LU85536A1 - CRYSTALLINE BENZOTHIAZINE DIOXIDE SALTS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME - Google Patents

Description

i

The present invention relates to new and useful benzothiazine dioxide salts. It relates more particularly to certain new water-soluble and non-hygroscopic crystalline salts of 5 N-1,1-dioxide (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzo- thiazine-3-carboxamide, which are of special interest because of the remarkable combination of chemotherapy and physical properties with which they are endowed.

In the past, various attempts have been made to obtain new and more potent anti-inflammatory agents. The majority of these efforts have involved the synthesis and testing of various steroidal compounds such as corticosteroids, or non-steroidal substances of an acidic nature such as phenylbutazone, indomethacin etc., including a new known agent such as piroxicam. The latter substance is a representative of a class of anti-inflammatory 4-hydroxy-2H-1,2-benzothiazine-3-carboxamides 1,1-dioxides described and claimed in United States Patent No. 3 591 584. However, in the pursuit of research into improved anti-inflammatory agents, there is a precise need for antiarthritic agents endowed with high solubility in water and other interesting properties and specially adapted for oral, topical or parenteral administration.

^ European patent application No. 66,459 A published on December 8, 1982 discloses the ethylenediamine, * monoethanolamine and diethanolamine salts of piroxicam.

In accordance with the present invention, it has just been discovered that certain new salts of crystalline, water-soluble and non-hygroscopic bases of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H- 1,1-dioxide 1,2-Benzothiazine-3-carboxamide were useful as non-steroidal therapeutic agents for alleviating painful inflammatory conditions such as those caused by rheumatoid arthritis for example. The new salts of the present invention are chosen from the group comprising the salts of ethylenediamine, monoethanol-2 amine and diethanolamine of N- (6-methyl-2-pyridÿl) -2-methyl 1,1-dioxide -4-hydroxy-2H-1,2-benzothiazine-3-carboxamide which is an acidic compound of formula:

OH

—CONHR

^ n "CH3 ° 2 - 5 in which R is the 6-methyl-2-pyridyl group. The novel ethylenediamine, monoethanolamine and diethanolamine salts of the present invention are non-hygroscopic, fast-dissolving crystalline solids, endowed with great solubility in water and also having excellent chemical and physical stability, they are therefore particularly useful as non-steroidal therapeutic agents for the treatment of painful inflammatory conditions, in particular those caused by 15 rheumatoid arthritis, and they are particularly suitable for use in various pharmaceutical dosage forms, such as forms for oral, topical or parenteral administration The diethanolamine salt is the most preferred salt of the present invention.

In accordance with the process used to prepare the new salts of the invention, N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzo-thiazine 1,1-dioxide -3-carboxamide is contacted with an at least equivalent molar amount of an organic amino base selected from the group consisting of ethylenediamine, monoethanolamine and diethanolamine. This reaction is normally carried out in a polar protic solvent such as water or a lower alkanol such as methanol, ethanol or isopropanol, etc., or in a halogenated hydrocarbon solvent such as methylene chloride, chloroform, carbon tetrachloride,; 3 dichlorethylene, s-tetrachloroethane, etc. In general, the reaction is carried out at a temperature which ranges from about 20 ° C to about 100 ° C for a period of from about 0.25 to about 1 hour.

When the reaction is complete, the salt constituting the desired product is easily isolated in a conventional manner, for example by first evaporating the solvent from the reaction mixture and then triturating the resulting solid residue or the crude concentrated product with a suitable system. 10 solvents such as ethyl acetate / chloroform, etc.

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

The starting materials necessary for the preparation of the novel salts of the present invention are all known compounds. For example, 1.1- N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothia2ine-3-carboxamide dioxide is described in United States patent 'America N ° 3 591 584 as well as in the article by JG Lombardino and collaborators published in the Journal of Medicinal Chemistry, volume 16, page 493 (1973), including its general synthesis starting from organic matter easy to obtain. The amino bases used to prepare the new amine addition salts of the present invention are all commercially available materials.

The N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-30 carboxamide 1,1-dioxide salts of the present invention are readily suitable for therapeutic use as antiarthritis agents. For example, the diethanolamine salt of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, preferred representative example of agent of the present invention, deploys an anti-inflammatory activity in the classic test of rat paw edema induced by carrageenan / described by CA Winter et al., in Proc. Soc. Exp. Biol. Med., Volume 111, page 544 (1962/7, in which it has been found to cause significant inhibition of swelling at a dose of 33 mg / kg when administered orally. Benzothiazine dioxide described in this specification offers other advantages, for example, compared to N- (6-methyl-2-10 pyridyl) -2-methyl-4-hydroxy-2H 1,1-dioxide -1,2-benzothiazine-3-carboxamide which is itself very slightly soluble in water, the: sel of diethanolamine dissolves spontaneously (that is to say instantaneously) in said solvent and, consequently , it must be more rapidly absorbed into the blood stream, upon oral administration, than the corresponding less soluble calcium salt or even than the anhydrous sodium salt of said particular compound (each of which is prepared according to the procedure already indicated in U.S. Patent No. 3,591,584.) In addition, this particular salt gives a clear, stable, conveniently formulated aqueous solution. even at relatively high concentrations (10 mg / ml). The other salts of the invention also give similar results. This fact is really surprising considering that the triethanolamine salt of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine 1,1-dioxide -3-carboxamide is hygrosco-pic and difficult to isolate, and that the simple salt

H

ammonium is very unstable when subjected to vacuum drying conditions. In addition, the corresponding sodium salt is also hygroscopic and sparingly soluble in water. In contrast, the novel salts of the present invention are all non-hygroscopic crystalline solids which can therefore be readily isolated in very pure form. These particular properties further facilitate the bulk processing of these salts for incorporation into ready-to-use pharmaceutical dosage forms which are particularly suitable for use for oral, topical or parenteral administration, etc. In addition, their relatively short half-life in plasma compared to the corresponding 6-desmethylated analogue (which is piroxicam) offers an additional advantage when treating acute medical conditions, such as pain, etc.

The salts described herein can be administered as anti-arthritis agents by either of the routes indicated above. In general, these salts are administered in doses ranging from about 5.0 mg to about 1000 mg per day, although variations necessarily take place depending on the weight and condition of the subject being treated and the particular route of treatment. administration that we choose. Preference is usually given to a dosage which ranges from about 0.08 mg to about 16 mg per kg of body weight per day, although variations may occur depending on the individual reaction to said drug, same as depending on the type of pharmaceutical formulation and the time intervals at which administration is carried out. In some cases dosages below the lower limit of the above-mentioned range may be suitable, while in other cases larger doses may be used, divided into several smaller doses by view of an administration distributed 30 during the day.

The salts of the present invention can be administered alone or in combination with pharmaceutically acceptable carriers by the various routes indicated above in a wide variety of dosage forms, i.e., they can be combined with 6 various inert pharmaceutically acceptable carriers in the form of tablets, capsules, soft and hard lozenges, dragees, hard candies, powders, sprayable compositions, creams, ointments, suppositories, jellies, pastes, lotions, ointments, aqueous solutions and suspensions, injectable solutions, elixirs, syrups, etc. These carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, the oral pharmaceutical compositions can be suitably sweetened and / or flavored. In general, the salts of the present invention are present in these dosage forms at concentrations 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 can be used as well as various disintegrants such as starch and in particular corn starch, potato starch or cassava starch, alginic acid and certain complex silicates, together with granulating binders such as polyvinylpyrrolidone, gelatin and gum arabic. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for making tablets. Solid compositions of a similar type can also be used as fillers in hard gelatin 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 agents or fragrances, coloring matter or coloring matters, and, where appropriate, emulsifiers and / or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and various similar mixtures.

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

The anti-inflammatory activity of the compounds of the present invention is demonstrated in the standard test for carrageenan-induced rat paw edema mentioned above. In this test, the inflammatory activity is determined, which is expressed by the percentage inhibition of edema formation in the hind paw of male albino rats (weighing 150-190 g) in reaction to a sub-injection. plantar of carrageenan.

Carrageenan is injected in the form of a 1% aqueous suspension (0.05 ml) one hour after oral administration of the drug, which is normally administered in the form of an aqueous solution. The formation of edema 8 is then assessed by measuring the volume of the leg receiving the injection, initially, as well as three hours after the injection of carrageenan. An increase in volume three hours after injection of carrageenan 5 is the individual response. Compounds are considered active if the difference in response between the animals treated with the drug (six rats / group) and a control group receiving the vehicle only is significant compared to the results offered by conventional compounds such as acetylsalicylic acid. the dose of 100 mg / kg or phenylbutazone at the dose of 33 mg / kg, administered orally in both cases.

Example 1 560 mg (0.00913 mole) of 2-aminoethanol was added to a suspension with proper stirring of 3.0 g (0.00869 mole) of 1.1 N- (6-methyl- 2-pyridvl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine ~ 3-carboxamide in 450 ml of water and the resulting mixture was heated in a steam bath (with vigorous stirring) for a period about 5 min. The yellow-green solution thus obtained was then filtered to remove a small amount of water-insoluble matter, and the resulting filtrate was then concentrated in vacuo to give a gum-like solid.

The trituration of this latter material with 300 ml of a mixture of solvents formed of chloroform and ethyl acetate (2: 3 by volume), followed by stirring at room temperature (20 ° C) during the overnight (4:00 p.m.) under an atmosphere of anhydrous nitrogen then gave a solid precipitate which was subsequently collected by suction filtration and dried under high vacuum over phosphorus pentoxide to constant weight. There was thus finally obtained 2.96 g (84%) of the monoethanolamine salt of N-1,1-dioxide (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-9 2H-1, Pure crystalline 2-benzothiazine-3-carboxamide melting at 193-195 ° C. The pure product was further characterized by its infrared absorption spectrum and by its elemental analysis.

5 CH H analysis

Calculated for c-jgH22N4 ° 5S 53.20 5.46 13.79

Found 52.97 5.46 13.51

Example 2

960 mg (0.0096 mole) of diethanolamine 10 was added to a suspension of 3.0 g (0.00869 mole) of 1.1 - N- (6-methyl-2-pyridyl) -2- dioxide methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide in 450 ml of water and the resulting mixture was heated in a steam bath for a period of five minutes. The yellow aqueous solution thus obtained was then filtered to remove some insoluble matter, then the resulting filtrate was concentrated in vacuo giving a yellow viscous oil * as the residual liquid. Treatment of the latter material with 300 ml of a mixture of solvents consisting of chloroform and ethyl acetate (2: 3 by volume), followed by stirring at room temperature (20 ° C) during the overnight (4:00 p.m.) under an atmosphere of dry nitrogen then gave a yellow crystalline precipitate which was subsequently collected by suction filtration and dried under high vacuum over phosphorus pentoxide to constant weight. In this way, 2.73 g (70%) of the diethanolamine salt of 1, i-dioxide of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1 were obtained in this way, Pure crystalline 2-benzothiazine-3-carboxamide melting at 166-167 ° C. The pure product was further characterized by the infrared absorption spectrum and by elemental analysis.

»Analysis C H N

Calculated for c2oH26N4 ° 6S 53.33 5.82 12.44 35 Found "53.00 5.31 12.41 10

Example 3

550 mg (0.00913 mole) of ethylenediamine (0.61 ml) was added with stirring to a suspension of 3.0 g> (0.00869 mole) of N-1,1-dioxide (6 -methyl-2-pyridyl) - 5 2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide in 450 ml of water and the resulting mixture was heated in a steam bath (without interrupting the vigorous agitation) during. a period of 5 min. The hot aqueous solution thus obtained was then filtered to remove a small amount of insoluble matter, then the resulting filtrate was concentrated in vacuo giving a residue a yellow-green gum-like oil. By trituration of the latter material with 300 ml of a mixture of solvents formed from ethyl acetate and chloroform (3: 2 by volume), followed by stirring at room temperature (20 ° C) during the overnight (16 h) under an atmosphere of anhydrous nitrogen, a yellow solid precipitate was then obtained which was subsequently collected by suction filtration and dried under high vacuum over phosphorus pentoxide to constant weight. There was thus finally obtained 2.88 g (82%) of the ethylenediamine salt of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1 1,1-dioxide, Pure crystalline 2-benzothiazine-3-carboxamide melting at 185-187 ° C. The pure product was further characterized by the infrared absorption spectrum and by elemental analysis.

C H N analysis

• Calculated for 53.33 5.75 17.27

Found 53.05 5.65 16.92 30 Example 4

A solid powdered pharmaceutical composition was prepared by mixing the following materials together in the weight proportions indicated below: 11

Ethylenediamine salt of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazide-3-carboxamide 1,1-dioxide ....... ................. 5.88 v. Microcrystalline cellulose ......... 34.00 5 Corn starch, U.S.P .............. 9.08

Magnesium stearate .............. 1.04

After properly mixing the composition. dried, tablets were formed from the resulting mixture, each tablet having such dimensions! 10 that it contains 5 mg of the active ingredient. Other tablets were also prepared in a similar manner, containing 10, 25 and 50 mg of the active ingredient, respectively, by simply using the appropriate amount of tablet mixture in each case.

15 Example 5

A solid pharmaceutical composition in powder is prepared by mixing the following materials 1 together in the weight proportions indicated below:

20 N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide monoethanolamine salt of 20 N- (6-methyl-2-pyridyl) ...... . 59.21

Anhydrous dicalcium phosphate ....... 230.10

Corn starch, U.S.P .............. 32.50

Sodium lauryl sulfate ............ 0.32 25 Magnesium stearate .............. 2.87

The dried solid mixture thus prepared is then suitably stirred so as to form a powdered product which is completely uniform in all respects.

Hard gelatin capsules (No. 2) containing the pharmaceutical composition are then prepared using a sufficient amount of material in each case for each capsule to contain 50 mg of active ingredient.

k

Example 6 12

An aqueous propylene glycol solution containing the diethanolamine salt of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzo-5 is prepared. thiazine-3-carboxamide by dissolving the latter compound in a mixture of propylene glycol and 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 used is chosen so that the resulting solution 10 contains 5 mg of active ingredient per ml of solution. The solution is then sterilized by filtration on a cellulosic membrane with a pore of 0.2 μιη. The sterile propylene glycolic aqueous solution thus obtained is then ready to be administered intramuscularly to animals.

Example 7

An aqueous solution for injection is prepared by firstly mixing 1 part by weight of the monoethanolamine salt of N- (6-methyl-2-20 pyridyl) -2-methyl-4-hydroxy-2H 1,1-dioxide. -1,2-benzothiazine-3-carboxamide with 2.5 parts by weight of disodium phosphate, using a mortar and pestle. The ground powder mixture thus obtained is then sterilized with ethylene oxide and then introduced into ampoules, under aseptic conditions, and the ampoules are sealed. To the . For the purposes of intravenous administration, a sufficient amount of distilled water is added to each of the charged ampoules, before use, so as to finally obtain a solution which contains 10 mg of the active ingredient 30 per ml of splution. injectable.

Example 8

A formulation of tablets is prepared by mixing the following materials together in the proportions by weight indicated below:

N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide monoethanolamine salt of 1,1-dioxide (6-methyl-2-pyridyl) ....... .............. 23.92

Microcrystalline cellulose ....... 311.03 5 Modified swelling starch, N.F ..... 84.00

Magnesium stearate ............ 0.945

Sodium lauryl sulfate .......... 0.105

After the dried composition has been properly mixed, tablets are punched from the resulting mixture, each tablet having dimensions such that it contains 20 mg of the active ingredient. Other tablets are also prepared in a similar manner, containing 5, 10 and 50 mg of the active ingredient, respectively, by simply using the appropriate amount of tablet mixture in each case.

Example 9

A formulation for tablets is prepared by mixing the following materials together in the weight proportions given below: 20 N- (6-methyl-2-pyridyl) -2-methyl-4 monoethanolamine salt -hydroxy-2H-1,2-benzothiazine-3-carboxamide .......... 23.69

Dicalcium phosphate, anhydrous ... 113.37

Poly vinylpyrrolidone ............. 50.00 25 Modified swelling starch, N.F ..... 10.00 * Magnesium stearate ............ 2.65

Sodium lauryl sulfate .......... 0.294

After the dried solution has been properly mixed, punch tablets are formed from the resulting mixture, each tablet having dimensions such that it contains 20 mg of the active ingredient. Other tablets are also similarly prepared, containing 5, 10 and 50 mg of the active ingredient, respectively, simply using the appropriate amount of the tablet mixture in each case.

Claims (6)

1. A non-hygroscopic water-soluble crystalline organic amine salt, characterized in that it is chosen from the group comprising the ethylene diamine, monoethanolamine and diethanolamine salts of 1,1-N-dioxide (6-methyl-2- pyridyl) -2-methyl-4-hydroxy-2H ~ 1,2-benzothiazine-3-carboxamide. 2. Compound according to claim 1, 4 characterized in that it is an ethylenediamine salt. * 10 3. Compound according to claim 1, characterized in that it is a monoethanolamine salt. 4. Compound according to claim 1, characterized in that it is a diethanolamine salt. 5. Pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier and an effective anti-arthritic amount of a compound according to claim 1. 6. Composition according to claim 5, characterized in that the compound is the diethanolamine salt of N- {6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,1-dioxide -1,2-benzothiazine-3-carboxamide. On