• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Improved antiinflammatory salts of piroxicam consist of a 1 : 1 salt of piroxicam with antidepressant doxepin, with bronchodilator pirbuterol or isoproterenol, with H2-antagonist inhibitor 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, with pyridoxine, a member of the vitamin B6 complex, or with anti- hypertensive trimazosin.
    公开号:SU1375136A3
    申请号:SU853971352
    申请日:1985-10-10
    公开日:1988-02-15
    发明作者:Джордж Ломбардино Джозеф
    申请人:Пфайзер Инк. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the production of: x-piroxicam, in particular, the preparation of pre-sepinic, pyridoxine, 2-guanidino-4- (2-methyl-4-imidazolyl) thiazole, pyrbuterol, isoproterenol or trimazosine salt of piroxicam, which have anti-inflammatory properties and fewer side effects effect on the gastrointestinal tract, which can be applied in medicine
    The aim of the invention is to create, on the basis of known methods, a method of producing new compounds with valuable pharmacological properties.
    The invention is illustrated by the following examples.
    PRIER I. I. Doxepin salt of piroxicam.
    Piroxicam (1.66 g; 0.005 mol) is partially dissolved in a nitrogen atmosphere in 60 ml of CHjOH. Doxepin is added to the contents (1.40 g} 0.005 mol in 40 MP, after which a bright solution is obtained within a minute. The mixture is stirred for 15 minutes, then evaporated to dry residue under vacuum in order to obtain, after extraction from the crucible, when under vacuum of the target product in the form of a freely flowing yellow powder in the amount of 2.58 g. H.pl. 115-1P C. The IR spectrum (in KBr) includes IN-amide 1ShK at 2.93 microns, the peak at 3 , 3 microns (absent in the mixture of piroxicam and dox11in), laiK carbonyl amide at 6.05 microns and SO4, at 7.55 and 8.55 microns.
    Calculated for C., ,,:
    C, 66.87; H 5.61; N Y, 17.
    Found,%: C 66.84; H 5.67; N 9,10.
    PRI mme R 2. Niridoxine salt of piroxicam.
    Pyridoxine (0.846 g; 0.005 mol) is dissolved in 100 ml of CHiOH, Pyroxicam (1.66 g; 0.005 mol) is dissolved in 100 MP, a solution of pyridoxine is added to the contents. The resulting solution is evaporated under vacuum, dried over and obtain 2.15 g of the target product. M.p. 178 ° G; (different). The IR spectrum (in KBG) shows relatively high peaks and differs from the physical mixture of pyridoxine and piroxicam in a 1: 1 ratio
    Calculated as dl, / ,,: C 55.19; H 4.83; N P, 8.
    Found,%: C 55.01, H 4.54; H 11.48.
    Example 3. 2-guanidino-4- (2-methyl-4-imidazolyl) thiazole salt of piroxicam.
    Piroxicam (0.994 g; 0.003 mol) is suspended in 20 ml. To the contents is added 2-guanidino-4- (2-methyl-4-imidazolyl) thiazole (0.667 g; 0.003 mol) in 25 ml CHjOH. The slurry is agitated for 75 minutes until it becomes a thick mass with no visible change. The mixture was heated under reflux for 10 minutes, giving a clear solution for 2 minutes. The mixture is cooled to room temperature, clarified by filtration (removing 120 mg of white precipitate). The mother liquor is evaporated to dryness under vacuum to obtain, after removal from the flask and drying at 45 ° C under a high vacuum, the desired product in the form of a free-flowing powder in an amount of 1.30 g, m.p. 182 s (with decomp.). The IR spectrum (in KBG) includes a broad band in the range 2.90–4.3 microns Omultiplet HH and); 5.87 microns (carbonyl amide) and 7.52 microns and 8.55 microns (SOj).
    Calculated for C, jH2j04N9S, x X 0.75 NgO,%: C 48.71; H 4.35; N 2.22.
    Found,%: C 48.53; H 4.38; N22.47.
    PRI me R 4. Pyrbuterol salt of piroxicam.
    A clarified solution of pyrbuterol (2.35 g, 0.0096 mol) in 25 ml under a nitrogen atmosphere is added to a suspension of piroxicam (3.17 g; 0.0096 mol) in 50 ml and a practically clear solution is obtained, which after stirring for After 20 minutes, they are clarified by filtration, and evaporated to dryness under vacuum to obtain after pouring out of the flask and drying in a desiccator over P 0 under a deep vacuum for 20 hours, 5.52 g of the desired product. M.p. 98 ° C (with decomp.). A small portion of this product, after drying at 58 ° C for 16 hours under high vacuum, melts upon decomposition.
    Calculated for H, 0%: G 55.00; And 5.98; N 11.87.
    Found,%: C 54.66; H 5.92; K 11.74.
    Hj, 0, N, S-H, 0,% W 11.87.
    The mass of this material (5.20 g) is dried to 4.90 g by drying under high vacuum for 66 hours. The IR spectrum (in KBr) includes a broad peak of 2.75-4.2 microns (NHj); 6.12 microns (carbonyl amide) and 7.58 microns and 8.55 microns (BO,).
    Calculated for C 55.0; H 5.98;
    Found,%: C 55.25; H 5.63; And 11.97.
    Additional product (0.27 g) is obtained in the form of a suspension of the residue in a flask using 5 ml of ethyl acetate by filtration and drying for 66 hours under high vacuum.
    In each case, the product is a free flowing, easily processed powder,
    PRI me R 5. Isoproterenol salt of piroxicam.
    Piroxicam (3.86 g; 0.0166 mol) under a nitrogen atmosphere is suspended in 50 ml of CHi, OH. Isoproterenol (2.46 g; 0.0166 mol) is partially dissolved in 100 ml of CH3OH, the suspension is added to the suspension of piroxicam. After stirring for 20 minutes, the resulting bright solution is evaporated to dryness to yield. After removing from the flask and drying under high vacuum for 66 hours, the desired product is in the form of a free flowing, easily processed powder in an amount of 6.20 g, m.p. with decomp.), the IR spectrum (in KBG) includes a broad peak from 2.78 to 4.3 microns (NH and H, O); 6.15 micron (carbONILamide) and 7.55 micron and 8.57 micron (SO,.,).
    Calculated for 2H, 0%: C 53.97; H 5.92; N 9.68.
    Found,%: C 54.22; H 5.30; And 9.80.
    Example 6, Trimazosin salt of piroxicam,
    4.70 g (0.01 mol) of trimazosin (free base) are slurried with 200 ml of CHjOH and added to a suspension of piroxicam (3.31 g; 0.01 mol) in 100 ml With stirring, the color changes to pale yellow, a partial solution is formed. After one hour, the latter is heated to 65 ° C with stirring for 30 minutes. The resulting bright solution is cooled to room temperature, clarified by filtration in order to remove traces of insoluble matter.
    five
    0
    0
    five
    washed and evaporated to dryness under vacuum. 6.84 g (89%) of the products are dried at over. M.p. 162-164 S.
    Calculated .dl 4jO ioNeS,% i С 54.82; H 5.52; N 14.61.
    Found,%: C 54.54; H 5.37; and 14.55.
    Preparation 1. Doxepin.
    Doxepine hydrochloride (10 g; 0.032 mol) was dissolved in 50 ml, sodium bicarbonate (3.2 g; O, 038 mol) suspended in 25 mp was added with stirring, the mixture was stirred for 20 min, and then extracted 3x50 ml of ether. The ether extracts are combined, dried (NajS04) and evaporated in vacuo to give doxepin as an oil (8.33 g).
    Preparation 2, Pyrbuterol.
    Under nitrogen atmosphere, pyrbuterol dichlorohydrate (3.0 g; 0.0096 mol) 5 is dissolved in CH, OH KOH (85%; 1.3 g; 0.0197 mol); B 30 ml of CHjOH are added dropwise over 10 min After stirring for 30 minutes, the precipitated KCl (1.25 g) is removed by 4 liters. The mother liquor is evaporated to a white foam (2.56 g). The latter is placed in 20 ml of a mixture of acetone and CHjOH in a 1: 1 ratio and settled for 18 hours. The added KC1 (0.09 g) is removed by filtration, and the mother liquor is evaporated, dried under high vacuum to obtain the desired product in an amount of 2, 35
    Preparation 3, Isoproterenol.
    By the method described in preparation 2, isoproterenol hydrochloride is converted to the appropriate base. Exit 2.46 g.
    Preparation 4. 2-Guanidino-4-. (2-methyl-4-imidazolyl) thiazole dihydrobromide.
    Method A. 2-methyl-4-acetylimidazole (4.00 g; 0.0322 mol) is dissolved in 48% HLg (40 ml; 0.351 mol) with increasing temperature to 33 ° C. The solution is heated to Within 17 minutes, Br, (1.65 ml; 5.15 g; 0, d322 mol) are added dropwise to the contents in 5 ml of 4B% HBg, maintaining (if necessary) this temperature with the help of external heating . Move-; sew the reaction mixture preheating0
    0
    the mixture is cooled for 1.5 h, cooled and the cream colored suspension is separated. The mixture is treated twice (20 ml each time) with water (dissolving the solid particles and returning to a thick suspension each time). Without further isolating the intermediate 2-methyl-4-broth tilimidazole, absolute ethanol (29.2 ml) is added to the mixture and then N- amidinothiourea (3.81 g; 0.0322 mol). The suspension is heated to boiling. The resulting solution is heated under reflux for 2 hours, resulting in a thick precipitate from the crystalline target product. The suspension is stripped to half the volume and cooled to room temperature. The desired product is isolated by filtration with a small amount of ethanol, washed and dried under vacuum to give 10.12 g (79% as a result of two stages). Purity is confirmed by the method thin layer chromatograph and, Rf 0.75 (ethanol: concentrated NH40H in the ratio 19: 1). M.p. (different).
    Calculated.-For CgHjjNfeS 2НВг х X U, 5H20,%: C 24.44; H 3.33; N 21.38
    Found,%: C 24.20; H 3.18; W 21.43.
    Method B. lio method A is subjected to bromination of 2-methyl-4-adhetilimidazole (4.00 g; 0.0322 mol.), But replacing 3.67 ml with 150.0322 mol) with 48% HBg and 4 ml. acetic acid for the initial loading of 48% HBg and loading (l ~ 65 ml) in 4 ml of acetic acid instead of 48% HBg. At the end of the 1.5-hour heating (without cooling, separation and processing), amide is added (3.81 g). The reaction is accompanied by the release of heat with an increase in temperature from 67 to 77 ° C. The resulting solution is matured at 80 ° C for one hour, and a thick precipitate begins. The target product (9.34 g), isolated similarly to method A (73% after two stages), is identical to the product obtained according to method A.
    Method C. To 48% HBg (16.9 ml), add 2-methyl-4-acetylimidazole (7.36 g; 0.059 mol) to form a light yellow pactBOpa. As: heating the reaction mixture to 45 ° C, Br, j (3.0 ml) is added dropwise.
    0 5
    about
    0
    five
    0.059 mol) in 48% HBg (3.3 mp). During the addition and heating, precipitation occurs. After stirring for 18 hours at 45 ° C, the reaction mixture is cooled to, diluted with 22 ml of absolute ethanol, and K-amidinethiourea (7.0 g) is added. The resulting suspension becomes almost light, and then turns into a precipitate, which is removed with a spatula. The resulting mobile suspension is stirred at 55 ° C for 2 h and cooled to 10 ° C. The target product (20.3 g; 86%), isolated by filtration by washing twice with 5 ml of absolute ethanol, is identical to the target product obtained in method A,
    Preparation of 5, 2-Guanidino-4- (2-methyl 4-imidazolyl) thiazole (free base),
    2-Guanidino-4- (2-methyl-4-imidazolyl) thiazole dibromide (13.4 g) is stirred with 66.9 ml and slowly adjusted to a pH of 10.0 over 2 hours using 22, 6 ml of 3 N, KOH, while maintaining the temperature in the range of 22 - 24 ° C. The target product is isolated using 4 liters of solution under vacuum with water washing, turned into a dense piece under a rubber partition. Again it is turned into a pulp in 28 ml of acetone in for 2 hours, filtered off, 12 ml of acetone are passed in and dried under vacuum to obtain the crystalline desired product (8.66 g), ERZHAN about 15% water.
    A piece of water (pellet) moistened with water prepared according to the method described above, without re-pulping with acetone, produces an anhydrous free base by dissolving 4.04 g of the piece moistened with water (by approximate estimation of a free base containing 1.60 g basis) in 80 ml of acetone serving as a fgagma, treating the solution with 0, 16 g of activated carbon, hot filtration, concentrating the filtrate to 15 ml, changing at room temperature for one hour. filtration with washing with acetone; and drying the product in the form of a flat cake at 40 ° C under vacuum. Yield - 1.57 g.
    Biological actinic tests were performed to determine the protective effect of reagents, combined with piroxicam in the form of salts, on piroxicam gastric lesions in a healthy, mobile rat.
    Adult male rats of the SD breed (Sprague-Dawley), specially deprived
    five-
    a pathogen weighing 140-160 g is acclimatized for approximately one week and examined after they have reached a weight of 200-225 g. For 16 hours, the rats are in motion. They are then divided into groups consisting of 9-10 animals each and normalized by average weight.
    In control experiments in rats, gastric ulcers were stimulated by oral administration of a single dose to each animal at a rate of 120 mg / kg of a solution of piroxicam (ethanolamine salt) containing 2 ml of 0.1% methloschellulose in water, pH 6, dissolved in the drug. 8 (MC). Doses of the combination of piroxicam salts are chosen in such a way as to expose the rats to an approximately equal molar dose; piroxicam (100 mg / kg free base). Preliminary studies on such combinations of piroxicam salts revealed technical problems associated with a lack of solubility in methylcellulose diluent, therefore two types of dosing carrier are used: the first carrier consists of a diluent containing equal parts of dimethyl sulfoxide and MC (DMSO / MC), which is administered orally in a volume of 2 ml per rat; the second carrier consists of 5 gelatin capsules, in which test sorted quantities of piroxicamolamine or a combination of piroxicam salts are placed, each rat receives one such capsule by oral (stomatologic) route.
    Six and a half hours after taking the prescribed doses, the rats are killed and opened. The stomachs are removed, diluted by the greatest curvature and washed with cold water, then separated by linear and dotted damage. The total amount of damage is taken into account. Data obtained for each group of rats by analyzing
    ten
    15
    20
    25
    zo - Q
    35
    45
    50
    55
    after calculating the mean +/- standard error relative to the total amount of gastric damage, compared with the control (animals that receive only piroxicam), unpaired data.
    The appointment of olyromin piroxicam in daCO / MC or in capsules leads to the same level of gastric damage. When comparing the piroxicam olamine-induced ulcerous disease with the ulcer disease observed with the application of any compound from the pyroxicamic combination, including CP-57361, doxepin, the main metabolic product of doxepin or isproterrenol, a marked decrease in the amount of gastric damage.
    Similar reductions in gastric erosion with respect to gastric erosion observed when using the same piroxicam olamine occur when capsules containing piroxicam compounds, including pyrbuterol, pyridoxine or trizozosin, are administered.
    A comparative analysis of the effect of piroxicam salts and piroxicam ethanolamine salt on gastric injuries of a healthy rat caused by piroxicam is given in the table.
    The data obtained confirm that equimolar levels of combinations of piroxicam salts (including CP-57361, doxepin, the main metabolic product (metabolite), doxepin, isoproterenol, pyrbuterol or trimasosin) result in a much smaller number of gastric lesions in a mobile healthy rat compared to rats, only accepting the piroxicam zthanolamine salt.
    These data also indicate that cytoprotective activity for these combination compounds is evident when using each of them in an amount of approximately 100 mg / kg P.O. (as part of the combined salt of piroxicam). It should also be noted that no adverse effects were observed in the rats studied during the experiments.
    Salt of piroxicam is dosed in a range equivalent to 0.1-1 mg Sh1roxycam (kg) per day. Vuoro drug take in equimolar
    quantity; 0,084-0,84 mg doxepine; 0.073-0.73 mg pyrbuterol; 0.064 - 0.64 mg isoproterenol; 0.067-0.67 mg of 2-guanidino-4- (2-methyl-4-imidaeolyl) thiazole; 0.131 - 1.31 mg of trimazioin or 0.048 - 0.48 mg of pyridoxine.
    In the oral course, the dosage amount of salt is mainly in the range equivalent to 5-50 mg / day of free piroxicam per adult patient, thus providing the following molar equivalent amounts of the second drug substance; 4.2 to 42 mg / day doxepin; 3.62 - 36.2 mg / day pirbuterol; 3.19 - 31.9 mg / day isoproterenol; 3.35 - 33.5 mg / day of 2-guanidino-4- (2-methyl-4-imidazolyl) thiaeol 6.57 - 65.7 mg / day trimaoosin or 2.55 - 25.5 mg / day pyridoxine.
    The amount of the second drug substance is generally sufficient to delay gastrointestinal side effects that might otherwise occur under the influence of piroxicam in susceptible patients.
    These salts are administered alone or in combination with pharmaceutically acceptable carriers and diluents. Pharmaceutical carriers include inert diluents or excipients, thereby forming dosage forms in the form of tablets, powders, capsules, and the like. The compositions also contain additional ingredients (for example, flavoring agents, binders, inert fillers
    etc.). For oral administration, tablets containing inert excipients (e.g., sodium citrate) with various components (e.g., starch, alginic acid, and some complex silicates) with binding agents (e.g., polyvinylpyrrolidone, sucrose, gelatin, and Arabian gum) are used. In addition, lubricating agents (magnesium stearate, sodium lauryl sulfate and talc) are often used to make tablets. As a filler in soft and hard gelatin-filled capsules, solid compositions of the usual type can be used, lactose, milk sugar and high molecular weight polyethylene glycols are preferred for this.
    Thus, we propose the 1st method to obtain valuable biologically active salts.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method for the preparation of doxepin or pyridocrinic, or 2-guanidino-4- (2-methyl-4-imidazolyl) thiazole, or pyrbuterol, or isoproterol, or trimazosine salt of piroxicam, which is piroxicam is reacted with doxepin, or pyridoxin, or 2-guanidino-4- (2-methyl-4-imidazolyl) thiazole or pyrbuterol, or isoproterenol, or trimazosine at a molar ratio of reagents of 1: 1 in medium inert with respect to the reaction of the solvent.
    Ethanolamine Piroxicam Piroxicam / CP-57361
    120 9.7 (1.9) 200 - -0.0 (0.0)
     The average value of +/- - standard error, determined
    10 rats for each group; significantly different (, 05) for rats receiving
    only piroxycamethanolamine (Olamine), in experiments for unpaired
    data; Slightly different from rats receiving piroxycamolamine in DMSO / MC diluent.
    CP-57361 - 2-guanidino-4- (2-methyl-4-imidazole1) thiazole}
    DISR / MC - dimethyl sulfoxide - 0.1% -methylcellulose.
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    同族专利:
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    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/659,733|US4567179A|1984-10-11|1984-10-11|Antiinflammatory salts of piroxicam|
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