because they exhibit a unique combination of chemotherapeutic and physical properties.

In the past period, numerous attempts have been made to find new and better anti-inflammatory agents. For the most part, these efforts involved the synthesis and testing of various steroid compounds, such as corticosteroids, or non-steroids of an acidic nature, such as phenylbutazone, indomethacin and the like, including a novel composition known as piroxicam. The latter belongs to the group of anti-inflammatory active 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide described and protected in U.S. Pat. No. 3,591,584. anti-inflammatory agents, there appears to be a need for antiarthritic agents with high water solubility and other desirable properties, particularly suitable for oral, topical or parenteral administration.

In accordance with the invention, it has now been found that certain novel crystalline non-hygroscopic, water-soluble salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1 Dioxides are useful as non-steroidal therapeutic agents for relieving painful inflammation, such as pain conditions in rheumatoid arthritis. These novel salts of the invention are the salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, which is an acidic compound of the general formula

OH

in which

R is 2-pyridyl, with ethylenediamine, monoethanolamine and diethanolamine.

The novel salts of ethylenediamine, monoethanolamine and diethanolamine of the present invention are crystalline, non-hygro228930, scoping, fast-dissolving solids with high water solubility, which in addition exhibit excellent chemical and physical stability. Accordingly, they are particularly valuable as non-steroidal therapeutic agents for the treatment of painful inflammatory conditions, particularly rheumatoid arthritis, and are particularly suitable for use in a variety of dosage forms, including those for oral, topical or parenteral administration. A preferred salt of the invention is a monoethanolamine salt.

In accordance with the invention, these novel salts are prepared by contacting N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with at least an equivalent number of moles of ethylenediamine, monoethanolamine or dlethanolamine. This reaction is normally carried out in a polar protic solvent such as water or a lower alkanol such as methanol, ethanol, isopropanol or the like, or a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride, 1,1,2,2-tetrachloroethane and generally. The reaction is carried out at a temperature in the range of about 20 to 100 ° C for about 0.5 minutes to 30 minutes. Upon completion of the reaction, the desired resulting salt is readily isolated by conventional means, for example by evaporation of the solvent from the reaction mixture followed by trituration of the solid residue or crude concentrated product with a suitable solvent system such as ethyl acetate / chloroform, etc. Alternatively. The method according to claim 1, characterized in that an aqueous salt solution, as formed in situ, is used after adjusting the concentration accordingly.

The starting materials used for the preparation of the novel salts according to the invention are generally known. For example, N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothlazine-3-carboxamide-1,1-dioxide (piroxicam) is described in U.S. Pat. No. 3,591,584 (JG). Lombardino) and JG Lombardino et al., Journal of Medicinal Chemistry, Vol. 16, p. 493 (1973J), including its overall synthesis from readily available organic materials. The amine bases used to prepare the novel addition salts of the invention, they are all commercially available substances.

The salts of the N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide of the invention are readily formulated for therapeutic use as antiarthritic agents. N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with monoethanolamine, a typical and preferred compound of the invention, exhibits anti-inflammatory activity in a standard test on edema induced by carrageenin on rat paws [see

C. A. Winter et al., Proc. Soc. Exp. Biol. Med., Vol. 111, p. 544 (1962)], which significantly inhibits swelling when administered orally at a dose of 33 mg / kg. However, the disclosed benzothiazine dioxide salts of the present invention have further advantages. For example, although N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (piroxicam) alone is poorly soluble in water, a salt of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with monoethanolamine soluble in water (dissolves immediately) and therefore it receives much more rapidly after oral administration into the blood than the corresponding less soluble calcium salt and even the anhydrous sodium salt of the above compound (both of which are prepared as described in U.S. Pat. No. 3,591,584). , stable aqueous solutions even at very high concentrations (above 100 mg / ml) the other salts of the invention behave similarly. This is a very surprising fact considering that both tromethammonium salt of N- (2-pyridyl) -2 methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide and the corresponding trie salt thanolammonium salts are very poorly soluble in water and that the simple ammonium salt is highly volatile when dried under vacuum.

In addition, the novel salts of the invention are crystalline, non-hygroscopic solids, which are thus easily isolated in a highly pure state. These particular properties further facilitate large-scale processing of these salts into appropriate dosage forms, especially adapted for either oral, topical or parenteral administration and the like.

The salts of the invention may be administered as antiarthritic agents by any of the above routes. Generally, these salts are administered at doses of about 5.0 mg to 1000 mg per day, although variations inevitably depend on the weight and condition of the patient being treated and the route of administration chosen. Usually, dosages ranging from about 0.08 mg to 16 mg per kilogram of body weight per day are preferred, although there may be variations depending on the individual response of the patient to the medicament as well as the type of pharmaceutical preparation and the time schedule. intervals at which the application is performed. In some cases, dosages below the lower limit of the above range may be appropriate, while in other cases a higher total dose divided into several lower doses administered during the day may be used.

The salts of the invention may be administered alone or in combination with pharmaceutically acceptable carriers by the various routes mentioned above, in a wide variety of different dosage forms. These active ingredients may be combined with various pharmaceutically acceptable inert carriers and formulated as tablets, capsules, soft and hard diamond lozenges, troches, lozenges, powders, sprays, creams, balsams, suppositories, jellies, pastes, lotions, ointments, aqueous solutions and suspensions, injectable solutions, elixirs, syrups, and the like. The above carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, and the like. In addition, pharmaceutical compositions for oral administration may be suitably sweetened and / or flavored. In general, these dosage forms contain the salts of the invention in concentrations ranging from about 0.5 to 90% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium cltronate, calcium carbonate, calcium monohydrogen phosphate and glycine may be used together with various disintegrating agents such as starches, preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, and together with granulating binders such as polyvinylpyrrolidone, gelatin and acacia. Glidants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful in the preparation of tablets. Solid compositions of a similar type may also be used to fill hard gelatin capsules. Preferred excipients also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. If aqueous solutions and suspensions and / or elixirs are to be prepared for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring agents and / or emulsifiers and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various combinations of these diluents.

For parenteral administration, the amine salt solutions of the invention in sesame or peanut oil, or in aqueous propylene glycol or aqueous ethanol, as well as sterile aqueous solutions in distilled water may be used. The aqueous solutions should be suitably buffered (pH above 8) and the liquid diluent pretreated to be isotonic. These aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-articular, intramuscular, and subcutaneous injection. In addition, the amine addition salts of the invention may also be administered topically in the form of creams, jellies, pastes, ointments, solutions and the like to treat inflammatory conditions of the skin or eye in accordance with standard pharmaceutical practice.

The anti-inflammatory activity of the compounds of the invention is evidenced by the aforementioned standard test for edema induced on the rat paw by carrageenin. In this test, anti-inflammatory activity was determined as a percentage of inhibition of edema induced on the hindpaw of a male white rat (150-190 g) by subplantar injection of carrageenin. Carrageenin is injected as a 1% aqueous suspension (0.05 ml) 1 hour after oral administration of the test substance, which is normally administered as an aqueous solution. Edema formation is determined by measuring paw volume at the start of the test and then 3 hours after carrageenin injection. The increase in volume measured 3 hours after carrageenin injection represents an individual response. Test compounds are considered to be effective if the difference in responses between the test compound treated animals (6 rats / group) and the control group of animals treated with vehicle alone is significant compared to the results obtained with oral administration of standard substances such as acetylsalicylic acid at a dose of 100 mg / kg; or phenylbutazone at a dose of 33 mg.

The invention is illustrated by the following non-limiting examples.

Example 1

A 250 ml Erlenmeyer flask equipped with a magnetic stirrer was charged with 500 mg (0.0015 mol) of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide. -1,1-dioxide and 75 ml of water. 180 mg (0.003 mol) of ethylenediamine (0.2 ml) was slowly added to the resulting suspension with stirring. The reaction mixture was heated on a steam bath for about 3 minutes, turning to a yellow solution. Evaporation of this solution to near dryness under reduced pressure gave a yellow gummy residue which was triturated with 200 mL of chloroform and 30 mL of ethyl acetate by stirring for 1 hour. The resulting yellowish solid was filtered off with suction and washed with fresh ethyl acetate on a suction funnel. There was obtained pure N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide salt with ethylenediamine, melting at 151-154 ° C. The pure product is further characterized by IR absorption spectroscopy and elemental analysis.

Analysis for:

C15H13N3O4S. C2H8N2 calculated:

% C, 52.16;% H, 5.40;% N, 17.89;

% H, 5.41;% N, 17.77.

Example 2

To a suspension of 2.0 g (0.00604 mol) of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 300 ml of water was added. 388 mg (0.00634 mol; 0.383) of 2-aminoethanol are added and the resulting mixture is heated on a steam bath for about 3 minutes. The resulting yellow solution was filtered to remove a very small amount of water-insoluble matter and the filtrate was concentrated in vacuo to a yellow oily residue which was triturated with 200 mL of ethyl acetate / chloroform (3: 2 by volume) by stirring overnight ( The solid precipitate was filtered off with suction, washed thoroughly with ethyl acetate, and dried under vacuum to constant weight to give 2.07 g (yield 87% / o pure N salt). - (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with monoethanolamine, melting at 174-178 [deg.] C. The pure product is further characterized by IR absorption spectroscopy and elemental analysis.

Analysis for:

C17H20N4O5S calculated:

52.03% C, 5.14% H, 14.28% N;

found:

H, 5.14; N, 13.93. Example 3

A 2 L 3-neck round bottom reaction flask equipped with a magnetic stirrer, dropping funnel (250 mL) and a thermometer was charged with a filtered solution of 55.0 g (0.166 mol) of N- (2-pyridyl) -2-methyl-4-hydroxy- 2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 660 ml of methylene chloride. This solution, which also contains 0.1 grams of the salt of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with a monoethanolamine as a seed, prepared by first dissolving the solid material in 610 ml of methylene chloride presented in an Erlenmeyer flask using gentle magnetic stirring. This dissolution is carried out at a temperature of 25 degrees Celsius. After transferring this solution to the above reaction flask, an additional 50 mL of methylene chloride was then used to rinse the Erlenmeyler flask. The reaction flask was then heated on a steam bath to 27 degrees Celsius and a solution of 10.7 g (0.175 mol) of ethanolamine in 110 ml of fresh methylene chloride was slowly added over 50 minutes with vigorous stirring. After the addition was complete, the reaction mixture was stirred at 27 ° C for 1 hour and the precipitated crystalline salt was filtered off with suction on a Buchner funnel. The resulting salt was dried in a vacuum oven at 35 ° C to constant weight to give 63.1 g of pure N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3 salt. -carboxamide-1,1-dioxide with monoethanolamine, melting at 171-174 degrees Celsius. Thus, the net yield of the pure product was 63.0 (96.8%). The pure product thus obtained is further characterized by NMR spectroscopy and elemental analysis. This product was found to be identical in all respects to the product prepared in Example 2.

Analysis for:

C17H20N4O3S calculated:

% H, 5.14;% N, 14.28;

found:

C, 52.09; H, 5.15; N, 14.30

To a suspension of 2.0 g (0.00604 mol) of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 300 ml of water was added. 687 mg (0.00634 mol) of diethanolamine was added and the resulting mixture was heated on a steam bath for 3 minutes. The resulting yellow solution was filtered to remove a very small amount of white solids and the filtrate was concentrated in vacuo to a yellow oily residue. To this residue was added 200 mL of ethyl acetate / chloroform (3: 2 by volume) and the mixture was stirred at room temperature (ca. 25 ° C) under an atmosphere of dry nitrogen overnight (18 h) to give a yellow resinous material. Isolates by solvent decantation. This resin material was triturated with 100 ml of chloroform, heated on a steam bath for 2 minutes (just to start boiling), then crystallized by scratching the vessel walls with a glass rod. The resulting mixture was allowed to cool to room temperature and at this temperature under a dry nitrogen atmosphere

Stir 2.5 hours. The solid crystalline product is filtered off with suction, washed with fresh chloroform and dried under vacuum to constant weight. 2.11 g (yield 80%) of pure N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with diethanolamine are obtained, o. mp 143-146 ° C. This pure product is further characterized by IR absorption spectroscopy and elemental analysis.

Analysis for:

C19H24N4O8S calculated:

% C, 52.28;% H, 5.54;% N, 12.84;

found:

H, 5.40; N, 12.55.

Example 5

By mixing the following ingredients in the following weight ratios, a dry solid pharmaceutical composition is prepared.

N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide salt with ethylenediamine 5.88 microcrystalline cellulose 34.00 corn starch 9.08 stearate magnesium 1.04

After thoroughly mixing the dried mixture, the resulting mixture is compressed into tablets containing 5 mg of active ingredient. Using the appropriate amount of the mixture, other tablets containing 10 mg, 25 mg and 10 mg, respectively, can be prepared in analogy. 50 mg of the active substance.

Example 6

By mixing the following ingredients in the following weight ratios, a dry solid pharmaceutical composition is prepared.

N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide salt with monoethanolamine 59,21 calcium monohydrogen phosphate anhydrous 230,10 maize starch 32,50 sodium lauryl sulfate 0.32 magnesium stearate 2.87

The thus prepared dry solid mixture is then thoroughly mixed to obtain a powdered product which is completely homogeneous in every respect. Hard gelatin capsules (No. 2) containing 50 mg of active ingredient are then prepared using an appropriate amount of this powdered material.

Example 7

An aqueous propylene glycol solution was prepared containing the diethanolamine salt of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide by the addition of the latter. the substance is dissolved in a mixture of propylene glycol and water (1: 4 by weight) containing 1% by weight of sodium tertiary phosphate, and the pH of the solution is adjusted to 8.0. every ml.

The solution is then sterilized by filtration through a cellulose membrane having 0.2 µm openings. The sterile aqueous propylene glycol solution thus obtained is suitable for intramuscular administration to animals.

Example 8

One part by weight of the monoethanolamine N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide salt is mixed thoroughly with 2.5 parts by weight of sodium monohydrogen phosphate. The dry mixture thus obtained is sterilized with ethylene oxide, dispensed under aseptic conditions into ampoules and sealed.

For intravenous administration, an appropriate amount of distilled water is added to the filled ampoule to form a solution containing 10 mg of active ingredient per milliliter.

Example 9

By mixing the following substances in the following weight ratios, a mixture for making tablets is prepared.

N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide salt with monoethanolamine 23,92 microcrystalline cellulose 311,03 modified gelatinized starch 84,00 magnesium stearate 0,945 sodium lauryl sulphate 0,105

The tablets are compressed from the dry mixture after mixing, each containing 20 mg of active ingredient. Using the appropriate amount of the mixture, other tablets containing 5 mg, 10 mg and 10 mg, respectively, can also be prepared in analogy. 50 mg of the active substance.

Example 10

By mixing the following substances in the following weight ratios, a mixture for making tablets is prepared.

N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide salt with monoethanolamine 23,69 calcium monohydrogen phosphate anhydrous 113,37 polyvinylpyrrolidone 50,00 modified gelatinized starch 10.00 magnesium stearate 2.65 sodium lauryl sulfate 0.294

The tablets are compressed from the dry mixture after mixing, each containing 20 mg of active ingredient. Using the appropriate amount of the mixture, other tablets containing 5 mg, 10 mg and 10 mg, respectively, can also be prepared in analogy. 50 mg of the active substance.

Claims (4)

A process for the preparation of crystalline, non-hygroscopic, water-soluble salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with ethylenediamine, monoethanolamine or diethanolamine, characterized in that N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide is reacted with at least an equimolar amount of ethylenediamine, monoethanolamine or divynAleze ethanolamine in a polar protic solvent at a temperature of 20 to 100 ° C. 2. A process according to claim 1, wherein the solvent is water. 3. The process of claim 1 wherein the reaction is carried out in a halogenated hydrocarbon solvent. 4. A process according to claim 3 wherein the solvent is methylene chloride.