• 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:
    Compounds of the formula <IMAGE> I wherein R1 is hydrogen or a conventional amino-protecting group, and R2 is a straight or branched chain alkyl group containing from 1 to 4 carbon atoms, allyl, 2-butenyl or 3-butenyl, and nontoxic pharmaceutically acceptable salts and solvates thereof, as well as processes for their preparation, are disclosed. The compounds in which R1 is hydrogen are potent antibacterial agents.
    公开号:SU1303029A3
    申请号:SU853909203
    申请日:1985-06-14
    公开日:1987-04-07
    发明作者:Абураки Симпеи；Камати Хадзиме；Нарита Юкио；Окумура Юн；Наито Такаюки
    申请人:Бристоль-Мейерз Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of cephalosporin derivatives, in particular, to methods for producing new cephalosporin derivatives of the general formula S st)
    ij | -c-coNH-r- eii
    QR сНз
    where R is methyl, ethyl, isopropyl or allyl,
    JJ C-COOC H

    I 2 OH
    nos
    ten

    TrHN
    Tn
    AS / N
    OH
     OR
    TrHN- T
    C-COOH

    OR
    rHN S
    N-r-cl

     coOCH (Ph) 2.
    S C-CONH-r-f
    p-GH | LsN2S1 COOCH (
    laai
     9
    OR
    N-C-CONH-T-r
    .J,
    SG 0
     2. OR
    COOCH (Ph
     C-CONH
     N
     g OR
    S
    exhibiting high antibacterial activity that can be used in medicine.
    The aim of the invention is to create, on the basis of known methods, a method of producing new compounds of general formula I, possessing valuable pharmacological properties.
    The method is carried out according to the following scheme:
    eleven
    in
    IV
    OR
    VI
    Vll
    one.
    COOCH (Ph) 2
    NZS-iQ
    2. UNLOCKING
    T-r 1 © x) ij
    coo CH
    The reaction of Compound VII with N-methylpyrrolidine is carried out in a non-aqueous organic solvent, such as methylene chloride, chloroform, diethyl ether, hexane, ethyl acetate, tetrahydro furan, acetonitrile, etc., or mixtures of such solvents, at a temperature from -10 to +50 C, preferably at room temperature. At least one mole of N-methylpyrrolidine should be used per mole of compound VII; preferably a 50-100% excess of N-methylpyrrolidine is used.
    Carboxyl protecting groups suitable for use in this reaction include aralkyl groups such as benzyl, p-methoxybenzyl, p-nitrobenzyl, and dipheiylmethyl (benzhydryl); alkyl groups such as t-butyl; haloalkyl groups, such as 2,2,2-trichloroethyl, and other carboxyl-protecting groups. All are easily removed with acid treatment. Particularly preferred carboxyl protecting groups are benzhydryl and t-butyl.
    Amino-protecting groups suitable for use in the reaction include trityl and acyl groups, such as chloracil. Amino protecting groups are preferred, which are easily removed by treatment with an acid, for example trityl.
    Synthesis 1:
    NG
    dt
    TrHN S
    s-coax
    N

    OR
    Ethyl ester of (g) -2-methoxyimino -2- (2-tritylaminothiazol-4-yl) acetic acid (III a) .45
    A mixture of ethyl (Z) -2-hydroxyl siiimino-2- (2-tritylamino-thiazol-4- -yl) acetic acid (II) (5.00 g, 10.9 mmol), CHJJ (2.04 ml, 32.8 mmol and K, jCO (4.54 g, 32.8 mmol) in dry 50 dimethyl sulfoxide (DMCO) (100 ml) was stirred at room temperature overnight, and then poured into water (250 ml). collected by filtration, washed with water and dried to obtain the target compound (5.15 g, quantitative yield). mp. (with dil.).
    03029
    W
    NMR: 5 (CBC1), 1.32 (AH, t); 3.98 (ЗН, s); 4.30 (2H, q); 6.42 (1H, s); 7.2 (1H, m); 7.25 (15H, s).
    The compounds Illb, IIIc and Illd are prepared by the same general procedure, but replacing methyl iodide with a suitable iodide. Their indicators are given in Table. one.
    Synthesis 2:

    C-COOH IV
    N
    OR,
    5 0 5
    0
    five
    0
    five
    0 5
    (g) -2-methoxyimino-2- (2-trit1-aminothiazol-4-yl) acetic acid (IVa).
    The ethyl ester of Ilia, obtained in the synthesis of 1 (6.00 g, 12.7 mmol) in ethanol (120 ml), is treated with 2n. NaOH (12.7 ml) at room temperature overnight. The reaction mixture was adjusted to pH 8 by the addition of dry powdered ice, and the solvent was distilled off under reduced pressure. The residue was dissolved in water (100 ml), and the solution was acidified by adding 1N. HC to pH 2, and then extracted with ethyl acetate (ml). The combined extracts are washed with a saturated solution of NaCl, dried and evaporated. The residue is crystallized from ethyl acetate-hexane to give 5.56 g (yield 98%) of the desired product. T.SH1. 138-143 C (with decomp.). NMR: B (CCM3), ppm: 3.89 (ZN, s); 6.52 (1H, s); 7.2 (15H, s).
    Compounds IVb, IVc and IVd are prepared according to the same general procedure. Their characteristics are given in Table. 2
    Synthesis 3.
    Benzhydryl ester of 3-hydroxymethyl-7-phenylacetamido-3-cephem-4-to arboxylic acid (VIII).
    To a stirred suspension of phosphate buffer (pH 7, 162.5 ml) and wheat bran (20 g dry matter), sodium salt of 7-phenylacetamido cephalosporanic acid (5 g, 12.1 mmol) is added at room temperature in one portion. The reaction was monitored by high pressure liquid chromatography until the end of the hydrolysis (5 h). The slurry is filtered to remove wheat bran, and the filtrate is cooled to 5-10 ° C to perform extractive esterification. Methylene chloride (32 ml) is added to the cooled solution, followed by the addition of a 0.5 M solution of diphenyldiazomethane in methylene chloride (24 ml). The pH is then adjusted to 3.0 by the addition of 28% phosphoric acid. After 1 h, the reaction mixture was allowed to warm to 20 ° C. Heptane (56 ml) was slowly added, and the desired crystalline product was collected by filtration. The yield of the target product 3.0 g (50%).

    Synthesis 4,
    7-Amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (V).
    Pyridine (3.2 g, 40 mmol) is added to a suspension of PCE (7.3 g, 40 mmol) in CH CI (100 ml), and the mixture is stirred for 20 minutes at 20 ° C. To the mixture is added methyl silyl) -acetamide (BSA, 4.00 ml, 15.6.6 mmol) at room temperature for 50 minutes, obtaining a clear solution. To this solution is added a solution of acid chloride, which is obtained from (Z) -2-MeT-20 oxyimino-2- (2-tritylaminothiazol-4-ShH) -acetic acid (IVa) (2.04 g, 4.60 mmol) and PCE (1.15 g, 5.52 mmol) in methylene chloride (20 ml). The mixture is stirred at room temperature and the benzhydryl ester is 3-hydroxy-25, for 30 minutes, poured into cold methyl-7-fench1-acetamido-5- cefem-4-y (200 ml) and extracted with ethyl acetate30
    -carboxylic acid, obtained by the method of synthesis 3 (5.1 g, 10 mmol), with stirring at -40 ° C in one portion. The mixture was stirred at -10 ° C for 15 minutes and left for 7 hours at (-10) - (-15) ° C. Propane-1,3-β-diol (10 ml) was added to the cooled solution (-20 ° C), and the mixture was left at -20 ° C for 16 hours and then stirred for 20 minutes at room temperature. The resulting solution was washed with ice-water (220 ml) and saturated aqueous NaCl solution (10 ml), dried over MgSO4 and concentrated in vacuo. The rubber-like residue (12 g) is dissolved in a mixture of CHCtj and n-hexane (2: 1) and chromatographed using a silica gel column (200 g) and the same solvent as eluent. The fractions containing the desired compound were evaporated in vacuo, and the residue was triturated with n-hexane to give the desired product (2.1 g, 51%). T. pl. 110 C (srazl.)
    IR spectrum: Y, KVg: 3400, 2800, 1785, 1725 cmtatom (W SO ml). The combined extracts are washed with aqueous NaCl, dried and evaporated. The residual syrup (4 g) is chromatographed on silica gel (150 g) in a column by elution with 10: 1 and 3: 1 mixtures. toluene and ethyl acetate, sequentially. The fractions containing the desired compound are combined and 35 are evaporated to give 2.61 g (68%) of compound VI as an amorphous powder.
    40
    HE
    one/,
    265 nm; E, 160
    YuM
    UV spectrum: A
    -dg - "- COCfa 5ШР: 5 (ОМСО", "-,), mln
    MAI
    NMR: S (CDCl1), ppm: 3.50 (2H, s); 4.02 (ЗН, s); 4.33 (2H, s); 4.98 (1H, d); 5.87 (1H, q); 6.65 (H, s); 6.90 (1H, s); 7.3 (25H, m).
    B. Benzhydryl ester of 3-iodomethyl-7- (g) -2-methoxyimino-2- (2-tri-, tri-amino-thiazol-4-yl) acetamido-3-cephem-4-carboxylic acid (Vila).
    A mixture of the 3-chloromethyl derivative Via (1.50 g, 1.79 mmol) and NaJ (1.34 g, 8.93 mmol) in methyl ethyl ketone (30 ml) was stirred at room temperature for an hour. After the solvent was distilled off, the residue was removed. in ethyl acetate (100 ml) and washed with water, aqueous Na S Cu with aqueous NaCl, dried and evaporated to give the title compound Vila (1.47 g, 89%) as an amorphous powder.
    3.69 (2H, s); 4.43 (2H, s); 5.09 (W, d, 5 Hz); 5.24 (W, d, 5 Hz); 6.87 (1H, s); 7.3 (10, m).

    Example 1. 7- (g) -2-Methoxy-imino-2 (2-aminothiazol-4-yl) acetamido-3- (methyl-1-pyrrolidinium) methyl-3-cephem-4-carboxylate (1a ).
    A. Benzhydryl ester of 3-chloromethyl-7- (E) -2-methoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido-3-cephem-4-carboxylic acid (Na).
    7-Amino-3-β-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester, obtained by the procedure of synthesis 4 (2.29 g, 5.52 mmol), is treated with bis- (trimethylsilyl) in CH CN (57 ml) -acetamide (BSA, 4.00 ml, 16.6 mmol) at room temperature for 50 minutes to obtain a clear solution. To this solution is added a solution of an acid chloride, which is obtained from (Z) -2-MeT-oxyimino-2- (2-tritylaminothiazol-4-ShH) -acetic acid (IVa) (2.04 g, 4.60 mmol ) and PCE (1.15 g, 5.52 mmol) in methylene chloride (20 ml). The mixture is stirred at room temperature for 30 minutes, poured into cold (200 ml) and extracted with ethyl acetate.
    tatom (W th ml). The combined extracts are washed with aqueous NaCl, dried and evaporated. The residual syrup (4 g) is chromatographed on silica gel (150 g) in a column by elution with 10: 1 and 3: 1 mixtures. toluene and ethyl acetate, sequentially. The fractions containing the desired compound are combined and evaporated to give 2.61 g (68%) of compound VI as an amorphous powder.
    NMR: S (CDCl1), ppm: 3.50 (2H, s); 4.02 (ЗН, s); 4.33 (2H, s); 4.98 (1H, d); 5.87 (1H, q); 6.65 (H, s); 6.90 (1H, s); 7.3 (25H, m).
    B. Benzhydryl ester of 3-iodomethyl-7- (g) -2-methoxyimino-2- (2-tri-tri-amino-thiazol-4-yl) acetamido-3-cephem-4-carboxylic acid (Vila).
    A mixture of the 3-chloromethyl derivative Via (1.50 g, 1.79 mmol) and NaJ (1.34 g, 8.93 mmol) in methyl ethyl ketone (30 ml) was stirred at room temperature for an hour. After the solvent was distilled off, the residue was removed. in ethyl acetate (100 ml) and washed with water, aqueous Na S Cu with aqueous NaCl, dried and evaporated to give the title compound Vila (1.47 g, 89%) as an amorphous powder.
    71303029
    NMR: S (CDCl 3), mly: 3.55 (2H,
    ABQ); 4.00 (3N, s); 4.25 (2H, s);
    4.97 (1H, d); 3.80 (1H, q); 6.65
    (1H, s); 6.90 (W, s); 7.3 (25H, m). C. 7- (Z) -2-MeTOKCHHMHHo-2- (2-aminothiazol-4-yl) acetamido-3- (1-methyl-1-pyrrolidinium) methyl-3-cephem-4-carboxylate (1a),
    Mixture of Vila compound (4.5 g,
    4.83 mmol) and N-methylpyrrolidine
    fO
     n
    (0.65 ml, 6.28 mmol) in (45 ml) was stirred at room temperature for 20 minutes. Ether (300 ml) is added to the mixture to isolate the quaternary salt of blocked cephalosporin, which is collected by filtration and treated with 90% trifluoroacetic acid (TFA) (40 ml) at room temperature with a stirred solution of 20.4 i (21.9 mmol) of the compound Vila in 150 ml of dry methylene chloride was added 2.42 g (28.5 mmol) of 1-methylpyrrolidine in one portion at room temperature. The mixture is stirred for 5 minutes and poured into 1000 ml of ether with vigorous stirring to form a precipitate, which is filtered off, washed with ether (ml) and dried in vacuum to obtain 19.3 g of a blocked product as a pale yellow powder. IR spectrum: V D ;,,
    cm: 3400,. J5 1780 (s), 1740, 1675, 1530.
    TLC: solvent — ethanol / CHSG, 1: 3,; 30 (R 0.95 for Vila compound).
    The solid is dissolved in the tour within an hour. The mixture is then pack-20. 185 ml of the mixture is trifluoroacetic acid under reduced pressure and temperature and water (99: 1), stirred in the temperature below 20 ° C. The residue is triturated for one hour at room temperature with ether, obtaining the salt TFA compounds and concentrated to 30 ml at a temperature of (2.40 g), which is dissolved in a tour below 10 ° C. The concentrate is poured into methanol (5 ml) and treated with W 25 in 1000 ml of ether with a vigorous solution of sodium 2-ethylhexoate (LEH stirring to form a precipitate, in ethyl acetate (8 ml) at room temperature, filtered, washed with ether for 30 minutes After rum (5it40 ml) and dried in vacuo with addition of ethyl acetate (100 ml) to obtain 10.6 g of a pale yellow precipitate (1.94 g), 30 g of powder are collected. The powder is dissolved in 20 ml by filtration Analyze with liquid methanol and filter the solution. To high pressure filtration chromatography This is added with 45 ml of 0.8 M NEG in Ni (HPLC), which indicates that crude ethyl acetate The resulting suspension of the product is 7% pure with a ratio of 400 ml of ethyl acetate and the filtration between the amp-isomer and d-isomer 35 8.08 g of solid was obtained: 1: 8. Purification of the product was carried out by means of a HPLC substance, which was a mixture of the target, repeated three times (Lichrosorb RP-18, your compound and the corresponding ml), elution with 5% water - d-isomer (&amp; Vc. l: 8) by data
    HPLC analysis (Likhrosorb RP-18, 10-40 with 15% methanol, 0.0 M phosphate blued SNOH or 0.01 M ammonium phosphate buffer (pH 7.2) containing 5% CHjOH, yielding 35 ml ( 1.5%) of the desired product as a colorless powder. Estimated purity (HPLC) is 90%. Mp.
    IR: V, cm: 1770,
    1660, 1620.
    UV spectrum: (phosphate buffer, pH 7), nm, (E): 235 (16200), 258 (15400),
    NMR: S (D, 0) ppm: 2.31 (4H, m); 3.08 (ЗН, s); 3.63 (4H, m); 4.09 (ЗН, s); 5.43 (1H, d, 8 Hz); 5.93 (W, d); 7.08 (1H, s).
    PRI mme R 2. 7- (g) -2-Methoxy-imino-2- (2-aminothiazol-4-yl) acet-amido-3- (I-methyl-1-pyrrolidinium) -methyl) -3-ifem-4-kprboxylate (I a).
    Fere, pH 7). A second run of 28.9 g (mmol) of Vila compound gives 16.0 g of crude product (/ Ci l: 8). The isolation of the desired l-isomer from
    45 combined raw product (24.08 g) using preparative HPLC (System 500, Waters Associates, PrepPAK 500 / S, /, 5-10% SI OH) gives 769 mg of compound
    50 ha.
    EXAMPLE 3 7- (Z) -2-Metoxy-imino-2- (2- (2-aminothiazol-4-yl) acetamido-3- (1-methyl-1-pyrrolidinium) - 55 methyl-3-cephem-4-carboxylate (Ta),
    . A series of experiments were conducted to determine the effect of the solvent, the amount of solvent and the reaction time on the yield of the compound Ta and from 8
    To a stirred solution of 20.4 ((21.9 mmol) of Vila compound in 150 ml of dry methylene chloride, 2.42 g (28.5 mmol) of 1-methylpyrrolidine are added in one portion at room temperature. The mixture is stirred for 5 minutes and poured into 1000 ml of ether with vigorous stirring to form a precipitate, which is filtered off, washed with ether (ml) and dried in vacuum to obtain 19.3 g of a blocked product as a pale yellow powder. IR spectrum: V D ;,,
    cm: 3400,. 1780 (s), 1740, 1675, 1530.
    Fere, pH 7). A second run of 28.9 g (mmol) of Vila compound gives 16.0 g of crude product (/ Ci l: 8). The isolation of the desired l-isomer from
    45 combined raw product (24.08 g) using preparative HPLC (System 500, Waters Associates, PrepPAK 500 / C, /5-10% SI OH) gives 769 mg of compound
    50 ha.
    EXAMPLE 3 7- (Z) -2-Metoxy-imino-2- (2- (2-aminothiazol-4-yl) acetamido-3- (1-methyl-1-pyrrolidinium) - 55 methyl-3-cephem-4-carboxylate (Ta),
    . A series of experiments was conducted to determine the effect of the solvent, the amount of solvent and the reaction time on the yield of the compound Ta and from 91303029 10
    wear in the reaction product. Ob-NMR: e (CDC1), ppm: 1.40 (3N, without procedure, to the following.); 3.53 (2H, ABQ., 2-CH);
    A solution of N-methylpyrrolidine (0.01 ml, 0.097 mmol) is added to a suspension of 3-vodomethyl derivative of Vila (A5 mg, 0.048 mmol) in a specified amount of the indicated solvent.
    4.37 (2H, s, -CH, jC); 4.60 (2H, q, -CHjCHj); 4.90 (1H, d, 6-H); 5.89 (1H, d 7-H); 6.88 (1H, s, H thiazole) 6.91 (1H, s, CH benzhydryl).
    B. Diphenylmethyl ester 7- (Z) - -2-ethoxyimino-2- (2-tritylamino-azol-4-sh1) acetamido-3-iodomethyl-3 in ether (0.1 ml) and the mixture is stirred at room temperature in teB . Diphenylmethyl ester 7- (Z) - -2-ethoxyimino-2- (2-tritylamino-azol-4-sh1) acetamido-3-iodomethyl-3 over a specified period. The reaction is 10-cephem-4-carboxylic acid (VII).
    The mixture was diluted with ether (5 ml) and the resulting precipitate was collected by filtration and mixed with 90% TFA. The mixture is stirred for an hour and evaporated to a dry residue under reduced pressure and at a temperature below 20 ° C to obtain the desired product. The uVu ratio for the product is determined by HPLC (Lihrosorb RP-I8; before and with saturated aqueous NaCl, the mobile phase is dried with 0.01 M ammonium-phosph-20 over MgSO4 and evaporated to give a fatt buffer (pH 7.2) containing 1.04 g (89%) of compound VII. 15% CH OH; retention time, 6.60 min, D - 5.56 min). Product yield and isomer ratio for
    A mixture of the compound VIb of Example 4A (1.07 g, 1.25 mmol) and NaJ (562 mg, 2.75 mmol) in acetone (20 ml) was stirred for an hour. The mixture of filter 5 is triturated, the filtrate is poured into water and extracted with ethyl acetate.
    The organic layer is consistent. washed with 5% water, in
    NMR: S (CDCl1), 3.55 (2H, q, 2-CH); 4.27 (2H, s, CH, -1); 5.02 (1H, d, 6-H); 5.87 (1H, d, 7-H 6.68 (1H, s, H thiazole ring); 6.93 (1H, s, CH benzhydryl).
    each experiment are given in table. 3
    PRI me R 4. 7- (g) -2-Ethoxyimino-2- (2-aminothiazol-4-yl) acetam

     (1-methyl-1-pyrrolidinium) meth-3-cephem-4-carboxylate (1).

    A. Benzhydryl ester of 3-chlorome-TSH1-7- (g) -2-ethoxyimino-2- (2-tritylaminothiazol-4-yl) acetamido-3- -cepheme-4-carboxylic acid (VI).
    To a solution of (g) -2-ethoxyimino-2- (2-tritylaminothiazol-4-yl) acetic acid (IV) (1.095 g, 2.4 mmol) in
    A mixture of compounds VIIb of Example 4B (333 mg, 0.35 mmol) and N-methylpyrrolidine (60 mg, 0.7 mmol) at, j
    (5 ml) is stirred for half an hour at 35 hours at room temperature and then evaporated in vacuo. The residue is washed with ether and dissolved in 90% aqueous TFA. After standing for half an hour at room temperature, five to five are added and the mixture is concentrated under reduced dichloromethane (500 mg). After overpressure. To the concentrate, stirring is added for one hour at the mixture to separate the quaternary pro- ductal temperature of the mixture as one duct, which is collected and the filtration is added to the cooled g g dissolved in a small amount of methanol. Chromatography solution -. Ru in HP-2 column (40 ml). Elution with 30% aqueous followed by lyophilization gave 0.062 g of a mixture of isomers A and L (: 1). 50 The mixture is purified by HPLC (Lihr / inn h Rosorb RP-18, 8300 mm, 15% is extracted with SSCC (100 ml). And the target G isomer (Ib) is more. The extract is washed with water, dried over pale yellow MgSO2 powder and evaporated under reduced pressure; 4 9 mg C2 77)
    The residue is chromatographed in a column.
    on silica gel. Elution of CHCt gives the UV spectrum: L-ox (phosphate buffer, named compound VIb as pH 7), nm, (): 235 (15000) 258 amorphous powder, 1.76 g (86%). (14,000).
    ice a solution of 7-amino-3-chlorometh-1-3-cephem-4-carboxylic acid benzhydryl ester (1.083 g, 2.4 moles) and BSA (1 ml) in dichloromethane (20 ml). After stirring for half an hour, the reaction mixture was poured into 10% aqueous NaHCO. (200 ml) and
    ABOUT
     NMR: g (CDC1), ppm: 1.40 (MN, t,); 3.53 (2H, ABQ., 2-CH);
    4.37 (2H, s, -CH, jC); 4.60 (2H, q, -CHjCHj); 4.90 (1H, d, 6-H); 5.89 (1H, d 7-H); 6.88 (1H, s, H thiazole); 6.91 (1H, s, CH benzhydryl).
    B. Diphenylmethyl ester 7- (Z) - -2-ethoxyimino-2- (2-tritylamino-azol-4-sh1) acetamido-3-iodomethyl-3-cephem-4-carboxylic acid (VII).
    It is washed with saturated aqueous NaCl, dried over MgSO4 and evaporated to give 1.04 g (89%) of compound VII.
    A mixture of the compound VIb of Example 4A (1.07 g, 1.25 mmol) and NaJ (562 mg, 2.75 mmol) in acetone (20 ml) was stirred for an hour. The mixture was filtered, the filtrate was poured into water and extracted with ethyl acetate.
    The organic layer is successively washed with 5% aqueous, water and saturated aqueous NaCl, dried over MgSO4 and evaporated to give 1.04 g (89%) of compound VII.
    NMR: S (CDCl1), 3.55 (2H, q, 2-CH); 4.27 (2H, s, CH, -1); 5.02 (1H, d, 6-H); 5.87 (1H, d, 7-H); 6.68 (1H, s, H thiazole ring); 6.93 (1H, s, CH benzhydryl).
    C. 7- (2) -2-Ethoxyimino-2- (2-aminothiazol-4-yl) acetamido-3- (1-methyl-1-pyrrolidinium) methyl-3-cephem-4-carboxylate (1b) .
    carboxylate (1b).
    A mixture of compounds VIIb of Example 4B (333 mg, 0.35 mmol) and N-methylpyrrolidine (60 mg, 0.7 mmol) at, j
    (5 ml) is stirred for half an hour at room temperature and then evaporated in vacuo. The residue is washed with ether and dissolved in 90% aqueous TFA. After standing for half an hour at room temperature, the mixture is concentrated under reduced pressure. Ether is added to the concentrate to separate the quaternary product, which is collected by filtration, and the g в is dissolved in a small amount of II 130 302912
    NMR: & () ppm: 1.43 (AH, t); obtaining 494 mg (90%) of the title 2.33 (4H, m,); 3.10 (ЗН, s); 3.64 target compound.
    (4H, m); 4.36 (2H, q); 5.44 (1H, d); 5.95 (1H, d); 7.08 (1H, s).
    EXAMPLE 5 7-t (Z) -2- (2-npon-oxyimino) -2- (2-aminothiazol-4-yl) acetamido-3-C (I-methyl-I-pyrrolidi - nii) methyl 7-3-cephem-4-carboxylate (1c),
    A. Diphenylmethyl ether 3-chloro-IR spectrum: KBG, cm: 3360 3040, 3020, 2960, 1785, 1720, 1680, 1600, 1520, 1500, 1450, 1370, 1300, 1230, 1150, 1115, 1080, 990, 900 , 840, 750, 700.
    .-. - UV spectrum: i (EtOH), nm (): 240
    methyl 7-C (g) -2- (2-propoxyimino) -2-10 (24900), 260 (19400}. - (2-tritylaminothiazol-4-yl) acetamido D-3-cephem-4-carboxylic acid ( Vi).
    A mixture of (g) -2- (2-propoxyimino) -2- - (2-triethylamino-thiazol-4-yl) acetic acid (IVc) (707 mg, 1.5 mmol) and
    NMR: S (CDCl1), ppm: 1.30 (6H, d, I 6H); 3.37 and 3.70 (1H, each d, I 16H); 4.22 (2H, s); 4.55 (Wm, J 6H); 4.95 (W, d, I 4.5 Hz 15 5.83 (1H, dd, I 4.5 E 9 Hz, q for
    ), 6.66 (W, s); 6.87 (1H, s);
    7.25 (25H, s).
    C. 7-C (Z) -2- (2-Propoxymino) -2-pe for one hour and poured into p of st- (2-aminothiazol-4-yl) acetamido-3- thief of the benzyl ether of 7 amino-3 -chloro-20- (1-methyl-1-pyrrolidinium) methyl-3p phosphorus phosphate (344 mg, 1, b5 mmol) in dichloromethane (14 ml) is stirred at room temperature with cephem-4-carboxylate (1c).
    Mets-1-3-cephem-4-carboxylic acid (677 mg, 1.5 mmol) and BSA (1.1 ml, 4.5 mmol) in dichloromethane (15 ml). The reaction mixture was stirred at room temperature for half an hour, diluted with ethyl acetate (200 ml) and water (3100 ml), dried over sodium sulfate and evaporated to give 1.4 g (100%) of the title compound.
    IR spectrum: KBG, 3360, 3020, 3060, 2960, 1785, 1725, 1680, 1520, 1500, 1450, 1375, 1300, 1250, 1160, 1090, 1060, 1010, 990, 840, 740, 700.
    -cephem-4-carboxylate (1c).
    A mixture of the compound of example 5B (545 mg, 0.55 mol) and 1-methyl pyrrolidine (70 mg, 0.82 mmol) in dichloro
    25 methane (10 ml) is stirred at room temperature for a half hour and diluted with ether (100 ml). The resulting residue is collected by filtration. Sediment solution in 90% TFA
    30 (, 5 ml) are stirred at room temperature for half an hour and evaporated in vacuo. The residue is triturated with ether to give 317 mg of crude product, which is chromagrafted.
    UV spectrum: L (EtOH), nm (): 240 35 HP-20 column (50 ml), eluted (24600), 260 (20700).
    NMR: S, CDCl j, ppm: 1.35 (6H, d, I Hz); 3.50 (2H, s); 4.35 (2H, s); 4.58 (1H, m, I 6H); 5.00 (1H, I 4.5 N); 5.91 (1H, dd I 4.5 and 40 (/ &amp; 6/1), 100 mg of which is purified
    water (500 ml) and 30% CHjOH (500 ml). The eluate in 30% concentrate and lyophilized to obtain 109 mg of a mixture of isomers a and a C
    9H; q for J 4.3 N); 6.68 (W, s); 6.88 (1H, s); 7.25 25H, s).
    B. Diphenylmethyl ester 3-iodomethyl-7- (Z) -2- (2-propoxyimino) -2 by jHIVD (Lichrosorb RP-18, 15% MeOH) to give 5 mg (3%) of the desired compound Ic
    UV spectrum: (buffer), nm, (
    - (2-tritylaminothiazol-4-Sh1) -acetam-45 (15100), 252 (14600). up to 3-cephem-4-carboxylic acid NMR: b (), mH: 1.42 (6H, d.
    (VI1c).
    A mixture of (Z) -2- (2-propoxymino) -2- - (2-triethylaminothiazol-4-yl) acetic acid (500 mg, 0.55 mmol) and sodium iodide (248 mg, 1.66 mmol) in acetone (10 ml) is stirred at
    J 6 Hz); 2.33 (4H, s); 3.10 (ЗН, s); 3.65 (4H, s); 3.83 and 4.23 (1H, each, d, J 17 Hz); 5.45 (1H, d, 50 I 4.5 Hz); 5.95 (1H, d, I 4.5 Hz) 7.05 (1H, s).
    EXAMPLE 6 7- (Z) -2-Allyloxy ymino-2- (2-amino thiaz-ol-4-yl-) ace t-amido-3- (1-methyl-pyrrolidinium) at room temperature 50 min After 55 gm-1-cephem-4-carboxylate (Id), evaporation of the residue is taken up in aqueous A. The 7-t (Z) -2 sodium thiosulfate (10 ml) is benzhydryl ester (10 ml), allyloxymino-2- (10 ml) and aqueous NaCl (10 ml), dried over sodium sulfate and evaporated with
    azol-4-yl) acetamido-3-chloromethyl-3-β-cephem-4-carboxylic acid (VId).
    IR spectrum: KVG, cm: 3360, 3040, 3020, 2960, 1785, 1720, 1680, 1600, 1520, 1500, 1450, 1370, 1300, 1230, 1150, 1115, 1080, 990, 900, 840, 750, 700
    (24,900), 260 (19,400}.
    NMR: S (CDCl1), ppm: 1.30 (6H, d, I 6H); 3.37 and 3.70 (1H, each, d, I 16H); 4.22 (2H, s); 4.55 (W, m, J 6H); 4.95 (W, d, I 4.5 Hz); 5.83 (1H, dd, I 4.5 E 9 Hz, q dl
    C. 7-C (Z) -2- (2-Propoxymino) -2- - (2-aminothiazol-4-yl) acetamido -3- - (1-methyl-1-pyrrolidinium) methyl -3-cephem-4 carboxylate (1c).
    A mixture of the compound of Example 5B (545 mg, 0.55 mol) and 1-methyl pyrrolidine (70 mg, 0.82 mmol) in dichloromethane (10 ml) was stirred at room temperature for half an hour and diluted with ether (100 ml). The resulting residue is collected by filtration. Sediment solution in 90% TFA
    (, 5 ml) stir at room temperature for half an hour and evaporate in vacuo. The residue is triturated with ether to give 317 mg of crude product, which is chromagrafted.
     column HP-20 (50 ml), elute
    (/ & 6/1), 100 mg of which is purified
    water (500 ml) and 30% CHjOH (500 ml). The eluate in 30% concentrate and lyophilized to obtain 109 mg of a mixture of isomers a and a C
    (/ & 6/1), 100 mg of which is purified
    by HPLC (Lihrosorb RP-18, 15% MeOH) to give 5 mg (3%) of the desired compound Ic
    UV spectrum: (buffer), nm, ():
     (15100), 252 (14600). NMR: b (), mCH: 1.42 (6H, d
    J 6 Hz); 2.33 (4H, s); 3.10 (ЗН, s); 3.65 (4H, s); 3.83 and 4.23 (1H, each, d, J 17 Hz); 5.45 (1H, d, I 4.5 Hz); 5.95 (1H, d, I 4.5 Hz); 7.05 (1H, s).
    EXAMPLE 6 7- (Z) -2-Allyloxy-imino-2- (2-amino thiaz-ol-4-yl-) ace t-amido-3- (1-methyl- -pyrrolidinium) glove 1 -3-cephem-4-carboxylate (Id), A. Benzhydryl ester of 7-t (Z) -2- allyloxyimino-2- (2-tritylamine)
    azol-4-yl) acetamido-3-chloromethyl-3-β-cephem-4-carboxylic acid (VId).
    to a suspension of 7-α-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzyl ester (1.35 g, 3 mmol) in methylene chloride (20 ml) is added BSA (1, 1 ml, 4, 5 mmol), and the mixture is stirred for half an hour at room temperature with the formation of a clear solution. A mixture of (Z) -2-allyl-hydroxyimino-2- (2-tritamine-aminothiazol-4- -yl) acetic acid (IVd) (1.40 g, 3.0 mmol) and phosphorus pentachloride (690 mg, 3.3 mmol) in methylene chloride (20 ml) is stirred for 15 minutes at room temperature and poured in one portion into a solution of trimethylsilylated compound V, the mixture is stirred for 20 minutes at room temperature and diluted with ethyl acetate (200 ml), washed with water bicarre under reduced pressure to obtain the title compound as an amorphous powder, which is used in the next step without further purification. ki Yield 2.52 g (99%).
    P. 7-1 (E) -2-Allyloxyimino-2- (2- -aminothiazol-4-yl) acetamido-3- (1- -methyl-1-pyrrolidinium) methyl-3-cephem-4-carboxylate (Id).
    ten
    f5
    A mixture of the compound of Example 6B (4.8 mg, 0.5 mmol) and N-methylpyrrolidine (0.05 ml, 0.5 mmol) in methylene chloride (5 ml) was stirred for 20 minutes at room temperature and diluted with ether (50 ml). ml) to precipitate a quaternary product (500 mg yield). The mixture of quaternary product and TFA (2 ml) was allowed to stand at room sodium carbonate and water, dried and at a constant temperature of one and a half
    chase under reduced pressure. Mae-ses and diluted with ether for a precipitated residue is purified on the sily of the crude salt of the TFA product (yield
    chromatography by chromatography (column 65 mg), which is chromatographed on
    column HP-20 (1,848 cm). Column
    (Waco gel, C-200, 30 g). The column is eluted with chloroform and the fractions containing the desired product are combined. Distillation under reduced pressure gave the desired product (VId) as an amorphous powder, yield 2.32 g (83%). M.p. SO-PZ S (decomp.).
    IR spectrum: KBG, cm: 3990, 1790, 1730, 1680, 1530, 1380, 1250, 1160, 1020.
    NMR: 5 (CDCl5) ppm: 3.50 (2H, 2-n); 4.32 (2H, s, 3-CH,); 4.6-6.1 (7H, m,, j 6.7-H); 6.70 (W, s, H thiazole); 6.90 (1H, s, Pb, CH); 7.1-7.6- (ZON and protons of phenyl).
    Calculated,%: C 64.05; H 4.45; N 7.73; S 7.08; C1 7.82.
    C gH Nj05S2Cl-l / 3 СНС1 ,,
    Found,%: C1 64.13: H 4.61;
    63.99; 4.64; N 7.50; S 6.85; C 7.55 7.30; 6.85; 7.46,
    B, Benzhydryl ester of 7-l (Z) -2-arylOK siimino-2- (tritylaminothia al-4-yl) acetamido-3-iodomethyl-3-cep-carboxylic acid Vlld.
    A mixture of the compound (VId) of Example 6A (2.30 g, 2.65 mmol) and sodium iodide (2 g, 13.3 mmol) in acetone (15 ml) was stirred for one hour at room temperature and then evaporated under reduced pressure. . The solution of the oil-like residue in ztylacetate (200 ml) is washed with 10% sodium thiosulfate and water, evaporated
    302914
    The title compound is obtained in the form of an amorphous powder, which is used in the next step without further purification. Yield 2.52 g (99%).
    P. 7-1 (E) -2-Allyloxyimino-2- (2- -aminothiazol-4-yl) acetamido-3- (1- -methyl-1-pyrrolidinium) methyl-3-cephem-4-carboxylate (Id).
    A mixture of the compound of Example 6B (4.8 mg, 0.5 mmol) and N-methylpyrrolidine (0.05 ml, 0.5 mmol) in methylene chloride (5 ml) was stirred for 20 minutes at room temperature and diluted with ether (50 ml). ml) to precipitate a quaternary product (500 mg yield). The mixture of quaternary product and TFA (2 ml) is left to stand at rooms (65 mg), which is chromatographed on
    column HP-20 (1,848 cm). Column
    5 elute with water and 30% aqueous methanol. The methanol eluate is evaporated under reduced pressure and the residue is lyophilized to give an amorphous powder (yield 124 mg), which contains the desired product (17%) and the corresponding d-isomer (83%). The mixture was purified by HPLC {Lihrosorb RO-18, 0.01 M, jPO, (pH: CHZON 85:15). The eluate is acidified to pH 3.
    g diluted with Ht and chromatographic on a column of HP-20 (1, cm). The column was eluted with water and then with 30% aqueous methanol. The methanol eluate is evaporated under reduced pressure,
    0 and the residue is lyophilized to give the desired compound (Id) as an amorphous powder (yield 13 mg, 5.1%), m.p. 55 C (decomp.).
    IR spectrum v) KBG, cm: 36005 2800, 1770, 1670, 1610, 1530, 1200.
    UV spectrum, A maize (pH 7 buffer), nm, (): 235 (16600), 253 (15600).
    HMPS (D, jO),: 2.1-2.5 (4H, m, H pyrrolidine), 3.10 (3N, s, CH);
    0 3.4-3.8 (4H, m, pyrrolidine); 5.95 (1H, q 4H, Z).
    The compounds of formula I exhibit high antibacterial activity against gram-positive and
    55 gram-negative bacteria and are suitable for the treatment of bacterial infections of animals, as well as humans. The compounds of formula I can be used to prepare the preparative
    forms intended for use parenterally, in the usual manner using known pharmaceutical carriers and exporters, and used in single or multiple doses. The compositions may be presented as solutions, suspensions or emulsions in oily or aqueous diluents using conventional dispersing, suspending and stabilizing agents; in the form of a dry powder diluted before use, for example, with sterile water that does not contain pyrogenic substances; in the form of candles, using conventional bases for this purpose, such as butter, cocoa or other glycerides. If necessary, the compounds may be prescribed in combination with other antibiotics, such as penicillins or other cephalosporins. Single. The dose contains 50-1500 mg of the active ingredient of the formula 1. For the treatment of adults, the dosage is
    H2 S
    N C-CCfNH-j-r L JJ
    N
    OCHq
    and ceftazidime formula
    500-5000 mg per day, depending on the frequency and method of administration. When administered intramuscularly or intravenously to an adult, the full dose is normally normally 750-3000 mg per day in separate dosages, although a higher daily dose may be required in the case of infections with bacteria of the genus Pseudomonas.
    Preferred are compounds of formula I in which R, methyl or ethyl. Compounds where K is methyl are most preferred. Minimum inhibitory concentration
    (MIC) of the proposed and two known compounds (cefotaxime and ceftazidim) are determined by the method of two-fold dilution of agar using Mueller-Hinton agar for 32 strains
    the test organisms are divided into six groups. The geometric mean MIC values determined in this experiment are shown in Table. 4 and 5. For comparison, use known
    cefotaxime formula
    ABOUT
    II
    SI2.0SSN
    g
    j and
    k X
    S
    -sp
    N
    -CONH
    ABOUT
    ti
    ti-t-y.
    Soo
    NE-V CHT
    I
    soon
    All tested compounds are more active than cefotaxime in relation to groups (G) -II and (C) -, with the most preferred compound Ta being clearly more active. All test compounds are more active than ceftazidime in relation to the (G) -Ia and (G) -Ib groups, with the most preferred compound being obviously more active than ceftazidime in all groups of test organisms, with the exception of (G) -III, which are somewhat more sensitive to ceftazidime.
    Absorption of the compound Ta and the known compounds (cefotaxime and ceftazidime) is measured on the brain after a single intramuscular injection of the test compound (dissolved in p.1M-phosphate buffer; pH 7) at a dosage of 20 mg / kg. Blood samples are collected from the orbital sinuses into heparin-treated capillary tubes and plated on Müller-Hinton medium using Morganella Morganii A9695 as the test organism. Blood levels of compounds in various intervals 17I
    The times, half-periods (t 1/2) and the area under the curves (AUC) are presented in Table. 6
    Tests were also carried out to detect organisms resistant to the compound of the formula Ta, cefotaxime and ceftazidime. MIC values for these three compounds in relation to 240 strains of Euterobacteriaceae are determined in the Müller-Hinton medium, and a MIC value equal to or greater than 8 for at least one of the tested compounds is arbitrarily taken as evidence of body resistance. Of the 240 strains, 27 were resistant to at least one of the tested compounds. The results are shown in Table. 4, talking about
    N
    C-C01 SH- II
    ,
    OR
    where R is methyl, ethyl, isopropyl or allyl,
    the fact that a mixture of 7-amino-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester and bis- (trimethylsilyl) acetamide is reacted with (Z) -2- (R-O-Siimo ) -2- (2-tritylaminothiazol-4- -yl) acetic acid, where R has the indicated value, the product is condensed
    Methyl
    100
    Illb
    Ethyl
    67
    IIIc Isopro 26
    Hid
    All il
     - The ester was hydrolyzed without isolation.
    03029 volume
    and
    that 3 organisms are resistant to compound 1a, 15 to ceftazidime, and 18 to cefotaxime. It is more active than ceftazidime with respect to all groups of gram-5 positive test organisms, excluding (G) 111 Ps. aeruginosa, which are somewhat more sensitive to ceftazidime.
    Thus, by the proposed method it is possible to obtain compounds of general formula 1 possessing valuable pharmacological properties.
    权利要求:
    Claims (1)
    [1]
    5 claims
    The method of obtaining cefapostrin derivatives of the general formula
    -NN
    - NV CH2-N (COO CH
    uh
    Sodium is treated with sodium iodide. The 3-iodine-methyl derivative obtained is reacted with N-methylpyrrolidine in an organic solvent or a mixture of organic solvents at room temperature, followed by removal of the protective groups by acid hydrolysis and isolation of the desired product.
    Table 1
    115 (decomp.) 120 (decomp.)
    97-98
    51-55
    Methyl Ethyl
    Izopropil
    Allyl
    98 138-143 1AO
    85 140-145 Not yet reported.
    85 166-169 170
    66
    170-178
    170
    Table 3
    Total number
    resistant
    strains
    27
    15
    18
    Note: (G) -1a: (5 strains sensitive to penicillin);
    ((5 strains sensitive to penicillin);
    (G) -Ia: (2 strains) + (1 strain) and (2 strains sensitive to cephalotin);
    (G) -Ib: (3 strains) and 3 strains resistant to cephalotin;
    (G) -II: (1 strain, (2 strains) and (2 strains);
    (G) -III :( 6 strains);
    (a) is the average of five experiments.
    Table 6
    Average value for 2 test;
     g
    1 trial;
    Mean value for 3 tests.
    Compiled by N. Narshgkov Editor N. Egorov Tehred I. Popovich Corrector M. Samborska
    Order 1227/57 Circulation 372Subscription
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Production and printing company, Uzhgorod, st. Lrozekna, 4
    Table 5
    类似技术:
    公开号 | 公开日 | 专利标题
    SU1303029A3|1987-04-07|Method for producing derivatives of cephalosporin
    DE2727753C2|1987-11-05|
    US4457929A|1984-07-03|3-Quaternary ammonium methyl)-substituted cephalosporin derivatives
    HU191990B|1987-04-28|Process for producing substituted vinyl-5-cepheme-4-carboxylic acid derivatives
    SU1250173A3|1986-08-07|Method of producing derivatives of cephalosporin
    SU1487814A3|1989-06-15|Method of producing 7-amino-3-/3-|-1-propene-1-yl/-3-cephem-4-carboxylate
    US4692443A|1987-09-08|3-bicyclicpyridinium-methyl cephalosporins
    CS258143B2|1988-07-15|Method of crystalline solavate production
    US4748172A|1988-05-31|3-bicyclicpyridinium-methyl cephalosporins
    FI76349B|1988-06-30|FOERFARANDE I ETT STEG FOER FRAMSTAELLNING AV CEFALOSPORINER MED EN ACYLAMIDOGRUPP I 7-SIDOKEDJAN I 7-STAELLNINGEN OCH EN HETEROCYKLISK TIOMETYLGRUPP I 3-STAELLNINGEN.
    GB2173798A|1986-10-22|Cephalosporanic acid derivatives
    US5142041A|1992-08-25|Cephalosporin intermediates
    US5462935A|1995-10-31|Cephalosporin compounds
    US5464829A|1995-11-07|Cephalosporin derivatives
    KR870002181B1|1987-12-28|Process for preparing cephalosporins
    SU1418329A1|1988-08-23|7-acylamidecephalosporins manifesting antibacterial properties
    RU2073680C1|1997-02-20|Crystalline acid additive salts of pure diastereomers of 1-|-ethyl ester of 3-cephem-4-carboxylic acid and method for their production
    SU1575940A3|1990-06-30|Method of obtaining carbacephalosporin compounds
    SU1037842A3|1983-08-23|Process for preparing 3-thiovinyl cephalosporins
    US4179502A|1979-12-18|7[2-Hydroxyiminoacetamido]cephalosporins
    US3971780A|1976-07-27|Thio-β-lactam cephalosporins
    SU1119607A3|1984-10-15|Method of obtaining cephalosporin derivatives
    JPH064643B2|1994-01-19|Cefalosporin compound
    EP0136177A2|1985-04-03|3-Azidocephalosporins as intermediates and novel antibacterial agents
    SU1326195A3|1987-07-23|Method of producing 7-/2-|-/z/-2-|acetamido/-3-/|methyl/-3-cephem-4-carboxylate
    同族专利:
    公开号 | 公开日
    US4406899A|1983-09-27|
    ZA831390B|1984-02-29|
    JPS58174387A|1983-10-13|
    JPH0326197B2|1991-04-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1399086A|1971-05-14|1975-06-25|Glaxo Lab Ltd|Cephalosporin compounds|
    GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins|
    GB1591439A|1976-10-01|1981-06-24|Glaxo Operations Ltd|7-syn cephalosporins|
    JPS623155B2|1977-02-18|1987-01-23|Takeda Chemical Industries Ltd|
    DE2714880A1|1977-04-02|1978-10-26|Hoechst Ag|CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION|
    ZA796130B|1978-11-15|1981-06-24|Glaxo Group Ltd|Cephalosporin antibiotics|GB1582884A|1977-05-19|1981-01-14|Beecham Group Ltd|Clavulanic acid derivatives their preparation and use|
    DK330880A|1979-08-03|1981-02-04|Beecham Group Ltd|PROCEDURE FOR THE PREPARATION OF CLAVULANIC ACID DERIVATIVES|
    EP0053893B1|1980-12-09|1985-03-20|Beecham Group Plc|Derivatives of clavulanic acid, their preparation and their use|
    US4562182A|1980-12-23|1985-12-31|Beecham Group P.L.C.|Compounds containing beta-lactams|
    US4525473A|1983-03-30|1985-06-25|Bristol-Myers Company|Cephalosporins|
    GB8410000D0|1984-04-17|1984-05-31|Fujisawa Pharmaceutical Co|Cephem compounds|
    GB8424692D0|1984-10-01|1984-11-07|Glaxo Group Ltd|Chemical compounds|
    EP0182210B1|1984-11-12|1991-02-27|Banyu Pharmaceutical Co., Ltd.|Cephalosporin derivatives|
    JPH06104674B2|1984-11-12|1994-12-21|萬有製薬株式会社|New cefalosporin derivative|
    DE3585434D1|1984-12-27|1992-04-02|Banyu Pharma Co Ltd|CEPHALOSPORINE COMPOUNDS.|
    US4883868A|1984-12-27|1989-11-28|Banyu Pharmaceutical Co., Ltd.|7-amino-3-methyl-3-cephem derivatives|
    US4698336A|1985-01-30|1987-10-06|Eisai Co., Ltd.|3-methyl-3-cephem derivatives|
    US5244891A|1985-08-05|1993-09-14|Bristol-Myers Squibb Company|Injectable compositions of cefepime dihydrochloride hydrate|
    FR2585705B1|1985-08-05|1989-01-13|Bristol Myers Co|CEPHALOSPORIN SALTS AND INJECTABLE COMPOSITIONS|
    US4994451A|1988-01-19|1991-02-19|Bristol-Myers Company|Cephalosporin salts and injectable compositions|
    AT393452B|1985-08-05|1991-10-25|Squibb Bristol Myers Co|Process for the preparation of a cephalosporin product for producing an injection solution|
    US4910301A|1985-08-05|1990-03-20|Bristol-Myers Company|Cefepime cephalosporin salts|
    JPH06102668B2|1985-08-06|1994-12-14|萬有製薬株式会社|New cefalosporin derivative|
    US4659812A|1985-08-20|1987-04-21|Bristol-Myers Company|Cephalosporin intermediates|
    US4714760A|1985-08-20|1987-12-22|Bristol-Myers Company|Cephalosporin intermediates|
    US4868294A|1986-07-11|1989-09-19|Bristol-Myers Company|Process for preparing cephalosporin intermediates|
    US4808617A|1985-12-18|1989-02-28|Bristol-Myers Company|Lyophilized or precipitated cephalosporin zwitterion and salt combination|
    US4680389A|1986-01-10|1987-07-14|Bristol-Myers Company|Temperature stable crystalline di and di adducts of cephalosporin derivatives|
    DE3789466T2|1986-03-17|1994-07-28|Fujisawa Pharmaceutical Co|3,7-disubstituted-3-cephem compounds and process for their preparation.|
    DE3775798D1|1986-03-19|1992-02-20|Banyu Pharma Co Ltd|CEPHALOSPORINE COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL AGENTS.|
    US4814328A|1986-03-19|1989-03-21|Banyu Pharmaceutical Co., Ltd.|Cephalosporin derivatives, and antibacterial agents|
    IL84128A|1986-10-13|1992-12-01|Eisai Co Ltd|3-propenylcephem derivatives, their preparation and pharmaceutical compositions containing them|
    CA2011116C|1989-03-06|1999-11-16|Murray A. Kaplan|Lyophilized bmy-28142 dihydrochloride for parenteral use|
    US6248881B1|1991-03-08|2001-06-19|Biochemie Gmbh|Intermediates and process for the production of 3-vinyl cephalosporins|
    US5698703A|1991-09-10|1997-12-16|Bristol-Myers Squibb Company|Syn-isomer of thiazolyl intermediate and process for the preparation thereof|
    US5594129A|1991-09-10|1997-01-14|Bristol-Myers Squibb Company|Process for the preparation of a cephalosporin antibiotic|
    CA2099692C|1992-07-24|2003-09-30|Gary M. F. Lim|Process for preparing cephalosporin intermediates|
    CA2101571A1|1992-09-08|1994-03-09|Elizabeth A. Garofalo|Crystalline dihydrate of a cephalosporin dihydrate salt and injectable compositions thereof|
    US5391729A|1992-09-08|1995-02-21|Bristol-Myers Squibb Company|Crystalline dihydrate of a cephalosporin salt|
    US5401842A|1992-09-08|1995-03-28|Bristol-Myers Squibb Company|Injectable compositions of a cephalosporin dihydrate salt|
    US5523400A|1993-04-16|1996-06-04|Hoffmann-La Roche Inc.|Cephalosporin antibiotics|
    JP2723088B2|1994-09-07|1998-03-09|藤沢薬品工業株式会社|Novel crystals of cephalosporin compounds|
    US5686588A|1995-08-16|1997-11-11|Yoo; Seo Hong|Amine acid salt compounds and process for the production thereof|
    TW526202B|1998-11-27|2003-04-01|Shionogi & Amp Co|Broad spectrum cephem having benzo[4,5-b]pyridium methyl group of antibiotic activity|
    ES2348299T3|2003-04-16|2010-12-02|Sandoz Ag|PROCEDURES FOR THE PREPARATION OF CEFEPIME.|
    ES2298850T3|2003-12-23|2008-05-16|Sandoz Gmbh|PROCESS FOR THE PRODUCTION OF INTERMEDIATES TO USE IN THE SYNTHESIS OF CEPHALOSPORINE.|
    CN100396688C|2004-05-20|2008-06-25|江苏恒瑞医药股份有限公司|Cephems phosphate and preparation process and use thereof|
    EP1773845A1|2004-07-16|2007-04-18|Hetero Drugs Limited|Process for preparing pure cephalosporine intermediates|
    EP2015755A4|2006-04-28|2010-02-24|Wockhardt Ltd|Improvements in therapy for treating resistant bacterial infections|
    CN101210023B|2006-12-30|2010-12-08|山东轩竹医药科技有限公司|Novel cephalosporin derivatives|
    CN103958527A|2011-10-04|2014-07-30|盐野义制药株式会社|Cephem derivative having catechol group|
    AU2016367284C1|2015-12-10|2018-09-20|Naeja-Rgm Pharmaceuticals Ulc|Cephem compounds, their production and use|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/354,851|US4406899A|1982-03-04|1982-03-04|Cephalosporins|
    [返回顶部]