• 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:
    Cephalosporin antibiotics of formula wherein R is hydrogen, an alkali metal cation, or a carboxylic acid protecting group; R1 is hydrogen or methoxy; R2 is hydrogen or an amino protecting group; R3 is hydrogen or C1-C4 alkyl; and R4 is C1-C4 alkyl.
    公开号:SU793403A3
    申请号:SU782699098
    申请日:1978-12-13
    公开日:1980-12-30
    发明作者:Самюэль Катнер Аллан
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the preparation of new antibiotics of the cephalosporin series, namely, (2-aminothiazol-4-yl) -2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives, which can be used in medicine. A known method for producing (2-aminothiazol-4-yl) -2-oxyiminoacetamido-3-cephem-4-carboxylic acid derivatives of the acid by acylation of the corresponding 7-amino-3-cephem-4-carboxylic acid derivative with a reactive derivative corresponding (is a hydrogen atom or methoxy group; 25 Rj is a hydrogen atom or an alkali metal cation; Ri is a hydrogen atom or alkyl alkyl. 2- (2-aminothiazol-4-yl) -2-oxyiminoacetic acid 1. The purpose of the invention is to obtain new derivatives (2-aminothiazol-4-yl} -2-oxyiminoacetamido-3-cephem-4-carboxylic acid means of enhancing a living organism. This goal is achieved by the present method of producing (2-aminothiazol-4-yl) -2-oxyiminoacetamido derivatives of -3-cephem-4-carboxylic acid of formula I which consists in the fact that I Ki 3,011 t |., C. (COOKs
    de RI and RX are as defined above;
    Rj-- a hydrogen atom, an alkali metal cation or a group protecting the carboxy group;
    Rfe-free or protected by an ilyl group, an amino group or a minohydrohalide / is subjected to interaction with an acid chloride, bromine anhydride or a reactive spurious ester of the formula / n
    g1 he
     0 PG TI
    OK where Kz is as defined above
    R7 is a hydrogen atom or an amino protecting group at a temperature of -20. to 50 ° C and, if necessary, the carboxy protecting group and / or the amino protecting group are cleaved off and the target product is isolated, where Rj is a hydrogen atom or an alkali metal cation. New cephalosporin carboxylic acids and their alkali metal salts are used to fight infections in warm-blooded mammals when administered parenterally with their non-toxic doses of 10 to 500 microns / kg body weight. Costs vary depending on the method of administration, it is determined by the type and severity of the infection, the frequency and duration of administration, the general condition of the patient, and the like. factors.
    The compounds can be used in the form of various oral and parenteral dosage forms in pure form or in mixture with other substances. The pharmaceutical composition may be a mixture of 0.01-99% of a compound of formula 1 and a pharmaceutical carrier. The compounds in the form of a salt are soluble in water and are usually used as solutions for intravenous, intramuscular or subcutaneous administration. The method of treating or preventing bacterial infections in humans or animals is based on administering to humans or animals an effective amount of a compound of formula I as a daily dose of 10 to 500 mg / kg body weight, for example, at intervals of 3 to 12 hours. compound in the form of a pharmaceutical composition.
    The compounds have superior action against typical gram-positive and gram-negative microorganisms ..
    Compound A was used in the table below, which is the (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3- (4-methyl-5-oxo-b-hydroxy-4,5-dihydro-1) sodium salt. , 2,4-triazin-3-ylthio) -methyl-3-cephem-4-carboxylic acid, and compound B, which is (2-amino-4-thiazolyl -2-methoxyimino-acetamide J-3- (4-ethyl -5-oxo-b-hydroxy-4, 5-dihydro-1,2,4-triazin-3-ilthio) -methyl-3-cephem-4-carboxylic acid. Both compounds are syn-isomers. Minimum concentration, mcc / ml, suppressing the reproduction of microorganisms, is given in the table.
    Examples are provided for a better understanding of the invention. In these examples, the aminothiazole group is a synisomer, unless specifically indicated. Getting the original product. A. To 20 ml of water was added 3.46 g (12.0 1 mol) of 7-formamido-3-acetoxymethyl-3-cephem-4-carboxylic acid and 2.0 g (12.55 mol) of 3-me1 e-capto-4 -methyl-5-oxo-b-hydroxy-4, 5-dihydro-1,2,4 triazine. The mixture was stirred and 1N was gradually added. caustic soda solution to pH 7.0. The resulting mixture was stirred at about 55 ° C for 26 hours. The resulting solution was evaporated to a volume of 20 ml and acidified to pH 1.2 by addition at 3 N hydrochloric acid. hydrochloric acid. The precipitate formed is filtered off and immediately placed in a steam vessel for drying in a vacuum. The dried substance is crushed in a mortar (2.75 g) and triturated three times with 150 ml of boiling isopropyl alcohol. The solution in isopropyl alcohol is evaporated to dryness, the residue is triturated twice with 30 ml of ethyl acetate. The undissolved material was filtered, washed with ethyl acetate, dried and yielded 1.56 g of 7-form0 amido-3- (4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1, 2,4-triazin-3-ilthio ) -methyl-3-cephem-4-carboxylic acid.
    B. The product from example 1, A (0.74 g) is stirred in 12 ml of dry
    5 methanol and add 1.5 ml of concentrated hydrochloric acid, during which time complete dissolution takes place. After a short period of time, a white precipitate begins to form. Stirring is continued for 1.7 hours, the mixture becomes thick with white precipitate. The precipitate is filtered and dried. According to thin layer chromatography, 0.346 g of the product is a very pure sample of the 7-amino-3-h. Hydrochloride. (4-methyl-5-oxO-6-OXI-4, 5-DIGIDRO-1,2,4-triazin-3- Ilthio) -methyl-3-cephem-4-carboxylic acid.
    B. To a suspension of 3.71 g (10 mol) of 7-amino-3- (4-methyl-5-oxo-6-oxy-4,5-dihydro-1, 2,4-triazin-3-ylthio) - methyl-3-cephem-4-carboxylic acid in 50 ml of methylene chloride and 50 ml of methanol added 5 tons of 1.94 g (10 mol of diphenyldiazomethane. The reaction mixture is stirred overnight at room temperature. An additional 500 mg of diphenyldiazomethane is added. After 2 The reaction mixture is filtered, the filtrate is evaporated in vacuo to an oil. This oil is dissolved in 25 ml of methylene chloride, the resulting solution is added dropwise with stirring to hexane. A light yellow-brown is formed. orphous precipitate. After filtration and drying, 2.8 g (52%) of 7-amino-3- (4-methyl-5-oxo-b-hydroxy-4,5-dihydro-1, 2,4-triaen-3 -lthio) -methyl-3-cephem-4-carboxylate benzhydryl.
    NMR spectrum (CDC1): S 3.33, (S, 3, N-CH); 3.5 (ffl, 4,,), 4.86 (q, 2,,), 7.0 (S, 1, benzhydryl CH), 7.36 (S, 10, ArN).
    Example 1. To a solution of 0.55 g (1 mol) of benzhydride Jr-7-amino-3- (4-methyl-5-oxy-6-oxime-4, 5-dihydro-1,2,4-triazium-3- Ilthio) -methyl-3-cephem-4-carboxylate and 866 mg (2 mol) of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid in 15 ml of methylene chloride; add 208 mg (1 mol) of dicyclohexylcarbodiimide after stirring the mixture within b h at room temperature, the reaction mixture is filtered. The filtrate is evaporated in vacuo to an oil, which is then dissolved in ethyl acetate and successively washed with dilute sodium bicarbonate solution, water and brine. The ethyl acetate solution is dried with anhydrous sodium sulfate and evaporated to dryness in vacuo to obtain 800 mg (83%) of benzhydryl (2-tritylamino-4-thiazolyl-2-labels; imino acetamido-3- (4-methyl-5-oxo-b-oxy-4 , 5-DIHIDRO-1,2,4-triazin-3-ylthiomethyl) -3-cephem-4-carboxylate as a red amorphous precipitate.
    NMR spectrum (SDS11, MD5O d-6): O 3.3 (S, 3-M-SPz); 3.7 (S, 2, C2.-H); 4.1 (s, 3, —OCHj); 5.2 (d, 1, J 5, OGTs,), 5.8 (q, 1, J Sr and 8.0 Hz, GT-H); 6.8 (S, 1, thiazolyl C5-i); 7.0 (S, 1, benzhydryl CH) and 7.4 (S, 25, trityl and beizhydryl AGN).
    Example 2. About 500 mg of the benzhydryl ether product from Example 1 are suspended in 10 ml of 50% formic acid and heated on the steam bath for 5 minutes. The mixture is then stirred at 50-60 ° C on a hot plate for 45 minutes. After cooling the mixture to about 30 ° C, it is filtered, the filtrate
    0 is evaporated in vacuo to an oily residue. Trituration of the residue with ethyl alcohol gives, after filtration, a light brown amorphous residue, which is taken up in methylene chloride. Yield 161 mg (56%). Liquid chromatography under pressure has shown that the product is a very pure (2-amino-4-thiazolyl) -2-methoxyimine acetamides-3- (4-methyl-5-OXO-6-OXI-4, 5-DIHYDRO-1 , 2,40-triazin-3-ylthio) -methyl-3-cephem-4g -carboxylic acid.
    NMR spectrum (DM50 d-6): § 3.29 (s, 3, N-CHi); 3.65 (s, 2,); 3.03 (s, 3, OCHj); 4.10 (q, 2, Cj-H);
    5 5.15 (d, 1, J 5.0 Hz Ce-H); 5.77. (q, 1, J 5.0 Hz and 8.0 Hz, C-j-H); 6.73 (s, 1, thiazolyl Cj-H); 7.20 (S, 2, NH | i); 9.58 (d, 1, J 8.0 Hz, in the side chain NH).
    0
    Example 3. A mixture of 84 ml of water, 42 ml of acetone, 2.42 g of sodium bicarbonate and 2.87 g of 7-amino-3- hydrochloride (4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1 , 2,4-triazin-3-ylthio) -methyl-3-tce5 fem-4-carboxylic acid is stirred and cooled in an ice-ethanol bath. After dissolving the solid, a solution of 2.34 g of 2- (2-chloro-acetylamino-4-thiazolyl) 0 -2-methoxyiminoacetic acid chloride in 42 ml of acetone is added. The reaction mixture was stirred in a cooling bath for 95 minutes and another 10 minutes after removal of the cooling bath. Acetone is distilled on a rotary evaporator at
    At room temperature, 50 ml of ethyl acetate is added to the residue and the mixture is acidified to pH 2.2 with dilute hydrochloric acid. The solution is filtered, the precipitate is washed with water and dried in vacuum.
    0 at room temperature, 3.76 g of the product of Example 2 is obtained in N-chloroacetyl form.
    The NMR spectrum in DMZO d-6 showed one proton singlet at S 7.44 h / 5 t / million; analysis on C1 showed 5.52%, calculated C1 for CJi „No Og S, Cl 5.62%. -Is about
    权利要求:
    Claims (2)
    [1]
    Example 4. 4.4 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid are converted into chloro acid anhydride and dissolved in acetone. The solution is added to an ice-cooled suspension of 4-nitrobenzyl-7-amino-3- (4-methyl-5-oxo-6-OXI-4, 5-DIGIDRO-1,2,4-triazin 5 -3-ylthio) hydrochloride -methyl-3-cephem-4-carboxylate (3, ab g) and 4.77 g of sodium bisulfite in 200 ml of acetone. After the addition, the ice bath is removed and the reaction mixture is stirred for 20 hours. Then the solids are filtered, diluted with ethyl acetate and washed successively with sodium bicarbonate solution, 1N. hydrochloric acid, water and brine. The ethyl acetate solution is then dried with sodium sulfate and evaporated to a yellow oil. This oil is dissolved in dichloromethane and filtered, the filtrate is purified by passing through a pad of silica gel, first eluted with dichloromethane, then with a 1: 9 mixture of ethyl acetate-dichloromethane. Obtain 2.4 g of 4-nitrobenzyl-7- 2- (2-tritylamino-4thiazolyl} -2-methoxyiminoacetamido} -3- (4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1, 2 , 4-triazin-3-ylthio) -methyl-.-3-cephem-4-carboxylate, mp 14014 ° C. The ether 4-nitrobenzyl group from this intermediate is removed by hydrogenation and 85 mg of the corresponding acid are obtained. from 1.5 g of the above intermediate compound. The acid is suspended in 5 ml of 50% formic acid. Suspension for a short time on a steam bath to a B-30 ° C and the mixture is stirred gently for 10 minutes. and filtering. After adding water to the filtrate, a precipitate is formed which is separated by filtration. The filtrate is evaporated in vacuo to give a yellow oil, which is dissolved in a few ml of denatured ethanol. The diethyl ether is added until the final formation of a precipitate. mg of product identical to the product of example
    [2]
    2. Example 5. 30 ml of the product from Example 3 are dissolved in 1 ml of solvent, a small amount of alkali is added and then 7.3 mg of thiourea is added. The reaction mixture was stirred at room temperature, after which the reaction was carried out by thin layer chromatography. The product of Example 2 is identified in pure form after a reaction time of 524 hours in different cases. Solvents and bases, used in this method:. dimethylformamide and triethylamine dimethylformamide and sodium acetate, water and sodium bicarbonate, pyridine Sbez additional alkali) ,. Example 6. The acylation is carried out as in Example 3, but the reaction is carried out at room temperature. Outcome of 1.85 g of 7-amino-3-C4-methyl-5-grxo-6-hydroxy-4, 5-DIHIDRO-1,2,4-three a.zin-3-ylthio-methyl-3- cephem-4-carboxylic acid and 1.58 g of 2- (2-chloro-acetylamino-4-thiazolyl} -2-methoxyiminoacetic acid chlorohydride) as anti-isomer. 1.06 g of the resulting product reacts at room temperature with thiourea and sodium bicarbonate. 0.55 g of 7-p- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3- (4-methyl-5-oxo-6-hydroxy-4,5-dihydro-1, 2,4- triazin-3-ylti) -methyl- -3-cephemcarboxylic acid, mainly as an anti-isomer. The NMR spectrum showed a one-proton inglet, indicating G-5 thiazole ring proton at S 7.98 parts / million. Formula of the invention Method of obtaining derivatives (2-aminothiazol-4-yl-2-oxyiminocetamido-3-cephem-4-carboxylic acid of the formula I -mn L-CCOCN mn-g e I, ch2 - $ - Xo, where R is a hydrogen atom or a methoxy group) R.2 is a hydrogen atom or an alkali metal cation, a hydrogen atom or an alkyl, 4 alkyl cjC, o tl and h ay and c in that the compound of formula II is CHfSJi JO; J --- N I; O where R and Yal have the above values, {is a hydrogen atom, an alkali metal cation or a carboxy protecting group; an amino group free or protected by a silyl group or an amine hydrogenshogenide is reacted with an acid chloride, bromine anhydride or a reactive ester of an acid of the formula | and xV-dc where Rj has the above-mentioned RT, a hydrogen atom or a group protecting an amino group, at a temperature of 79340310
    tour from -20 to and in the case of non-information sources,
    Obliquity cleave a group that is protected — taken into account in the examination of the carboxy group and / or group
    protecting the amino group, and injecting yut1. USSR patent application
    the target product, where R is an atom of hydrogen-No. 2462904 / 23-04, cl. C 07 O 501/06,
    yes or alkali metal cation. 1976.
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    同族专利:
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    AT364189B|1981-09-25|
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    IE782502L|1979-06-20|
    LU80669A1|1979-04-13|
    GB2010256B|1982-09-08|
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    IE47696B1|1984-05-30|
    CA1140112A|1983-01-25|
    ZA787110B|1980-08-27|
    AU518484B2|1981-10-01|
    CS204957B2|1981-04-30|
    PT68888A|1979-01-01|
    DE2861493D1|1982-02-18|
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    IT7831016D0|1978-12-19|
    FR2412553B1|1982-10-15|
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    IT1112300B|1986-01-13|
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    RO75804A|1981-02-28|
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    HU181875B|1983-11-28|
    FR2412553A1|1979-07-20|
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    PH15368A|1982-12-10|
    EG13666A|1983-12-31|
    FI783846A|1979-06-21|
    EP0002605B1|1981-12-30|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    CA1100129A|1974-08-02|1981-04-28|William H.W. Lunn|Cephalosporin compounds|
    GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins|
    NL7805715A|1977-06-03|1978-12-05|Hoffmann La Roche|METHOD FOR PREPARING ACYL DERIVATIVES.|JPS5760345B2|1974-12-19|1982-12-18|Takeda Chemical Industries Ltd|
    MC1259A1|1978-05-30|1980-01-14|Hoffmann La Roche|ACYL DERIVATIVES|
    CH641468A5|1978-05-30|1984-02-29|Hoffmann La Roche|CEPHEM DERIVATIVES.|
    ZA806977B|1979-11-19|1981-10-28|Fujisawa Pharmaceutical Co|7-acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof|
    FI67385C|1979-11-21|1985-03-11|Hoffmann La Roche|PROCEDURE FOR FRAMSTATION OF AV-7--2-ACETAMIDO) -3-CEFEM-4-CARBOXYL SYRATER DERIVATIVES|
    US4409387A|1979-11-29|1983-10-11|Hoffmann-La Roche Inc.|Cephalosporin derivatives|
    US4349672A|1979-11-29|1982-09-14|Hoffmann-La Roche Inc.|Cephalosporin derivatives|
    NZ196552A|1980-03-25|1984-07-06|Hoffmann La Roche|Cephalosporin derivatives and pharmaceutical compositions;intermediate cephalosporins|
    GR75711B|1980-06-30|1984-08-02|Sanofi Sa|
    DK379581A|1980-10-06|1982-04-07|Hoffmann La Roche|PROCEDURE FOR THE PREPARATION OF ACYL DERIVATIVES|
    FR2494278B1|1980-11-20|1983-04-15|Rhone Poulenc Sante|
    US4698338A|1986-02-19|1987-10-06|Eli Lilly And Company|7[2--2-benzyloximino]acetamido-3[4-alkyl-5-oxo-6-hydroxy-3,4-dihydro-1,2,4-triazin-3-yl]thiomethyl cephalosporins|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/862,318|US4200745A|1977-12-20|1977-12-20|7[2--2-alkoxyimino]acetamido 3[4-alkyl-5-oxo-6-hydroxy-3,4 dihydro 1,2,4-triazin 3-yl]thio methyl cephalosporins|
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