CS243495B2 - Method of benzothiazindioxide's crystalline non-hydroscopic water-soluble salt preparation - 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

More specifically, it relates to certain novel crystalline, non-hygroscopic, water-soluble salts of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine. -3-carboxamide-1,1-dioxydes, which are particularly valuable in terms of their unique combination of chemotherapeutic and physical properties ·

Various attempts have been made in the past to obtain new, better anti-inflammatory agents. Most often, these attempts involve the synthesis and testing of various steroid compounds such as corticoeteroids or non-steroidal compounds of acidic nature such as phenylbutazone, indomethaein and the like, including novel agents known as piroxicam. The latter is a member of the group of anti-inflammatory 4-hydroxy-2H-1,2-benzothiazine-3-carboxide-1,1-dioxides described in U.S. Pat. No. 3,591,584. However, there is a continuing need for anti-arthritic agents in the ongoing search for better anti-inflammatory agents. high water solubility and other desirable properties, particularly for oral, topical or parenteral administration. Published European Patent Application, 66,459 A, published December 6, 1982, claims the othylondianonium, monoethanol-ammonium and diethanolammonium salts of piroxicam.

It has been found and object of the present invention that certain novel crystalline footgroscopic water-soluble basic salts of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiszine-3-kerboxeaid -1,1-dioxide are useful as non-steroidal theropeutic agents for the alleviation of painful inflammatory conditions, such as those caused by, for example, rheumatoid erthritis. The novel salts of the present invention are selected from the group consisting of ethylenediammonium, monoethanolammonium, and diethanolammonium salts of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-12-benzothiazine-3-carboxamide-1,1-dioxide. which is an acidic compound of the general formula

OH

Wherein R is 6-methyl-2-pyridyl.

The novel ethylenediammonium, monoethanolammonium and diethanolammonium salts of the invention are crystalline, footgroscopic, rapidly soluble solids with high water solubility, which additionally exhibit excellent chemical and physical stability. These compounds are particularly valuable as non-steroidal therapeutic agents for the treatment of painful inflammatory conditions, particularly those caused by rheumatic arthritis, and are particularly useful for the preparation of various pharmaceutical dosage forms including those used for oral, topical or parenteral administration. According to the present invention, the most preferred salt is the diethanolammonium salt.

In the process of adding new salts according to the invention, N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazide-3-knobexanide-1,1-dioxide is contacted with at least one molar equivalent of an organic amine 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 and the like. or _a halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride and s-tetrachloroethane, and the like. Generally, the reaction is carried out at a temperature in the range of about 20 ° C to about 100 ° C for about 15 minutes to one hour. Upon completion of the reaction, the desired product is readily isolated by conventional means, for example by first evaporating the solvent from the reaction mixture and then grinding the resulting solid residue or crude concentrate in a suitable solvent system such as ethyl acetate / chloroform. in situ salt solutions by adjusting the concentration of the solution.

The starting materials required for the preparation of the novel salts of the invention are all known. For example, N- (6-methyl-2-pyridyl) -2-methyl-44-hydroxy-2H-1,2-thiophenothiamine-3-oxylbenzamide is described in U.S. Pat. No. 3,591,584, as well as in Lombaadino, ie, and in the Journal of Meeicinal Chembstry Vol. 16, p. 493 (1973), including syntheses from readily available organic mitts. _y Anbnické bath used to prepare the novel amine salts of this invention are all commercially available maatrrály.

N- (6зbethyl-2зpyrCiyl323-bet ^ yl343.yi _<rroэyf · 2H-1,2-benzothiazin33 karboaamid-1, 1 · -ííoxííu the present invention is readily upi ^ i ^^^ on September thcrapeutCcké pouužtí as agents against For example, N - (6-chloro-2-propyl) -benzyl-4-hydroxy-1,2,3-thiazine-3-carboxylate-1,1-lithium diethanolammonium salt, a typical polle agent of the present invention, exhibits anti-inflammatory activity in a standard test. carragenine-induced swelling of the rat paw (described by CA Winter et al., Proc. Soc. Exp. Biol. Med. Vol. m, p. 544 (1962)), which was found to cause significant inhalation swelling at a dose of 33 mg / kg The oral salts of benzoethane-dCox described herein have advantages.

Nappíklad N- (6-betth ^'r L2 pyriiyl) -2mcthyl 4-l¾ilroxyз2H-1-2зlenzothitzin 3зkarloxtbid 1,1-ííoxíí Solem itself is poorly soluble in water and iCcthailLtltboniová salt of N- (6-beenyll2-ppllLdl It is readily soluble in the water and is therefore more readily absorbed in the bloodstream after oral administration than the corresponding less soluble calcium salt (or anhydrous calcium salt). U.S. Patent No. 3,591,584). Further, this salt of the invention provides clear, stable solutions in water even at a relatively high concentration (10 mgml). The other salts of the invention give similar results. This is indeed a surprising fact, since the triethanothmonium salt of 4- (6-chloro-1-carboxymethyl-2-carboxylic acid-2-carboxylic acid-2-carboxylic acid). -1.1 "IioxCiu is hygroscopic and difficult to isolate, and the simple ammonium salt is highly volatile in vacuum drying. The corresponding sodium salt is also hygroscopic and poorly soluble in water. On the other hand, the novel salts of the invention are crystalline non-hygroscopic solids, which are therefore easily isolated in highly pure form. These properties have further facilitated the processing of these salts in bulk into pharmaceutical dosage forms which are particularly suitable for oral, topical or parontoral applications and the like. Furthermore, the relatively short plasma half-life as compared to the corresponding 63-methylanalog (pCroxicam) provides a further advantage in the treatment of human onemoonines such as pain and the like.

The disclosed salts can be administered as antiarthritic agents by any of the above methods. Generally, these salts are administered in doses ranging from about 5.0 mg to about 1000 mg per day, although variations are possible, in weight and condition of the patient and method of administration.

Typically, a dosage level of from about 0.08 mg to about 16 mg / kg body weight per day is preferred, and variations in the patient's sensitivity to the drug are possible. as well as the nt type of pharmaceutical preparation and the nt time intervals at which the drug is administered. In some cases, a dosage level lower than the lower limit of the range may be sufficient, while in other cases higher doses may be mixed in several divided doses administered throughout the day.

The salts according to the invention can be applied either by self-administration or in admixture. with pharmaceutically acceptable carriers by the various routes set forth above, within a wide range of dosage forms, for example a farm and internally acceptable internal carriers in the form of tablets, capsules, soft or hard pills, lozenges, powders, sprays, jams, ointments, suppositories, jellies, pastes, aqueous solutions and euapeeinl solutions, syrups, and the like. Nothing includes solid diluents or diluents, sterile aqueous media and various non-toxic organic solvents and the like. In addition, the oral pharmaceutical salt may be suitably sweetened with flavor. Lunch salts of the invention are in such dosage forms at concentrations of from about 0.5% to about 90% by weight.

For oral administration, the tablets contain excipients such as icrocxratal cellulose, sodium citrate, calcium carbonate, calcium phosphate and glycine and can be taken together with various disintegrating agents such as starch and preferably cucumbers, potato or tapioca starch, alginic acid and certain complex silicates together with granulating binders such as polyvinylpyrrolidene, gelatin and acacia. Furthermore, mounts such as magnesium stearate, sodium lauryl sodium phosphate are often useful for tabletting purposes. Likewise, solid compositions of a type similar to those for hard gelatine capsules may be used, with the preferred mottrials being lactoaccharides or milk cucr as well as high molecular weight polyethylene glycols. When aqueous solutions or suspensions and / or infusions are used for applications, the active ingredient may be combined with various sweetening or flavoring agents, coloring agents and, optionally, emulsifying and / or suspending agents, as well as diluents such as water, ethanol, pyrplexyl glycol. , glycerin and their various ^ иЬ ^ все.

For applications, solutions of these can be used with amines in active or peanut oil or in aqueous glycol or aqueous ethanol, as well as sterile aqueous solutions in water. The aqueous solutions must be suitably powdered (pH 8) and the liquid diluents first rendered into an aqueous solution. These aqueous solutions are suitable for injection. The oily solutions are suitable for intensive, intra-articular, and non-articular purposes. Likewise, the aforementioned amine addition salts can be applied topically in the treatment of skin or eye conditions. For this purpose, creams, jellies, pastes, lotions, solutions and the like prepared in accordance with pharmaceutical practice are used. .

The anti-inflammatory effect of the compounds of the present invention has been demonstrated by the above-mentioned standard test utilizing the tricotin-induced swelling of rat paws. In this test, the anti-inflammatory effect is determined as a percentage of the swelling produced on the hindpaw of male white rats. ) ^ 1 150 190 g) subcutaneous injection ctrrageeiiiž ·

The suspension is administered as a 1% aqueous suspension (0.05 ml) one hour after oral administration of the drug, which is applied as an aqueous solution. Edema formation is then countered by measuring paw volume at baseline and three hours after injection. Ctrrtgekiiiž · Increasing edema three hours after carrageenin injection is an individual response. Compounds are active if the difference in response from drug-treated animals (six rats per group) and the control group receiving vehicle only is significant compared to the results obtained with the standard compound tcetylstlicylic acid at an oral dose of 100 mg / kg or phenylbuaalon in dose 33 µ / kg.

He said 1

To a well-stirred suspension of 3.0 g (0.008% 69 N- (6-alkyl-2-lyyl) -2-methyl-4-yl ₎ oxy-2H-1,2-methyl-3-pyridyl-1,1-dicoxide in 450 ml of water was added 560 mg (0.009 13 mol) of the mixture, and the resulting mixture was heated in a steam bath (stirred vigorously) for about five minutes. The green-yellow solution thus obtained is filtered to remove small amounts of water-insoluble matter. Concentration of the filtrate in vacuo afforded a gummy solid. Rozrn0lněním this Osato ^^ mm0e in 300 ml of chloroform and ethyl ± ^ o ^ INITIATIVE ^(2: 3 ^ emuvě) and then agitated for 16-day ^p din ^ s heartbeat that room (2 ⁰ ° C) under an atmosphere of dry nitrogen yielded The solid product was then filtered and dried under high vacuum over phosphorus pentoxide to a constant weight. To give 2.96 g (84%) of pure moniothanolamonio ▼ Star SOH N- (б mekluУ-2-lyriíyl) -2-OktUyl-4Uydrl: χг-2H-1,2-ijnzojhUazii ^{KTR-3-d i} jχamid l ^ -doxita m. ^p. 193-1 ⁹⁵ Net pmdUkt to ^d, but reinforces Charact infra ^- venýta absorption spectrum and analysis.

Calcd for C 18 H 18 N 4 O 4 S: 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 (0.008 69 mol) of N (6-methyl-2-pyridyl) -2-methyl-4-pyridyl-2H-1,2-benzothiazine-3-carboxBBid-1,1-dioxide in 450 ml 960 mg (0.009 6 mol) of diethanolemine was added to the water, and the resulting mixture was heated on a steam bath for 5 minutes. The yellow aqueous solution thus obtained was filtered to remove insoluble materials and the filtrate was concentrated in vacuo to give a yellow viscous oil. Treatment of this matariálu with 300 ml of chloroform and ethyl acetate (2: 3 by volume), and 16 hours stirring at room temperature ^{(2 0} ° ^C) under an even choke zi ^ SFEA yellow ^k r ^y st ^ali ^ (^ ^k ^ and the precipitate Drying under high vacuum over an axis of oxygen to give a constant crystalline mono-ammonium salt yielded 2.73 g (70%) of the pure crystalline diethrone ammonium salt of N '(6-oethanol). 2-'Plridll) -2 'mettyl "4-hydroxl-2H-1,2' eβnzsthiazinзЗírabOoχrii - 1,1-dioxi.au, mp 166-1 ⁶ 7 ° C. the pure product was further charaktarisuje J-absorbent nfrečerentým speetren and elemental analysis.

Analysis; calculated for ^C 20 ^H 26 ^N 4 ° 6 ^{N S} : 53.33 H: 5.82% N: 12.44% found. C: 33.00; H: 5.31% N; 12.41 «·

Example 3

To 3.0 g (0.008 69 ad) of N- (ω-ethyl-2-yl) -pentyl) -2-methyl-4-pyridyl-2H-1,2-benzothiazine-3-carboxamide; of xroid-1,1-dioxide in 450 ml of water was added with stirring 550 mg (0.009 13) of ethylenediamine (0.61 ml) and the resulting mixture was heated with vigorous stirring for 5 minutes. The hot aqueous solution thus obtained is then filtered to give a small amount of insoluble matter and subsequent concentration of the obtained filtrate in vacuo to give a gummy green-yellow oily residue. Rosmrlnёnír this material in 300 ml of ethyl acetate chloroforau ^(3: 2 by ^{b Jem)} and - následijcím stirring at, Melting místněji ⁽²⁰ ° ^C) overnight ^{(1 6} hourly ^ under dry nitrogen 2íská yellow solid precipitate which ae octffltruje Dry under high vacuum over phosphorus pentoxide to constant weight to give 2.88 g (82%) of pure crystalline ethylenediamine salt of N - [(6-methyl-1,22] plidyl) -2-methyl-4-methylpyrrolidine]. @ 1 H-enzothiazine @ 4 -tartoximide-1, m.p. 185 DEG ^- 187 DEG C. The pure product was further characterized by infectious absorption spectra and elemental analysis.

Analysis; calculated for C C ^ ^ ^ ^N ^O ^S: C; H, 53.33; 5.75 »N: 17.27% found; C; % H, 5.65;% N, 16.92.

Example 4

A solid pharmaceutical composition is prepared by drying the following ingredients in the above ratios:

ethylendamoniové salt of N- ^(6-2 ieSihl- 2pylidsl) -2 β1 · ~ ^ ^] ^ 3 ^ 1-4-Β ^ ^{<^ ι} ^ <^ 2Χ ^ - ^ 1 ^ Ϊ ^ - _f 1 2 benzothirzin -3 ' ^k arbsxθid-11,11-Oxo5,88

mcrocrystalline customs duty 34,00 maize starch, U. S. P.9,08 magnesium stearate1,04

After thorough mixing of the solids, the mixture is tabletted so that each tablet contains 5 mg of active ingredient. The other tablets are also prepared in a net manner from the recipients of the respective mixture. and contain 10, 25 and. 50 mg of active ingredient.

Example 5

A solid pharmaceutical composition is prepared by mixing the following substances in the given weight ratios:

б Monoethanolammonium salt of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothlazine-3-carboxemld-1,1-dioxide 59,21 calcium phosphate anhydrous 230,10 maize starch, USP 32.50 sodium lauryl sulfate 0.32 magnesium stearate 2.87

The thus prepared dry solid mixture is then mixed thoroughly to give a powdery product perfectly uniform in all directions. It is then filled with hard gelatin capsules (No. 2) so that each capsule contains 50 mg of the active ingredient.

Example 6

Aqueous propylene glycol solution containing N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxide diethylammonium salt is prepared by dissolving this compound in a mixture propylene glycol-water (1: 4 by weight) containing 1% by weight sodium phosphate and adjusted to pH 8.0 The amount of active compound used to prepare the solution is such that the final solution contains 5 mg of active ingredient per ml of solution. The as solution is then sterilized by filtration through a cellulose membrane having a pore size of 0.2 <µm. The sterile aqueous propylene glycol solution thus obtained is suitable for intrsmuscular administration to animals.

Example 7

An aqueous injectable solution is prepared by first thoroughly mixing one part by weight of the monoethanolammonium salt of N- (6-methyl-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1. 1-dioxide β 2.5 parts by weight · Na ₂ HP0 ^ in a mortar · The dry mixture thus obtained is then sterilized with ethylene oxide and then aseptics are placed in vials and sealed · For intravenous application and sufficient distilled water and each vial are added to be completed before use so that the solution contains 10 mg of active ingredient per ml of injectable solution ·

Example 8

The mixture for tabletting ae is prepared by mixing the following substances in weight ratios:

monoethanolammonium salt of N- (6-methyl-2-pyrldyl) -2-

-methyl-4-hydroxy-2H-1,2-benzothlazine-3-carboxamide-1,1-dioxide23,92 microcrystalline cellulose 311.03 modified gelatin starch, N. F.84,00 magnesium stearate0,945 sodium lauryl sulphate0,105

After complete mixing, the tablets are compressed from the mixture obtained so that each tablet contains 20 mg of active ingredient. Other tablets are also prepared in a similar manner and contain 5, 10 and 50 mg of active ingredient.

Example 9

The tabletting tablet is prepared by mixing the following substances in weight ratios:

monoethanolammonium salt of N- (6-methyl-2-pyridyl) -2-, methyl-4-hydroxy-2H-1,2-benzothiazin-3-carboxamide-1,1-dioxide calcium phosphate anhydrous

23.69

113,37 c Λ polyrinylpyrrolidone modified gelatin starch N.F. magnesium magnesium stearate sodium lauryl sulphate

50.00

10.00

2.65

0.294

After complete mixing and dry mixture is compressed to tablets containing 20 mg of active ingredient. Other tablets are prepared from the corresponding excipients in an analogous manner and contain 5, 10 and 50 mg of the active ingredient.

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of a crystalline, non-hygroscopic, water-soluble salt of benzothiazinium dioxide selected from the group consisting of ethylenediamine, mono-thiazol-ammonium and ethanilimmonium salt of N- (6-methil-2-pyridyl) -2-methyl-4-hydroxy-2H-1,2- 1- (6-Methyl-2-pyridyl) 22-methyl-4-pyridyl-2H-1,2-benzylthiazine; The 3-carboxylic acid-1-dloxide is reacted with at least an equivalent amount of ethylenediamine, monnothanolamine or diethanolamine, based on N-6-methyl-4'-pyrrinyl) 22-methyl-4-hydroxy-2H1,2-bezzothihziz-3-ol. 10-1,1- ^^ ^ ^ 31 wherein the reaction is carried out in a polar protic solvent or in a halogenated hydrocarbon to dissolve at temperatures ranging from 2 ° ^{0-1 0C.} 2. A process according to claim 1, wherein the solvent is water. 3. The process according to claim 1, wherein the solvent is meethrlene chloride.