JPS6350355B2 - - Google Patents

Description

[Detailed description of the invention]

This invention relates to new and useful benzothiazine dioxide salts. More particularly, the invention particularly values N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2- for its unique combination of chemotherapeutic and physical properties. The present invention relates to certain novel crystalline, non-hygroscopic and water-soluble salts of benzothiazine-3-carboxamide 1,1-dioxide. In the past, various attempts have been made to obtain new and better anti-inflammatory agents. In most cases, these efforts have been the synthesis and testing of various steroidal compounds such as acidic corticosteroids or nonsteroidal substances such as phenylbutazone, indomethacin, etc. (including a new drug known as piroxicam). These latter compounds are the anti-inflammatory agent 4-hydroxy-2H-1,2 described and claimed in U.S. Pat. No. 3,591,584.
-benzothiazine-3-carboxamide 1,1-
It is one of the dioxides. However, as the development for improved anti-inflammatory agents continues, there is a clear need for anti-arthritic agents that have high water solubility and other properties desirable for oral, topical or parenteral administration. According to the present invention, certain novel crystalline non-hygroscopic water-soluble N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide Base salts are useful as non-steroidal therapeutic agents for alleviating painful inflammation such as that caused by rheumatoid arthritis. The novel salt of the present invention is an acidic compound of the formula N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide: (wherein R is 2-pyridyl) selected from the group consisting of ethylenediamine, monoethanolamine and diethanolamine salts. The novel ethylenediamine, monoethanolamine and diethanolamine salts of the present invention are crystalline, non-hygroscopic, rapidly dissolving solids with high water solubility, and have excellent chemical and physical stability properties. It is therefore of particular value as a nonsteroidal therapeutic agent for the treatment of painful inflammatory conditions, especially those caused by rheumatoid arthritis, and is intended for oral, topical or parenteral administration. It is used in various dosage forms. The above monoethanolamine salts are preferred salts of this invention. According to the method used to prepare the novel salts of the invention, N-(2-pyridyl)-2-methyl-4
-Hydroxy-2H-1,2-benzothiazine-
The 3-carboxamide 1,1-dioxide is contacted with at least an equimolar amount of an organic amine base selected from the group consisting of ethylenediamine, monoethanolamine and diethanolamine. This reaction is usually carried out in polar solvents such as water or lower alkanols such as methanol, ethanol or isopropanol, or in halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, ethylene dichloride and S-tetrachloroethane. It takes place inside. Generally, this reaction occurs between about 20°C and about 100°C.
It is carried out for about 30 minutes at a temperature range of ℃. Upon completion of this reaction, the desired salt product is easily isolated by conventional methods. For example, the reaction mixture is first evaporated of the solvent and the resulting solid residue or crude concentrated product is isolated by trituration with a suitable solvent system such as ethyl acetate and chloroform. As another method, it is also possible to eliminate the need for isolation by using an aqueous solution of the salt produced in the reaction site by appropriately adjusting the concentration in the solution. The starting compounds required to prepare the novel salts of this invention are all known compounds. For example, N-
(2-pyridyl)-2-methyl-4-hydroxy-
2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (piroxicam) is available from JG
Lombardino U.S. Patent No. 3591584 and J.G.
Lombardino et al., Journal of Medicinal
Described in Chemistry Vol.16, p.493 (1973),
A total synthesis from readily available organic compounds is described. All amine bases used to prepare the novel amine addition salts of this invention are commercially available compounds. N-(2-pyridyl)-2-methyl-4 of the present invention
-Hydroxy-2H-1,2-benzothiazine-
3-Carboxamide 1,1-dioxide salts are readily available for therapeutic use as anti-arthritic agents. For example, N
The monoethanolamine salt of -(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide exhibits anti-inflammatory activity in the standard carrageenan-induced rat paw edema test. [CA Winter et al.,
Proc.Soc.Exp.Biol.Med., Vol.111, p.544
(1962)]. When administered orally, it was found that edema was substantially suppressed at a dose of 33 mg/Kg. The benzothiazine dioxide salts described herein exhibit additional advantages. For example, even though N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (piroxicam) itself is only very slightly soluble in water. At least, the monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide is easily and quickly soluble (i.e. (dissolves instantaneously) and the corresponding less soluble calcium or anhydrous sodium salts of this compound (both of which are covered by U.S. Pat.
No. 3,591,584) is absorbed more rapidly into the bloodstream upon oral administration. Therefore,
This particular salt is present in very high concentrations (>100mg/ml)
The result is a conveniently formulated, stable aqueous solution that is even transparent. Other salts of this invention produce similar results. This is N-(2-pyridyl)-2-methyl-4
-Hydroxy-2H-1,2-benzothiazine-
Given that the tromethamine salt of 3-carboxamide 1,1-dioxide and the corresponding triethanolamine salt are both only sparingly water soluble, the simple ammonium salt is highly unstable when dried under vacuum. The case is truly amazing. Furthermore, the novel compounds of the present invention are crystalline, non-hygroscopic solids and are therefore easily isolated in highly pure form. These particular properties facilitate bulk processing of the salts into final pharmaceutical dosage forms suitable for use either for oral, topical or parenteral administration. These salts can be administered as anti-arthritic by any of the routes mentioned above. Generally, these salts are about 5.0
mg to about 1000 mg/day, but will necessarily vary depending on the weight and condition of the patient being treated and the route of administration chosen. Doses from about 0.08 mg to about 16 mg/Kg (body weight) per day are usually preferred, although variations may occur depending on the individual's response to the drug and the type of pharmaceutical formulation and time interval of administration. Dew. In some cases, dosages below the lower limit of the above range may be appropriate, while in other cases higher dosages may be divided into several smaller doses administered during the day. The salts of this invention can be administered by the various routes mentioned above, alone or in combination with pharmaceutical carriers, in a wide variety of dosage forms. i.e. tablets, capsules, soft and hard lozenges, troches, hard candies, powders, sprays, creams, ointments, suppositories, jewelries, pastes, lotions, ointments, aqueous solutions and suspensions in combination with various pharmaceutical inert carriers. It can be made into injectable solutions, elixirs, syrups, etc. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. Additionally, oral pharmaceutical compositions can be suitably sweetened or flavored. Generally, the salts of this invention are present in a range of about 0.5% to about 90% by weight. For oral administration, various adjuvants such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, starch, preferably corn, potato or tapioca starch, alginic acid and certain silicic acids. Tablets containing disintegrants such as salt complexes and granulating binders such as polyvinylpyrrolidone, gelatin and gum acacia can be used. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are very useful in tabletting. Solid compositions of a similar type can also be used as fillers in hard gelatin capsules. Preferred materials are lactose and 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, colorants or dyes, and, if desired, emulsifying and/or suspending agents. It can be mixed at any time with diluents such as water, ethanol, propylene glycol, glycerin, and various similar combinations thereof. For parenteral administration, solutions of these amine salts in sesame oil, peanut oil or aqueous solutions of propylene glycol or ethanol, and sterile aqueous solutions in distilled water can be used.
These aqueous solutions are suitably buffered (PH>8),
The liquid diluent is first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-arterial, intramuscular and subcutaneous injection. Additionally, the amine addition salts can be administered topically in creams, pastes, pastes, ointments, solutions, etc., in accordance with standard pharmaceutical application procedures, to treat inflammatory conditions of the skin and eyes. The anti-inflammatory activity of the compounds of the invention is evaluated by the standard carrageenin-induced rat paw edema test described above. In this test, anti-inflammatory activity is measured as the % inhibition of edema in response to carrageenan injection subcutaneously into the hind sole of male albino rats (150-190 g body weight). One hour after oral administration of the compounds of the invention, carrageenan is injected as a 1% aqueous solution (0.05 ml). The compounds of the invention are usually administered in the form of an aqueous solution. Edema formation is measured by measuring the initial volume of the paw injected with carrageenan and the volume of the paw 3 hours after carrageenin injection. The increase in volume 3 hours after carrageenan injection indicates an individual response. The difference in response between drug-treated animals (6 rats per group) and a control group that received vehicle only was
A drug (compound) is determined to be active if it is significantly compared to the results obtained when administered orally with a standard compound such as Kg or phenylbudazone 33 mg/Kg. Example 1 In a 250 ml Erlenmeyer flask equipped with a magnetic stirrer, 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 were charged. Start stirring and slowly add 180 mg (0.003
mol) of ethylenediamine (0.2 ml) was added.
The reaction mixture thus obtained was then heated on a steam bath for about 3 minutes to obtain a yellow solution. The solution was evaporated to near dryness under reduced pressure to give a yellow gum, which was then combined with 200 ml of chloroform and
The mixture was triturated with 30 ml of ethyl acetate by stirring for 1 hour. The resulting pale yellow solid was then collected by suction filtration and washed on the filter funnel with fresh ethyl acetate. In this way, N-(2-pyridyl)-2 with a melting point of 151-154°C was finally obtained.
-Methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide A pure ethylenediamine salt of 1,1-dioxide was obtained. The pure product was further identified by infrared absorption spectroscopy and elemental analysis. Elemental analysis value: Calculated value as C ₁₅ H ₁₃ N ₃ O ₄ S・C ₂ H ₈ N ₂ :
C, 52.16; H, 5.40; N, 17.89 Working values: C, 51.81; H, 5.41; N, 17.77 Example 2 2.0 g (0.00604 mol) of N-(2-
pyridyl)-2-methyl-4-hydroxy-2H-
Adding 388 mg (0.00634 mol) of 2-aminoethanol (0.383 ml) to a suspension of 1,2-benzothiazine-3-carboxamide 1,1-dioxide,
The resulting mixture was heated on a steam bath for about 3 minutes. The resulting yellow solution was then filtered to remove very small amounts of water insoluble material, and the resulting liquid was concentrated under vacuum to yield a yellow oil as a residual liquid. This was triturated with 200 ml of a mixture of ethyl acetate and chloroform (3:2 by volume) and stirred at room temperature (25°C) overnight (16 hours) under a dry nitrogen atmosphere to obtain a solid precipitate, which was It was recovered by suction. The recovered solid was thoroughly washed with ethyl acetate, dried under vacuum to a constant weight, and finally reached a melting point of 174-
N-(2-pyridyl)-2-methyl-4- at 177℃
Hydroxy-2H-1,2-benzothiazine-3
-2.07 g (87%) of pure monoethanolamine salt of carboxamide 1,1-dioxide was obtained. The pure product was further identified by infrared absorption spectra and elemental analysis. Elemental analysis value: as C ₁₇ H ₂₀ N ₄ O ₅ S Calculated value: C, 52.03; H, 5.14; N, 14.28 Actual value: C, 51.72; H, 5.14; N, 13.93 Example 3 Magnetic stirrer, dropping funnel (250 ml) and a 2 liter, 3-neck, round-bottom reaction flask equipped with a thermometer.
55.0g dissolved in 660ml methylene chloride
(0.166 mol) of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide was charged. N-(2-pyridyl)-2-methyl-4-hydroxy-2H- as seed crystals
Monoethanolamine salt of 1,2-benzothiazine-3-carboxamide 1,1-dioxide
This solution containing as much as 0.1 g was prepared by first dissolving the salt in 610 ml of methylene chloride in an Erlenmeyer flask at 25° C. with gentle magnetic stirring. The solution was transferred to the reaction flask described above using an additional 50 ml of methylene chloride as a wash. At this point the Erlenmeyer flask and its contents were heated to 27°C by a steam bath and the whole system was constantly and vigorously shaken while 10.7 g (0.175 g) dissolved in 110 ml of fresh methylene chloride mol) of ethanolamine was slowly added over 50 minutes. Upon completion of this step, the reacted reaction mixture was stirred (ie, granulated) at 27° C. for 1 hour and filtered through a Buchner funnel to obtain the crystalline salt. This product is heated in a vacuum oven.
Dry to constant weight at 35°C, and in this way 63.1 g of N-(2-pyridyl)-2-methyl-4
-Hydroxy-2H-1,2-benzothiazine-
A pure monoethanolamine salt of 3-carboxamide 1,1-dioxide (melting point 171 DEG -174 DEG C.) was obtained. The net yield of pure product was 63.0 g (96.8% yield). This purified product was further determined by nuclear magnetic resonance spectroscopy and elemental analysis and was identical in all respects to the product of Example 2. Elemental analysis value: C ₁₇ H ₂₀ N ₄ O ₅ S Calculated value: C, 52.03; H, 5.14; N, 14.28 Actual value: C, 52.09; H, 5.15; N, 14.30 Example 4 2.0 g in 300 ml water ( 0.00604 mol) of N-(2-
pyridyl)-2-methyl-4-hydroxy-2H-
1,2-Benzothiazine-3-carboxamide 1,1-dioxide 687 mg (0.00634 mol) of diethanolamine was added to the suspension and the resulting mixture was heated on a steam bath for 3 minutes. The yellow solution thus obtained was filtered to yield a very small amount of white solid, and the resulting liquid was concentrated in vacuo to yield a yellow oil as a residual liquid. This was treated with a solvent system of 200 ml of ethyl acetate and chloroform (3:2 by volume) and stirred overnight (18 hours) at room temperature (~25°C) under a dry nitrogen atmosphere to give a yellow gum. . This was recovered by solvent decantation. Then this gum-like substance
The mixture was triturated with 100 ml of chloroform, heated on a steam bath for 2 minutes (just until reflux), and thoroughly stirred to induce crystallization. The mixture was then cooled to room temperature and stirred at that temperature for 2.5 hours under an atmosphere of dry nitrogen. The solid crystals were taken out by suction filtration, washed with fresh chloroform, dried under vacuum until the weight remained constant, and finally dried with N2 with a melting point of 143-146°C.
2.11 g (80% yield) of pure diethanolamine salt of -(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide were obtained. The pure product was further identified by infrared absorption spectra and elemental analysis. Elemental analysis value: C ₁₉ H ₂₄ N ₄ O ₆ S Calculated value: C, 52.28; H, 5.54; N, 12.84 Actual value: C, 52.04; H, 5.40; N, 12.55 Comparative example Proxicam monoethanolamine salts, diethanolamine salts and ethylenediamine salts and other salts, i.e. sodium, calcium, N-
The physical properties of methylglucamine, tromethamine, triethanolamine, lysine, and arginine salts are compared and summarized in the table below.

[Table] From the above results, it can be concluded that only monoethanolamine salt, diethanolamine salt and ethylenediamine salt have the desired combination of crystallinity, solubility and non-hygroscopicity. Other salts investigated were
all have at least one of these important characteristics
It is defective in that it lacks a species, often two or three species. For example, the sodium, calcium, tromethamine and triethanolamine salts do not exhibit the required solubility and are therefore not worthy of use in drug dosage forms capable of rapidly releasing significant piroxicam activity. N-methyl-D-glucamine, lysine and arginine salts, which do have a solubility suitable for this purpose, are rendered unacceptable by being amorphous and hygroscopic. Furthermore, monoethanolamine salt, diethanolamine salt and ethylenediamine salt were obtained as anhydrous compounds. On the other hand, triethanolamine salt is 1
It was obtained as a hydrate, and sodium salt, calcium salt, N-methyl-D-glucamine salt, lysine salt and arginine salt were also obtained as hydrate or solvate. This is a significant disadvantage since water of crystallization or other incidental solvents exhibit unfavorable interactions with excipients and generally reduce the stability of solid formulations of salts of this type. Monoethanolamine salts, diethanolamine salts and ethylenediamine salts do not exhibit this drawback. Additionally, the piroxicam salts were tested for specific dissolution rate and dissolution rate, and the results are shown in the following table:

[Table] As shown by the above data, the monoethanolamine salt, diethanolamine salt and ethylenediamine salt of piroxicam of the present invention have a unique combination of physical properties such as crystallinity, high solubility and rapid dissolution, and non-hygroscopicity. It is clear that the prior art does not suggest any salt of piroxicam that has these properties. Example 5 A dry solid pharmaceutical composition was prepared by mixing together the following materials in the following weight proportions: N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2- Ethylenediamine salt of benzothiazine-3-carboxamide 1,1-dioxide... 5.88 Microcrystalline cellulose... 34.00 Corn starch (United States Pharmacopoeia) 9.08 Magnesium stearate... 1.04 After thorough mixing of this dry composition, the obtained The mixture was compressed into tablets sized to contain 5 mg of active ingredient. Other tablets containing 10 mg, 25 mg and 50 mg of active ingredient each can be similarly prepared using only appropriate amounts of the above tablet mixture. Example 6 A dry solid pharmaceutical composition was prepared by mixing together the following materials in the following weight proportions: N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2- Monoethanolamine salt of benzothiazine-3-carboxamide 1,1-dioxide 59.21 Anhydrous dicalcium phosphate 230.10 Corn starch (United States Pharmacopoeia) 32.50 Sodium lauryl sulfate 0.32 Magnesium stearate 2.87 The dry solid mixture thus obtained It was then thoroughly agitated to give a completely homogeneous powder product in all respects. A sufficient amount of the above pharmaceutical composition was used to prepare hard gelatin (No. 2) capsules containing 50 mg of active ingredient per capsule. Example 7 The diethanol salt of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide was prepared containing 1% by weight of trisodium phosphate. PH
An aqueous propylene glycol solution of the salt was made by dissolving it in a 1:4 weight ratio of propylene glycol and water adjusted to 8.0%.
The amount of compound used was 5 per ml of the solution obtained.
mg of active ingredient. The solution was then sterilized by passing through a cellulose membrane with pores of 0.2 μm size. The sterile aqueous propylene glycol solution thus obtained is suitable for intramuscular injection into animals. Example 8 1 part by weight of monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 2.5 parts by weight of disodium phosphate. and by intimately mixing them in a mortar and pestle. The ground dry mixture was then sterilized with ethylene oxide and then sealed in vials under sterile conditions. For intravenous injection purposes, a sufficient amount of distilled water was added to each filled vial before use to obtain a final solution containing 10 mg of active ingredient per ml of injection solution. Example 9 A tablet formulation was made by mixing the following ingredients in the following weight proportions. Monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide... 23.92 Microcrystalline cellulose... 311.03 Magnesium stearate... ... 0.945 Sodium Lauryl Sulfate ... 0.105 After thoroughly mixing this dry composition, the resulting mixture was compressed into tablets of a size in which each tablet contained 20 mg of active ingredient. 5, 10 and 5mg each by just using the appropriate amount of the above tablet mixture.
Other tablets containing the active ingredient were prepared. Example 10 A tablet formulation was prepared by mixing the following ingredients in the following proportions. Monoethanolamine salt of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide... 23.69 Anhydrous dicalcium phosphate... 113.37 Polyvinyl Pyrrolidone... 50.00 Modified pre-gelatinized starch (NF)... 10.00 Magnesium stearate... 2.65 Sodium lauryl sulfate... 0.294 After thorough mixing of the dry composition, each tablet is 20 mg from the resulting mixture. Tablets of a size containing the active ingredient were compressed. Other tablets containing 5, 10 and 50 mg of active ingredient each were prepared in a similar manner using only the appropriate amount of the tablet mixture.

Claims (1)

[Scope of Claims] 1 A water-soluble base salt of N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (provided that the base is ethylenediamine , monoethanolamine and diethanolamine). 2. The compound according to claim 1, which is an ethylenediamine salt. 3. The compound according to claim 1, which is a monoethanolamine salt. 4. The compound according to claim 1, which is a diethanolamine salt. 5 N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide Water-soluble base salt of 1,1-dioxide (provided that the base is ethylenediamine, monoethanolamine and diethanolamine) an anti-arthritic agent selected from the group consisting of: 6 N-(2-pyridyl)-2-methyl-4-hydroxy-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide monoethanolamine salt according to claim 5. Arthritis drugs.