• 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:
    The method of obtaining cephalosporins of the general formula (I) or carboxymethyl, 1,3,4-thiadiazol-2-yl, 4H-1,2,4-triazol-3-yl, 2-11 iridyl, 2-pyridyl-1-oxide, 2-pyrimidinyl or 5-methyl-1,3,4-oxadiazol-2-yl, hydrogen atom or hydroxy group, R, hydrogen atom or oxyl acyloxy group, or their salts, characterized in that the compound of general formula (II) SR - / VcH-CCINH O CH-S-RI o co: x) 0 soon where RJ is tetrazol-5-yl, substituted in the 1-position by methyl, ethyl, 2-dimethylaminoethyl where and R have the indicated values, or its salt is reacted with the compound of the general formula (TLI) is R Where R has the indicated values, o in an inert solvent at 30-90 ° C, preferably in the presence of a basic or acidic agent.
    公开号:SU1151213A3
    申请号:SU813338763
    申请日:1981-09-29
    公开日:1985-04-15
    发明作者:Матида Есимаса；Сайто Исао；Номото Сейитиро；Неги Сигето；Канаи Такео；Китох Киосуке；Кацу Канемаса；Охиа Юкио；Кагасу Такесу
    申请人:Эйсам Ко,Лтд (Фирма)；
    IPC主号:
    专利说明:

    1 The invention relates to a process for the preparation of new cephalosporins or their salts, which possess antimicrobial activity and can be used as medicinal substances in medicine. A known method for producing biologically active B-7- (Y- (4-hydroxy-6-methyl-nicotinamido) -cC- (p-ox and phenyl) acetamido-3- (1-methyltetrazol-5-yl) thiomethyl-3-cephem-4 -carboxylic acid by reacting (4-hydroxy-6-methyl-nicotinamido) (p-hydroxyphenyl) -acetamido-3-adhetoxymethyl (or carbamoylmethyl) -3 cephem-4-carboxylic acid with 5-mercapto-1-methyl tetrazole or its alkaline salt at room temperature or when heated in an inert solvent 1. The aim of the invention is to obtain new antibiotics of the cephalosporin series, which expand the arsenal of TV exposure to a living organism. The goal is to obtain cephalosporins of the general formula CH-C0NH iNy # -CHrS-Fi where R is tetrazol-5-yl substituted with 1-position by methyl, ethyl 2-dimethylaminoethyl or carboxymethyl, 1,3,4 -thia diazol-2-yl, 4H-1,2,4-tria-sol-3-yl, 2-pyridyl, 2-pyr dil-1-oxide, 2-pyrimidinyl or 5-methyl-1,3,4- oxadiazol-2-ylJR is a hydrogen atom or an oxy group on K ,, iRd is a hydrogen atom or an oxy-yl acyloxy group or their salts, which means that the compound of the general formula R; / VcH-CONH S (W N-ssf CH OCOCH: x) St COOH 132 where K „, K and R have the indicated values or its salt, according to jected reacted with a compound of the general formula RI-S - H wherein R is as defined above, in an inert solvent medium at LP-EO C preferably in the presence of basic or acidic agent. The compounds of general formula (I) exhibit high antimicrobial activity and are effective not only against gram-positive bacteria, but also against gram-negative bacteria. In particular, these compounds are effective against bacteria Pseudomonas aeruginosa, Serratia marcescens, Proteus morganu, and the like. that cause difficult to treat infections. The compounds of this invention exhibit low toxicity when tested for toxicity. For example, the acute toxicity values of LDj-Q for compounds such as the sodium salt of 7/9-D-2- (6,7-dioxychromone-3-carboxamido) -2-phenylacetamido-3- (1-methyltetrazol-5-yl) thiomethyl} -3-cephem-4-carboxylic acid, sodium salt of (6,7-dioxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-3- (5-methyl-1,3,4-thiadiazole) 2-Sh1) -thiomethyl-3-cephem-4-carboxylic acid and sodium salt (6,7-diacetoxychromone-3-carboxamido) -2-phenylacetamido-3- (1-methyltetrazol-5-yl) thiomethyl-3-cephem -4-carboxylic acid. The dosage of the compound according to the invention, when used as an antimicrobial medicament, can be varied extensively from 2 to 300 mg / kg per day, preferably from 10 to 100 mg / kg per day. This medicine may be administered orally in the form of a powder, granules, tablets, capsules, syrup, and the like. or parenterally in the form of an injection, suppository, etc. Cr and mep 1. (Chromone-3-carboxamide) -2-phenylataseta scho-3- (1 methyltetrazol-5-yl) thiomethyl-3-cephem-4 - carboxylic acid. (Chromone-3-carboxamido) -2-phenylacetamido2-3-acetoxymethyl-3-cephem-4-carboxylic acid.
    311512
    N, 0-iijc- (trimethyl and 1 sg.l) acetamide (7.91 ml, 52 mmol) was added to a suspended suspension of cefaloglycine (3.2D4 g, 8 mm (5l) in dichloromethane (65 ml) at 0 ° C and the mixture stirred for 5 to 20 minutes at 0 ° (;. a solution of acid chloride B-2- (chromone-3-carboxamido) -2-phenylacetic acid (1.67 g, 8 mmol) in dichloromethane (40 ml) was added dropwise to the indicated the mixture while stirring at 0 ° C and stirring is continued for 30 minutes at 0 ° C and an additional 15 minutes at room temperature. The solvent is evaporated and the residue is dissolved in ethyl acetate tS (1 L). The resulting solution is a follower but washed with 0.5N hydrochloric acid, water and brine, dried over magnesium sulfate and evaporated to dryness. The residue 20 was triturated with ethyl ether to give 2.56 g (55%) of the desired compound. Melting point about 170 -200 C (decomposition). IR spectrum (see nudzhol): 1788, 25 1740, 1720, 1665, 1615.
    (Chromone-3-carboxamido) -2-phenylacetamido3 -3- (1-methyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
    A mixture of 250 mg (0.433 mmol) of the described compound 5-mercapto-1-methyltetrazole (76 mg, 0.65 mmol), sodium bicarbonate (91 mg) and phosphate buffer (9 ml, pH 6.4) is stirred at 60 -70 ° C 3.5 h. The reaction solution is acidified with 1N. hydrochloric acid and the mixture is extracted with ethyl acetate. The extract is washed with water, dried over magnesium sulfate and the solvent Q is removed. The residue was triturated with ethyl ether to give 81 mg of powder, which was further purified by thin-layer chromatography on silica gel (a benzene: dioxane-acetic acid 4: 1: 1 mixture was used as the developing solvent) to obtain 7.6 mg of the target compounds. Melting point 175178 ° C (decomposition). . 50
    IR (nudzhol): - 1780, 1660, 1620, 1610. Nuclear Magnetic Resonance Spectrum (S, acOTOH-dg): 3.71 (2H, s), 3.95, (ZN, s), 4.38 (2H, s), 5.06 (1H, d, Hz), 5.90 (1H, DA. Hz, 10 Hz), 6.00 55 (1H, d, Hz), 7.12-8.26 (9H, m), 8.46 (1H, d. Hz), 8.92 (1H, s), 11.38 (1H, d. Hz).
    13-L
    Example 2. (6,7-Dioxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamidoZ-3-C (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid .
    Exit 52.6Z. Melting point 190-192 ° C (decomposition).
    IR (, nudzhol): 1772, 1660, 1615. Nuclear Magnetic Resonance Spectrum (5, DMSO-d): 3.60 (2H, broad), 4.22 (1H, d, 12 Hz), 4, 56 (1H, d, Hz), 5.02 (1H, d, Hz), 5.6-5.8 (2H, m), 6.70 (2H, d, Hz), 6.97 (1H, c), 7.24 (2H, d, Hz), 7.40 (1EI, s), 8.84 (1H, s), 9.35 (1H, d, Hz), 9.57 (1H, s ), 10.24 (1H, d, Hz).
    Example 3. (6,7-Dioxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-3-f (1-ethyl tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.
    Yield 64.0%. Melting point 214-216 ° C (decomposition).
    IR spectrum, nudzhol): 1770, 1664, 1615.
    NMR spectrum (S, DMCO-dfe): 1.40 (3N triplet, 1 7 Hz), 3.5-3.8 (2H, m) ,. 4.0-4.3 (2H, m), 5.00 (1H, d, Hz 5.29 (2H, quadruplet, Hz), 5.65 (1H, s), 5.70 (1H, m) , 6.71 (2H, d, Hz), 6.97 (1H, s), 7.24 (2H, d, Hz), 7.41 (1H, s), 8.84 (1H, s), 9.32 (H, s), 9.42 (1H, s), 9.42 (1H s), 10.08 (1H, s), 10.25 (1H, d, 1 8 Hz), 10 73 (1H, s).
    Example 4. 7uZ-Sv-2- (6,7-Dioxychromon-8-carboxamido) -2- (4-hydroxyphenyl) acetamido-3-1- (2-dimethylaminoethyl) tetrazol-5-yl1-thiomethyl-3-cephem -4-carboxylic acid.
    A mixture of (6,7-dioxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (245 mg), 5-mercapto-1- (2-dimethylaminoethyl) tetrazol (277 mg), sodium bicarbonate (67 mg) and phosphate buffer (pH 6.4, 20 ml) were stirred for 4 hours at 65 ° C. After that, 135 mg of sodium hydrogen carbonate is added to it and stirring is continued for another 9 hours at 65 s. The reaction mixture is then cooled to 0 ° C and acidified with 1N. hydrochloric acid. The precipitate is washed with water, then with a mixture of methanol and ether and finally with ether. The result is the target product (150 mg, yield
    50.8%). Melting point 248250 ° C (decomposition).
    IR (nudzhol): 770, 1663, 1615. NMR spectrum (5, DMCO - d): 2.51 (6H, s), 3.12 (2H, T, Hz), 3.5- 3.7 (2H, m), 4.1-A, 3 (2H, m), 4.53 (2H, t, Hz), 4.97 (1H, d, Hz), 5.6-5, 8 (2H, m), 6.71 (2H, d, Hz), 6.97 (1H, s), 7.23 (2 ", d, 1 8 Hz), 7.40 (1H, s), 8.83 (1H, s), 9.34 (1H, d, Hz), 10.24 (1H, d, Hz).
    Example 5. Sodium salt of (6,7-dioxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-3- (4H-1,2,4-triazol-3-yl) -thiomethyl-3-cephem- 4-carboxylic acid. Vkod 51.0%. Melting point 230245 C (decomposition).
    IR (nudzhol): 1770, 1660, 1610. NMR spectrum (S, DMCO-d): 3.40, (2H, m), 4.64 (1H, d, Hz) 4.84 (1H , d, Hz), 4.92 (1H, d, I 5 Hz), 5.56 (2H, m), 6.02 (1H, broad, s), 6.68 (2H, d, Hz) , 6.89 (1H, s), 7.16 (2H, d, Hz), 7.80 (1H, s), 8.48 (1H, s), 8.50 (1H s), 9.32 (1H, d, Hz), 10.84 (1H, d, Hz).
    Example 6. (6,7-Dioxychromon-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-3- (1-carboxymethyl-tetrazol-5-yl) thiomethyl-3-cep-4-carboxylic acid.
    A mixture of (6,7-dioxychromone-3-carbox. Amido) -2- (4-hydroxyphenyl) acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (245 mg), 5-mercapto-1-tetrazolyl acetic acid ( 256 mg) of sodium hydrogen carbonate (252 mg) and phosphate buffer (pH, 4 70 ml) are stirred for 15 hours at 60-70 ° C. Afterwards, the reaction mixture is acidified with 1N. hydrochloric acid, the precipitated precipitate is filtered and successively with water, a mixture of ether and methanol and ether. The result is the target product (132 mg, yield 45.5%). Melting point 230-231 s (decomposition).
    IR (nudzhol): 1770, 1664, 1615. Nuclear Magnetic Resonance Spectrum (S, DMCO-d): 3.50 (1H, d, Hz), 3.72 (1H, d, Hz), 4.21 (1H, d, Hz), 4.48 (1H, d, Hz), 5.00 (1H, d, 5 Hz), 5.30 (2H, s), 5.6-5.9 (2H m), 6.75 (2H, d,), 7.00 (1H, s) 7.26 (2H, d, Hz), 7.44 (1H, s).
    8.86 (1H, s), 9.38 (1H, d, Hz),
    10.26 (1H, d, 5 Hz). Example 7.) -2- (6,7-Dioxychromon-3-carboxamido) -2- (4-hydroxy-nyl) acetamido-3- (2-pyridylthiomethyl) -3-cephem-4-carboxylic acid.
    Yield 59.0%. Melting point 218-220 ° C (decomposition).
    IR spectrum (cm, nudzhol): 1764, 1672, 1656, 1612. NMR spectrum (S, DMCO-d): 3.1-3.6 (2H, m), 4.1-4.6 (2H , m), 4.89 (1H, d, Hz), 5.52 (1H, dd, and 8 Hz), 5.71 (1H, d, Hz), 6.70 (2H, d, Hz) , 6.87 (1H, s),
    7.0-7.2 (1H, m), 7.24 (2H, h, Hz), 7.31 (1H, s), 7.5-7.7 (1H, m), 7.67, 9 ( 1H, m), 8.3-8.5 (1H, m), 8.75 (1H, s), 9.28 (1H, d, Hz), 10.38 (1H, d, Hz).
    Example 8. (6,7-Dioxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido-3 - 2- (pyridyl-1-oxide) thiomethyl 1-3-cephem-4-carboxylic acid.
    Yield 45.8%. Melting point 240-242 ° C (decomposition).
    IR spectrum (cm. Nudzhol): 3450, 3300, 1792, 1666, 1620. NMR spectrum (, DMCO-d): 3.4-3.7 (2H, m), 4.04, 2 (2H, m ), 5.06 (1H, d, Hz), 5.74 (1H, dd, and 3 Hz), 5.69 (1H, d, Hz), 6.71 (2H, d, Hz), 6, 98 (1H, s), 7.1-7.5 (ZN, m), 7.25 (2H, d, Hz), 7.41 (1H, s), 8.238, 34 (1H, m), 8 , 85 (1H, s), 9.38 (1H, d, Hz), 9.44 (1H, s), 10.09 (1H, s), 10.27 (1H, d, Hz), 10 74 (1H, s).
    Example 9. (6,7-Dioxychromone-3-carboxamido) -2- (4-hydroxyphenyl) acetamido 3- (2-pyrimidinylthiomethyl) -3-cephem-4-carboxylic acid.
    Yield 35.3%. Melting point 205-207 ° C (decomposition).
    IR (nudzhol): 1780, 1717, 1662, 1617. Nuclear Magnetic Resonance Spectrum (5, DMCO-dg): 3.41 (1H, d, Hz), 3.71 (1H, d, Hz), 3 , 91 (1H, d, 1 13 Hz), 4.58 (1H, d, Hz), 5.01 (1H, d, Hz), 5.6-5.8 (2H, m), 6.71 (2H, d, Hz), 6.98 (1H, s), 7.21 (1H, t, Hz), 7.25 (2H, d, Hz), 7.24 (1H, s), 8, 59 (2H, d, Hz), 8.85 (1H, s), 9.36 (1H, d, Hz), 9.45 (IH, s), 10.15 (1H,
    10.27 (1H, d, Hz), 10.72 (1H, s). Example 10. (6,7-Dioxychromon-3-carboxamido) -2- (4-oxnphenyl) acetamido-3- (5-methyl-1,3,4-oxadiazol-2-yl) thiomethyl-3-cephem-4 - carboxylic acid. The yield is 48.5%. Melting point 227-229 ° C (decomposition). IR (cm, nudzhol): 3440, 3280, 1782, 1720, 1668, 1620, NMR spectrum (S, DMCO-d): 2.40 (3N, s), 3.30-3.8 (211, m ), 4.11 (1H, d, 1 14 Hz), 4.35 (1H, d, Hz), 5.00 (1H, d, Hz), 5.69 (1H, d, 1 8 Hz), 5.72 (1H, dd, and 8 Hz), 6.72 (2H, d, Hz), 6.99 (1H, s), 7.24 (2H, d, Hz), 7.41 (1H, c), 8.84. (IH, s), 9.36 (1H, d, Hz), 10.25 (1H, d, Hz). Example 11. (6.7 diacetoxychromon-3 carboxamido) -2- (4-hydroxyphenyl) acetamido-3- (1-carboxymethyltetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid. A mixture of (6,7-diacetoxychromone-3-car-oxamido) -2- (4-hydroxyphenyl) acetamido-3-acetoxymethyl-3-cephem-4-carboxylic acid (2 .08 g), 5-mercapto-1-tetrazolyl acetic the acids (1.9 F) in acetonitrile (400 ml) are heated under reflux for 16 hours. The reaction mixture is then evaporated to a volume of about 5 ml and 50 MP ether is added to it. The precipitate is filtered off and recrystallized from a mixture of methanol and chloroform. The result is 1.61 g of the desired product. IR (nudzhol): 17601770, 1670, 1660, 1610. NMR spectrum (S, DMCO-d): 2.36 (6H, s), 3.52 (1H d, Hz), 3.68 ( 1H, d, Hz), 4.18 (1H, d,), 4.45 (1H, d, Hz), 4.98 (1H, d, Hz), 5.28 (2H, s), 5, 67-5.80 (2H, m), 6.74 (2H d, Hz), 7.28 (2H, d, Hz), 7.87 (1H, s), 8.05 (1H, s), 9.02 (1H s), 9.40 (1H, d, Hz), 9.99 (1H, D, Hz). The compounds obtained in these examples are tested for their antimicrobial activity outside the body. The minimum inhibitory concentration (MIC) is determined by diluting conventional agar of the Japanese Society of Chemotherapy. The compounds are dissolved in suitable solvents (sterilized water for sodium salts and aqueous acetone in a 1: 1 ratio for free acids and are serially diluted twice. Cefazolin sodium salt is selected as the control compound. Aliquots (1 ml) from each dilution Mixed with 9 ml of Mueller Hinton agar in Petri dishes to obtain agar plates containing the compound in a regularly diluted concentration. After the agar has hardened, the plates are placed in an incubator at 37 ° C for 1.5-2 hours with slightly ajar roofs ke in order to evaporate the acetone from the plates. The test organisms are grown for 18 hours at 37 ° C in Trypticase Soy culture broth and diluted in saline solution to an approximate content of 10 cells forming colonies in 1 ml. The loop with each cell suspension is placed on the indicated plate the agar and plates are incubated in an incubator for 18 hours at 37 ° C, after which the MIC value is determined. The MF values of the compounds of Examples 1, 2, 4, 5, 6, and 8 are determined for their sodium salts; for free carboxylic acids. The results are shown in the table. Example 12. Tablet formulation, mg Compound of Example 3 250 Crystalline cellulose 80 Calcium carboxymethylcellulose salt 38 Calcium stearate 2 Tablets are prepared using the indicated composition.
    Example Connection
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING CEPHALOSPORINS OR THEIR SALTS.
    A method of producing cephalosporins of the general formula (I) where R ( is tetrazol-5-yl substituted at the 1-position with methyl, ethyl, 2-dimethylaminoethyl or carboxymethyl, 1,3,4-thiadiazol-2-yl, 4H-1,2 , 4-triazol-3-yl, 2-pyridyl, 2-pyridyl-1-oxide, 2-pyrimidinyl or 5-methyl-1,3,4-ox adiazol - 2-yl,
    R ^ is a hydrogen atom or an oxy group ',
    R ^ hR ^ is a hydrogen atom or an oxy or acyloxy group, or salts thereof, characterized in that the compound of general formula (II) where R 2 , R and have the indicated meanings, or its salt is reacted with a compound of the general formula (TII)
    R 4 - S - H, where it has the indicated meanings, in an inert solvent at 30-90 ° C, preferably in the presence of a basic or acidic agent.
    类似技术:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    JP7963179A|JPS565487A|1979-06-26|1979-06-26|Cephalosporin compound, its preparation, and antimicrobial comprising it|
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