CS228929B2 - Method of preparing 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 water-soluble salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide which they are particularly valuable because of their unique chemotherapeutic 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-dioxides described and protected in U.S. Pat. No. 3,591,584. As research and the search for improved anti-inflammatory agents continue there appears to be a need for antiarthritic agents suitable for parenteral administration.

In accordance with the invention, it has now been found that certain novel water-soluble salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazole-3-carboxamide-1,1-dioxide they are useful as non-steroidal therapeutic agents for relieving painful inflammations, such as rheumatoid arthritis pain conditions.

The 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 lysine and arginine.

These salts can be used to relieve the arthritic effects mentioned above, especially when administered parenterally.

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 This reaction is normally carried out in a polar protic solvent such as water or a lower alkanol such as methanol, ethanol, isopropanol, and the like. Generally, the reaction is carried out at a temperature in the range of about 20 to 100 ° C. from about 0.5 minutes to about 30 minutes, although it is usually most convenient in practice to carry out the reaction at reflux of the solvent After 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 and subsequent trituration solid or crude concentrated product with a suitable solvent system such as a mixture of ethyl acetate and chloroform, etc. Alternatively, isolation can be avoided by using an aqueous salt solution as formed in situ after appropriate concentration adjustment.

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-benzothiazine-3-carboxamide-1,1-dioxide (piroxicam) is described in U.S. Patent 3,591,584. (JG Lombardiim), as well as JG Lombardino et al., Journal of Medicinal Chemistry, Vol. 16, p. 493 (1973), including its overall synthesis from readily available organic materials. The amine bases used to prepare new addition salts. according to the invention are all commercially available substances.

The N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide salts of the present invention can be readily formulated for therapeutic use as antiarthritic agents. For example, salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with lysine and arginine show anti-inflammatory activity in a standard edema-induced test on rat paws with carrageenin [see CA Wintei et al., Proc. Soc. Exp. Biol. Med., vol. 111, p. 544 (1962)] However, the present benzothiazine dioxide salts of the invention have other advantages. N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide alone (piroxicam J is only slightly soluble in water; 2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with lysine and arginine soluble in water very well (dissolves immediately) and therefore much faster after oral administration to the blood than the corresponding less soluble calcium salt and even than the anhydrous sodium salt of the above compound (both are prepared as described in U.S. Pat. The salts of the invention further form clear, stable aqueous solutions even at very high concentrations (above 50 mg / ml). This is a very surprising fact considering that both the tromethammonium salt of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide, thus, the corresponding triethanolammonium salt is very poorly soluble in water, and that the simple ammonium salt is very volatile when dried under vacuum.

The salts of the invention may be administered as anti-arthritic agents either orally, parenterally, or topically. 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 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 time intervals. in 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 citrate, 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 polyvinylpyrrolldone, 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 administered orally, the active ingredient may be combined with various sweetening or flavoring agents, coloring agents and, optionally, 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 8), and the liquid diluent should be pretreated to be isotonic.These aqueous solutions are suitable for intravenous injections.The oil solutions are suitable for intraarticular, intramuscular and subcutaneous injections. apply inflammatory conditions of the skin or eye to the amine addition salts of the invention topically in the form of creams, jellies, pastes, ointments, solutions and the like, 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 gm by subplantar injection of carrageenin). test substance, which is normally administered in the form of an aqueous solution Edema formation is determined by measuring the paw volume at the start of the test and then 3 hours after the carrageenin injection The increase in volume measured 3 hours after the carrageenin injection is an individual response. when the difference in responses between animals treated with test substance (6 rats / group and control group of animals treated with vehicle alone) is significant compared to results obtained with standard compounds such as acetylsalicylic acid at 100 mg / kg or phenylbutazone at a dose of 33 mg / kg, both being oral.

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

Example 1

In a 1000 ml Erlenmeyer flask equipped with a magnetic stirrer and reflux condenser was charged 3.5 grams (0.0105628 mol) of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine 3-carboxamide-1,1-dioxide, 1.54 g (0.0105628 mol) of L-lysine (Aldrich Chemical Company, Inc., Milwaukee, Wisconcinj and 700 ml of ethanol.) The resulting yellow suspension was heated to reflux and Water (10 ml) was added slowly at reflux, the resulting yellow solution was cooled to room temperature (ca. 25 ° C) and evaporated to dryness under reduced pressure, 400 ml of diethyl ether was added to the yellow foam. The suspension was stirred overnight (ca. 16 hours) and then filtered in the usual manner to give 4.5 g (89%) of pure amorphous salt of L-lysine with N- (2-pyridyl) -2- methyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (as hemihydrate with 0.25 mol of diethyl ether). the product is characterized by mass spectroscopy and IR adsorption spectra, as well as elemental analysis. Analysis for:

C15H13N3O4S. C6H14N2O2.0.5H2O.

. 0.25 C2H5OC2H5 calculated:

% C, 52.31;% H, 6.08;% N, 13.86;

nilP7Pnn ·

C, 52.52; H, 6.14; N, 13.77. Example 2

To a suspension of 5.0 g (0.0151 mol) of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide in 400 ml of water was added. 2.77 g (0.0159 mol) of L - (+ β-arginine) (Fisher Scientific Company, New York, NYJ) was added and the resulting mixture was heated on a steam bath for 5 minutes while filtering to remove a small amount of insoluble matter by filtration. The yellow oily residue was triturated with a mixture of 80 ml of chloroform and 150 ml of ethyl acetate and then stirred at room temperature (about 25 ° C) under an atmosphere of dry nitrogen overnight (about 16 hours). The mixture is filtered off with suction and dried to constant weight under a vacuum of 1 mmHg at 57 [deg.] C. 5.36 g (yield 70%) of the pure amorphous salt of L-arginine with N- (2-pyridyl) -2-methyl- 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide (as hydrate) melting at 142-145 [deg.] C. The pure product is further characterized by: elementary analysis.

Analysis for:

C15H13N3O4S. C6H14N4O2. H2O calculated:

H, 5.58; N, 18.73;

1Ί £ ΐ1θΖθΓ3.0 *

H, 5.72; N, 18.69.

Example 3

An aqueous injection solution is prepared as follows.

part by weight of L-lysine salt with N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-doxide together with 2.5 parts by weight of sodium monohydrogen phosphate mix thoroughly by spreading in a mortar. The pulverized 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 ampoule so filled to give a solution containing 10 mg of active ingredient per milliliter.

Claims (3)

A process for the preparation of water-soluble salts of N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with lysine or arginine, characterized in that: by reacting N- (2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide with at least an equimolar amount of lysine or arginine in the polar Of the protic solvent at a temperature of 20 to 100 ° C. 2. A process according to claim 1, wherein the solvent is water. 3. A process according to claim 1, wherein the solvent is an alkanol having from 1 to 4 carbon atoms.