• 专利附录
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    • 专利摘要:
    1. THE METHOD OF OBTAINING CRYSTALLINE WATER-SOLUBLE NIGIGOSCOPIC ETHYLENEDIAMIN, MONOETHANOLAMINE OR DIETHANOLAMINUM SALT N -
    公开号:SU1122225A3
    申请号:SU823450445
    申请日:1982-06-01
    公开日:1984-10-30
    发明作者:Джордж Ломбардино Джозеф
    申请人:Пфайзер Инк.(Фирма)；
    IPC主号:
    专利说明:

    eleven
    The invention relates to a method for producing new chemical compounds, namely to a method for producing a crystalline water-soluble non-hygroscopic ethylenediamine, monoethanolamine or diethanolamine salt of N - (2-pyr-adyl) -2-methyl 4-OXY-2H-1, 2-benzthiazine-3-carboxamide , 1-dioxide.
    These salts of K | - (2-pyridyl) -2methyl-4-hydroxy-2H-, 2-benzthiazine-Zcarboxamide-t, I-dioxide have anti-inflammatory effects and can be used as nonsteroidal therapeutic agents to alleviate painful inflammatory conditions, caused by rheumatic arthritis -.
    Known M- (2-pyridyl) -2-methyl4-OXI-2H-1, 2-benzthiazine-3-carboxamide-f, 1-dioxide (piroxicam), which has anti-inflammatory activity. Piroxicam is obtained by reacting 1-I-dioxy-2-methyl-4-hydroxy-2H-1,2-benzthiazine-3-carboxylic acid methyl ester with 2-aminopyridine in dry xylene at the boiling point of the reaction mixture in a nitrogen atmosphere. Piroxicam is the closest analogue in the structure and action of the new salts N- (2-pyridyl /) - 2-methyl 4-OXY-2H-1, 2-benzthiazine-3-carboxyl amide-, 1-dioxide Q.
    However, Piroxicam is very poorly soluble in water.
    The aim of the invention is to prepare new salts of N- (2-pyridyl) -2methyl-4-hydroxy-2H-, 2-benzthiazium-3-carboxamide-1, 1-dioxide, which have an increased solubility in water.
    This goal is achieved by the fact that according to the method of obtaining crystalline water-soluble non-hygroscopic ethylenediamine, monostanolamine or diethanol amine salt} {- (2-pyridyl) -2-methyl-4ОКСИ-2Н-1, 2-benzthiazine-3-carboxamide-1, 1-dioxide I molar equivalent of N - (2-pyridyl) -, 2-methyl-4-oxy2H-1, 2-benzthiazine-3-carboxamide I, 1-dioxide is reacted with 1-2 molar equivalents of ethylene diamine, or monoethanolamine, or diethanolamine at 20 -120 ° C in a polar proton solvent or a halohydrocarbon solvent.
    Water is used as the polar proton solvent.
    22252
    Methylene chloride is used as the halohydrocarbon solvent.
    The desired product is evaporated by evaporation of the solvent from the reaction mixture, followed by trituration of the obtained solid residue or the crude concentrated product with a solvent, such as a mixture of
    10 ethyl acetate. - chloroform, etc.
    The desired product can be isolated by crystallization.
    Example. In a 250 ml Erlenmeyer flask with magnetic
    15 with a stirrer, thrown 500 mg (0.0015 mol) of N- (2-pyridyl) -2-methyl-4-ox) and-2H-, 1,2-benzthiazine-3-carboxamide-1,1-dioxide and 75 ml of water . Stirring is started and 180 mg is slowly added to the resulting suspension.
    (o, 003 mol) ethylenediamine (0.2 ml). The resulting reaction mixture is heated on the steam bath for 3 min and get a solution of yellow
    25 colors. By evaporating this solution almost dry under reduced pressure, a yellow resin is obtained, which is then triturated with 200 ml of chloroform and 30 ml of ethyl acetate by stirring the mixture
    30 for 1 hour. The resulting light yellow solid is isolated by suction filtration and washed on a filter funnel with a fresh portion of ethyl acetate.
    35 So, get a clean
    ethylenediamine salt of N - (2-pyridyl 2-methyl-4-hydroxy-2H-1,2-benzthiazine-Zbarbokkamkf -1, 1-dioxide with mp 151154 C. Pure product is additionally characterized using IR absorption spectrum and elemental analysis.
    Calculated,%: C 52.16; H 5.40; N 17.89. 5CisH NjO S
    CgHtNa Found,%: C 51.81; And 5.41;
    17.77.
    Example2. To a suspension of 2.0 g 50 (0.00604 mol) of N- (2-pyridyl) -2-methyl4-OXI-2H-1, 2-benzthiazine-3-carboxamide-1, I-dioxide in 300 ml of water 388 mg (0.00634 mol) 2- was added. amino ethanol (0.383 vai and forming a shuka; the mixture is heated on the steam bath for about 3 minutes. The resulting yellow solution is then filtered to remove
    a very small amount of water-insoluble substances, after which the filtrate is concentrated in vacuo to give a yellow oil as a residual liquid. Rubbing into powder of this substance together with 200 ml of ethyl acetate-chloroform mixed solvent (3: 2 by volume, followed by stirring at room temperature (25 ° C) overnight (| 6 hours in a dry nitrogen atmosphere gives a solid precipitate, which is sequentially separated by filtration with suction. After thorough washing of the isolated solid with ethyl acetate and drying in vacuo to constant weight, 2.07 g (87% n-440) of pure H- (2-pyridyl | -2-methyl4 hydroxy-2H-) monoethanolamine salt is finally obtained. 1, 2-benzthiazine-3 boksamid-1, 1-dioxide, mp 174-177 C. The pure product was further characterized by infrared absorption spectrum and elemental analysis .VychislenoD:. C 52.03; H 5.14;
    N 14.28.
    C ,, Found,%: C 51.72; H 5.14;
    1 13.93.
    Prima rz. In a 2 liter round bottom reaction flask equipped with a magnetic stirrer, an addition funnel (250 ml) and a thermometer, place the filtered solution consisting of 65.0 g (0.166 mol) H - (2-pyridyl) 2-methyl-4- hydroxy-2H-1, 2-benzthiazin3-carboxamide-1, 1-dioxide, dissolved in 660 ml of methylene chloride. A solution containing 0.1 g of monoethanolamine - (2-pyridyl) 2-methyl-4-hydroxy-2H-1, 2-benzthiazine-. 3-carboxamide-1, i-dioxide as a seed crystal, is prepared in advance by dissolving the solid in 610 ml of methylene chloride contained in an Erlenmeyer flask at 25 ° C, with gentle stirring using a magnetic stirrer. An additional 50 ml of methylene chloride is then used as a wash as the solution is transferred.
    into the indicated reaction flask. At this point in time, the last of the indicated flasks and its contents are heated to using a steam bath, and then the whole system is subjected to constant and thorough mixing.
    while a solution consisting of 10.7 g (o, 175 mol) of ethanolamine, dissolved in 110 ml of fresh methylene chloride, is slowly added to this system over 50 minutes. At the end of this stage, the spent reaction mixture is stirred (i.e., granulated) at
    27 C for 1 h and then filtered on a Büchner funnel to obtain a crystalline salt. The last product is dried in a vacuum oven at 35-C to constant weight and 63.1 g of pure monoethanolamine S salt of H- (2-pyridi 1) -2-methyl-4-oxy2I-1, 2-benzthiazine-3 carboxamide 1 are obtained , 1 dioxide with so pl. 171-174 ° Cc. The total yield of the purified product is 63.0 g (96.8%). The purified product was additionally characterized using nuclear magnetic resonance spectrum and elemental analysis, and it is identical in all respects with the product of Example 2. 5 Calculated,%: C 52.03; H 5.14; N 14.28.
    Found,%: C 52.09; H 5.15; N 14.30.
    Q Example 4. To a suspension of 2.0 g (0.00604 mol) of N - (2-pyridyl). 2-methyl-4-hydroxy-2H-1,2-benzthiazine-3-carboxamide-1, 1-dioxide in 68 ml of water was added 687,00634 mol) diethanolamine and the mixture was heated on the steam bath for 3 minutes. The resulting yellow solution is then filtered, removing a very small amount of white solid, and then concentrated
    0, the obtained filtrate in vacuo to give a yellow oil as the remaining liquid. Treatment of the latter material with 200 ml of a mixed solvent of ethyl acetate - chloroform (3: 2 by volume), followed by stirring at room temperature (25 ° C) overnight (l8 h) in a dry nitrogen atmosphere as a result gives a Celtic resin, which is subsequently isolated decantyr solvent. The resin is triturated with 100 ml of chloroform and heated on the steam bath for 2 minutes (only until boiling), followed by scratching, in order to cause crystallization. The mixture is cooled to room temperature and then stirred for 2.5 hours under a dry nitrogen atmosphere. $ i After removal of the solid crystalline material by filtration with suction and washing it with fresh solvent — chloroform followed by drying in —.vacuum to constant weight — finally, 2.11% yield (80%) of pure diethanolamine salt K — 2-pyridyl2-methyl- 4-hydroxy-2H-1, -benzthiazine-Zcarboxamide-1, 1-dioxide with mp. 1443 IAG C. The purified product is further characterized by an IR absorption spectrum and elemental analysis. Calculated,%: C, 52.28; H 5.54; “12.84. C | q N ,,. S, Found,%: C 52.04; H 5.40; N, 12.55. EXAMPLE 5. A dry pharmaceutical composition is prepared by mixing the following materials in a weight ratio: Ethylene diamine. Salt VI - (2-pyridyl) -2-methyl-. 4-OXY-2H-1,2-benzthiazin3-carboxamide-1, 1-dioxide 5.88 Microcrystalline cellulose34.00 Corn starch (US Pharma) -9.08 Magnesium stearate 1.04 After thoroughly mixing, the dry composition from the obtained mixture is stamped tablets, each tablet containing 5 mg of the active ingredient. Other tablets prepared in the same way contain 0.25 and 50 mg of the active ingredient. EXAMPLE 6 A dry solid pharmaceutical composition is prepared by mixing the following materials in weight ratios: the monostanolamine salt N - (2-pyridin) -2-methyl4-OXY-2H-1, 2-benzthiazine. Z-carboxamide-1,1 dioxide 59, 21 Anhydrous dicalcium phosphate230.10 Corn starch. (U.S. Pharmacopoeia) 32.50 Sodium lauryl sulphate 0.32 Magnesium stearate 2.87 The mixture is thoroughly mixed to obtain a uniform, powdery product. Then hard gelatin capsules are prepared (No. 2, each containing 50 mg of the active ingredient. Example. An aqueous solution of propylene glycol containing the d-ethanolamine salt of M - (2-: pyridyl) -2-methyl-4-hydroxy-2H-1,2-benzthiazine -3-carboxamide-1, 1-dioxide, prepared by dissolving this compound in a mixture of propylene glycol - water (1: 4, by weight) containing 1% by weight of trisodium phosphate and using a pH value of 8.0. so that the resulting solution contains 5 mg of the active ingredient in 1 ml. Then the solution is sterilized by filtration cutting a porous cellulose membrane with a pore size of 0.2 µm. A sterile water-propylene glycol solution suitable for intramuscular administration to animals. EXAMPLE 8 An aqueous solution for injection is prepared by mixing 1 part by weight of monoethanolamine salt I - (2- pyridyl -2-methyl-4-hydroxy-2H1, 2-benzthiazine-3-carboxamide-1,1-dioxide with 2.5 parts by weight of disodium phosphate using a mortar and pestle. The resulting ground dry mixture is sterilized with ethylene oxide and then aseptically transferred t in ampoules H sealed them. For intravenous administration, such a quantity of distilled water is added to each of the filled ampoules before use, in order to obtain a solution containing 10 mg of the active substance in 1 ml of solution. EXAMPLE 9 Tablet formulations are prepared by mixing the following materials in weight ratios: N - (2-pyridyl) -2-methyl4-OXY-2H-1, 2-benzthiazine-3-carboxamchd-1 monoethanolamine salt , 1-dioxide 23.92 Microcrystalline cellulose 31.1,03 Modified pregelatinized starch, NF 84.00 Magnesium stearate 0.945 Sodium lauryl sulfate 0.105 After thorough mixing of the dry composition, tablets are stamped from the mixture obtained, each tablet containing 20 mg of the active ingredient. Other tablets prepared in the same way. 71 contain 5.10 and 50 mg of the active ingredient. EXAMPLE 10 Tablet formulations are prepared by mixing the following materials in weight ratios: Konoethanolamine salt H - (2-cyridyl) -2-methyl 4-oxy-2H-1, 2-benzthiazine-3-carboxamide-1 , 1-dioxide ... 23,69 Anhydrous dicalcium phosphate 113, 37 Polyvinylpyrrolidone 50.00 Modified, pred. Gel starch, NF 10.0 Magnetic stearate 2.65 Magnesium lauryl sulfate, 0.294 After thoroughly mixing the dry composition, the resulting mixture is stamped into tablets, each tablet containing 20 mg of the active ingredient. Other tablets prepared in the same way contain 5.10 and 50 mg of the active ingredient. The new ethylenediamine, monoethanolamine and diethanolamine benzthiazine dioxide salts are crystalline, non-hygroscopic, fast-dissolving solids with high solubility in water and possessing stable chemical and physical properties. They can be used as non-steroid therapeutic agents for the treatment of inflammatory pain conditions caused by rheumatoid arthritis in various forms of pharmaceutical dosage for oral, topical or parenteral administration. Salts of K- (2-pyridyl) -2-methyl-4OXI-2H-1, 2-benzthiazine-3-carboxamide-1, 1-dioxide are used for therapeutic treatment as anti-arthritis agents. For example, the monoethanolamine salt of M-2-pyridyl) -2-methyl-4-OXY-2H1, 2-benzthiazine-3-carboxamide-1,1-dioxide exhibits anti-inflammatory activity in the standard test on carrageenin-induced rat paw. It is established that it causes significant inhibition of the tumor at a dosage level of 33 mg / kg, administered orally. Anti-inflammatory activity is defined as the percentage inhibition of the formation of NIN tumors on the hind paw of female albino rats (weighing 150-190 g) in response to a subplantational injection of carragenin. Carragenin is administered in the form of a 1% aqueous suspension (o, 05 ml) 1 hour after oral administration of the drug, which is usually given in the form of an aqueous solution. Tumor formation is determined by measuring the volume of the injected paw, the initial one, as well as 3 hours after the carrageenin injection. The increase in volume 3 hours after the injection of carragenin is an individual reaction. The compounds are considered active if the difference in the reaction between the animals that were given the drug (group of 6 rats) and the control group to which only the vehicle was administered was significant compared with the results obtained for standard compounds like acetylsalicylic acid at a dose of I00 mg / ml or phenylbutazone at a dose of 33 mg / kg by the oral route of administration of both drugs. I The described salts of benzthiazine dioxide over the analogue in structure and action - piroxicam have additional advantages. For example, if H - (2-pyridyl) -2methyl-4-hydroxy-2H I, 2-benzthiazine-Zcarboxamide-I, 1-dioxide (piroxicam) is very poorly soluble in water, the N-(2-pyridyl) monoethanolamine salt -2-methyl-4-hydroxy-2H-1,2-benzthiazine-3-carboxamide-1, 1-dioxide immediately dissolves in the indicated solvent and therefore is more rapidly absorbed by the blood stream when administered per os, than the corresponding less soluble calcium salt or anhydrous sodium sopN- (2pyridyl) -2-meTsh1-4-oxn-1,2-benzazaz-3-carboxamide-1, 1-dioxide. In addition, this salt gives a clear, stable aqueous solution even at very high concentrations (more than 100 mg / ml). Other new salts also have similar results. It is known that the trimethylamine salt N- (2-pyridyl) -2-metsh1-A-oxy2H-1, 2 benzthiazine-3-carboxamide 1, 1-dioxide and the corresponding triethano; 1amine salt is poorly soluble in water. The simple ammonium salt is very unstable when it is dried in a vacuum. The new benzothiazine dioxide salts are crystalline, non-hygroscopic solids, which are easily absorbed in pure form. This facilitates the gross processing of specified salts into complete forms of pharmaceutical dosages, which are suitable for use either for oral or local or parenteral administration, etc. The advantage of the proposed salts over the known anti-inflammatory agent (piroxicam) is the improvement of water solubility (determined by the equilibrium solubility of compounds at 25 ° C in water, which is essential for resorption of the tablet when it is taken and release of the active principle. Equilibrium solubility in water at mgA / ml: for piroxicam 0.01, for the monoethanolamine salt of piroxicam 100, i.e., using a new moroethanolamine salt of piroxicam, a 10,000-fold improvement in water solubility is observed. the case of constant surface area with water for piroxicam is 0.0032 mgA / ml / cm2 / min, and for new ethylenediamine salt 1.3 mgA / ml / cm / / min, i.e., explosive solubility is observed salt. In addition, determination of the dissolution profile for a 5 mg tablet containing the piroxicam monoethanolamine salt as an active principle (as in Yu), which was carried out using the rotating blade method (prescribed by the United States Pharmacopeia) (rotation speed 50 rpm, pH dissolution medium) 2 at), showed a rapid release of active ingredient la of the tablets (for 5 min). The salts described may be administered as anti-arthritic agents in doses varying from about 5 to about 100 mg per day depending on the weight and condition of the patient. Preferred dosages range from 0.08 mg to 16 mg per kg of body weight per day. (depending on the individual response to the indicated drug, as well as the type of pharmaceutical formulation and the duration of the treatment period. In some cases, the dosage is less than the lower or more than the upper limits of the specified interval, which are divided into several smaller doses — for daily administration. Benzthiazine dioxide salts can also be prescribed in combination with various pharmaceutical properties as acceptable inert carriers in the form of tablets, capsules, soft and hard cakes, solid candles, powders, dispensers, creams, ointments, suppositories , jellies, pastes, lotions, lapping, aqueous solutions and suspensions, injectable solutions, elixirs, syrups, etc. Such carriers include solid diluents or; fillers, sterile aqueous media and various non-toxic organic solutions teli, etc. Oral pharmaceutical compositions can be sweetened and / or flavored. Said salts are present in such dosage forms at concentration levels varying from about 0.5 to 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, along with various crushers such as starch, preferably corn, potato or tapioca, alginic acid, and some complex silicates together with granulated binders, such as polyvinylpyrrolidone, gelatin, and acacia. In addition, lubricating materials such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of this type can be used as fillers in hard gelatin capsules; preferred materials also include lactose or milk sugar, as well as high molecular weight polyethylene glycol. For oral administration of aqueous solutions and suspensions and / or elixirs, the active ingredient can be combined with various sweeteners; or perfuming agents, coloring materials or colorants and, in addition, emulsifying and / or suspending agents.
    II112222512
    agents in combination with diluents, the buffer pH is greater than 8, and liquid,
    such as water, ethanol, propylene diluent, initially converts glycol, glycerin and their various into isotonic. Aqueous solutions
    combinations. are suitable for intravenous
    For parenteral administration of 5 injections, oily solutions are for
    solutions of amine intra-articular, intramuscular
    salts in sesame oil or ground leg and subcutaneous injections. Besides,
    walnut or aqueous propylene glycol may be a local purpose of aqueous ethanol, as well as sterile additive salts of amines
    aqueous solutions in distilled treatment of inflammatory conditions
    Noah water. Aqueous paicTBopM should be the skin or eye with creams,
    contain the proper amount of the liquid, pastes, ointments, solutions.
    权利要求:
    Claims (3)
    [1]
    1. METHOD FOR PRODUCING CRYSTALLINE WATER-SOLUBLE NON-HYGROSCOPIC ETHYLENE DIAMINE, MONETHANOLAMINE OR DIETHANOLAMINE SALT
    N - (2-Pyridyl) -2-methyl-4-hydroxy-2H-1,
    [2]
    2-BENZTHIAZIN-Z-CARBOXAMIDE - !, 1-DIOK-
    Sida, characterized in that λ . that I is the molar equivalent of M ~ (2-pyridyl)
    2- methyl-4-hydroxy-2H-1,2-benzthiazine-
    [3]
    The 3-carboxamide-1,1-dioxide is reacted with 1 to 2 molar equivalents of ethylenediamine or monoethanolamine or diethanolamine at 2 ° -12 ° C. in a polar protic solvent or a halogen-hydrocarbon solvent.
    2. The method according to π. I, with the fact that water is used as a polar proton solvent.
    3. The method according to π., 1, characterized in that methylene chloride is used as a halide-hydrocarbon solvent.
    Λ and
    1 1122225
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US26898081A| true| 1981-06-01|1981-06-01|
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