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    • 专利摘要:
    3-Thiovinyl-cephalosporin of formula (I) having syn or anit, E or Z forms and their mixtures including their acid addition, metallic and N-base addition salts are new. In (I) R is e.g. alkyl, L-2-amino-2-carboxy-ethyl; phenyl; 2-, 3- or 4-pyridyl and their (N-oxides) 2-pyrimidinyl; 3-pyridazinyl substd. in position 6 and opt. N-oxidised or tetrazolo(4,5-b)pyridazin-6-cyl; 4) 1,4-dialkyl or 1-alkyl-5,6-dioxo 1,4,5,6-tetrahydro-1, 2,4-trazin-3-yl or 2-alkyl-5,6-dioxo-1,2,5,6-dioxi-1,2,5,6-tetrahydro-1,2,4-triazin-- 3-yl; 6) Ro is H, alkyl, vinyl or cyanomethyl; R1 is H or a group-CH(R2)(OOCR3) (easily removed by enzymes) (where R2=H or alkyl and R3= alkyl or cyclohexyl. The alkyl and acyl radicals above except where specifically specified are opt-branched and contain 1-4C atoms). (I) are a antibacterials active against gram-negative and gram-positive. In vitro tests show (I) are active against penicillin G sensitive Staph aireus (Staph aureus Smith) at 0.5-15 mg/cc and against penicillin G resistant strains (Staph. aureus MB 9) at 1-30 ug/cc. They are active against E. coli Monod at 0.001-ug/cc and against Kledsiella pneumonae at 0.06-30 ug/cc. Some cpds. are active against Proteus morganii (0.01-30ug/cc) and Enterobacter aerogenes (0.1-30ug/cc)sub-cultaneous LD50 of (I) in mice is 1.5-2.5 g/kg. Admin. may be oral, rectat, parenteral or topical.
    公开号:SU1037842A3
    申请号:SU802984450
    申请日:1980-09-25
    公开日:1983-08-23
    发明作者:Фарж Даниель；Ле Руа Пьер；Мутоннье Клод；Пейронель Жан-Франсуа
    申请人:Рон-Пуленк Эндюстри (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a method for producing new antibiotics of the cephalus of the sporic series, namely, new 3-tiovinylcephalosporins, which can be used in medicine as a medicine. A known method for producing biologically active (3-aminothia; eolyl-4) -acetylamido 3-3-heterocyclic thiomethyl-3-cephem-4-carboxylic acids by reacting 7- (4-bromo-3-oxobutyrylamino) -3-acetoxymethyl-g3- cephem-4-carboxylic acid with thiourea in an inert organic solvent at room temperature followed by the interaction of (2-aminothiazolyl-4) acetamidoJ-3-acetoxymethyl-3-cephem-4-carboxylic acid with the corresponding heterocyclic thiol 1. Purpose of the Invention is the preparation of new antibiotics cephalosporino a number of products expanding the arsenal of means of influencing a living organism. This goal is achieved based on the well-known 2-α-aminothiazole reaction by the proposed method for the preparation of 3-thiovinyl cephalosporins of the formula S with oo gg CH CH-S in the form of syn-isomer of configuration E, where R; j is 2-pyridyl-1-oxide, 6-methyl-3-pyridainyl-1.-oxide, 5,6-dioxo -1,4,5,6-tetrahydro-1,2,4-triazinyl-3, substituted in position with 4 allyl, 2,3- dioxypropyl, 2-oxopropyl, thiazolidinyl-2-methyl, ethyl, monosubstituted in position 2-OXY-, OXO-, methoxy-, methylthio formyloxy-, acetoxy-, carbamoyl CI-, acetylamino-, amino-acetylamino-, methoxycarbonyl but-, methylsulfonylamino-, glycyloxy-, hydroxy or methoxyimino- in the form of a mixture of these and anti-isomers or a methylureylene group, or ethyl disubstituted in position 2 by an oxy- and formyl group, or RI is 1-methyl-3-carbamate toxic- 1,2,4-trnazolyl-5 # 1,3,4-thia diazolc-B, substituted in the 2-methyl position, acetylaminomethyl or dimethylaminomethyl, or tetrazolyl-5, 3Cl is displaced in the 1 position with methyl / formylmethyl, 2-hydroxyethyl or 2 acetylaminomethyl; R is a hydrogen atom, methyl or cyanomethyl, or a salt thereof, which is a compound of the formula BrCHgOOC-OOBH. -H.i CH “cH-a-iLi N. Ooois tin as syn-isomer of configuration E | where R and R2 have the indicated values and RJ is a hydrogen atom or an ester protecting group such as benzhydryl, reacts with thiourea in an inert organic solvent at room temperature and, if necessary, removes the protective ester group by acid hydrolysis and isolates the desired product In free form or in the form of salt. The compounds of formula I according to the invention can be purified by physical means, for example, crystallization or chromatography. The new cephalosporin derivatives obtained by the proposed method, as well as their pharmaceutically acceptable salts, possess antibacterial properties both in wine conditions and in vitro conditions for gram-positive and gram-negative bacteria. Under in vitro conditions, the products of formula 1 are active at a concentration in the range of 0.5 to 15 mcg / cm per strain of l of penicillin-sensitive staphylococci (Staphylococcus aureus Smith), at a concentration in the range of 1-30 mcg / cm - on strains of penicillin-resistant Staphylococcus aureus (Staphylococcus auraus MB9 ), with a concentration in the range of 0.001 to 1 µg / cm - on E. coli (Escherichia coli strain Monod) and at a concentration of 0.06 in the range of 0.06. 30 kgm / cm - For the causative agent pneumogue, NII GK1eBs1e11a: pneumo.niae), In addition, some compounds exhibit an active effect at a concentration of 0.01-30 μg / cm on Proteus morgani and at a concentration of 0.1-30 μg / cm on Enterobacter aerogenes. Under in vivo conditions, the products of the formula I have an active effect (as revealed in tests on mlh) on Staphylococcus aureus Smith, sensitive to penicillin G at a dose of 0.2-15 mg / kg per day when administered by subcutaneous injection and for intestinal bacilli (Escherichia, Monod strain) With a dose of 0.001-10 mg / kg per day when administered by subcutaneous injection. In addition, the dose of the products of formula 1 ranges from 1.5 g / kg to a value of 2.5 g / kg when these products are introduced into the body No. 1 by subcutaneous injection. Example 1K solution of 1.4 g of 2-benehydryloxycarbonyl-7- (4-bromo-2-oxyimino-3-oxobutyrs but) -3-C2- {2-methyl-1,3,4-thiadiazoles -5) -thiovinyl - 8-oxo-5-thia-1-azabicycloG4, 2.0 Zokten (syn-isomer of configuration E) in 35 cm of ethanol, 25 cm of tetrahydrofuran and 5 cm 3 of water are added 0.18 thiourea and this solution is stirred for 4 hours at 20 ° s The solution is evaporated to dryness in vacuo (20 mm Hg). The residual product of evaporation is grown, washed with 10 cm of water, the pH is adjusted to 7 by adding a solution of sodium bicarbonate, the precipitate is filtered, it is washed with 5 cm and dried. As a result, 1.3 g of a solid light beige product is obtained, which is dissolved in 10 cm3 of chloroform. The resulting solution was added dropwise to 100 cm of isopropyl ether with stirring. The resulting sprout: the sediment is filtered off, the solution is dissolved in 25 cm of tetrahydrofuran to form a solution, and the solution is filtered in the presence of vegetable black and evaporated to a residual volume of 5. vacuum (20 mm Hg.) 25 ml of ethyl acetate is added to this solution. The solid precipitate is filtered off, washed with 10 cm of ethyl dedetate and dried. The resultant is 0.9 g of 2-benzhyd rhyloxycarbonyl-7-2-rxiimine-2- ( 2-aminothia9-alkyl-4) acetamido (2-methylthiadiazol-1,3,4-iL-5) ti vinyl J-8-oxy-5-thia l-azabicyclof 4,2, Ozokten-2 (syn-isomer of configurations E) in the form of a solid beige color, .. - Characteristic lines of the IR spectrum (KBG, cmg-): 3380, 3200, 3100.1785 1720, 1685, 1630, 1535, 1500, 1445 1210, 950, 760, 745, 705 Proton NMR spectrum (350 MHz, DMSO, a /, cGv ppm, J in Hz): 2.71 (singlet, 3N, -CH, g eterocycle); 3.72 and 3.98 (3 doublets, I 18.2N, -SCHj-); 5.28 Chdulet, J 1H, H at 6 5.90 (doublet, J 4 and 9, 1H, H at 7 ) 6.80 (singlet, 1H, H thiazole); 6.98 (singlet, 1H, -СООСН:, 7.05 (doublet, J 1b, 1H, -CH-CHS-); 7.2 (doublet, J 16, 1H,); 9.65 (doublet, J 9, 1H, -QpNH-); 11.85 (broad singlet, 1H, NOH) 0.3 g of 2-benzhydryloxycarbonyl-7-C2-oxyimino-2 - (2-aminothiazolyl-4 acetamido-3- 2- (2-methyl-1,3,4-thiadiazolyl-5) -thiovinyl-8-oxo-5-thia-1-azabicyclo 4,2,0 Zoctene-2 ( The syn-isomer of configuration E) is dissolved in 6 cm of formic acid at a concentration of 98%. B cm of distilled water is added and the mixture is heated for IS minutes. The resulting turbid solution is cooled, filtered in the presence of vegetable black, and the filter is evaporated to dryness under vacuum (20 mm Hg). 10 cm3 of ethanol is added to the evaporation residue, the solution is evaporated to dryness in vacuo (20 mm Hg). the operation is repeated two more times and then the suspension of the residual product of evaporation in 10 cm of ethanol is heated to reflux and refluxed, cooled, filtered and dried under vacuum (0.5 mm Hg). As a result, get 0.07 g of 2-carboxy-7-2-oxyimino-2- (2-amino-4-thiazolyl) -acetamido-3-2- (2-methyl-1 3, 4-thiadiazolyl-5) thiovinyl. -3-OXo-5-thia-1-azabicyclo 4, 2.03 octane-2 (syn-isomer of configuration E) in the form of a yellow solid. Characteristic lines of the in-spectrum spectrum (KBG, 3600, 2200, 1770, 1660, 1630-, 1530, 1390, 950.. Proton NMR spectrum (350 MHz, iDMSO, d, cg in ppm, J in Hz); 2, 74; (singlet, 3N, -CHH), 3.64 and 3.90 (2 doublets, J 18, 2H, -SCH2-); 5.20 (doublet, J 4, 1n, H in 6); 5, a () Chdublet, 4 and 9, 1H, H at 7); 6.65 (singlet, 1H, H thiazole); 7.08 (singlet broad, 2H, -NH2); 7.10 and 7.20 (2 doublets, 4,14, 2H, -CH CH-S-); 9.46 (doublet, 9, 1H, -CONH-); 11.28 (singlet wide 1H, NOH). PRI mme R 2. 0.51 g of 7-amine-2-; -carboxy-3-C2- (1-methyl75-: tetrazllyl, -thiovinyl) -8-okEO; -5-thia-1-azobicyl 4, o5octene-2 (configuration E) is dissolved in 10 cm of water with 0, 63 g of sodium bicarbonate and 7.5 cm of acetone. The mixture is cooled to -8 ° C and added dropwise, a solution of 0.363 g of 4-bromo-2-methoxyimino-3-oxobutyryl chloride (syn-isomer) is added in 5 mg to 5 min. acetone. The mixture is stirred for 50 minutes at a temperature of (-8) - (5) ° C. Then it is filtered, the acetone is evaporated at 20 ° C and at 20 mm Hg, diluted with 50 cm of water, 50 cm of ethyl acetate The aqueous phase is diluted with 100 cm of water, 150 cm of ethyl acetate is added and acidified to a pH of 2.3 by the addition of 4N hydrochloric acid solution. The washed layer is washed with 100 cm of a saturated solution of sodium chloride, dried over sodium sulfate and evaporated to dryness at 20 ° C and at 20 mm Hg, Art. A solution of the product thus obtained in 5 cm of ethanol is added at 20 ° C to a solution of 0.11 g of thiourea in 5 cm of ethanol and 10 cm of water. The mixture is stirred for 35 minutes at 2p, the pH is adjusted to 6 by adding sodium bicarbonate and acidified by adding 1 cm of formic acid. The mixture is evaporated to dryness
     and at 20 mm pt.cT. and dissolving the evaporation residue three times in 50 cm of ethanol, evaporating the solvent after each dissolution to dryness at and at 20 mm Hg. The residual evaporation product is extracted with 250 cm of ethanol while heating and refluxing is refluxed, evaporated to a residual volume of 25–20 ° C and at 20 mm Hg, withstand
    15 min at 5 ° C, again filtered and the solid residue was washed with 5 cm of ethanol and twice with 10 cm of ether. 0.28 g of (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3-2-carboxy-3- 2- (1: -methyl-5-tetrazapil} -thiovinyl-8-oxo-5-thia- (1-aza-bicyclo f4, 2.0 octene-2 (syn-isomer of configuration E) in the form of a powdery yellow product.
    Proton NMR spectrum (350 MHz,. DMSO, d, cH ppm, J in Hz): 3.66 and 3.86 (2 doublets, J 17, 2H-SH -); 3.90 (singlet, 3N SCH); 4.0 (singlet, 3N, -IR); 5.20 (doublet, 1H, Hb6); 5.80 (doublet of doublets, J 4 I 9, 1H, H to 7); 6.83 (singlet, 1H, H in 5 thiazole); 7.0 (doublet, J 16, 1H,); 7.1 (doublet, jr 16, 1H, CHS-) i 9.7 (doublet, J 9, 1H, -CONH-).
    Similarly, compounds 3-31, shown in the table, are prepared.
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    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING .3-THIOVINYLCEPHALOSPORINS of the general formula as a syn-isomer of configuration E, where R ^ is 2-pyridyl-1-oxide, b-methyl-3-pyrida9inyl-1-oxide, 5, b-dioxo-1,4, 5, b-tetrahydro-1,2,4-triazinyl-3, substituted at position 4 with allyl, 2,3 ~ dioxipropyl, 2-oxopropyl, thiazolidinyl-2-methyl, ethyl monosubstituted at position 2, hydroxy, oxo, methoxy, methylthio, formyloxy, acetoxy, carbamoyloxy, acetylamino, aminoacetylamino, methoxycarbonylamino, methylsulfonylamino, glycyloxy, hydroxy or methoxyimine mixtures of syn and anti isomers or methylureyl by a group or ethyl disubstituted at position 2 by an oxy and formyl group, or Rj— 1-methyl-3-carbomethoxy-1,2,4-triaz0lyl-5, 1,3,4-thiadiaeolyl-5, substituted At position 2, methyl, acetylaminomethyl or dimethylaminomethyl, or tetrazolyl-5, substituted at position 1 with methyl, formylmethyl, 2-hydroxyethyl or 2-acetylaminomethyl;
    Rg is a hydrogen atom, methyl or cyanomethyl,. * or their salts, characterized in that the compound of general formula
    BrCHjCOC-COHH L as syn ^ configuration of the isomer E, wherein R ^ and R 2 have the meanings indicated * R 3 - hydrogen or complexity [noefirnaya protecting group such as benzhydryl, is reacted with thiourea in an inert organic solvent at room temperature and if necessary, removing the protecting ester group by acid hydrolysis with pro- and vydelyayut'tselevoy duktv free form or in salt form.
    , SU.J 037842
    类似技术:
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    同族专利:
    公开号 | 公开日
    ZA803037B|1981-05-27|
    FR2474504A1|1981-07-31|
    JPS55154980A|1980-12-02|
    JPS6217592B2|1987-04-18|
    FR2474504B1|1983-03-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4645769A|1985-03-01|1987-02-24|Merck & Co., Inc.|1-oxa-1-dethia-cephalosporin compounds and antibacterial agent comprising the same|
    DE3775798D1|1986-03-19|1992-02-20|Banyu Pharma Co Ltd|CEPHALOSPORINE COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL AGENTS.|
    EP0630899B1|1992-09-18|2002-02-13|Otsuka Kagaku Kabushiki Kaisha|Cephem compound, process for producing the same, and medicine containing the same|
    CA2935651A1|2007-10-09|2009-04-16|Gladius Pharmaceuticals Corporation|Broad spectrum beta-lactamase inhibitors|
    EP3441071A1|2013-03-12|2019-02-13|Gladius Pharmaceuticals Corporation|Derivatized cephalosporins|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7913095A|FR2474504B1|1979-05-23|1979-05-23|
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