GB2146328A - Benzothiazine dioxide salts - Google Patents

Abstract

The ethylenediamine, monoethanolamine and diethanolamine salts of N-(6-methyl-2-pyridyl)-2- methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide are anti-arthritic agents.

Description

SPECIFICATION Crystalline benzothiazine dioxide salts This invention relates to new and useful benzothiazine dioxide salts. More particularly, it is concerned with certain novel crystalline, non-hygroscopic, water-soluble salts of N-(6-methyl-2pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1 1-dioxide, which are of especial value in view of their unique combination of chemotherapeutic and physical properties.

In the past, various attempts have been made to obtain new and better anti-inflammatory agents. For the most part, these efforts have involved the synthesis and testing of various steroidal compounds such as the corticosteroids or non-steroidal substances of an acidic nature such as phenylbutazone, indomethacin and the like, including a new agent known as piroxicam.

The latter substance is a member of a class of antiinflammatory 4-hydroxy-2H-1 ,2-benzothiazine3-carboxamide 1,1-dioxides described and claimed in U.S. Patent No. 3,591,584. However, in the continuing search for improved anti-inflammatory agents, there is a definite need for antiarthritic agents having high water-solubility and other desirable properties and especially adapted for oral, topical or parenteral administration. In Published European Patent Application No. 66,459A, published December 8, 1982, there are disclosed the ethylenediamine, monothanolamine and diethanolamine salts of piroxicam.

In accordance with the present invention, it has now been found that certain novel crystalline, non-hygroscopic, water-soluble base salts of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2 H- 1 , 2- benzothiazine-3-carboxamide 1 ,1-dioxide are useful as non-steroidal therapeutic agents for alleviating painful inflammatory conditions such as those caused by rheumatoid arthritis, for example. The novel salts of this invention are selected from the group consisting of the ethylenediamine, monoethanolamine and diethanolamine salts of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1,1-dioxide, which is an acidic compound of the formula:

wherein R is 6-methyl-2-pyridyl.The novel ethylenediamine, monoethanolamine and diethenaolamine salts of this invention are crystalline, non-hygroscopic, rapidly-dissolving solids with high water solubility and in addition, possess excellent chemical and physical stability. Accordingly, they are particularly valuable as non-steroidal therapeutic agents for the treatment of painful inflammatory conditions, especially those caused by rheumatoid arthritis, and are particularly adapted for use in various pharmaceutical dosage forms, including those designed for oral, topical or parenteral administration. The diethanolamine salt is the most preferred salt of this invention.

In accordance with the process employed for preparing the novel salts of this invention, N-(6 methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1 ,1-dioxide is contacted with at least an equivalent amount in moles of an organic amine base selected from the group consisting of ethylenediamine, monoethanolamine and diethanolamine. This reaction is normally carried out in a polar protic solvent like water or a lower alkanol such as methanol, ethanol or isopropanol, etc., or in a halogenated hydrocarbon solvent like methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride and s-tetrachloroethane, etc.In general, the reaction is conducted at a temperature that is in the range of from about 20"C. up to about 100"C. for a period of about 0.25 to about one hour. Upon completion of the reaction, the desired salt product is easily isolated in a conventional manner, e.g., by first evaporating the solvent from the reaction mixture, followed by trituration of the resulting solid residue or crude concentrate product with a suitable solvent system such as ethyl acetate/chloroform, etc.

Alternatively, it is also possible to avoid the need for isolation by employing aqueous solutions of the salt as formed in situ by appropriate adjustment in concentration of the solution.

The starting materials required for preparing the novel salts of this invention are all known compounds. For instance, N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2 H- 1 , 2-benzothiazine-3-carboxamide 1,1-dioxide is described in U.S. Patent No. 3,591,584 to J. G. Lombardino, as well as in the paper of J. G. Lombardino et al., appearing in the Journal of Medicinal Chemistry, Vol.

16, p. 493 (1973), including its overall synthesis from readily available organic materials. The amine bases employed to prepare the novel amine addition salts of this invention are all commercially available materials.

The N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 , 2-benzothiazine-3-carboxamide 1 , 1 -diox- ide salts of the present invention are readily adapted to therapeutic use as anti-arthritic agents.

For instance, the diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1 ,1-dioxide, a typical and preferred agent of the present invention, exhibits anti-inflammatory activity in the standard carrageenin-induced rat food edema test [described by C. A. Winter et al., Proc. Soc. Exp. Biol. Med., Vol. 111, p. 544 (1 962)], where it was found to cause a substantial inhibition in swelling at the 33 mg./kg. dose level when given by the oral route. The herein described benzothiazine dioxide salts exhibit additional advantages.For instance, even though N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1 ,1-dioxide per se is very poorly water-soluble, the diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1 ,1-dioxide is readily flash soluble (i.e., instantaneously soluble) in said solvent and therefore should be more rapidly absorbed into the blood stream upon oral administration than the corresponding less soluble calcium salt or even the anhydrous sodium salt of said particular compound (both of which are prepared according to the procedure already set forth in U.S. Patent No. 3,591,584).

Additionally, this particular salt afford a water-clear, conveniently formulated stable aqueous solution even at relatively high concentration levels (10 mg./ml.). The other salts of this invention also afford similar results. This is a truly surprising fact when one considers that the triethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2 H-i , 2-benzothiazine-3-carbox- amide 1 ,1-dioxide is hygroscopic and difficult to isolate and that the simple ammonium salt is found to be highly unstable when subjected to drying conditions under vacuum. Furthermore, the corresponding sodium salt is also hygroscopic and poorly soluble in water. On the other hand, the novel salts of this invention are all crystalline, nonhygroscopic solids which are, accordingly, readily isolated in highly pure form.These particular properties further facilitate the bulk processing of said salts into finished pharmaceutical dosage forms that are especially adapted for use in either oral, topical or parenteral administration, etc. Additionally, their relatively short plasma half-life as compared to the corresponding 6-desmethyl analog (which is piroxicam) affords a still further advantage when treating such acute human disease conditions as pain and the like.

The herein described salts can be administered as anti-arthritic agents by either of the routes previously indicated. In general, these salts will be administered in doses ranging from about 5.0 mg. up to about 1000 mg. per day, although variations will necessarily occur depending upon the weight and condition of the condition of the subject being treated and the particular route of administration chosen. A dosage level that is in the range of from about 0.08 mg. to about 1 6 mg. per kg of body weight per day is usually preferred, although variations may occur depending upon the individual response to said medicament, as well as on the type of pharmaceutical formulation and the time intervals at which such administration is carried out.In some instance, dosage levels below the lower limit of the aforesaid range may be adequate, while in other cases higher levels may be employed, divided into several smaller doses for administration throughout the day.

The salts of this invention may be administered alone or in combination with pharmaceutically acceptable carriers by the various routes previously indicated in a wide variety of dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, soft and hard lozenges, troches, hard candies, powders, sprays, creams, salves, 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. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the salts of this invention are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight.

For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch and preferably corn, potato or tapioca starch, alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in hard geletin capsules; preferred materials also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous solutions and suspensions and/or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

For parenteral administration, solutions of these amine salts in sesame or peanut oil or in aqueous propylene glycol or aqueous ethanol may be employed, as well as sterile aqueous solutions in distilled water. The aqueous solutions should be suitably buffered (pH 8) and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection purposes. Additionally, it is also possible to administer the aforesaid amine addition salts topically when treating inflammatory conditions of the skin or eye by way of creams, jellies, pastes, ointments, solutions and the like, in accordance with standard pharmaceutical practice.

The anti-inflammatory activity of the compounds of the present invention is demonstrated in the previously mentioned standard carrageenin-induced rat foot edema test. In this test, antiinflammatory activity is determined as the percent inhibition of edema formation in the hind paw of male albino rats (weighing 150-190 g) in response to a sub-plantar injection of carrageenin.

The carrageenin is injected as a 1 % aqueous suspension (0.05 ml) one hour after oral administration of the drug, which is normally given in the form of an aqueous solution. Edema formation is then assessed by measuring the volume of the injected paw initially as well as three hours after the carrageenin injection. The increase in volume three hours after carrageenin injection constitutes the individual response. Compounds are considered active if the difference in response between the drug-treated animals (six rats/group) and a control group receiving the vehicle alone is significant on comparison with the results afforded by standard compounds like acetylsalicylic acid at 100 mg/kg or phenylbutazone at 33 mg/kg, both by the oral route of administration.

EXAMPLE 1 To a well-stirred suspension of 3.0 g. (0.00869 mole) of N-(6-methyl-2-pyridyl)-2-methylA- hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1 ,1-dioxide in 450 ml. of water, there was added 560 mg. (0.00913 mole) of 2-aminoethanol and the resulting mixture was heated on a steam bath (with vigorous agitation) for a period of approximately five minutes. The green-yellow solution so obtained was then filtered to remove a small amount of water insolubles, followed by concentration of the resulting filtrate in vacuo to yield a gummy solid.Trituration of the latter material with 300 ml. of a chloroform/ethyl acetate (2 :3 by volume) solvent system, followed by stirring at room termperature (20"C.) overnight (16 hours) under a dry nitrogen atmosphere, then gave a solid precipitate which was subsequently recovered by means of suction filtration and dried under a high vacuum over phosphorus pentoxide to constant weight. In this manner, there were ultimately obtained 2.96 g. (84%) of the pure crystalline monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 2-benzothiazine-3-carboxamide 1 1-dioxide, m.p. 193-195"C. The pure product was further characterized by means of infrared absorption spectra and elemental analysis.

Anal. Calcd. for C,8H22N405S: C,53:20; H, 5.46; N, 13.79. Found: C, 52.97; H, 5.46; N, 13.51.

Example 2 To a suspension of 3.0 g (0.00869 mole) of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H 1 ,2-benzothiazine-3-carboxamide 1,1-dioxide in 450 ml. of water, there was added 960 mg.

(0.0096 mole) of diethanolamine and the resulting mixture was heated on a steam bath for a period of five minutes. The yellow aqueous solution so obtained was then filtered to remove some insolubles, followed by concentration of the resulting filtrate in vacuo to yield a yellow viscous oil as the residual liquid. Treatment of the latter material with 300 ml. of a chloroform/ethyl acetate (2: 3 by volume) solvent system, followed by stirring at room temperature (20"C.) overnight (16 hours) under a dry nitrogen atmosphere, then gave a yellow crystalline precipitate which was subsequently recovered by means of suction filtration and dried under a high vacuum over phosphorus pentoxide to constant weight.In this manner, there were ultimately obtained 2.73 9. (70%) of the pure crystalline diethanolamine salt of N-(6-methyl-2pyridyl)-2-methyl-4-hydroxy-2 H-1 , 2-benzothiazine-3-carboxamide 1 ,1-dioxide, m.p. 1 66-1 67 'C.

The pure product was further characterized by means of infrared absorption spectra and elemental analysis.

Anal. Calcd. for C20H26N406S: C, 53.33; H, 5.82; N, 12.44. Found: C, 53.00, H, 5.31; N, 12.41.

EXAMPLE 3 To a suspension of 3.0 g. (0.00869 mole) of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H- 1,2-benzothiazine-3-carboxamide 1,1-dioxide in 450 ml. of water, there was added 550 mg.

(0.00913 mole) of ethylenediamine (0.61 ml.) with stirring and the resulting mixture was heated on a steam bath (with continued vigorous agitation) for a period of five minutes. The warm aqueous solution so obtained was then filtered to remove a small amount of insolubles, followed by concentration of the resulting filtrate in vacuo to yield a gummy green-yellow oil as residue. Trituration of the latter material with 300 ml. of an ethyl acetate/chloroform (3 : 2 by volume) solvent system, followed by stirring at room temperature (20"C.) overnight (16 hours) under a dry nitrogen atmosphere, then gave a yellow solid precipitate which was subsequently recovered by means of suction filtration and dried under a high vacuum over phosphorus pentoxide to constant weight.In this manner, there were ultimately obtained 2.88 g. (82%) of the pure crystalline ethylenediamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2- benzothiazine-3-carboxamide 1,1-dioxide, m.p. 185-187"C. The pure product was further characterized by means of infrared absorption spectra and elemental analysis.

Anal. Calcd. for Ct8H23NsO4S: C, 53.33; H, 5.75; N, 17.27. Found: C, 53.05; H, 5.65; N, 16.92.

Example 4 A dry solid pharmaceutical composition is prepared by blending the following materials together in the proportions by weight specified below.

The ethylenediamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine3-carboxamide 1,1-dioxide 5.88 Microcrystalline cellulose 34.00 Corn starch, U.S.P. 9.08 Magnesium stearate 1.04 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such a size that it contains 5 mg. of the active ingredient. Other tablets are also prepared in a similar fashion containing 10, 25 and 50 mg. of the active ingredient, respectively, by merely using the appropriate amount of the tablet blend in each case.

EXAMPLE 5 A dry solid pharmaceutical composition is prepared by combining the following materials together in the proportions by weight indicated below: The monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiaz- ine-3-carboxamide 1 ,1-dioxide 59.21 Dicalcium phosphate, anhydrous 230.10 Corn starch, U.S.P. 32.50 Sodium lauryl sulfate 0.32 Magnesium stearate 2.87 The dried solid mixture so prepared is then thoroughly agitated so as to obtain a powdered product that is completely uniform in every respect. Hard gelatin (No. 2) capsules containing the pharmaceutical composition are then prepared, employing a sufficient quantity of material in each instance so as to provide each capsule with 50 mg. of the active ingredient.

EXAMPLE 6 An aqueous propylene glycol solution containing the diethanolamine salt of N-(6-methyl-2 pyridyl)-2-methyl-4-hydroxy-2 H- 1 , 2-benzothiazine-3-carboxam ide 1 ,1-dioxide is prepared by dissolving the latter compound in propylene glycol-water (1 :4 by weight) containing 1% by weight of trisodium phosphate and adjusted to an apparent pH of 8.0. The amount of compound employed is such that the resulting solution contains 5 mg. of the active ingredient per each ml.

of solution. The solution is then sterilized by means of filtration through a 0.2 m pore size cellulose membrane. The sterile aqueous propylene glycol solution so obtained is then suitable for intramuscular administration to animals.

EXAMPLE 7 An aqueous injectable solution is prepared by first intimately admixing one part by weight of the monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2 H- 1 , 2-benzothiazine-3- carboxamide 1,1-dioxide with 2.5 parts by weight of disodium phosphate with the aid of a mortar and pestle. The ground dry mixture so obtained is then sterilized with ethylene oxide and thereafter aseptically placed into vials and sealed. For purposes of intravenous administration, a sufficient amount of distilled water is added to each of the filled vials before use so as to ultimately provide a solution which contains 10 mg. of the active ingredient per each ml. of injectable solution.

EXAMPLE 8 A tablet formulation is prepared by blending the following materials together in the proportions by weight specified below: The monoethanolam ine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H- 1, 2-benzothiaz- ine-3-carboxamide 1 ,1-dioxide 23.92 Microcrystalline cellulose 311.03 Modified pregelatinized starch, N.F. 84.00 Magnesium stearate 0.945 Sodium lauryl sulfate 0.1 or After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such a size that it contains 20 mg. of the active ingredient. Other tablets are also prepared in a similar fashion containing 5, 10 and 50 mg. of the active ingredient, respectively, by merely using the appropriate amount of the tablet blend in each case.

EXAMPLE 9 A tablet formulation is prepared by blending the following materials together in the proportions by weight specified below: The monoethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2 H- 1 , 2-benzothiaz- ine-3-carboxamide 1 ,1-dioxide 23.69 Dicalcium phosphate, anhydrous 113.37 Polyvinylpyrrolidone 50.00 Modified pregelatinized starch, N.F. 10.00 Magnesium stearate 2.65 Sodium lauryl sulfate 0.294 After the dried composition is thoroughly blended, tablets are punched from the resulting mixture, each tablet being of such a size that it contains 20 mg. of the active ingredient. Other tablets are also prepared in a similar fashion containing 5, 10 and 50 mg. of the active ingredient, respectively, by merely using the appropriate amount of the tablet blend in each case.

Claims (13)

1. A crystalline, non-hygroscopic water-soluble organic amine salt selected from the group consisting of the ethylenediamine, monoethanolamine and diethanolamine salts of N-(6-methyl 2-pyridyl)-2-methyl-4-hydroxy-2H-l , 2-benzothiazine-3-carboxamide l,l-dioxide.

2. A compound as claimed in claim 1 which is an ethylenediamine salt.

3. A compound as claimed in claim 1 which is a mononethanolamine salt.

4. A compound as claimed in claim 1 which is a diethanolamine salt.

5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective anti-arthritic amount of a compound as claimed in claim 1.

6. The composition as claimed in claim 5 wherein the compound is the diethanolamine salt of N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1 ,1-dioxide.

7. A process for preparing a salt as claimed in claim 1, characterized by reacting N-(6 methyl-2-pyridyl)-2-methyl-4-hydroxy-2H-1 ,2-benzothiazine-3-carboxamide 1,1-dioxide with ethylenediamine, monoethanolamine or diethanolamine.

8. A process as claimed in claim 7, characterized by the fact that at least an equivalent amount in moles of ethylenediamine, monoethanolamine or diethanolamine is employed with respect to the N-(6-methyl-2-pyridyl)-2-methyl-4-hydroxy-2 H- 1,2-benzothiazine-3-carboxamide 1,1-dioxide.

9. A process as claimed in claim 7 or 8, characterized by the fact that said reaction is carried out in a polar protic solvent.

1 0. A process as claimed in claim 9, characterized by the fact that said solvent is water.

11. A process as claimed in claim 7 or 8, characterized by the fact that said reaction is carried out in a halogenated hydrocarbon solvent.

1 2. A process as claimed in claim 11, characterized by the fact that said solvent is methylene chloride.

13. A process as claimed in any one of claims 7 to 12, characterized by the fact that said reaction is conducted at a temperature of from 20"C to 100"C.

1 4. The ethylenediamine, monoethanolamine or diethanolamine salt of N-(6-methyl-2-pyri dyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1 ,1-dioxide which has been prepared by a process as claimed in any one of claims 7 to 1 3.