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    • 专利摘要:
    An optically active compound represented by the following formula <CHEM> wherein R represents a group selected from the class consisting of linear or branched C1-C4 alkyl groups, C3-C4 alkenyl groups, C3-C4 alkynyl groups, a carboxy-substituted methyl group, a cyano-substituted methyl group, C3-C6 cycloalkyl groups which may be substituted by carboxy, carboxy-substituted C1-C5 alkyl groups, a benzyl group and a phenyl group, and a pharmaceutically acceptable salt thereof; a process for producing the same; and their use as antibacterial agents.
    公开号:SU1195908A3
    申请号:SU833610702
    申请日:1983-05-30
    公开日:1985-11-30
    发明作者:Накагава Сусуми；Накано Фумио；Исизима Руосуке；Иватсуки Икио；Ивадаре Сиуичи
    申请人:Баниу Фармасьютикал Ко.,Лтд.(Фирма)；
    IPC主号:
    专利说明:

    Priority signs: 05/31/82 at R-methyl, ethyl, N-propyl, isopropyl, 2-propenyl, 2-propint, carboxymethyl, cyanomethyl, 1-carboxy-1-mbtsh1ethyl, cyclopentyl, phenyl or benzyl;
    03.24.83 with R - 1-carboxy-1-methylpropyl, 1-carboxy-1-cyclopropyl, 1 - carboxy - 1 - cyclopropyl,. .
    butyl, 1-carboxy - 1 - cyclo a 1 carboxy - 1 - cycle pentyl or
    1 - carboxy - I - cyclohexyl.
    I
    The invention relates to a process for the preparation of novel biologically active chemical compounds, namely, derivatives of 2-oxo-1-azetidine sulfonic acid or their salts with alkali metals, which have an antibacterial effect.
    The aim of the invention is to obtain new derivatives of 2-oxo-1 a3 etidine sulfonic acid, with a broad spectrum of antibacterial action and high efficiency.
    Example 1. o-Benzyl-N-Boc-t-fluorotreinine hydroxamate.
    1.1 g (7.29 mmol) of L - (-) - a-fluorotreonine and 1.5 ml (10.9 mmol; triethylamine was dissolved in 4 ml of water, and a solution of 1.9 g (8.02 mmol) Boc- S in 4 MP dioxane. The mixture was stirred at room temperature for 20 hours. 11 ml of water was added to this reaction solution.
    and the mixture was washed with two portions of 15 ml of ethyl acetate. Then the aqueous layer was treated with 11 ml of ethyl acetate and the pH of the mixture was adjusted to 2 with 6 n. hydrochloric acid solution. The ethyl acetate layer was separated and then tsvuy were extracted in portions of 6 ml of ethyl acetate. The extracts were combined, washed with two portions of 7 ml of 5% hydrochloric acid, saturated with sodium chloride, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to obtain 1.93 g of N-BOC-L-p-fluorotreonine as oils. 2 .32.32 g (14.6 mmol) p-benzylhydroxylamine hydrochloride was dissolved in 64 ml of water and the pH of the solution was adjusted to 4.5 with 6N. sodium hydroxide. A solution of 1.93 g of N-Boc-L-β-fluorotreonin in 16 ml of tetrahydrofuran was added to the solution. Then,
    maintaining the pH of the solution to 4.5 with 6 n. hydrochloric acid, a solution of 3 g (14.6 mmol) of K, H-di5 cyclohexyl carbodiimide in 48 ml of tetrahydrofuran was added dropwise with stirring. Stirring was continued until the pH change became imperceptible. Then, tetrahydrofuran was distilled off under reduced pressure, and 80 ml of ethyl acetate was added. Insoluble N, N-dicyclohexyl urea was separated by filtration and the ethyl acetate layer was separated. The ethyl acetate layer was then extracted in two portions of 40 ml of ethyl acetate. The ethyl acetate extracts were combined dried with sodium sulfate and concentrated under reduced pressure. The precipitated crystals are separated by LILILTRATION and washed with ether. The yield was 1.95 g (yield from L-β-fluorotreonine. 78.1%). Melting point 122-123 °.
    IR spectra (KVg),: 3350,
    5 1665, 1530, 1370, 1310, 1250, 1170.
    NMR (dimethyl sulfoxide-d g) cG, ppm: 1.42 (9H, singlet); 3.94, 7 (4H, multiplet); 4.83 (2H, singlet) i 5.4 (1H, chuplet, J 5 Hz),
    0 6.45 (1H, .duplet, J 7.5 Hz),
    7.43 (5H, singlet), 11.28 (1H, singlet).
    Example 2. (3S, 4R) - (-) - 3- -Bac-amino-1-benzyloxy-4-fluorome5 til-2-oxoazetidine.
    1. 1.46 g (4.26 mmol) 0-benzyl-H-Vosperfluorotinhydroxamate was dissolved in 42 ml of anhydrous acetonitrile and 1.55 g was added
    0 (5.54 mmol) triphenylphosphine,
    0.54 ml (5.54 mmol) of carbon tetrachloride and 0.54 ml (6.4 mmol) of triethylamine. The mixture was stirred at room temperature for 18 hours.
    3
    nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure and chromatographed on a silica gel column using 4: 1 hexane-ethyl acetate as the eluent. The product was concentrated and the residue was crystallized from isopropyl-ether to obtain 390 mg (28.3%) of the intended compound. Melting point 86-87 C.
    cijo (, CHjOH). Found,%: C 59,32; H 6.75; N 8.70.
    .
    Calculated,%: 59.25; H 6.53; N 8.64.
    IR spectra (KBr), cif: 3330, 1760, 1710 ,. 1540, 1285, 1170, 995.
    NMR (dimethyl sulfoxide-d) cH, ppm:
    1.41 (9H, singlet), 3.9-4.4 (2H,
    multiplet); 4.7 (2H, double doublet, J 48 and 3 Hz) -; 4.99 (2H, singlet) i 7.48 (5H, singlet); 7.67 (1H, doublet, J = 7 Hz).
    2. 17.15 g (50.1 mmol) O-benzyl-N-Boc-fluorotreonine hydroxymate and 21 g (65.1 mmol) of triphenylphosphine were dissolved in 430 ml of anhydrous acetonitrile. Maintaining a solution temperature of 5 ° C, a solution of 9.47 ml (65.1 mmol) of diethyl azodicarboxylate in 20 ml of anhydrous acetonitrile was added dropwise over 20 minutes. The reaction mixture was stirred at 15 ° C for 4 hours and concentrated under reduced pressure, was separated by silica gel column chromatography and crystallized from isopropyl ether to give 6.78 g (41.7Z) of the title compound.
    Froze (3S, 4R) - (-) - 3-Bpc-amino-4-fluoromethyl-2-oxo-azetidine.
    1. 10 g (30.8 mmol) (3S, 4R) - (-) - 3-Boc-amino-1-benzyl-oxy-4-fluorometsh-1-2-oxo-azetidine was dissolved in 500 ml of methanol and 1 g was added to the solution 10% palladium on coal. Oxo-asetide compounds were hydrogenated at atmospheric pressure for 2 hours. The catalyst was separated by filtration, the filtrate was prepared to obtain (3S, 4R) - (-) - 3-Boc-amino-4-fluoromethyl-1-hydroxy-2-oxo-azetidine.
    908. 4.
    2. A solution of 1-hydroxyazetidinone obtained in Example 3.1 in 150 ml of methanol and 150 ml of water was adjusted to pH 7 with 10% sodium hydroxide solution. Keeping the pH of the solution at 7, a 20% aqueous solution of titanium trichloride was added dropwise at 2 hours, then the mixture was stirred
    2 hours the pH of the reaction mixture brought
    to 8 and added 600 ml of 8% sodium chloride solution and 1200 ml of ethyl acetate. The insoluble matter was removed by filtration and the organic layer was separated from the aqueous layer. Then the aqueous layer was extracted with 600 ml of ethyl acetate. The extracts were combined, dried over sodium sulfate, and concentrated under reduced pressure. The residue was crystallized from isopropyl ether to give 1.82 g (yield from 1-benzyloxy compound 27.1%) of the desired compound.
    Melting point 189-190 ° (decomposition).
    d ° -110.2 (, CHjOH). Found,%: C 48.99; H 7.00, N 12.56.
     CgH jFNjOj.
    Calculated,%: C 49.54; H 6.92; N .12,84.
    IR spectra (KBr), cm: 3270, 1760, 1750, 1685, 1540, 1295, 1170,
    1000
    NMR (dimethyl Isofhosphide-d), h. per million: 1.39 (9H, singlet), 3.34, 0 (1H, multiplet), 4.2-4.9 (3N, multiplet), 7.56 (1H, doublet,
    J 7Hz), 8.2 (1H, broad singlet).
    Example 4. (3S, 4R) - (-) - 3-p (2) -2- (2-Amino-4-thiazolyl) -2-methoxyimino-acetamide j-4-fluoromethyl-2-OXO-1-acetidine sulfonic acid . 1.610 mg (1.37 mmol) of (L) -2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid was added at -10 ° C to a solution of 315 ig (1.51 mmol)
    phosphorus pentachloride in 15 ml of methylene chloride. The reaction mixture was stirred at 30 minutes, cooled to. Then added 0.42 ml (3.02 mmol) of triethylamine and
    5 ml of water and the mixture was stirred
    : U) and within 3 minutes The organic layer was collected and dried over anhydrous potassium carbonate sulphate.
    five
    sodium to form chlorine acid solution.
    Separately, a solution of 300 mg (1.73 mmol) of (3S, 4R) - (-) - 3-Boc-Akino-4-fluoromethyl-2-oxoazetidine in 1.5 ml of cold trifluoroacetic acid was stirred for 1 h under ice cooling and infused under reduced pressure. Then add 5 ml of ethyl acetate and a mixture of evaporation. 20 ml of ethyl acetate was added to the residue and the mixture was cooled to -10 ° C. Triethylamine (0.96 ml, 6.88 mmol) was added and the acid chloride solution prepared in advance was added dropwise over 10 minutes. The mixture was stirred at a temperature of from -10 ° C to 30 minutes after removing the cooling bath. The mixture was stirred for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was extracted with ethyl acetate and water. The organic layer was taken, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was chromatographed on a scrubber gel wash using chloroform-methanol (97: 3) as eluent. The fractions containing the desired product were concentrated under reduced pressure, the precipitate was separated by filtration using ether. 600 mg (80.3%) of (3S, 4R) - (-) -, -3- (E) -2- (2-tritylamino-4-thiazolSl1) -2-methoxyiminoacetamide -4-fluoromethyl-2- oxoazetidine.
    2. Pyridine-sulfuric anhydride complex (525 mg, 3.3 mmol) was added to a solution of 600 mg (1.1 mmol) (3S, 4R) - (-) - 3- C (Z) -2- (2-tritylamino -4-thiazole1) -2-methoxyiminoacetamide} -4-fluoromethyl-2-oxoazetidine in 10 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for 3 days. Then dimethylformamide was distilled under reduced pressure and the residue was partitioned between ethyl acetate and water, the organic layer was collected, dried over sodium sulfate, then chromatographed on a flash silica gel column using chloroform-methanol (97: 3) as eluant. 1 fraction containing target pro 95908. 6
    duct, concentrated under reduced pressure to obtain (3S, 4S- (-) - (2) -2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamideJ-4-fluoromechane -1-oxoazetidine-1-sulfonic acid .
    3. The resulting (3S, 4R) - (-) - 3- (Z) -2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamideJ-4-fluoro (0 mets1-2-oxo-1 -azetidine- sulfonic acid was dissolved in 10 ml of formic acid and left to stand for 2 days. The solvent was removed from the reaction mixture at
    15 under reduced pressure, the residue was ground into powder using acetone and collected by filtration. The obtained powder was chromatographed on a washing column with a strong column using chloroform-methanol (6: 4) as an eluant to give 65 mg (yield after two stages, sulfonation and detritulation of 15.4%) of the target
    25 connections.
    IR spectra (KBr): 3450, 1770, 1665, 1625, 1530, 1270, 1240, 1050.
    PRI me R 5. (3S, 4R) - (-) - 330 C (2) -2- (2-amino-4-thiazolyl) -2- (1-carboxy-1-methylethoxyimino) acetamide | -4-fluoromethyl-2-oxo-1-acetic acid sulfonic acid.
    1. 784 g (1.37 mmol) (Z) -2- (2-v-tritylamino-4-thiazolyl) -2- (1-tert-butoxycarbonyl-1-methylethoxyimino) acetic acid was added at -10 ° C to a solution of 315 mg (1.51 mmol) of phosphorus pentachloride in 15 ml of methylene chloride. The reaction mixture was stirred for 30 minutes, cooled before and after adding 5 ml of water and 0.42 ml (3.02 mmol) of triethylamine was stirred at 0 ° C for 3 minutes. The organic layer was dried over anhydrous potassium carbonate-sodium sulfate to obtain an acid chloride solution.
    Separately, a solution of 300 mg (1.37 mmol) of (3S, 4R) - (-) - Boc-amino-4-fluoromethyl-2-oxoazetidine
    in 1.5 ml of cooled trifluoroacetic acid was stirred under conditions of ice cooling for 1 h. The reaction mixture was concentrated under reduced pressure and 5 ml of ethyl acetate was added to the residue. The mixture was again concentrated. 20 ml of ethyl acetate was added to the residue and 0.96 ml (6.88 mmol) of triethylamine was added, then a solution of acid chloride was added dropwise, the resultant was obtained, and the addition was carried out for 10 minutes. The mixture was stirred at a temperature of from -10 to for 30 minutes and then at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was extracted by adding ethyl acetate and water. The organic layer was collected, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified on a wash column with silica gel using chloroform-methanol (97: 3) as a solvent mixture (97: 3 to give 340 mg (36.8%) (3S, 4U - (-) - 3-C (g) -2- ( 2-tritylamino-4-thiazole1) -2- (1 -t-butoxycarbonyl-T-methylethoxyimino) -acetamide -4-fluoromethyl-2-oxoazetidine IR spectra (KBr): 3400, 1770, 1740, 1670, 1590, 1570.1200, 1190, 104.0, 995. 2. Pyridine-sulfuric anhydride complex (240 mg, 1.5 mmol) was added to a solution of 340 mg (0.51 mmol of azetidinone obtained in Example 5.1 in 6 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for 3 days. The organic mixture was concentrated under reduced pressure and extracted by adding ethyl acetate and water. The organic layer was separated, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was chromatographed on a silica gel wash column using elution mixture Khoroform - methanol to obtain 180 (47.3%) (3S, 4R) - (-) - 3-C (Z) -2- (2-tritylamino-4-thiazolyl) -2- (1-treT, -butoxycarbonyl-1-methylethoxyimino ) -acetamide-4-fluoromethyl-2-oxo-1 -azetidine sulfonic acid. IR spectra (KBg), cm-: 3400, 1755, 1725, 1670, 1590, 1570, 1280 1245, 1200, 1140, 1045. 3. Solution of the compound obtained in Example 5.2 (180 mg, 0.24 mmol), in 5 ml of formic acid was left to stand for 4 days, then concentrated. The residue was triturated with acetone and collected as poroipse by filtration. The solid was chromatographed on a silica gel wash column using chloroform-methanol (7: 3) as eluent. The fractions containing the desired product were concentrated under reduced pressure (NII. The residue was separated by filtration using acetone and the target compound was obtained as a powder (60 mg, 55.3%). IR spectrum (KBr), 1775, 1665, 1530 , 1535, 1400, 1270, 1240, 1200, 1165, 1050. Example 6. (3S, 4R) - (-) - 3-CH2-Amino-4-fluorometh-2-oxo-ethane 3, 0 g (13.7 mmol) (3S, 4U - (-) - 3-Boc-amino-4-fluoromethyl-2-oxo-azetidine was dissolved in 15 ml of trifluoroacetic acid cooled to. The solution was stirred at this temperature for 1 hour. The reaction mixture was evaporated under reduced pressure and to benzene was added to the residue. evaporated. This operation was repeated twice. The residue was dissolved in 100 ml of ethyl acetate and the solution was cooled to 0 ° C. 5 ml of triethylamine was added and then 2 ml (13.7 mmol) of benzyl porphyrate was added dropwise with stirring. then added cold water. The ethyl acetate layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified on a silica gel column using ethyl acetate-hexane (7: 3) as an eluant and crystallized from isopropyl ether to give. , 8 g (52%) Spruce compound. Melting point 98-100 C. IR spectrum (KBG), cm: 3280, 1760, 1745, 1690, 1545, 1270, 1145, 1.020, 1000. H 11 R (dimethylsulfoxide-dg) "L, h. Per million: 3 , 7-4.1 (1H, miltiflet) j 4.2-4.9 (ZN, multiplet); 5.11 (2H, singlet); 5.96 (1H, doublet, J 8 Hz), 6.6 (1H, singlet); 7.36 (5H, singlet). Example 7. Tetra-n-butylammonium (3S, 4k) - (-) - 3-Cg-amino-4-fluoromethyl-2-oxo-1-azetidine sulfonate.
    9
    The pyridine-sulfuric anhydride complex (1.91 g, 12 mmol) was added to the I solution of 1.51 g (6 mmol) (3S, 4R) () 3-Cr-amino-4 fluoromethyl-2-oxoazetidine in 20 ml of dimethylformamide. The mixture was stirred at room temperature for 5 days. The reaction mixture was poured into 300 ml of cold 0.5 M potassium phosphate solution, the pH of the monobasic solution was adjusted to 5.5, rinsed three times with 100 ml of methylene chloride each, and 2.04 g (0.6 mmol) of tetra-n-butylammonium was added. acid sulfate. The aqueous solution was extracted in 100 ml portions of methylene chloride. The extracts were washed with 8% sodium chloride solution, dried over sodium sulfate and concentrated. The precipitated crystals were collected by filtration after adding ethyl acetate. Thus, 2.5 g (73%) of the title compound were obtained.
    Melting point 113-115 ° C.
     : -12.1 (, C, iHjOH).
    Found: C 58.43) H 8.79; N 7.40.
    C H jNjFO S.
    Calculated,%: C 58.61 H, 8.43; N 7.32.
    IR Spectrum (KBr), 1765, 1720, 1530, 1280, 1135, 1040.
    NMR (dimethyl sulfoxide-d with) cH, ppm; 0.95 (12H, triplet, J 6.5 Hz); 1.10-1.80 (16H, multiplet)) 3.05-3.40 (8H, multiplet) 3.93 (1H, multiplet); 4.53 (1H, doublet, J 8.6 Hz), 4.72 (2H, double doublet, J 42 and 2 Hz); 5.08 (2H, singlet), 7.40 (5H, singlet), 8.05 (1H, doublet, J 8.8 Hz).
    Example 8. Potassium (3S, 4R) - (-) - 3- (g) -2- (2-amino-4-thiazole1) -2-methoxyiminoacetamide J-4-fluoromethyl-2-oxo-1-acetidine sulfonate.
    1. 350 mg of 10% palladium on carbon was added to a solution of 700 mg (1.2 mmol) of tetra-n-butylammonium (35 4K) - (-) - 3-Cr-amino-4-fluoromethyl-2-oxo- 1-azetidine sulfonate in 15 ml of dimethylformamide and azetidine compound were hydrogenated for 1 h. The catalyst was removed by filtration through Celite, washing with 2 ml of dimethylformamide. The filtrate industrial solution was combined and added 178 mg (1.3 mmol) of 1-hydroxybenzotriazole and 241 mg (1.2 mmol) of (Z) -2- (20810
    -amino-4-thiazolyl) -2-methoxyiminoacetic acid. While cooling with ice, 260 mg (1.26 mmol) of N, N -dicyclohexylcarbodiimide were added and the mixture was stirred at room temperature for 17 hours. The filtrate was separated by filtration and distilled under reduced pressure. The residue was purified by chromatography on silica gel using acetone acetone (4: 1-1: 2) mixture to give 524 mg (70%) tetra-n-butylammonium (35, 4K) - (-) - 3-C (g) -2 - (2-amino-4-thiazolyl) -2-methoxyiminoacetamide} -4-fluoromersh1-1-acetidine sulfonate.
    IR spectrum (KBG), cm-: 1770, 1670, - 1620, 1535, 1270, 1040.
    NMR (dimethyl sulfoxide-d) cG, h per million: 0.95 (12H, triplet, J = 7 Hz), 1.10-1.80 (16H, multiplet)} 3.00-3.50 (8H, multiplet); 3.70-4.10 (4H, multiplet); 4.76 (2H, multiplet); 4.82 (1H, double doublet, J 7.5 and 2.0 Hz) j 6.76 (1H, singlet) 7.21 (2H, broad singlet); 9.36 (1H, doublet, J 7.5 Hz).
    2. A solution of 479 mg (0.77 mmol) of the tetra-n-butylammonium salt obtained in Example 8.1 in 20 ml of water was treated with activated carbon and passed through a column filled with 5 ml of Diaion resin SK-102 (K. Fractions containing the target the product was lyophilized to obtain 260 mg (87.2%) of the target compound. d: -23.5 ° (, H ,, 0). IR spectrum (KBr), cm-i: 1775, 1665, 1620, 1535, 1380, 1270, 1245, 1050, 960, 815, 720, 650.
    NMR (BrO) e / ppm: 4.03 (3N, singlet); 4.15 (1H, multiplet); 4.92 (2H, multiplet); 5.01 (1H, doublet, J 2.5 Hz); 6.97 (1H, singlet).
    Example 9. Potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thiazolyl) -2- (1-carboxy-1-methylethoximino) acetamide-4-formethyl-2 -Oxo-1-azethidine alfonate.
    1. A solution of 2.14 g (3.73 mmol) of tetra-n-butylammonium (3S, 4R) - (-) - 3-Cb2-amino-4-fluoromethyl-2-oxo-1-azetidine sulfonate in 75 ml of dimethylformamide was subjected to hydrogenation for 2 hours in the presence of 640 mg of 10% palladium on
    eleven
    : corner. The catalyst was separated by filtration, to the filtrate was added 1.64 g (3.73 mmol) of 2- (2-amino-4-thiazolyl) -2-1-diphenylmethoxycarbonyl-1-methylethoxyiminoacetic acid, O, 55 g (4.07 mmol) 1-hydroxybenzotryazole and 0.77 g (3.75 mmol) of N, N -dicyclohexylcarbodiimide, the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated under reduced pressure to remove dimethylformamide. Methylene chloride was added to the residue and the insoluble material was removed by extraction. The residue was subjected to chromatography on a silica gel wash column using acetone methylene chloride (3: 7-6: 4) as eluent. The resulting solid was mixed with 9.4 ml of anisole and the mixture was cooled to. Trifluoroacetic acid (47 ml) was added, the mixture was stirred at OC for 15 minutes. Ethyl acetate was added to the residue and the residue was separated by filtration. The isolated product was crystallized from ethyl acetate to give 1.20 g (70%) of (3S, 4R) - (-) (2-amino-4-thiazolyl) -2- (1-carboxy-1-methylethoxyimino) acetamide -4 -fluoromethyl-2-oxo-1-azetidine sulfonic acid.
    2. 720 mg of the compound obtained in Example 9.1 were suspended in 25 ml of water and, when cooled, the pH of the medium was 5.5 to 0.4 n. potassium hydroxide solution. The solution was liofstilized. Acetonitrile was added to the residue and the mixture was concentrated. three times. The residue was triturated with ether and filtered off to give 840 mg of the title compound.
     -16.4 (,).
    IR Spectrum (KBG), cm: 3400, 1780, 1670, 1590, 1540, 1400, 1370, 1275, 1245, 1250, 1160, 1050.
    NMR (dymvylsulfoxide-d) cG, ppm: 1.40 (3N, singlet); 1.44 (ZN, singlet)} 3.8-4.3 (1H, multiplet) i 4.3-5.2 (ZN, multiplet) 6.80 He, singlet), 7.23 (2H, broad singlet ).
    Example 10. Potassium (3S, 4R) () 3- (g) -2- (2-amino-L-thiazolyl) -2-phenyl xyiminoacetamide-4-fluoromethyl-2-OXO-1-azetidine sulfonate.
    19590812
    170 mg of 10% palladium, 574 mg (1 mmol) of tetra-n-butylammonium (3S, 4K) - (-) - 3-Cb2-amino-4-fluoromethyl5 -2-oxo-1- azetidine sulfonate in
    20 ml of dimethylformamide and tetra-n-butylammonium salt of hydrogenation at room temperature for 2 hours. The catalyst was separated by filtration and
    10 to the filtrate added 263 mg
    (1 mmol) (g) -2- (2-amino-4-thiazolyl) -2-phenoxyiminoacetic acid, 148 mg (1.1 mmol) -1-hydroxybenzotriazole (NEW t) and 206 mg (1. mmol)
    15 K, N-dicyclohexes1 carbodiimide
    (DSS). The mixture was stirred at room temperature for 18 hours. The reaction mixture was evaporated under reduced pressure, and methyl methylene chloride was added to the residue. The insoluble matter was separated by filtration. The filtrate was subjected to chromatography on a silica gel wash column using a mixture as eluent.
    25 acetone - methylene chloride (3: 7 - 6: 4). The fractions containing the desired product were separated and concentrated to dryness under reduced pressure. The residue was dissolved in water and passed through a Diaion S (K) column. The fractions containing the target product, liofilizovane with obtaining
    . -340 mg (70.6%) of the title compound as a white powder.
    iZO
    : -16.9 (, H, 0).
    IR spectrum (KBG), cm-: 3470, 3370, 1780, 1670.11620, 1595, 1540, 1490, 1280, 1200, 1055.
    NMR (dimesh1sulfoxide-1) cGh. 40 per million: 3.8-4.2 (1H, multiplet); 4.4-5.2 (3N, multiplet) j 7.0-7.5 (8H, multiplet); 9.63 (1H, doublet, J 8 / Hz).
    Example 11. Potassium (3S, 4R) 45 - (-) - 3- (2) -2- (2-amino-4-thiazole1) -2-ethoxyimoacetamide 3-4-fluoromethyl-2-OXO-1-azetidine sulfonate.
    Following the procedure of Example 10, 200 mg (46.1%) of the title compound were obtained using (Z) -2- - (2-aminr-4-thiazolyl) -2-ethoxyiminoacetic acid;
    oif,: -26 (, H, 0).
    IR spectrum (KBG), cm: 3450, 1775, 1660, 1620, 1535, 1270, 1240, 1050.
    NMR (dimethylsulfoxide-d /):, hours per million: 1.21 (3N, triplet.
    j 7 Hz); 3.8-4.2 (1H, multiplet) 4.21 (2H, quadruplet, J 7 Hz)} 4.3-5.2 (ZN, multiset 6.74 (1H, singlet) 7.20 (2H, broad singlet)} 9.30 (1H, doublet, J 8 Hz).
    Example 12. Potassium (3S, 4R) - (-) - 3-t (Z) -2- (2-amino-4-thiazole1) -2-benzyloxyiminoacetamideJ-4-fluoromethins1-2-oxo-1-azetidine sulfonate.
    Following the procedure of Example 10, using 420 mg (84.8%) of the title compound using (2) -2- (2-amino-4-thiazolyl) -2-benzyloxyminoacetic acid.
     -b zO) infrared spectrum (KVg), 3450,
    1775, 1670, 1620, 1535, 1270, 1245, 1050.
    NMR (dimethyl sulfoxide-d) (G, ppm: 3.8-4.2 C1H, multiplet) 1 4.3-5.1 (3N, multiplet); 5.18 (2H, singlet) $ 6.79 (1H, singlet); 7.23 (2H, broad singlet) 7.39 (5H, singlet) 9.45 (1H, doublet, J 8 Hz).
    Example 13. Potassium (3S, 4R) - (-) - 3 -. (G) -2- (2-amine-4-thiazolyl) -2-n-propoxyiminoacetamide-4-fluoromethyl-2-oxo-1-azetidine sulfonate .
    Following the procedure of Example 10, using (g) -2- (2-amino-4-thiazolyl) -2-n-propoxyiminoacetic acid, 350 mg (78.2%) of the desired compound were obtained.
     -23 ° (, HZU).
    IR spectrum (KBG), cm-: 3450 ,, 1775 1665, 1620, 1530, 1270, 1245, 1050.
    NMR (dimethyl Isofhosphide-dJ) s /, ppm: 0.89 (GD, triplet, J 7 r) v 1.61 (2H, multiplet); . 3.7-4.2 (1H, multiplet) J 4.02 (2H, triplet, J 7 Hz) 4.3-5.3 (3N, multiplet) j 6.73 (1H, singlet)} 7.2 (2H, broad singlet); 9.31 (1H, doublet, J 8 Hz).
    Example 14. Potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thiazolyl) -2-2-propene10xiiminoacetamide-4-fluoromethyl-2-oxo-1-azetidine sulfonate.
    Following the procedure of Example 10, using (2) -2- (2-amino-4-thiaz olyl) -2 - (2-p one of shoxyimino) acetic acid, 290 mg (65.1%) of the desired compound were obtained.
    bi: -25.6 (, H, 0).
    IR spectrum (KBG), cm-: 3450, 1770, 1660, 1620, 1270, 1240, 1050, I 1005.
    NMR (dimethyl sulfoxide-dg) (G ppm: 3.7-4.2 (1H, multiplet) -, 4.3-5.5 (7H, multiplet) 6.76 (1H, yinglet); 7, 22 (2H, broad singlet) 9.36 (1H, doublet, J 8 Hz). Example 15. Potassium (3S, 4R) 0 - (-) - 3-C (2) -2- (2-amino-4 -thiazolyl) -2-cyanomethoxyiminoacetamide -4-fluoromethyl-2-oKco-l-azetidine sulfonate.
    Following the procedure of Example 10 using 5 (2) -2- (2-amino-4-thiazolyl) -2-cyanomethoxyiminoacetic acid, 310 mg (69.7%) of the desired compound were obtained.
    (Vl -25 ,, H, 0 ;. 0 IR spectrum (KBr), 3450,
    1770, 1660, 1620, 1530, 1270, 1240, 1050, 1020.
    NMR (dimethyl sulfoxide - d /) cr, ppm: 3.7-4.2 (1H, multiplet) j I4.3-5.2 (2H, singlet) i 6.92 (1H,
    singlet); 7.34 (2H, broad singlet) 9.60 (1H, doublet, J 8 Hz). : Example 16. Potassium (3S, 4R) - (-) - 3- (Z) -2-amino-4-thiazo-Schl) -20-cyclopentyloxymino acetamide 1-α-fluoromethyl-2-OKco-l-azetidiisulfonate. Following the procedure of Example 10, using (2) -2- (2-amino-4-thiazolyl) -2-cyclopentyloxyimnous acetic acid, 360 mg (76%) of the desired compound were obtained.
    sample -15.6 (,). IR spectrum (KBG), cm-: 3450, 1775, 1660, 1620, 1530, 1270, 1240, 1050, 990.
    NMR (dimethyl sulfoxide-d) /, ppm: 1.7 (8H, multiplet), 3.74, 2 (1H, multiplet); 6.73 (1H, singlet); 7.23 (2H, broad singlet) 9.24 (1H, doublet, J 8 Hz). .
    Example 17. Potassium (3S, 4R) - (-) - 3-I (Z) -2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetamide-4-fluoromethyl-2-oxo-1-azetidine sulfonate. Following the procedure of Example 10, using (Z) -2- (2-amino-4-thiazolyl) -2-isopropoxyiminoacetic acid, 300 mg (67.1%) of the desired compound were obtained. 5 -22.7 ° (, H, 0).
    IR spectrum KBG), cm-: 3450, 1775, 1660, 1620, 1530, 1270, 1240, 1050, 985. 15 NMR (dimethyl sulphoxide dg), cr, ppm: 1.2 (6H, doublet, J 6 Hz), 3.7-4.2 (1H, multiplet) 4.2-5.2 (4H, multiplet) y6.71 (1H, singlet) 7.20 (2H, broad singlet) - 9.22 TiH , duttet; J 8 Hz). Example 18. Potassium (3S, 4R) - (-) -3- (Z) -2- (2-amino-4-thiazolyl-2- (2-propinsioxyiminoimino) acetamistra J-4-fluoromesh1-2-oxo-1 -azetidine sulfonate Following the procedure of Example 10, using (g) -2-amino-4-thiazolyl) -2- (2-propynyloxyimino) acetic acid, 310 mg (69.9%) of the desired compound were obtained. -28.2 (,). IR (KBB), cm--: 3450, 2120, 1770, 1660, 1620, 1530, 1265, 1240, 1050, 1015, 1005. NMR (dimethyl sulphoxide-dj) tf. hours per million 3.48 (1H, triplet, J 2 Hz 3.7-4.2 (1H, multiplet), 4.3-5.2 (5H, multislet) 6.80 (IH, singlet) -, 7, 23 (2H, broad singlet); 9.41 C1H, doublet, J V Hz). Example 19. Potassium (3S, 4R) - (-) - 3-C (g) -2- (2-amino-4-thiazolyl) -2-car6methoxyiminoacetamide 3-fluoro-methyl 1 -2-oxo-1-azetidine sulfonate. . 574 mg (1 mmol) tetra-n-butylammonium (3S, 4K) - (-) - 3-Cb2-amino-4-fluoromethyl-2-oxo-1-azetidine sulfonate. dissolved in 20 ml of dimethylformamide and 170 mg of 10% palladium on carbon was added. The tetra-n-butylammonium salt was hydrogenated at room temperature for 2 hours. The catalyst was separated by filtration. To the filtrate were added 411 mg (1 mmol) i (Z) -2- (2-amino-4-thiazolyl) -2-diphenylmethoxycarbocylmethoxyimino-acetic acid, 148 mg (1.1 mmol) of 1-hydroxybenzotriazole and 206 mg (1 mmol) . N, N -dicyclohexylcarbodiimide. Oiecb stirring at room temperature for 18 h. The reaction mixture was then evaporated under reduced pressure and methylene chloride was added to the residue. Insoluble material was removed by filtration. The filtrate was chromatographed on a column of silica gel using acetone-methylene chloride (3: 7 6: 4) as eluent. The fractions containing the desired product were concentrated to dryness. 2.9 ml of anisole was added to the residue, and the 08J6 mixture was cooled to -15 ° C. Chilled trifluoroacetic acid (14.4 ml) was added, the mixture was stirred at a temperature of less than 15 minutes. Trifluoroacetic acid was distilled off under reduced pressure. To the residue was added ethyl acetate and the precipitate was filtered off. The precipitate was suspended in 20 ml of water and the pH of the suspension was adjusted to 5.0 with 0.4 n. potassium hydroxide solution with cooling and stirring. The solution was lyophilized to obtain 430 mg (92.3%) of the title compound as a white powder. 2j.-i9 ° (, Н, 0). IR (KBG), cm-1: 3450.1770, 1660, 1610, 1535, 1270, 1245, 1050. NMR (dimethyl sulphoxide-d) cl, ppm: 3.8-4.3 (1H, cartoon); 4.33 (2H, singlet) -, 4.4-5.3 (3N, multiplet) -, 6.85 (1H, singlet); 7.20 (2H, broad singlet) 11.6 (1H, doublet, J 8 Hz). Example 20. N-Cbz-Fluoro-Thinonamide. 1.50% solution of dimethylformamide - water 13.7 g (0.1 mml) L (-) t Fluorthreonine and 20.9 ml (16 mol) of triethylamine were cooled and, keeping the temperature at 5-10 ° C, added dropwise with stirring 21.6 ml (0.15 mol) of benzyl chloroformate. The mixture was stirred at this temperature for 1 h. Then the reaction mixture was poured into 350 ml of ice-water and washed with 200 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 2.5 with 6N. hydrochloric acid and extracted with ethyl acetate to give .25.7 (95%) N-Cbz-L-Y-fluorotreonin. , 2. Under ice cooling conditions, 21.6 g (0.105 mol) of N, N-dicyclohexylcarbodiimide was added to | A solution of 27.1 g (0.1 mol) of N-Cbz-L-r-,. -fluorotreonine and 16.1 g (0.11 mol) of K-hydroxy-succinate site (POZi) in 200 ml of tetrahydrofuran. The mixture was stirred at room temperature for 2 hours. The precipitated N, N-dicyclohexylurea was separated by filtration. The filtrate was added dropwise with stirring to an ice-cooled solution consisting of 32 ml 7.5 n. ammonia and 32 ml of tetrahydrofuran, the mixture was stirred for 2 hours. The reaction mixture was evaporated under reduced pressure. Remainder
    17
    dissolved in ethyl acetate and washed with a saturated aqueous solution of sodium chloride, the solution containing 5% sodium bicarbonate. Ethyl acetate was evaporated under reduced pressure, and the precipitated crystals were washed with a small amount of ethyl acetate to obtain 23.2 g (90%) of the desired compound.
    Melting point 141-145 0. +9.4 (,) .. IR spectrum (KBr), 3420, 3310, 3220, 1690, 1640, 1535, 1420, 1300, 1250, 1060, 1015, 870, 695.
    NMR (dimethyl sulfoxide-d) sL; hours per million: 4.0-4.30 (ZN, multiplet) 4.60 (1H, multiplet); 5.08 (2H, singlet) i 5.40 (1H, doublet, J 5 Hz), 6.88 (1H, doublet, J 8. Hz 7.20 (1H, broad singlet) ;, 7.307, 50 (6H singlet)
    Example 21. N-Cbz-0-Methylsulfo-lt fluorotreoninamide.
    3.36 g (13 mmol) of N-Cbz-L-jj-fluorotreoninamide was dissolved in 13 ml of anhydrous pyridine. While stirring, 1, -2 ml (15.3 mmol) of methanesulfonyl chloride was added dropwise to the solution at a temperature of less than 5 ° C. (iecb was continuously stirred at this temperature for 2 hours. The reaction mixture was then poured into ice water and mixed with ice and stirred for 30 minutes. The smeared crystals were separated by filtration to obtain 3.79 g (83.7% of the desired compound).
    IR Spectrum (KBr): 3430, 3320, 1670, 1620, 1535, 1350, 1250, 1185, 1070, 1050, 970, 930, 820, 750, 695.
    NMR (dimethyl sulfoxide-d p cG, - ppm: 3.16 (GD, singlet) 4.60 (1H, double doublet, J 9.5 Hz) j 4.70, (2H, double doublet, J 5 -and 3.7 Hz); 4.9-5.2 (3N, multiplet) j 7.35-7.50 (6H, -multiplet) i 7.557, 80 (2H, multiplet) -.
    Scheme 22. N-Cbz-0-Methylsulfonyl-L-g-fluoro-threonine (L-sulfo) -amide-tetra-n-butyl-ammonium salt.
    To a solution of 8.84 ml of 2-picoline in 45 ml of methylene chloride with stirring, keeping the temperature of the solution less, chlorosulfonic acid (2.99 ml) was added under cooling conditions. To the resulting solution was added a suspension of 3.79 g
    590818
    M-CHg-o-methylsulfonyl-L-1p-fluorotreoninamide in 60 ml of methylene chloride and the mixture was boiled with reverse holo; 16 hours. The reaction mixture was cooled and poured into 300 ml of a 0.5 M sodium phosphate solution (pH 4.5). The aqueous layer was separated and added to it. 5, 08 g of tetra-n-butylammonic acid sulfate. Received by
    10 solution was extracted with two portions of 74 ml of methylene chloride. The extracts were mixed to dryness under reduced pressure to obtain 5.65 (74%) of the title compound in
    5 form of foam.
    NMR (dimethyl Isofhosphide-d /) cL, ppm: 0.94 (12 N, triplet, J, 2 Hz), 1.1-1.8 (16H, multiplet), 3.05-3.50 (11H , multiplet) J
    0 4.50 (1H, multiplet), 4.52 (2H, double doublet, J 47.5 and 3.7 Hz) J 5.05-5.30 (ZN, multiplet) i 7.307, 50 (6H, singlet ) i 9.96 (1H, broad singlet).
    5 Example 23. Tetra-n-buttshtammonium (3S, 4R) - (-) - 3-CHg-amino-4-fluoromethyl-2-oxo-1-azetidine sulfonate.
    A solution of 3.75 g (5.6 mmol) of N Cbz0-C-methylsulfonyl-b - y-1 1 Tortreonin (N-sulfo) amide of tetra-n-butidimmonium in 9 ml of 1,2-dichloroethane was added to the mixture boiling under reflux, 2.0 g potassium carbonate,
    5 7.2 ml of water and 58 ml of 1,2-dichloroethane, and boiling with reflux for 20 minutes. The reaction mixture was cooled and methylene chloride was added to it. Organic layer
    Q was isolated and evaporated under reduced pressure to give an oily residue. The residue was chromatographed on a silica gel wash column using
    5 eluent mixture of ethyl acetate-acetone (4: 1). The fractions containing the desired product were separated and concentrated under reduced pressure. The crystalline residue was separated and washed
    Q with a small amount of ethyl acetate to obtain 0.51 g (15.9%) of the desired compound.
    PRI me R 24. Potassium (3S, 4R) - (-) - 3- (Z) -2- (1-carboxy-1-cyclo5 oxyimine o) acetamide j-4-fluorome-2-oxo -1-azetidine sulfonate.
    A solution of 631 mg (1.1 mmol) of tetra-n-butyl ammonium (3S, 4R) - (-) 19.
    -3-CЬ2-amino-4-fluoromethyl-2-oxo-azetidine-1-sulphate) nata in .20 ml of dimethylformamide was subjected to catalytic reduction in the presence of 190 mg of 10% palladium on carbon to give a dimethylformamide solution (3S, 4K) - ( -) - 3-amino-4-fluoromethyl-2-oxo-azetidine-1-sulfonic acid. 497 mg (1.1 mmol) of 2- (2-amino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl-1-cyclobutoxyimino) acetic acid, 164 mg (1.2 mmol) of 1-hydroxybenzotriazole (HOBt ) and 227 mg (1.1 mmol of N, N -dicyclohexylcarbodiimide (DOS), the mixture was stirred at room temperature for 20 hours. The reaction mixture was boiled dry under reduced pressure. Methylene chloride was added to the residue, the insoluble matter was removed by filtration. The solution was chromatographed on a washing column with silica gel using a mixture of acetone - methylene chloride (3:74, 5: 5.5). The mixture was cooled to -15 ° C and 12.6 ml of trifluoroacetic acid was added to it.The mixture was stirred at OC for 15 minutes, 50 ml of ethyl acetate and 10 ml of methanol were added to the reaction mixture, the mixture was concentrated to 5 ml under reduced pressure. To the concentrate were added 30 ml of ethyl acetate and the precipitated insoluble matter was separated by filtration, suspended in 20 ml of water and dissolved by adjusting the pH of the solution to 6 with n. potassium hydroxide solution. The solution was lyophilized, dissolved in a small amount of water and passed through a column filled with Diaion HP-20 resin. The column was zoned with water. The fractions containing the expected product were lyophilized to obtain 180 mg (yield 33.2%) of the target compound.
    o (| f.-15,0 (,) ..
    IR spectrum (KBG), cm-: 1770, 1660, 1585, 1535, 1395, 1270, 1245, 1205, 1120, 1050.
    NMR (dimethylsulfoxide-d j) ", 4. per million: 1.6-2.5 (6H, multiplet) j 3.8-4.2 (1H, multiplet) 4.3-2 (ZN, multiplet) J 6.80 (1H, singlet); 7.22 (2H, broad singlet); 11.67 (1H, doublet, J 8 Hz).
    Example 25. Potassium (3S, 4R) - (-) - 3- C (Z) -2- (2-amino-4-thiazolyl) 9590820
    -2- (1-carboxy-1-cyclopentoxyimino) acetamide-4-fluoromethyl-2-oxo-1-azetidine sulfonate.
    Following the procedure of Example 24 using 1.1 mmol of (3S, 4R) - (-) - 3-amino-4-fluorometsh1-2-oxo-1-azetidine sulfonic acid and 512 mg (1.1 mmol) (g) -2 - (2-amino-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl, Q -1- (cyclopentoxyimino) acetic acid) obtained 170 mg (yield 30.6%) of the target compound. -10.4® (, H O). IR spectrum (KBG), cm-: 1775, 1660, 5 1585, 1535, 1395, 1270, 1245, 1200, 1050.
    NMR (dimethyl sulfoxide-d) ppm: 1.4-2.3 (8H, multiplet) J 3.8-4.2 (1H, multiplet) - 4.3-5.2 Q (3N, multiplet), 6.80 ( 1H, singlet); 7.20 (2H, broad singlet); 12.1 (1H, doublet, J 8 Hz).
    Example 26. (3S, 4R) - (-) - 3- (g) -2- (2-Amino-4-thiazole1) -2- (15 -carboxy-1 -methylpropoxy) acetamido -4-fluoromethyl-2- potassium oxo-1-azetidine sulfonate.
    Similarly to the procedure described in Example 24, using as the starting compound Q (g) -2- (2-ami.no-4-thiazolyl) -2- (1-diphenylmethoxycarbonyl-1-methylproporcyimimino) acetic acid as Q, 80 mg ( yield 21.0% of the title compound
    JK-spectrum (KBG), cm--: 1770, 1660, 1580, 1595, 1395, 1270, 1245, 1050.
    NMR (DMSO-a SG, h, per million: 0.88 (3N, t, Hz) -, 1.40 (3H, S) i 1.80
    (2H, q, JV Hz) -, 3,, 25 (1H, m) i 4.3 -v5.2 (3H, m), 6.80 (1H, S), 7, 2 (2H, .BrS ) i 11.7 (1H, d, Hz).
    Example 27. (3S, 4R) - (-) - 3- (g) -2- (2-Amino-4-thiazolyl) -2- (1-carboxy-1-cyclopropoxyimino) acetamido 2-4-fluoromersh -1-2 -oxo-1-azetidine sulfoxial of the cyclo-ga.
    Using as the starting compound (E) -2- (2-amino-4-thiazole1) -2- (1-tert-butoxycarboxy1-1-cycdopropoxyimino) acetic acid, the process is carried out in the same manner as in Example 24, by crystallization of insoluble ethyl acetate from a mixture of 95% ethanol and methylene chloride, taken in a 1: 2 ratio, and 390 mg (yield, 36.0%) of the desired compound are obtained. Melting point 163-195 ° С -27.0 (, Н, 0), Ж-spectrum (КВг), 1750, 1670, 1630, 1570, 1250, 1240, 1200 1050. NMR (daso-df,) сГ, h per ppm: 1.3 -1.5 (4H, t); 3.7 4.1 (1H., Ha 4.3-5.1 (ZN, t), 7.1 (1H.S) - 9.45 (1H, d, Hz. Found: C 34, 25 | H 2.98-, N 15.29i S 14.30.: -C, jH, FN, -OgS2. Calculated,%: C 34.59; H 3.13 j N 15.51; S 14, 21. The compounds of the formula (l) or their pharmaceuticals. Acceptable salts may be used for the prevention or treatment of bacterial infections. The proposed compounds may be used in pure form or in combination with a pharmaceutically acceptable diluent or carried orally or parenterally. and capsules are usually applied with gum arabic, gelatin, sorbitol, tragacanth, polyvinyl pyrrolidone, lactose, sucrose, wheat starch, calcium phosphate, magnesium glycine stearate, talc, polyethylene glycol, silica, sodium lauryl sulfate, and so on. stearate gel and aluminum, edible oils, lecithin, sorbitan monooleate, gum arabi almond oil, coconut oil, oily esters, propylene glycol, ethanol, methyl parahydroxybenzoate, propionic acids and sorbic acid. Suppositories may contain conventional suppository. bases such as cocoa butter and glycerides. The antibacterial composition of the invention may be administered orally, in various forms, such as capsules, tablets, granules, liquid preparations, suspensions, emulsions, syrups or elixirs, as well as parenterally, for example, in the form of injections of suppositories and external or local agents such as oil 311, krEg-m, lotions, coating agents, powders and drops. The content of the compound of formula (I) or its salt in the COMPOSITION is 0.199% by weight. The dose of a compound of formula (I) or a salt thereof may vary depending on the condition of the patient, the type of controlled bacteria, and so on. The average single dose is 50; 100; 250 or 500 mg and has been found to be effective in the treatment of infections caused by many pathogenic bacteria. The daily dose is usually 1-1000 mg or more. The antibacterial composition is effective in treating and preventing bacterial infections such as hematosepsis, bronchitis, pneumonia, pulmonary abscess, peritonitis, pyelonephritis, cystitis, urethritis, cholecystitis, infections in the uterus (for example, endometritis and myometritis), secondary infections after burns, and surgical operations caused by granopositive bacteria such as E. CoEi, KCebsieKCa, Serratia, Enterobacter, Sagmonegfa, Pseudoliionas and Proteus. The table shows the minimum inhibitory concentrations of some of the active compounds of the invention (compounds AP). B. The table is conventionally designated as the following compounds: potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thiazolyl) -2-methoxyimioacetamido 3-4-fluoromethyl-2-oxo 1- azetidine sulfonate (A); potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thia zolyl) -2-e to xyminoacetamido 3-4-fluoromethyl-2-oxo-1-azetidine sulfonate (B) ; potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thiazolyl) -2-carboxymethoxyiminoacetamido} -4-fluoromethyl-2-axo-1-aetidine sulfonate (C) j. potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thiazolyl) -2- (1-carboxy-1-methyl ethoxyimino) acetamido-5-fluoromethyl-2-oxo- 1-azetidine sulfonate (D); potassium (3S, 4R) - (-) - 3-C (Z) -2- (2-amino-4-thiazolyl) -2-benzyloxyiminoacetamido-4-fluorometide-2-oxo-1-azetidine sulfonate (E); potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thiazolyl) -2- (1-carboxyl-1-cyclobutoxyimino) acetamidoJ-4-fluoromethyl-2-oxo -1-azetidine sulfonate (F) i
    23
    potassium (3S, 4R) - (-) - 3-C (Z) - (2-amino-4-thiazolyl) -2- (1-carboxy-1-cyclopentoxyimino) acetamidoJ-4-fluoromethyl-2-oxo-1 -az ethidine sulfate (G)}
    potassium (3S, 4R) - (-) - 3- (Z) -2- (2-amino-4-thiazolyl) -2-n-propoxyiminoacetamido-4-fluoromethyl-2-oxo-1-azetidine sulfonate (H) -,
    potassium. (3S, 4R) - (-) - 3- (Z) - (2-amino-4-thiazolyl) -2-isopropoxy with noacetamide to 3-4-fluoromethyl-2-oxo-1-azetidine sulfonate (I) J
    potassium (3S, 4R) - (-) - 3- (Z) -2-amino-4-thiazole-11-2- (-propenyloxy imino) acetamido3-4-fluoromethyl 2-oxo -1-azetidine sulfonate (J) j
    potassium (3S, 4R) - (- r) (Z) -2- (2-amino-4-thiazolyl) -2- (2-propynyloxyimino.) acetamido) -4-fluorometsh1-2-OXO-1-azetidine sulfonate (TO);
    potassium. (3S, 4R) - (-) - 3-t (Z) -2- (2-amino-4-thiazolyl) -2-cyanomethoxyiminoacetamido-4-fluoromethyl-2-oxo-1-azetidine sulfonate (L);
    potassium (3S, 4R) - (-) - 3-C (Z) -2- (2-amino-4-thiazole1) -2-cyclopentylAntibacterial Test bacteria
    ABCDEPT1 Escherichia NIHJ rO, 05 0.05 0.2 K8ebsieC a pneumoniae D-11 0.05 U, 05 0.2 Serratia marcescens IAM-1223 0.1 0.05 0.1 Interobacter aerogenes lAM-12348 0.1 0 , 1 SagmoneBKa paratyphi A-1015 0.05 0.05 0.05 Pseudomonas aeru 25 25 25 ginosa D-15 Pseudomonas aeruginosa A-9930 25 25 25 Aeinetobacter IAM-12087 12.5 25 25
    1959082 4
    hydroxyiminoacetamido-4-fluoromethyl-2-oxo-1-aze, tidinsulfonate (M),
    potassium (3S, 4R) - (-) - 3- (Z) -2- (2 / - (2-amino-4-thiazolyl) -2-phenoxy 5 noacetamido} -4-fermol II-2-oco-1- azethydinyslfonat CN)
    potassium (3S, 4R) - (-) - 3-C (Z) -2- (2-amino-4-thiazole1) -2- (1-carboxy-1-methyl) opoxyimino) acetamido -410-fluoromethyl-2 -oxo-1-azetidinsulfonate (O) -,
    (3S, 4R) - (-) - (Z) -2- (2-aMHHO-4thiazolyl) -2- (1-carboxy-1-cyclopropoxyimino) acetamido-4-fluorome15 tyl-2-oxo-1-azetidine sulfonic acid .
    Aztreonam was used as a control known compound: 20O
    C -, - CNHv.vCHj
    N

    al
    II
    N CH,
     I
    iH, N
     e
    0-c-soon
    about
    SOj t. sns current 10
    H activity of compounds, the number of cleSi / ml nutrient agar: 0.05 0.2 0.05 0.05 0.05: 0.05, 05, 0.05 1.56 0.05 0.78: 0.05: Q, 05 0.05 0.1 6.25 0.05 0.1 0.05 0.05 0.05 0.05 0.05 12.5 256.25 6.25 25 6.25 7251.56 1 , 56 25 25 725 25 25 25 Proteus vu garis 0.1 rO, 05 0.1 A-9438 I Proteus mirabi is 0.05; 0.05 0.05 A-9554 Proteus morganii 6.25 12.5. 6.25 A-9553 ABca Jigenes faeca ic ATCC-8750 12.5 12.5 725 Staptifocbccus 25 25 25 aureus 209-P StaphyJococcus epiderraidis 25 6.25 25 IAM-12012 Sarcina utea 6.25 1.56 725 PCI-1001 BaciBSus subtigis 25 6.25 25 PCI-219
    Escherichia
    cogi NIHJ XU, 05 0.05 0.05
    KEebsieefa
    pneumoniae
    D-11, 0.1-0.1
    Serratia marcescans IAM-1223 -CO, 05 0.05 0.1
    Interobacter aerogenes:
    IA I-12348 0.2 -0.1
    Table continuation
    0.1 rO, 05 0.2 0.05 0.05 40.05
    0.05 0.05 0.05
    0.2 0.1 0.39 0.05 0.05 0.05
    6.25 0.2 1.56 1.56: 0.05 0.1 / 0.05 0.05 .0.05 0.05 6.25, 05 .0.05 0.1 12.5 252512, 5 1.56 25 25 725 25 25 25 6.25 25 25 6.25 25 1.56 12.5 0.39 25 12.3 1.56 25 3.13 25 12.5 6.25
    27119590828
    --Table continuation
    权利要求:
    Claims (1)
    [1]
    The method of obtaining derivatives of 2-oxo-1-azetidine sulfonic acid of the General formula
    NN
    N — _ c-CO ^ nSC ,,,, cn r ABOUT OM.
    ΗχΝ S. 0R . 4θ 3 Η where R is straight or branched C 1 -C 4 ~ alkyl which may be substituted with a carboxy or cyano group, -Cj cycloalkyl which may be substituted with a carboxy group, Cj alkenyl, Cj alkynyl, phenyl or benzyl, or their alkali metal soley.s · e wherein, • July 1 · that the compound of general formula wherein r, d - a hydrogen atom or tetrabutylammonium tilammony sulfonate, is reacted with a reactive derivative at the carboxy group of the compound of general formula lTy g 'S00N r 2 hn S x oh where R has the indicated meanings and
    R 2 is a hydrogen atom or a protective group such as trityl, and if R has a carboxy substituent, the carboxy group is protected as an ester ^ such as diphenylmethyl or tert-butyl in an inert organic solvent at a temperature of from -10 ° C to room and in the case when R is a hydrogen atom, the resulting product is subjected to sulfonation by treatment with a complex of sulfuric anhydride with pyridine in an inert organic solvent at room temperature and / or, if necessary, the groups are removed, protecting guides amino- and / or carboxyl group, and isolating the desired product as the free sulfonic acid or its salts with alkali metal.
    SU ..., 1195908>
    Priority by signs:
    05/31/82 at R - methyl, ethyl, H-propyl, isopropyl, 2-propenyl, 2-propynyl, carboxymethyl, cyanomethyl, 1-carboxy-1-methylethyl, cyclopentyl, phenyl or benzyl;
    03/24/83 at R - 1-carboxy-1-methylpropyl, 1-carboxy-1-cyclopropyl, 1 - carboxy - 1 - cyclobutyl, 1 - carboxy - 1 - cyclo pentyl or 1 - carboxy - 1 - cyclohexyl.
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    同族专利:
    公开号 | 公开日
    DE3364927D1|1986-09-04|
    EP0095778B1|1986-07-30|
    HU189290B|1986-06-30|
    CA1203806A|1986-04-29|
    EP0095778A1|1983-12-07|
    KR900005112B1|1990-07-19|
    KR840004746A|1984-10-24|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    DE2756113A1|1977-12-16|1979-06-21|Thomae Gmbh Dr K|NEW 4-HYDROXY-2H-1,2-BENZOTHIAZINE-3-CARBOXAMIDE-1,1-DIOXIDES, THE PROCESS FOR THEIR MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINING THESE|
    EP0021678B1|1979-06-08|1984-11-07|Takeda Chemical Industries, Ltd.|1-sulpho-2-oxoazetidine derivatives, their production and pharmaceutical compositions thereof|
    EP0048953B1|1980-09-29|1988-03-09|E.R. Squibb &amp; Sons, Inc.|Beta-lactam antibiotics|FR2515182B1|1981-10-23|1986-05-09|Roussel Uclaf|NOVEL PRODUCTS DERIVED FROM 3-AMINO 2-OXO AZETIDINE 1-SULFAMIC ACID, THEIR PREPARATION PROCESS, THEIR APPLICATION AS MEDICAMENTS AND THE INTERMEDIATE PRODUCTS NECESSARY FOR THEIR PREPARATION|
    FR2558467B2|1981-10-23|1987-03-20|Roussel Uclaf|NEW PRODUCT DERIVED FROM 3-AMINO 2-OXO AZETIDINE 1-SULPHAMIC ACID, ITS PREPARATION PROCESS, ITS USE AS A MEDICAMENT AND AN INTERMEDIATE PRODUCT NECESSARY FOR ITS PREPARATION|
    EP0096296B1|1982-06-03|1987-07-29|F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft|1-sulfo-2-oxoazetidine derivatives|
    GB8504072D0|1985-02-18|1985-03-20|Fujisawa Pharmaceutical Co|Cephem compounds|
    FR2585021B2|1985-07-18|1989-05-19|Roussel Uclaf|NOVEL 3-AMINO 2-OXOAZETIDINONE DERIVATIVES COMPRISING, IN POSITION 1, A NITROGEN HETEROCYCLIC RADICAL, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS MEDICAMENTS|
    US4684722A|1986-01-06|1987-08-04|E. R. Squibb & Sons, Inc.|Monosulfactams|
    WO2003012900A1|2001-07-31|2003-02-13|Tokuyama Corporation|Novel onium salt, electrolyte for nonaqueous cell containing the novel onium salt for nonaqueous cell, and method for optimizing negative electrode using electrolyte containing onium salt|
    WO2015148379A1|2014-03-24|2015-10-01|Novartis Ag|Monobactam organic compounds for the treatment of bacterial infections|
    EA202092620A1|2015-09-23|2021-06-30|Новартис Аг|SALTS AND SOLID FORMS OF MONOBACTAM ANTIBIOTICS|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP57091471A|JPH0343272B2|1982-05-31|1982-05-31|
    JP58047852A|JPH0340028B2|1983-03-24|1983-03-24|
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