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    • 专利摘要:
    NEW MATERIAL:A compound shown by the formulaI(R<1> is H or carboxyl- protecting group; R<2> is aromatic hydrocarbon group, acylamino, etc.; R<3> is H or alkoxy; R<4> is H or halogen; R<5> is H or amino; A is -CH2-, etc.; Z is S,S O; one of dotted lines in the cephem ring is double bond) and its salt. EXAMPLE:7-[2-(2-Aminothiazole-4-yl)acetamido]-3-[2-(5-acetamido-1,2,3, 4-tetrazolyl) methyl]-DELTA<3>-cephem-4-carboxylic acid. USE:An antibacterial agent effective against Gram-positive and Gram-negative bacteria. Stable to beta-lactamse, having low toxicity. PROCESS:A compound shown by the formula II or its salt is reacted with an aromatic hydrocarbon, etc. in an organic solvent in the presence of an acid, etc., to give a compound shown by the formula III. This compound is reacted with a compound shown by the formula IV, to give shown by the formulaI.
    公开号:SU1418329A1
    申请号:SU823520351
    申请日:1982-12-09
    公开日:1988-08-23
    发明作者:Садаки Хироси；Нарита Хироказу；Имаизуми Хироюки；Кониси Есинори；Инаба Такихиро
    申请人:Тояма Кемикал Компани,Лтд. (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to new chemical compounds, namely, 7-a1CHL-amidocephalosporins of the general formula
     -J ™ Y
    N- COOR,
    (I)
    where R is hydrogen, sodium, pivaloyl oximethyl or 1-pivaloyloxyethyl;
    , R, - 3-chloro-1, 2, 4 - triazolyl or 5-methyl-15 2.354-tetrazolines, which are attached to the exomethylene group in position 3 of the depumer ring via nitrogen-carbon bond in the form of syn-isomers, exhibiting antibacterial properties , or to their hydr hordes.
    The purpose of the invention is to search for new cephalosporin compounds with high antibacterial activity with low toxicity.
    And p and m e. P 1 about
    1. In -16 ml of NsN-dimethylacetamide is dissolved 3.15 g of 2- (2-tert.aminoxycarboxamidothiazol-4 ™ yl) --M-2- (syn) - methoxyiminoacetic acid and according to Kan. 1.69 g of phosphorus oxychloride is added at -20 ° C. The resulting mixture was stirred at this temperate for 1.5 hours and then dropwise added to the solution at (-30) (-20) C, 3.16 g of 7-amino 8 - (3-chloro-TS2e4-three). azpli.p) webs - i32 cefem-4-carboxylic acid and 6.1 g of PeO-bis (trimetnleilyl) acetamide in 32 ml of anhydrous chloro
    ristog about methylene. After adding
    dropwise, the reaction is carried out at this temperature for 1 h, then at 0-10 ° C for 0.5 h and then at room temperature for 0.5 h. After completion of the reaction, distilled under reduced pressure, the chloride chloride and the obtained residue are introduced into a mixture of solvents w 80 ml of water and 100 ml of ethyl acetate. The organic layer is then separated and 80 ml of water is added. The pH of the sodium carbonate is then adjusted. The aqueous layer is separated and 80 ml of et1-acetate is added, after which the pH is adjusted to 1.5 with 2N hydrochloric acid under ice-cooling. The organic layer is separated, washed successively with 500 ml of water and 50 ml of saturated aqueous hydrochloride. rub and dry - t, anhydrous
    0
    five
    g
    five
    0
    five
    magnesium sulfate. The solvent is then removed by distillation under reduced pressure. Sulfuric ether is added to the residue. And the resulting crystals are filtered off, yielding 5.62 g (yield 91.8%) of 7- (25 2 tert. Amyloxycarboxamidoti-) -2- (syn) methoxyiminoacetamido-8- (3- chloro-1,2,4-triazolyl) -4-cephem-4-carboxylic acid with a melting point of 198-200 ° C (with decomposition).
    II. In 30 ml of trifluoroacetic acid, 5.62 g of the obtained 7-2- (2-tert, amyloxycarboxamidothiazol-4-yl) 2 (syn) -methoxyacetamido-8- (3-chloro-1, 2, 4-triazolyl) methyl-. - - 4-carboxylic acid cephaem. The reaction is carried out at room temperature.
    within 30 min. After completion of the reaction, the solvent is distilled off under reduced pressure. Sulfuric ether is added to the residue and the resulting crystals are filtered, washed thoroughly with ether and dried, to give 5.23 g (yield 33.1%) of the trifluoroacetic acid salt (2-aminothiazol-4-yl) -2- ( syn) methoxyiminoacetamido - 3- (3-chloro-1,2,4-triazolyl) -methyl-L-cephem-4-carboxylic acid with a melting point of 162 ° C (with decomposition).
    IR spectrum (KBG), cm:) 1715; 1670; 1.630,
    III, In 25 ml of water, 6.13 g of trifluoroacetic salt of (2-aminothiazol-4-yl) -2- (syn) methoxyimo-yo-acetamide-3- (3-chloro-1,2,4-triazolyl) methyl -, / -cepheme-4-carboxylic acid and sodium bicarbonate is added to the resulting suspension with ice-cooling, bringing the pH of the suspension to 8.0, at which the suspension turns
    in solution. The pH is then adjusted to 2.5 with concentrated hydrochloric acid at the indicated temperature, as a result of which the crystals precipitate. The crystals are filtered, washed thoroughly with water and then with acetone and dried, yielding 4.71 g (yield 94.5%) of 7-C2- (2-aminothiazol-4-W-) -2- (syn) - methoxyiminoacetamido-3- (3-chloro-1,2,4-triazolyl) -methyl- / -cepheme-4-carboxylic acid with a melting point of at least.
    IR spectrum (KBG), cm: f, M65, 1660; 1625,
    Similarly, (2-aminothiazol-4-yl) -2- (syn) -megoxy-amino-acetamido-3-2- (5-methyl-1,2,3, 4-tetrazolyl) methyl cephem-5-carboxy Vc is obtained , o 1760;
    314
    new acid with a melting point above 200 ° C.
    IR spectrum (KBG), cm: V. 1765; 1660; 1625.
    Iv. The compound obtained in II was treated with 1N aqueous plant-fopoM NaOH with ice cooling to give (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido 7-3- (3-chloro-1,2, 4-triazolyl) -methyl- / 9-cepheme-4-carboxylate sodium with a melting point of 168 ° C (with decomposition).
    IR spectrum (KBG), cm 1670; 1605.
    Similarly, 7- {2- (2-aminothiazol-4-yl) -2- (syn) methoxy-imino-acetamido} -3- 2- (5-methyl-1,2,3, 4-tetrazolyl) -methyl is obtained. - / 1-cepheme-4-carboxyl sodium with a melting point of 183-187 ° C (with decomposition).
    IR spectrum (KVg), 1665; 1610.
    The compound obtained in stage II is reacted with concentrated hydrochloric acid in a 90% ethanolic aqueous solution (V / V) to obtain the hydrochloride (2-aminothiazol-4-yl) -2- (syn) methoxy-amino-acetamido-1- 3- (3-chloro-1,2,4-triazolyl) -methyl-L-cephem-4-carboxylic acid.
    IR spectrum (KVg). cm: Vc-c.1770; 1720; 1680; 1620.
    Using the procedure described, hydrochloride (-2-amino-aziol-4-sh1) -2- (syn) -methoxyiminoacetamido (5-methyl-1,2,3,4-tetrazolyl) -methylJ-4-cefem-4 -carboxylic acid with tfiA 136-158 ° C.
    Example 2. To a mixed solvent of 8 ml of anhydrous methylene chloride and 2.2 ml of H, K-dimethylacetamide, 3.7 g of phosphorus oxychloride are added at O-5 ° C, the mixture is reacted at the same temperature for 30 min The reaction mixture is then cooled to (-15) -, 2.4 g of 2- (2-aminothiazol-4-yl) -2 (syn) -methoxyiminoacetic acid is added and the mixture is reacted at the same temperature. for 20 minutes To the reaction mixture, a solution of 4.47 g of beer hydrochloride oo-Loxymethyl 7-amino-3-2- (5-methyl 1-1, 2, 3, 4-tetrazolyl) methyl 3-4 is added dropwise. -4-carboxylic acid 1.01 g of triethylamine in 20 ml without 329
     aqueous methylene chloride. After instillation, the mixture reacts at -10 ° C for 30 minutes, at 0 ° C for 30 minutes, and then at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off under reduced pressure, and 50 ml of water and 50 ml of ethyl Q acetate were added to the residue, after which the pH was adjusted to 7.0 with sodium bicarbonate. The organic layer is separated, washed successively with 30 ml of water and 30 ml of a saturated aqueous solution of sodium chloride.
    5 and dried over anhydrous magnesium sulphate. The solvent was distilled off under reduced pressure, and sulfuric ether was added to the residue. The resulting crystals are collected by filtration and get
    Q 5.1 g (yield 86%) of pivaloxyloxymethyl ester (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido} -3-2- (5-methyl-1,2,3,4- tetrazolyl) -methylJ-4-cepheme-4-carboxylic acid with a melting point of 127-128 ° C (with decomposition).
    IR Spectrum (KBG), 1780; 1753; 1675.
    Similarly, the following coJQ units are obtained:
    pivaloyloxymethyl-7- | 2- (2-amino-thiazol-4-yl) -2- (syn) -methoxyimino-acetamno-1-3-E (3-chloro-1,2,4-triazo-lil) methyl-4 3-cephem -4-carboxylate with a melting point of 118-122 ° C (with decomposition);
    1-pivaloyloxyethyl-7- 2- (2-aminothiazol-4-yl) -2- (syn) methoxyiminoacetamino-3-2- (5-methyl-1,2,3,4-tetrazo-, lil) methyl -4-cephem-4-carboxylate with a melting point of 127-130 ° C with decomposition;
    pivaloyloxymethyl-7-G2- (2-aminothiazol-4-sh1) -2- (syn) -metok -siiminoacetamido-3-2- (5-methyl-1,2, 3,4-tetrazolyl) methyl-1-l hydrochloride -cephem-4-carboxylate having a melting point of 144-148 ° C;
    1-pivaloyloxyethyl-7- 2- (2-aminothiazol-4-IL) -2- (syn) methoxyiminoacetamido1-3- 2- (5-metsh-1, 2,3,4-tetrazolyl) -methyl hydrochloride - / l3-cephem-4-carboxylate (recrystallization from methanol) with a melting point of 150 (decomposition); (2-Aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido-3-1 (3-chloro-1,2,4-triazolyl) methyl-L -ce5 hydrochloride pivaloyloxymethyl ester
    fem-4-carboxylic acid with a melting point of 134-136 ° C (with decomposition),
    The pharmacological effects of the compounds obtained are tested.
    SRI.
    Antibacterial activity.
    In accordance with the standard method, the culture obtained by cultivating the bacteria in the heart broth broth for 20 hours is sown in the heart extract agar and cultured at 37 ° C for 20 hours, after which the growth of the bacteria is checked visually
    in position 3 of the cephem core, referred to as G (3-chloro-1,2,4-triazolyl) -methylJ- -.
    The oral administration experiment is carried out as follows.
    Each test compound is administered orally to mice (tCP, male at 4 weeks of age) at a dosage of 2 mg per individual, and the urine compound is determined. The results are presented in Table 2. After absorption by the living organism, all test compounds easily split off the ether.
    but. The minimum inhibitory concentration group, giving the corresponding
    Radiation (MIC, kg / mp) is the concentration j at which the growth of bacteria is inhibited. The number of bacteria inoculated is 10 cells, the plate is 10 cells / ml (Table 1).
    The following compounds are taken for testing.
    (2 aminothiazol-4-yl-2- (syn)-methoxyimino-acetamide-3 -2 -2 (5-me-TSH1-1,2,3,4-tetrazole) -methyl 3-cemem-4-carboxylic acid (BUT).
    (2-aminothiazol-4-yl) -2- (syn) - methoxyiminoacetamido-3- (3-chloro-1, 2,4-triazolyl) -methyl J- -cephem-4-carboxylic acid (B),
    7-C2- (2-aminothiazol-4-yl) -2- (syn) -methoxyiminoacetamido-3- 2- (5-methyl-1,2,3,4-tetrazolyl) methyl-3-hydroxychloride hydrochloride 4-carboxylic acid (C),
    (2-Aminothiazol-4-yl) -2- (syn) methoxyiminoacetamido T-3- (3-chloro-1,2,4-triazolyl) methyl-dz-cephem-4-carboxylic acid hydrochloride (D).
    20
    free carboxylic acids. Consequently, the amount is determined by the strong carboxylic acids entering the urine and taken as an extract from the urine. The route of administration is as follows. The test compound is suspended in a 0.5% CMC solution and then administered orally.
    The method of quantitative analysis 25 is carried out using the paper disk method with the test bacteria listed in Table 2.
    These measurements are made from the bases or their hydrochloride bases.
    Acute toxicity test conducted.
    To determine the acute toxicity of the three test compounds, mice were injected intravenously. As experimental animals, ICP mice (male, 4 weeks old) or oral rats (S DC, 6 weeks old) are taken. Results are summarized in that bl.
    权利要求:
    Claims (1)
    [1]
    These measurements are made for free bases and their hydrochlorides. Invention Formula
    thirty
    The position of the 1,2,4-triazolyl bond is not determined 40 because 1,2, A-triazo, sludge is attached to the exomethylene group at the 3-positions of the cephem ring through a carbon-nitrogen bond, but it is not stated which of the nitrogen atoms 45 of the 1,2,4-triazolyl group are attached to the examethylene group in position 3 of the cephem core. The position of the substituent in the 1,2,4-triazolyl group is determined by indicating the position of the 50 substituent in the starting compound. The same is used in the present description when it is already indicated which of the nitrogen atoms in 1,2,4-triazole is attached to the exomethylene group in position 3 of the cephem ring. For example, compounds in which the 3-chloro-1,2,4-triazole group is attached with an exametic group
    20
    40 45
    50 55
    free carboxylic acids. Therefore, the amount of free carboxylic acids entering the urine is determined and taken as an extract from the urine. The route of administration is as follows. The test compound is suspended in a 0.5% CMC solution and then administered orally.
    The method of quantitative analysis 25 was carried out using the paper disk method with the tested bacteria listed in Table 2.
    These measurements are carried out for pre-bases or their hydrochloride.
    Conducted acute toxicity test.
    To determine the acute toxicity of the three test compounds, mice were administered intravenous injections. As experimental animals, mice of the ICP species (male individuals 4 weeks old) or orally to rats were taken (S DC, 6 weeks old). Results are summarized in that bl. .
    These measurements are made for free bases and their hydrochlorides. Invention Formula
    7-Acylamido Cephalosporins of the General Formula
    thirty
    .CONH-TH
    -snz
     .B,
     XnCH, COOR,
    where R is hydrogen, sodium, simethyl pivaloyl or 1-pivapoyloxyethyl;
    R is H-chloro-1,2,4-triazolyl or 5-methyl-1,2,3,4-tetrazolyl, which are attached to the exomethylene group in position 3 of the cephem ring via a nitrogen-carbon bond, in the form of syn-isomers or hydrochlorides exhibiting antibacterial properties.
    E.coli N1HJ
    B.coli TKZ / Penicillinascing bacteria
    Kl.pnucmonia Y-50 Klebsiella spp, Y-72 Kl.pnucmoniae Y-41 Ent.eloacae 11D977 Ser.mareescens 11D 620 Pro.mirabilis T-216 Pro.mirabilis T-111
    Pro.vulgaris 76
    (bacterium producing sporinase)
    Al.faccalis B-1 Al.calioaceticus A-6
    -N (I N-
    Nn
    Ipj
    33.1 m. AT
    35.0 To
    lower value for 5 measurements.
    47.0 KI
    pn at
    Table 1
    1 ,,, 1 0.1 0.1


    0.390.39 0.39 0.39
    0, 1, 0.1 / 0.1
    0.390.39 0.39 0.39
    0.20.78 0.2 0.78
    0, 1 0.1 0.1
    Table 2
    33.1 M.lutenix ATCC 9341
    35.0 To
    47.0 KI
    pneumoniae ATCC 10031
    Introduction by mouth.
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    同族专利:
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    IL74413D0|1985-05-31|
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    SU1249017A1|1986-08-07|
    JPS6052755B2|1985-11-21|
    PL233143A1|1983-05-23|
    IL74413A|1986-08-31|
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    SU1190987A3|1985-11-07|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    JPH0332554B2|1983-06-20|1991-05-13|Sankyo Co|
    JPH0662635B2|1984-04-26|1994-08-17|富山化学工業株式会社|New production method of cefalosporins|
    JPS6137788A|1984-07-31|1986-02-22|Taito Pfizer Kk|Novel cephalosporin compound|
    JPS6251688A|1985-08-30|1987-03-06|Taito Pfizer Kk|Novel cephalosporin compound|
    JPH08831B2|1985-09-20|1996-01-10|富山化学工業株式会社|Purification method of cephalosporins|
    DE3775798D1|1986-03-19|1992-02-20|Banyu Pharma Co Ltd|CEPHALOSPORINE COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL AGENTS.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP55175263A|JPS6052755B2|1980-12-13|1980-12-13|
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