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    • 专利摘要:
    Novel aminomethyl oxooxazolidinyl benzene derivatives, including ()-N[3-[4-(1-hydroxyethyl]-phenyl]-2-oxo-5-oxazolidinylmethyl]acetamide, possess useful antibacterial activity.
    公开号:SU1528317A3
    申请号:SU853988501
    申请日:1985-12-04
    公开日:1989-12-07
    发明作者:Эделмэн Грегори Уолтер
    申请人:Е.И.Дюпон Де Немур Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    cus dureus and Escherichia coli with a dose of ED5o of 1.3-80.5 and 26.3-120 mg / kg
    (sc) or 2.1–79.2 and 17.4–120 mg / kg (orally). 4 tab.
    The invention relates to a process for the preparation of new chemical compounds, namely, derivatives of 3- (4-substituted phenyl) -5-adylamidomethyloxazolidinov-2, which have a bacteriostatic effect and can be used in medicine as bacteriostats capable of reducing allergies. —Gic reactions and exhibiting the product: in vivo in vivo activity.
    The aim of the invention is to obtain new 3- (4-substituted phenyl) -5-adylamidomethyloxazolidinone-2, possessing a new type of biological effect for this series.
    Target products are compounds of the formula
    ABOUT
    RI / VN 1-LCH NH-CO 2 7, (I)
    Example 1. Preparation of (l) l - (acetyl hydrazone) -ethyl-phenyl 2-OXO-5-oxazolidinylmethyl-acetamide
    n o
    NNCNS
    Cl-. ,
    A. Preparation of (1) -5-hydroxymethyl-3-phenyl-2-oxazolidinone, 4-methylbenzenesulfonate.
    To a mixture of 51.5 g of (1) -5-hydroxymethyl-3-feNyl-2-oxazolidinone in 250 ml of dry pyridine under a nitrogen atmosphere in an ice bath with stirring is added a solution of 53.0 g of p-toluenesulfonyl chloride in 50 ml of pyridine. Upon completion of addition, the mixture is cooled down. The mixture is left to stand for 1 hour, after which a few drops of water are added (while the temperature rises to as a result of the reaction of water with an excess of p-toluenesulfonyl chloride). Pour the reaction mixture into ice water. The white solid is filtered off, washed well with water and dried. The yield of the product is 70.0 g, Topl. 146.3-147.8 ° C. This product is used further without purification.
    B. Preparation of (1) -5-azidomethyl-3-phenyl-2-oxazolidinone.
    A mixture of 5.0 g (14.4 mmol) of (1) -5-hydroxymethyl-3-phenyl-2-oxazolidinone, 4-methylbenzenesulfonate, 2.1 g of sodium azide and I g of 18 crown-6 in 35 MP of DMF is heated 3 h at 100 ° C. The mixture is then poured onto ice water and filtered. The yield of the dried product is 2.47 g, m.p. 71.5-72.5 ° C. After recrystallization from diethyl ether, 1.44 g of product is obtained, mp. 72.5-73 ° C.
    B. Preparation of (1) -5-aminomethyl-3-phenyl-2-oxazolidinone.
    A mixture of 37.0 g (170 mmol) of (1) -5-azidomethyl-3-phenyl-2-oxazolidinone, 26 ml of triethylamine and 19.5 ml of 1.3-propanedithiol in 150 ml of methanol is heated to 50 ° C. After 2 3.9 liters of nitrogen is released. The solvent is then removed and the residue is crystallized out with stirring with ether (yield of crude product is 28.3 g). This substance can be used without further purification.
    D. Preparation of (1) —Y- (3-phenyl-2-ox-zolidin-5-ylmethyl) acetamnda.
    A solution of 12.5 g (65.0 mmol) of (1) -5-amnnomethyl-3-phenyl-2-oxazolidinone in 50 ml of dry pyridine is stirred with the addition of 7 mp of acetic anhydride. The mixture was allowed to stand overnight, after which it was concentrated. The residue is stirred with water, the solid formed is separated by filtration and dried. The yield is 10.2 g. 122.4-124.5 ° C. The resulting product is recrystallized from ethanol to obtain 5.02 g of product with m.p. 126.8-127, 3 ° C. A second fraction is also obtained, which is recrystallized from ethanol to obtain 3.08 g of product, m.p. 127.3-127.8 ° C.
    D. Preparation of (1) (4-acetylphenyl) -2-oxo-5-oxazolidinylmethyl 0 And
    acetamide (I; R, - SP, C-, Rj - CHj). 25 ml of methanesulfonic acid are mixed under dry nitrogen with
    by adding 3.5 g (15 mmol) of (1) -N- (3-phenyl-2-oxazolidin-5-ylmethyl) acetamide. Then 3 ml of acetic anhydride are added. The mixture was stirred for 2.5 hours, poured onto ice and the product was extracted with dichloromethane. The collected dichloromethane extracts are dried with sodium sulfate. After evaporation of the extract, a crude yellow product (4.6 g) is obtained, which is recrystallized from acetonitrile to give 2.33 g of the title compound with so-called. 190.5-191, 0 C.
    ten
    a solution of 50 g (0.33 mol) p-chlorophenyl- is quickly added dropwise. isocyanate and 27.9 ml (44.67 g, 0.326 mol) of epibromohydrin in 50 ml of xylene. Then the resulting reaction mass is cooled to room temperature and the solvent is removed. The crude Hhtfi product is recrystallized from methanol to yield 79. g (dl) -5- (bromomethyl) -3- (4-chloro) phenyl 2-oxazolididinone.
    B. Preparation of (dl) -2-a3iwo-N-3- (4-chlorophenyl) -2-oxooxazolidin-5E. Preparation of (1) -N- -3 (4- (1-h-5-ylM) ethyl 3-acetamide. Razonethyl) phenyl) -2-oxo-5-oxazol-Mixture 20.0 g (68.8 mmol) pochendydinylmethyl acetamide. more than compound, 4.70 g
    A mixture of 1.7 g (6.2 mmol) of (1) -N- (72.3 mmol) of sodium azide (NaN)
    3- (4-acetylphenyl) -2-oxooxazolidine- and 1.52 g (6.88 mmol) of 15-crown-5 in
    20
    Acetamide 5-ylmesht and 0.25 ml of 98% hydrazine in 25 ml of absolute ethanol are heated at reflux for 1.5 hours, as a result of which the reaction to about HF is completed. 25 additional 0.125 ml of 98% hydrazine are added, after which the mass is heated for another 2 hours at reflux temperature. The mass is then concentrated to dryness, the residue is diluted with ethanol and the product is crystallized out. The yield is 1.2 g, m.p. above 235 s. These NMR analysis confirm the structure of the product.
    W, To a solution of 1.0 g (3.62 mmol) (l) (4- (l-hydrazonethyl) phenyl) - g 2-oxo-5-oxazolidiylmethyl 11 acetamide in 10 ml of THF and 10 ml of triethyl amine with stirring 0.5 ml of acetic anhydride.
    100 ml of DMF with stirring under nitrogen are heated to 85 ° C. and incubated overnight. Then, the resulting reaction mass is cooled to room temperature, poured into 400 ml of ice water and the resulting product is separated by filtration, washed with water and used even in the wet state for the next reaction without further purification.
    B. To a solution of this compound in 1.5 liters of absolute ethanol with stirring under nitrogen atmosphere, add 4.0 ml (4.20 g, 69.9 mmol) of glacial acetic acid and 1.0 g of 10% palladium coal (Pd / C). Then hydrogen is passed through the reaction mass. After 1 h, a TLC analysis is performed, the data of which show the absence of starting material
    A table is added to the resulting solution. The reaction mass is then filtered out with 0.1 g of 4-dimethylamylopyridine and discharged through CeLite® and washed
    1 ml of acetic anhydride. ethanol. After removing the solvent
    The mixture is stirred for 1 h, then it is concentrated, diluted with water and the solid is filtered off, the output 1.01 g, so pl. 216.2-216.8 ° Co
    Example 2. Preparation of methyl ester (dl) (4-chlorofoam) -2-oxoxazo; 1idin-5-ylmetsh carbamic acid (1; R (C1, K, -0-CH3).
    A. Preparation of (dl) -5- (bromomethyl) -3- (4-chlorophenyl) -2-oxazolidinone.
    A hot solution of 2.0 g (23.0 mmol) of lithium bromide (LiBr) and 5.0 g (22.9 mmol) of tributylphosphine oxide in 800 ml of xylenes (after complete removal of water by azeotropic distillation) is stirred in a nitrogenous atmosphere and
    a solution of 50 g (0.33 mol) p-chlorophenyl- is quickly added dropwise. isocyanate and 27.9 ml (44.67 g, 0.326 mol) of epibromohydrin in 50 ml of xylene. Then the resulting reaction mass is cooled to room temperature and the solvent is removed. The crude-Hhtfi product is recrystallized from methanol to give 79. g (dl) -5- (bromomethyl) -3- (4-chloro) phenyl 2-oxazolididinone.
    B. Preparation of (dl) -2-a3iwo-N-3- (4-chlorophenyl) -2-oxooxazolidin-5ilM) distilled acetamide. A mixture of 20.0 g (68.8 mmol) and 100 ml of DMF was obtained with stirring under nitrogen atmosphere and heated to 85 ° C. and kept overnight. Then, the resulting reaction mass is cooled to room temperature, poured into 400 ml of ice water and the resulting product is separated by filtration, washed with water and used even in the wet state for the next reaction without further purification.
    B. To a solution of this compound in 1.5 liters of absolute ethanol with stirring under nitrogen atmosphere, add 4.0 ml (4.20 g, 69.9 mmol) of glacial acetic acid and 1.0 g of 10% palladium coal (Pd / C). Then hydrogen is passed through the reaction mass. After 1 h, TLC analysis is carried out, the data of which show the absence of starting material: 18.0 g of (dl) oxo-3- (4-chlorofeyl) oxazolidin-5-yl methyl ammonium acetate; A solution of 5.0 g (17.4 mmol) of the compound in 100 ml of a mixture of THF and water (1: 1) is prepared. The pH of this solution is then adjusted to 10-11 by adding a 25% aqueous solution of NaOH under nitrogen and
    2.7 ml (3.29 g, 34.8 mmol) of methyl chloroformate. After 1 h, TLC data showed no starting material. The reaction mass is then evaporated and a brown solid is obtained, which is washed with water. The crude product is purified by flash chromatography on a silica gel column (the solvent is a mixture of methylene chloride).
    Lenchloride and methanol) and get 1.89 g of the specified compound with tg. 123-124 C, M 284.
    Example 3. Preparation of (1) -N- 3- (4-bromophenyl) -2-oxooxazolidin-5 ylmethyl acetamide (1; K (- Br, Rj - CH3).
     A. Preparation of 4-methylbenzenesulfonate (1) -5-hydroxymethyl-3-phenyl-2-oxazolididinone,
    To a solution of 149.0 g (0.77 mol) of (1) -5-hydroxymethyl-3-phenyl-2-oxazolidinone in 500 ml of pyridine in a nitrogen atmosphere at room temperature, add a solution of 150, drop by drop, 0 g (0.79 mol) of tosyl chloride in 25Q ml of pyridine. After adding the solution, the mixture is stirred for another 1 hour. The reaction mass is then left to stand for 3 days at ambient temperature. Then tosyl chloride (30.0 g) J is added, after which the mass is stirred for 4 hours. Then, 18.9 g of tosyl chloride are added and after 2 h, another 50.0 g of tosyl chloride. The mixture is stirred overnight, then it is cooled to 10 ° C and water is added in separate portions in order to decompose excess tosyl chloride, keeping the mass below 20 ° C. The cooling mass in an ice bath is diluted with water (2 L). The resulting crystalline product is collected by filtration. And dried overnight in a vacuum oven at 60 ° C. The resulting hardened brown oil with 1 liter of acetonitrile is ground to an off-white powder. The mother liquor is concentrated and the concentrate is diluted with 3 liters of water to obtain an additional amount of whitish solid. The collected solids (total weight 199.0 g) are recrystallized from acetonitrile (decolourized with charcoal). Re-recrystallization from acetonitrile does not completely remove the contaminating particles (mp. 142.5 147.5 and 145-152 ° C).
    B. Preparation of (1) -H- (3-phenyl-2-oxooxazolidin-5-ylmethyl) phthalimide. A mixture of 46.4 g (0.134 mol) of methyl benzene sulfonate (1) -5-hydroxymethyl-3-phenyl-2-oxazolidinone, 26.1 g (0.141 mol) of potassium phthalimide and 0.27 (0.001 mol) of 18-crown 6 in 200 ml of fresh DMF with mixing
    five
    0
    5 0 j О 5 о

    in nitrogen atmosphere, heated to 70 ° C. The resulting solution is stirred overnight at 70 ° C, cooled to room temperature, and diluted with water to 1 l. The result is a solid (1) -C- (3-phenyl-2-oxooxazole Din-5-ylmetsh1) phthalimide, which is separated by filtration, washed with water and air-dried to obtain 39.9 g of the indicated product, mp. 167.3.
    In Preparation (1) (4-bramphenyl) -2-oxooxazolidin-5-ylmethyl phatsgsmide,
    To a solution of 5.0 g (15.5 mmol) of (1) -Y- (3-phenyl-2-oxooxazolidin-5-ylmethyl) phthalimide in 75 ml of trifluoroacetic acid (TFA) with stirring at room temperature dropwise a solution of 2.49 g (0.79 ml, 15.5 mmol) of bromine in 25 ml of TFA is added. After 4.5 hours, sodium bisulfite (NaHSOj) is added, then the reaction mixture is filtered and the solvents are removed. The isolated light orange substance is triturated with 200 ml of water to give 5.59 g of a white solid. Recrystallization of the crude product with acetonitrile gives 3.7 g of (1) (4-, bromophenyl) -2-oxox oxydine-5 -sh1me- Ti-uf phthalimide, so pl. 190-191 c.
    G. Preparation of (1) -5-aminomethyl-3- (4-bromophenyl) -2-oxazolidinone.
    To a suspension of 5.85 g (14.6 mmol) of (1) - (4-bromophenyl) -2 oxooxazolidin-5-ylmethyl phthalimide in 50 ml of absolute ethanol with stirring, add 0.51 ml (0.515 g, 16.1 mmol a) hydrazin. The reaction mixture is stirred overnight, then it is filtered and washed with ethanol, after which the solvent is removed. The resulting oil is weighed in 100 ml of water. The pH of the slurry is adjusted to 3 with hydrochloric acid. Then, the slurry is stirred overnight. The pH of the reaction mass is set to 7. It is again adjusted to 3 (with hydrochloric acid), after which the mass is stirred for 1 hour and filtered, after which the solvents are removed. The resulting white solid is weighed in ethereal ether, filtered, washed with ethyl ether and dried in air. The result is 1.76 g of the product in the form of hydrochloride.
    915
    D. Prepare a solution of 840 g (2.7 mmol) of (1) -5-amino-methyl-3- (4-bromophenyl) -2-oxazolidinoH hydrochloride in 50 ml of a mixture of THF and water (2: 1). With cooling in an ice bath and in a nitrogen atmosphere, the pH of this solution was adjusted to 10 by the addition of a 25% solution of sodium hydroxide and (NaOH). Then 0.52 ml (0.55 g, 5.5 mmol) of acetic anhydride is added. The cooling mass is stirred for 1 h, then it is warmed to room temperature and stirred overnight. Then the solvents are removed and the crude product is triturated with water, filtered, rinsed with water and dried in air to obtain 400 mg (1) (4-bromophenyl) -2-oxooxazoles din-5-ylmethyl3 zcetamide, m.p. 179.8-182, J ° C, M 312, 314.
    Example 4 Preparation of (dl) - (4-chlorophenyl) oxazolidin-5-ylmethyl-acetamide (1; R is C1, R2 is CHj)
    The pH value of the solution is 5.0 g (17.4 mmol) (dl) (4-chlorophenyl) - 2-oxooxazolidine-5-shL ammonium acetate in 100 MP of a mixture of THF and water (1: 1) using a 25% hydroxide solution sodium is adjusted to 10-11, after which the solution is exposed to a nitrogen atmosphere. Then 3.3 ml (3.56 g, 34.9 mmol) of acetic anhydride are added with stirring. After 1 h, TLC data show the absence of starting material. The solvents are then removed. The resulting crude product was washed with water and dried to give 3.87 g of the title compound. Mp. 155-156 ° C, M 268.
    Example 5. Preparation of (dl) - (4-fluorophenyl) -2-oxooxazolidine 5-ylmethyl acetamide (1; R - F, R - CH,).
    If in example 2 the p-chlorophenyl isocyanate is modified with p-fluorophenidisocyanate, then 2 g of (dl) -N-L3- (4-fluorophenyl) -2-oxooxazol din-5-ylmethyl acetamide are obtained, mp. 135-136 C, 252.
    Example 6. Preparation of (1) -N-3 (4- (1-hydroxyethyl) phenyl) -2-oxo-5-oxazolidinylmethyl acetamide (1; OH I R. - CH, CH-, Kg - CHO.
    Q c ,,
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    about Q
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    710
     To 2.00 g (1.2 mmol) (l) (4-acetylphenyl) -2-oxooxazolidin-5-ylmethyl acetamide in 50 ml of ethanol with stirring, add a solution of 1.0 g of sodium borohydride in 5 ml of water. . After dissolution of the solid and after 15 minutes, TLC data indicates the completion of the reaction. The solvent is then removed by concentration in vacuo. The residue is diluted with water and acidified with dilute hydrochloric acid, after which the product is extracted with dichloromethane. The resulting extracts are dried with sodium sulfate and concentrated. The residue was recrystallized from acetonitrile to give 0.66 g of the title product, mp. 128.8-129.8 ° C.
    Example 7. Preparation of (1) - (4-iodophenyl) -2-oxo-5-oxazolidinylmethyl) acetamide (1; R — Y, R2 — CHj).
    To a solution of 23.5 g (0.10 mol) of (1) - K- (3-phenyl-2-oxazolidin-5-ylmethyl) acetamide and 44.2 silver trifluoroacetate in 200 ml of chloroform with stirring at ambient temperature a solution of 27.9 g (0.11 mol) iodine in 200 ml of chloroform. A silver coating is formed on solid silver trifluoroacetate. After 4 hours, 20.0 g of silver trifluoroacetate was added and the mixture was stirred for another 2 hours. The mixture was then taken up. The resulting solid is washed with chloroform and dichloromethane. The chloroform solution is then washed with sodium carbonate solution. The dried chloroform solution is concentrated to obtain 10.0 g of a crude product, mp 147-170 ° C. After recrystallization from acetonitrile, 8.0 g of the title compound are obtained, m.p. 194-195 Co
    Example 8. Preparation of (l) -N- (4-ethynylphenyl) -2-oxo-5-oxazolidinylmethyl acetamide (ij R, R. - CH).
    A. Preparation of (1) -C-p- (4-trimethyl-C1-1-ethylethylphenyl) -2-oxo-5-oxazolidinylmethyl acetamide.
    To 5.0 g of (1) (4-iodophenyl) -2-oxo-5-ox saz olidinyl methyl acetamide and 1.6 g of trimethylsilylacetylene in 20 ml of DMF and 20 MP of triethylamine were added 0.193 g of bis (triphenol phosphate) - palladium chloride -11 and 0.26 g of copper iodide - 1. After stirring in the
    eleven
    4.5 hours while the reaction solution is concentrated. The resulting residue is dissolved in acetonitrile and diethyl ether and washed with water. The solution in acetonitrile and diethyl ether is concentrated to dryness and purified by chromatography on silica gel (solvent: a mixture of ethylene glycol dimethyl ether and cyclohexane 1: 1) to give 3.4 g of the title compound, mp. 145 ° C. A mass sample of this compound shows a molecular ion peak of 330.
    B. To 2.0 g (1) (4-trimethyl silylethinphenyl) -2-ox-5-oxazole dinylmethyl-dacetamide, dissolved in an amount of about 50 ml of methanol at room temperature, add 10 ml of 1N. potassium hydroxide. After stirring for 90 minutes, the reaction solution is acidified with dilute aqueous hydrochloric acid to a pH value of 3. Then water is added to the acidified solution and extracted with chloromethane. Dried dichlormeth new extracts are concentrated with the soil of the crude solid. The latter is purified by chromatography on silica gel (eluent: a mixture of ethylene glycol dimethyl ether and hexane 1: 1). The collected fractions are concentrated and recalled from dichloromethane and



    hexane to obtain 0.98 g of the title product,. 169.5-171.5 ° C. Mass spectrum data obtained in a similar manner shows a molecular ion peak at 258.
    Similarly, the compounds of Examples 9-20, shown in Table 1, are prepared, showing the structures and characteristics of oxazolidone-2 (I).
    Dosage. The bacteriostats of formula (I) can be introduced by any standard techniques that ensure the contact of the active principle with the site of exposure in the body of the hydrophobic body. They may be administered together with other pharmaceutical preparations, either as a separate therapeutic agent or in combination of therapeutic agents. They may be administered as such, but usually they are administered with pharmaceutical carriers selected in accordance with the chosen type of administration and accepted pharmaceutical practice.
    0
    five
    8317
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    12
    The dose administered depends on the pharmacodynamic characteristics of the particular agents and the method and type of administration; the age, health and weight of the patient, the nature and extent of the symptoms, the type of concurrent treatment, the frequency of treatment and the target effect. Typically, the daily dose of the active ingredient may be 5-20 mg / kg body weight. In the case of more potent compounds of formula (I), the daily dose is usually 5-15, preferably 5-7.5 mg / kg, and it is taken 2-4 times per day or as a preparation with a long release. Drugs can also be entered parenterally.
    A deliberate therapeutic level in the human body should be provided by oral administration of a dose of 5–20 mg / kg body weight, taken 2–4 times a day. In case of acute, i.e. life-threatening infections, the dosage can be increased accordingly.
    Compositions suitable for internal use contain from 1.0 to 500 mg of active ingredient per preparation. In these pharmaceutical compositions, the active ingredient is usually in an amount of 0.5 to 95% by weight, calculated on the total weight of the composition. The active ingredient can be administered orally in solid dosage forms, for example, in the form of capsules, tablets or powders, or in the form of liquid pink forms, for example, elixirs, syrups and suspensions, it can also be administered parenterally in sterile liquid dosage forms. Gelatin capsules contain the active ingredient and powdered carriers, for example, lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. The same diluents can be used to make tablets. Both tablets and capsules can be made in the form of drugs that provide a long-term release of drugs for several hours. Tablets may be coated with sugar or a film that masks the unpleasant odor and protects the tablet from exposure to the atmosphere or provides selective decomposition of the tablet in the gastrointestinal tract.
    Liquid preparations for oral administration may contain coloring and flavoring agents for ease of use by the patient.
    Suitable carriers for parenteral solutions are water, suitable oil, physiological saline solution, aqueous dext with water and 10% by volume of propylene glycol. The resulting solution is converted to an isotonic state with chlorine sodium and sterilized.
    Suspension. An aqueous suspension for oral administration is prepared so that each 5 ml contains 75 mg of finely dispersed active
    troz (glucose) and related sugar Q ingredients, 200 mg of sodium carboxymethylcellulose, 5 mg of benzoate per ri, 1.0 g of sorbitol solution, and 0.025 mg of vanillin.
    solutions and glycols, for example, propylene glycol or polyethylene glycol. Solutions for parenteral administration contain a water-soluble salt of the active ingredient, suitable stabilizer-5 indicates that compounds of the formula
    (I) are biologically active against gram-negative and gram-copulatory bacteria, including p-lactamase-isolating isolates
    ziruyushchy agents and, if necessary, buffer substances. Suitable stabilizers are antioxidants, for example sodium bisulfate, sulfite.
    (I) are biologically active against gram-negative and gram-copulatory bacteria, including p-lactamase-isolating isolates
    sodium or ascorbic acid, or 2o of the Staphylococcus aureu s.
    25
    35
    mixtures of these compounds. Citric acid, its salts and the sodium salt of ethylenediaminetetraacetic acid are used. In addition, parenteral solutions may contain preservatives, for example, benzalkonium chloride, methyl- or nropylparaben, and chlorobutanol.
    Pharmaceutical formulations for administering the compounds of the invention. ZO
    Capsules A large number of capsules are obtained by filling in standard two-part hard gelatin capsules, 75 mg of powdered active ingredient, 150 mg of lactose, 24 mg of talc and 6 mg of magnesium stearate.
    Soft gelatin capsules. Prepare a mixture of the active ingredient in soybean oil and inject it with a volume pump into a gelatin to form soft gelatin capsules containing 75 mg of the active ingredient. The capsules are washed and dried.
    Tablets, A large number of tablets are prepared by standard methods so that one tablet contains 75 mg of the active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 250 mg of microcrystalline cellulose, 11 mg of corn starch and 98.8 mg of lactose. Appropriate coating coatings can be used to improve taste or slow absorption.
    Injection solutions. A composition suitable for perenteral administration by injection is prepared by stirring 1.5 May,% active ingredient 45
    50
    55
    The proposed active principles could have been found useful in the treatment of bacterial infections in humans and animals, including diseases of the respiratory, gastrointestinal, urinary and central nervous systems, blood interstitial fluids, soft tissues and bones.
    The compounds of formula (I) in vitro have a bacteriostatic action. The determination of the daily minimum bacteriostatic concentration (MBC) of the compounds of formula (I) on the tested strains of Staphylococcus epide midis and Escherichia coli is carried out according to the standard ry method of microorganism maintained using Mühler-Hinton broth.
    The effect of compounds (I) in vivo is determined by intraperitoneal administration to mice of cultures of an infecting microorganism diluted in order to achieve 90-100% mortality in control animals during the day. As diluents in case of infection with E.coli Trypsinase-soy broth is used, and in the case of Staphylococcus aureus, a 5% solution of CBJHioro stomach powder is used. Compounds are dissolved or weighed in Methocel® 0.25% aqueous solution (Methocel®: Hydr xypropyl Methylcellulose E15 Premiu Dow Chemical Company) for oral administration or sterile distilled water containing 5 / i DMSO (Fisher Scientific Company) for skin use, Myppam is administered
    one with water and 10 vol.% propylene glycol. The resulting solution was converted to an isotonic state with sodium chloride and sterilized.
    Suspension. Aqueous suspension for oral administration is prepared in such a way that every 5 ml contains 75 mg of finely dispersed active
    ingredient, 200 mg of sodium carboxymethylcellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, and 0.025 mg of vanillin.
    Application, Tests Conducted
    show that compounds of formula
    (I) are biologically active against gram-negative and gram-positive bacteria, including the p-lactamase-producing isolates of the microorganism Staphylococcus aureu s.
    five
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    ABOUT
    Q
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    0
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    The proposed active principles may be useful in the treatment of bacterial infections in humans and animals, including diseases of the respiratory, gastrointestinal, urogenital and central nervous systems, blood, interstitial fluids, soft tissues and bones.
    The compounds of formula (I) in vitro have a bacteriostatic effect. The determination of the daily minimum bacteriostatic concentration (MBC) of the compounds of formula (I) on the tested strains of Staphylococcus epidermisis and Escherichia coli was carried out according to the standard or microdilution method using Muller-Hinton broth. The results are shown in the scoreboard2
    The effect of compounds (I) in vivo is determined by intraperitoneal administration to mice of cultures of an infecting microorganism diluted in order to achieve 90-100% mortality in control animals during the day. As diluents in case of infection with E. coli microorganism is used trypsinase-soy broth, and in the case of Staphylococcus aureus, a 5% solution of CBJHioro stomach powder. Compounds are dissolved or weighed in Methocel® 0.25% aqueous solution (Methocel®: Hydroxypropyl Methylcellulose E15 Premium, Dow Chemical Company) for oral administration or sterile distilled water containing 5 / i DMSO (Fisher Scientific Company For subcutaneous administration, the compounds are administered the proposed compounds at the time of infection and 4 hours after it. Mortality is recorded every day until the end of the test, 7 days after infection, and the effective dose of ED is calculated according to the method of the authors L.G.Kecd and H.Mucnd.
    The results are shown in Tables 3 and 4, where EDzo is a dose with 50% effective, NT. - has not been tested. When studying compounds of formula (I), it was found that in laboratory tests the class of oxazolidinones generally does not cause serious painful changes in animals at a dose of up to 480 mg / kg. The only insignificant toxic effect of some members of this class of compounds is related to prolonged anorexia.
    Thus, the compounds obtained in accordance with the proposed method are promising for the creation of bacteristatic preparations,
    权利要求:
    Claims (2)
    [1]
    Invention Formula
    The method of obtaining 3- (4-substituted phenyl) -5-acylamidomethyloxazolidinov-2 of the general formula
    about
    -L
    , CH —NH-CO-R
    (I)
    in the form of 1-isomers or a mixture of d- and 1-stereoisomers, where P .. is halogen, ethynyl, mono- or trisubstituted with halogen C -C-acyl, 1-hydroxy- or 1-methoxy-C2-C4- alkyl, 1-hydrazono-C 2.-C4-alkyl, or 1-C, 2.-C4-acylhydrazono-C
    [2]
    2.-SF-alkyl;
    R2 is a C-C-alkyl or a C, -C-alcoxy-group,
    characterized in that the compound of the general formula
    About N (0
     (Ii)
    in the form of a 1-isomer or a mixture of d- and 1-stereoisomers, where Yae is hydrogen, fluorine, chlorine or bromine,
    subjected to interaction with carboxylic anhydride of the General formula
    Rj-COOH, (III
    where R2 has the indicated values, in an inert solvent in the presence of a base at a temperature from to room temperature and isolate the target product, where Rj | - fluorine, chlorine or bromine, or the resulting compound of the general formula
    CH2-NH-CO-R2
    (Iv)
    where R has the indicated meanings, reacts with the corresponding carboxylic anhydride in methanesulfonic acid medium at ambient temperature and isolates a pellet product, where R is mono- or trisubstituted with halogen, is acyl, or an intermediate product, where R is unsubstituted C-C - acyl, is subjected to reduction with an alkali metal borohydride in an alcohol environment at ambient temperature to obtain the desired product, where R is 1-hydroxy-C2-C-alkyl, or an intermediate product, where R is unsubstituted C-acyl, is mutually It is treated with hydrazine in absolute alcohol at the boiling point of the reaction mixture and the desired product is isolated, where R, is 1-hydrazono-C-C4-alkyl, or is reacted with an anhydride of the corresponding carboxylic acid in an inert organic solvent in the presence of base at ambient temperature and isolate the desired product, where R -1-C2, -C acylhydrazono-C-Cf-alkyl, or a compound of formula (IV) is reacted with silver trifluoroacetate and iodine in an inert organic solvent at ambient temperature, the product is isolated with an ieline, where R is iodine, or it is reacted with trimethylssyl acetylene in an inert organic solvent in the presence of a base, palladium (II) bis (triphenylphosphine) chloride and copper (I) iodide at heating to 45 C followed by removal of the trimethylsilonyl group by acid hydrolysis and isolation of the target product, where RJ is ethinyl.
    SNS (SNG) SNON
    HE
    OSSN ShzSNon SN / SN
    9n
    (
    about
    N-NHCH
    he
    SNSNSn he
    he is nos -nClClCHj COСНзСН СН6н
    20CF CH Table 1
    CH 125-129
    CH, 146.1-150.1 dl
    CH:
    (M 292.1423)
    CHj122-124
    CH, 148-1601
    CHS270-27 dl
    sn.
    (P 306.1579)
    CHj108-104dl.
     99-101dl
    175.8-178.8 1 1
    CH,
    19152831720
    table 2
    MBD broth for microdilution, Compound /
    by example
    Staphylococcus Escherichia epidermidis coli
    16,, 0
    ,, 0
    36,, 0
    4128, 0
    ,, 0
    63,150.0 18 1.6100.0
    712, 0
    816.0; 128.0
    Table 3
    Connection. „
    microorganism that infects
    Staphylococcus Escherichia aureuscoli
    1--4,424,7
    279.2; -120.0
    36,, 0
    442.0; -120.0
    523, 0
    62,117.4, 4100.0
    750,0NT
    Table 4
    The compound infecting ED microorganism for example
    Staphylococcus Escherichia aureus coli
    16,, 0
    280,5HT
    34,, 0
    410, 0
    521, 0
    , 326.3, 4100.0
    712.2 120.0
    Compiled by ZoLatypov Editor NoBobkova Tehred M. Didyk Proofreader V. Kabatsy
    Order 7519/58 Circulation 352 Subscription
    VNIIPI State Committee for Inventions and Discoveries at SKIT USSR 113035, Moscow, Zh-35, 4/5 Raushsk nab.
    Production and publishing plant Patent, Uzhgorod, st. 1; 1garina, 101
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US67674584A| true| 1984-12-05|1984-12-05|
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