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    • 专利摘要:
    Heterocyclyl derivatives of oxy-imino-substituted cephalosporins are disclosed, such, for instance the compound 3-[(8-amino-6-tetrazolo[1,5-b]pyridazinyl)-thiomethyl]-7-[2-(2-amino-4 -thiazolyl)-2-methoxyimino-acetamido]-3-cephem-4-carboxylic acid and its pharmaceutically and veterinarily acceptable salts. The compounds of the application have high antibacterial activity against Gram-positive and Gram-negative bacteria, including strong beta-lactamase producer Gram-negative microorganisms.
    公开号:SU1005664A3
    申请号:SU802921249
    申请日:1980-05-08
    公开日:1983-03-15
    发明作者:Наннини Джулиано；Перроне Этторе；Касабуона Ферруччио；Грассо Сильвио
    申请人:Фармиталиа Карло Эрба С.П.А.(Фирма)；
    IPC主号:
    专利说明:

    R is an amino or carboxy group or a carbamoyl, or their salts with alkali metals, comprising the fact that compounds of the formula 1 HZ ... A NII lY n 2 3 -If l /, where R has the indicated values, are reacted with an acid Formulas, Rii “i. T c-soon II h (111) in the form of syn-isomer, where RI and R2 have the indicated, above, given for R and R2, besides the hydrogen atom, or with its reactive derivative, in a solvent in the presence of bases and, if necessary, in the presence of a condensing agent, when the scientific research institute is cooled or at room temperature and, if necessary, the protective groups are removed, if they exist and, if necessary, are converted, the free state is added to the alkali metal salt Il the target product, obtained in the form of an alkali metal salt, To translate the free acid. In the compound of formula II, the free carboxy groups can be protected, if necessary, prior to the reaction. Examples of protecting groups are t-butyl, benzhydryl, p-methoxybenzyl, p-nitrobenzyl trityl, or trialkylsilyl. The protecting groups can then be removed at the end of the reaction, for example, by mild acid hydrolysis or by catalytic hydrogenation. A reactive derivative of a compound of formula III is, for example, its acid halide, anhydrite mixed anhydride, azide, reactive ester or salt, for example, formed by an alkali metal or alkaline earth metal, ammonia or an organic base. The reactive can be, for example, p-nitrophenyl ether, 2, -dinitrophenyl ether, pentachlorophenyl ether, N-oxysuccinimide ester or N-hydroxyphthalimide ester. The compounds of the present invention have a high antimicrobial activity in both animals and humans, not only that which is in place, and that they are well-established, and that they are usually susceptible to cephalosporins, such as staphylococci, streptococci, KEebsieEa, EscherichiacoEi, Proteus mi, EscherichiacoEi, Proteus mi, dipherococci, diplococci, EscherichiacoEi, Proteus mi, EscherichiacoEi, mi, Proteus mi, Diphococcus, Mi. Eus and Neisseria, but also against strong gram-negative microorganisms producing beta-lactamase, for example KfebsieZEa aerogenes 1082E, Escherichia coPi Tern, Enterobacter cloacae P-99, indole-positive Proteus, etc., as well as against Pseudomonas aerugino strains sa, which are usually resistant to the cephalosporins. Therefore, these compounds are particularly suitable for the treatment of infections caused by gram-negative bacteria, such as diseases of the urinary tract and the respiratory tract. The activity of the compounds obtained by the proposed method, both against bacteria, usually susceptible to cephalosporins, and against those producing beta-lactamase is higher than the activity of cefazolin and cefuroxime. For example, the compound 3-G (8-amino-6-tetrazolo-1, 5, 3-pyridazinyl) -thiomethyl-7-L2 (2-amino-thiazolyl) -2-methoxyiminoacetamido-3 cephem-4-carboxylic acid (syn-isomer ) (FCE 20127) is about 2 times more active than cefazolin against streptococci and about 30 more active than cefazolin and cefuroxime against most gram-negative bacteria, in addition, the connection of F CE 20127 is about 20-60 times more active than cefuroxime, against some manufacturers of beta-lactamase, such as KlebsieHa aerogenes 1082 E, Enterobacter cloacae P99, Escherichia coli Tern. Compound F CE 20127 was also tested on a range of 10 strains of Pseudomonas aeruginosa, k strains of Proteus vufgaris and strains of Proteus morganii, it was found to be several times
    more active than cefazolin and cefuroxime,.
    Compound 3 1 (8-carboxy-6: -tetrazolo P, 5-b, pyridazinyl) -thiomethyl3-7- {J2- (2-amino-thiazolyl) -2-methox-inoacetamido-3-cephem-carboxylic acid (syn -isomer.) (HSE ZOjSS) is about 5 times more active than cefazolin versus streptococci and about 32 times more active than cefazolin and 0 times more active than cefuroxime against most gram-negative bacteria. Against Enterobacter aerogenes ATCC 8308, Enterobacter cloacae 1321 E, and Typht Watson and ShIgeEla Sonoei ATCC 11060, the F CE 20485 F connection is more active than cefazolin and c. 50-100 times more active than cefuroxime.
    In addition, the compound FCE is at least 100-500 times more active than cefazolin and cefuroxime against Proteus vulgaris X20 and Proteus mirabiEis ATCC 9921. In addition, the compound F CE 20A85 showed significant activity outside the body against Pseudomonas aeruginosa G and Bacteroides fragi is UR1 9032.
    Another important property of compound F CH 20485 is the very long half-life of plasma in mice (about 90 minutes) and rats (about 100 minutes) after intravenous administration, while the half-life of plasma with cefazolin is 16 and 20 minutes. Therefore, Compound FCE showed high activity when tested in the body, for example, in mice infected with the microorganisms Eschericha ja coEi G, KEebsietEa pneumoniae ATCC 10031, Proteus mirabitls ATCC 9921, Escherichia Tern, Haemophi2us influenzae, SaEmoheE2a typhiiIthiIiIthiAi, and Saherochia Tern, Haemophi2us influenzae. this compound was 20–200 times more active than cefazolin.
    The toxicity of the compounds according to the invention is completely insignificant. For example, the approximate acute toxicity () of compounds F СЁ t0127 and F СЕ 20.485 for mice, found by a single intravenous administration of increasing dosages and measured on the seventh day of such treatment, was higher than 2000 mg / kg. Similar activity and toxicity
    other compounds of the invention also possess.
    Therefore, the compounds of the invention are useful in the treatment of infections caused by either gram-positive or gram-negative microorganisms, such as diseases of the respiratory tract, such as bronchitis, bronchopneumonia, pleurisy; hepatobiliary and abdominal Diseases, such as cholecystitis, peritonitis; infection of the blood and cardiovascular system, for example, septicemia and infection of the urinary tract, such as pyelonephritis, cystitis; obstructive and gynecological infections, for example cervicitis, endometritis; infections of the ear, nose and throat, such as otitis, sinusitis, parotitis. The compounds of the invention may be administered either to humans or animals in various dosages, for example, orally, in the form of tablets, capsules, drops, and syrups; roentally in the form of suppositories, parenteral, for example, intravenously or intramuscularly (in the form of solutions or suspensions), with intravenous administration being preferred at the onset stage; by inhalation in the form of aerosols or solutions for spraying; intravaginally, for example, bougienage, or topically in the form of lotions, creams and ointments.
    Pharmaceutical or veterinary compositions containing the compounds of the invention in combination with a pharmaceutically or veterinary acceptable excipient are prepared using conventional excipients, usually carriers and / or diluents used for other cephalosporins. Common carriers or diluents are, for example, water, gelatin, lactose, starch, magnesium stearate, talc, seed oil, cellulose, and the like. Daily dosages in the range of 1-100 mg per kg of body weight can be used for various animal species, with the exact dosage depending on the age, weight and condition of the creature to be treated and on the frequency and route of administration. The preferred route of administration for the compounds of the invention is parenteral; in this case, the compounds can be administered to adults in an amount of 100-200 kg per dose, preferably 150 mg I-times,
    dissolved in an appropriate solvent, for example, sterile water or hydrochloric lidocaine solution for intramuscular injections or sterile water, physiological saline solutions, dextrose solution or intravenous fluids or electrolytes for intravenous injection.
    In addition, the compounds can be used as antimicrobial agents for prophylactic purposes, for example during cleaning, or as surface disinfecting compositions, for example, at concentrations of about 0.2-1 by weight of such composition mixed, suspended or dissolved in conventional inert dry or aqueous carriers for use by washing or spraying. In addition, they are useful as nutritional supplements to animal food.
    Below are examples illustrating the invention.
    Estimation of melting points in some cases is difficult, since these compounds tend to retain the solvent.
    The spectra were recorded in the solid phase (KBr) or in Nujol oil using a Perkin-Elmer 125 spectrophotometer. The UV spectra were recorded in a buffer phosphate solution at pH J, or in the NaHCOa solution on a Bausch Lomb instrument.
    NMR spectra were recorded on a Bruker NX-90 instrument (90 MHz) for final products and on a Perkin-Elmer R-24B instrument (60 MHz) for intermediate substances in a solution of DMSO (dimethyl sulfoxide) or CDCf using tetramethylsilane as an internal standard.
    EXAMPLE 1. 3-C (8-Amino-6-tetrazolor, 5-b-pyridazinyl) -thiomethyl-7-E2- (2 amino-4-thiazolyl) -2-methoxyiminoacetamido Z-C-cephem-4 carboxylic acid (syn-isomer).
    A stirred solution of anhydrous hlbristogram of methylene (.70 ml) containing 2- (2-tritylamino-4-thiazolyl) -2-methoxy acetoacetic acid (syn-isomer) (4, g, 0.01 mol) and triethylamine (ml, 10 mmol), cooled to 0 ° C. and phosphorus pentachloride (2.08 g, 10 mmol) is added in portions. After stirring for 10 minutes at and 1 hour at room temperature, the mixture is evaporated under reduced pressure, dissolved in a mixture of acetone and benzene, again evaporated, in order to remove traces of phosphorus oxychloride, and dissolved in 50 ml of anhydrous acetone. are triethylamine hydrochloride. The acetone solution of 2- (2-tritylamino-thiazolyl) -2-methoxyiminoacetyl chloride obtained in this way is added. drops to a well-cooled ice-cooled solution of 6-amino 3 f (8-amino-6-tetrazolo 1,5 bJ-pyridazinyl) -thiomethyl 3 cephem-4-carboxylic acid (3.8 g, 10 mmol sodium bicarbonate (0, 8 g) and triethylamine (2.82 ml) in a mixture of water and acetone (75 ml: 50 ml). The suspensions are stirred for 1/2 hour at 0-5 ° C and then 1.5 hours at room temperature, dissolved in 500 ml of ethyl acetate, washed with aqueous hydrochloric acid (50 ml), then with an aqueous solution of sodium chloride (100 ml), dried with sodium sulfate and evaporated to dryness. The residue is stirred in 5 ml of chloride methylene, then 50 ml of ethyl acetate and 50 ml of diethyl ether are added .. The precipitate formed is collected, dissolved in warm methylene chloride (30 ml), cooled and treated with diethyl ether (100 ml) under stirring. After 20 minutes of stirring a white solid is filtered off, washed with ether and dried, thus obtaining f3 g 3 (8-amino-6-tetrazolo 1, 5-b pyridazinyl) -thiomethyl-7 1.2- (2-tritylamino-thiazolyl) -2-methoxyiminoacetamido D -Z-cephem -carboxylic acid (syn-isomer) as a white powder.
    The above mentioned compound (2.0 g) was added in portions to a stirred hot (55 ° C) solution of formic acid (13 ml) in 13 ml of water. Stirring and heating are continued at the same temperature for 25 minutes and then the solid is filtered off from the cooled mixture. The solid is triturated in 90% formic acid (19 ml), 2 ml of water are then added and pure triphenylmethanol is filtered off.
    The acidified mother liquors were combined and evaporated to give a precipitate. After complete removal of water and formic acid, followed by trituration with anhydrous ethanol, a solid is obtained (1.225 g). The crude product is suspended in water (70 ml) and a sufficient amount of NaHCO-j is added to obtain a solution. The pH of the solution is reduced to 2.0 by adding 2N. hydrochloric acid and after 20 minutes the precipitated product is collected, thoroughly washed with water and dried for 18 hours at 75 ° C. In this way, 1, -13 g of the desired product is obtained, which decomposes without melting at a temperature above 225 ° WITH. Found, o: C 37.90; H 3. N 26,78; S 16.83 Calculated: C 38.53; N W-. N 27.33; S 17.07 IR spectrum (cm-), (Kvg): 33203180 NIH, 1520 - CONH (sec. Amide), 1030 (-N-0-CH), 1760 (beta-lactam)} NMR, 100 MHz (DMCO - dg); ppm 3.7. (2H, double -2-CH, i), J 17 Hz, 3.88 (3N, p., -IR); 4.3b (2H, d., 3-CH.S) J 13 Hz, 5.20 (IN, d, 6-H) J 5 Hz; 5.83 (1H, d, 7-H) J 5 Hz + 8 Hz; 6.41 (1H, s., 7-H in the pyridazine ring); 6.82 (1H, s ,, 5-H in the thiazo ring); 6.807, 80 (2H, br., S., NH in the thiazol ring), 8.02 (2H, br., S., -MH3 in the pyridazine ring); 9, B9 (1H, d., -CONH) J 8 Hz. Using this method, 3 G (8-carboxy-6-tetrazolo 1,5-bJ pyridazinyl) -thiomethyl3-7-C2- (2-amine-4-thiazolyl) -2-oxyiminoacetamido-3-cephem-4-carboxylic acid is obtained. acid (synisomer). Found, I: C 39.71; H 3.06; N 22.88; S 15.82 ChoN th Diff. Calculated,%: C 39, J60; H 2.99; N 23.09; S 15.86 IR spectrum (KVg) (cm): 17757С (beta-lactam); 1715 C O (carboxylic acid); 1660-CONH (sec, amide.). NMR spectrum, 100 MHz, (DMSO - d) (cg ppm): 1.26 (GH, t, 3.73 (2H, dd, 2-CHi), C, 22 (2H, q, - 0-CH2.CH,) i, 52 (2H, dd, 3-CH,), 5.18 (1H, d, 6H), 5.82 (1H, dd, 7-H 6.82 (1H , S, 5-H on the thiazole ring Cs), 7.30 (2H, broad. S —NHj, on the thiazole ring), 8.02 (1H, S, 7-H on the pyridazine ring), 9.7 (1H ,, -CONH). Example 2.3-C (8-Aminocarboyl-6-tetrazolo 1, 5-bz pyridazinyl) -thiomethyl -7-2- (2-amino-4-thiazolyl) 2-methoxyiminoacetomyo-3-cephem - "- carboxylic the acid (syn-isomer) is obtained by reacting 2- (2-tritylamino-thiazolyl) -2-methoxy-amino-acetic acid with 7 amino-3-C8-aminocarbonyl-6-tetrazolo, 5-1 pyridazinyl) -thiomethyl3-3 Cef eat- -. -carboxylic acid, not using the TOD11KU described in example 1e 1; mp 220C (decomp.) Found:% 38.71; H 2.9b; N 25.81; S 16; 01 Calculated,%: C 38.57; H 2.89; N 26; OH; S 16.26 Thin-layer chromatography (TLC): CHC: Me OH: HCOOH:: 75: 20: 20. Rf Q, k27- Amino-3-C8-aminocarbonyl-6-tetrazolo O, 5-bz pyridazinyl) -thio-. Methyl-3-cephem-4-carbonic acid used as the starting material is prepared as follows. 6-Chloro-8-aminocarbonyltetrazolo (1,5-b) pyridazine. To an ice-cooled solution of 3-hydrazino-4-aminocarbonyl-6-chloropyridazine (+, 2 g, 0.024 mol) c. Acetic acid solution was added dropwise a solution of sodium nitrite (1.55 g) in 10 ml of water. After stirring for 1 hour at 5-10 ° C, the precipitated precipitate is filtered, crystallized from water, filtered again and dried under vacuum to obtain 3.44 g (77.5%) of the above compound, m.p. (different). Found: C 30.11; H 1.44; N 42.00; All 17.69. With Hj CENgO Calculated,%; C 30.24; H 1.52; N 42.32; All 17.85. 6-mercapto-8-aminocarbonyltetrazolo (1,5-b) pyridazine. X To a stirred solution of NaSH-H O (10 g, 0.135 mol) in 150 ml of water was added 10 g (0.05 mol) of 6-chloro-8-aminocarbonyl tetrazolo (1,5-b) pyridazine and the mixture was thoroughly mixed 90 min After cooling at 0 ° C, the reaction mixture was acidified with 11-1 hydrochloric acid. After cooling for 1 hour, a solid is taken out, washed with a small amount of cold water. Get the above connection, so pl. 185 1874 (decomp), IR spectrum (nujol): SH cm - С About 1675 cm -. of those in the CNSG :: CH, HE, J NOOS 1 bO: 70: 30 net product. UV spectrum (phosphate buffer, PH 7,): LdAax 262; 8l8 Found: C 30, b5; H 2.00; N, 53; S 16.16. .C5-H4Nf, OS Calculated,%: С 30.60; H 2.05; N 2, 16,347-Amino-3-1 (8-carboxy-6-tetrazolo. Azolo C1,5-b-pyridazinyl) -thiomethyl-3-cephem-4-carboxylic acid. Pyridazine (2 g, 10 mmol) and 2.8 g of sodium bicarbonate in 90 ml of phosphate buffer (pH 6) were added to a hot (50-55c) solution of 6-mercapto-8-aminocarbonyltetrazolo 1,5-b and 90 ml of phosphate buffer (pH 6). 4.6 g (0.017 mol) of 7 ACC (7-aminocephalosporanic acid) and the mixture is heated for k h at. After cooling, 7-amino-3- (8-aminocarbonyl-6-tetrazolor, 5b pyridazinyl) -thiomethyl-3-Cephem-carboxylic acid, which has precipitated in the precipitate, is collected by filtration. The solid is suspended in 150 ml of a mixture of acetone and water (1: 2}, stirred for 30 minutes and filtered again. The collected precipitate is washed with acetone and dried in vacuum at. The desired product is obtained (80), mp. 228-230 С (fold) Found: C 37.93; H 2.93; N 27.13; S 15.5 H% B0452. Calculated: C C. 38.22; H 2.9 b; N 27.3; 5 , 15.70 IR spectrum (nudhyul): / C 0. Beta-lactams, 1780. UV spectrum (M NaHCO): Lmax and 332. Example 3. 3- (8-Carboxy-6-tetrazlo O, 5 bz pyridazinyl) - thiomethyl -7- 2- (2-amino-4-thiazolyl) -2.-methoxyiminoacetamido3 -3-cephem-4-carboxylic acid (syn-isomer). A stirred solution of anhydrous chl crude methylene containing 2- (2-tritylamine-thiazolyl) -2-methoxymia no acetic acid (syn-isomer) (11.35 6412 25.6 mmol) and triethylamine (3.61 ml, 25.6 mmol) is cooled at and 5.6 g (27 mmol) of phosphorus pentachloride are added in parts. After stirring for 15 minutes at 0 ° C and 1 hour at room temperature, the mixture is evaporated under reduced pressure, dissolved in anhydrous benzene, and again evaporated to remove traces phosphorus oxychloride. This treatment is repeated twice (2-50 ml). The residue is suspended in 50 ml of anhydrous acetone, then triethylamine hydrochloride is removed by filtration. Acetone solution of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetylchloride, thus obtained, is added dropwise to a 7-amino solution of ice which is thoroughly mixed and cooled with ice, and the ice-cooled solution of γ-amino (8-carboxy-6-tetrazolor, 5 -Pyridazinyl; -thiomethyl3-3-cepheic-carboxylic acid (10 g, 23.2 mmol) and 15 g of sodium bicarbonate in a mixture of vOD1 and acetone (500: 250 ml). The mixture is stirred for 30 minutes at 0-5 ° C and then for 90 minutes at room temperature, the insoluble substance is filtered off and the acetone is removed by evaporation in vacuo. The pH of the aqueous phase is up to 2.0 with hydrochloric acid and extracted with ethyl acetate (3 times +00 ml), washed with aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue is stirred with diethyl ether for 20 minutes, a white solid is filtered off, washed with ether and dried. 3-1 (B-carboxy-6-tetrazolo 1,5-b pyridazinyl) -thiomethyl-7-2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetamido-3-cefeM-k -carboxylic acid, which is added dropwise to a hot (55 sec.) stirred solution of formic acid (ml). Stirring and heating at the same temperature are carried out for 30 minutes and then the solid is filtered off from the cooled mixture. The filtrate is evaporated to dryness in vacuum, leaving a precipitate. After complete removal of water and formic acid, followed by rubbing with water, a solid is obtained. The crude product is crystallized from ethanol to give 9.1 g (60) of the desired product, which decomposes at. Found: C 38.10; H 2.91; N 23, S 15, 07 S, Calculated,%: C 38.50; H 2.72; N 23.63; S 16.23 of those in the SNC: Meon: UNSAC: H, j, 0: 75: 20; 20, Rf 0.25. IR spectrum (KBG): 3500-2300 cm associated - COOH; 17b5 C O beta-lactam; 1710 cm - WITH acid 1650 cm sot. Amide; I620j-1580 cm- (C N oxime, -V (C-M) + (G (S - H); 1540 CM-lV (C-N) + (f (N - H) amide NMR spectrum, 100 MHz (LMCO - d) ppm: 3.68 (1H, d, 2-CHi}, 3.86 (1H, d, 2-CH2), 3.92 (ZN, s; ;.M-OCHN ), 4, 3b (1H, d, 3-CH,), 69 (Illr, 3-CHi-S), 5.21 (1H, d, 6-H), 5.85 (1H , d, d, 7-H), 6.83 (1H, s., 5-H in the thiazole ring 7.30 (2H, brs, -NHj in the thiazole ring), 8.02 (1H , Syng., 7H, in the pyridazine ring), 9.28 (1I, d., -CONH). 7-Amino-3-C (8-carboxy-6-tetrazo, 5b pyridazinyl) -thiomethyl -3 cefen-4 The carboxylic acid used as the starting material is obtained as follows: 3 Hydrazino-A-carboxy-6-chloropyridazine A mixture of 20 g (0.103 mol) 3,6-Dichloro-4-carboxypyridase Yin and 22 ml of 98% hydrazine hydrate in 200 ml of 50% ethanol are refluxed under stirring for 1 hour. After cooling, a solid precipitate is collected and washed with 20 ml of anhydrous ethanol. The solid is suspended in 100 ml of water , the mixture is adjusted to pH 1-2 with 23% hydrochloric acid; After cooling, the solid is filtered, dried under vacuum at, obtaining M8.29 g (93) of the above compound, m.p. 1 2014. Found: C 31, H 2,6k; N, 29.32; C 18.53 SdgNuSem.o. Calculated,%: C 31, H 2.67; N 29.71; Se 18.80 NMR spectrum (DHCO - d): 7.8 (1H s., 5-H in the pyridazine ring), 9.2 (H, broad, s, -COOH, -NHNHj.). 6-Chloro-8-carboxytetrazolo 1, 5-pyridiazine. 4It To a ice-cooled suspension of 3-hydrazino-carboxy-b-chloropyridazine (1.88 g, 10 mmol) in acetic acid, a solution of sodium nitrite (0.70 g) in water (5 ml) is added dropwise, stirred for 1 hour at 5 1 (G C, the precipitated precipitate is filtered and washed with anhydrous ethanol. The solid is suspended in 2N hydrochloric acid, the mixture is stirred for 30 minutes, the solid is filtered off, washed with cold water and dried in vacuum at, obtaining 1.73 g ( 87) of the above compound, t, pl. Found,%: C 29.95; H 0.98; N 35.15; ce 17.58. Calculated: C 30.09; H 1.00; N 35, 09; C8 17.7 6 IR spectrum (nujol): C O1730 CM-NMR spectrum (DMCO - d): 8.33 (1H, p., 7-H in the pyridazine ring). 6-Mercapto-8-carboxytetrazolo P, 5 b pyridazine To a stirred solution of NaSH (10 g, 0.135 mol) in 150 ml of water was added 10 g (0.05 mol) of 6-chloro-87carboxyl tetrazol-1, pyridazine, and the mixture was vigorously stirred for 2 hours. After cooling, the reaction mixture was acidified with hydrochloric acid After cooling for 1 h, the solid is separated, washed with a large amount of cold water to obtain 9 g (91.5%) of the above compound, m.p. 210C (decomp.). Elemental analysis Found: C 30, H1; H 1.52; N 35.61; S 16.19 C5H3% 025 Calculated,%: C 30.5; H 1.53; N 35.52; S 16.26 IR spectrum (KVg): (S-H), 1725 (-C 0). UV spectrum (phosphate buffer at pH 7): woKC 25.8 ..; U “9b2. 7-Amino-p8-carboxy-6-tetrazolo D 5-bzpyridazinyl) -thiomethyl -3-cephem - + - carboxylic acid. To a hot solution (4.) of 6-mercapto-8-carboxy-tetrazolo 1, 5-b pyridazine (8.2 g, 41.5 mmol) and 11.69 g of sodium bicarbonate in 2b5 ml of phosphate buffer (pH 6.4) 18.5 g of 7-ACC (68 mmol) are added in portions. and the mixture is heated, stirring, for 5 hours. After cooling, the insoluble matter is filtered out and the solution is acidified with hydrochloric acid to a pH of 4.4. The residue is filtered, washed with a mixture of acetone and water (3: 1) and then acetone, to obtain the sodium salt of the above compound (75). m.p. above 270 C (decomp.). . Found: C 35.80; H 2.66; N 22.43; S 14.66; Na 5.10 Calculated,%: C 36.19; H 2.33; N 22.72; S 14.86; Na 5.32 IR spectrum (nujol): C O, beta lactam, 1770 UV spectrum (GHCO) Than 432. The sodium salt is suspended in water and acidified with hydrochloric acid. A solid is obtained, which is filtered, washed with water, so pl. (different). Found: C, 38.45; H 2.90; N 23.55; S 15 calculated: C 38.13; H 2.70; N 23.94; S 15.76. The same method is used, 3 C (8-amino-6-tetrazolo D, 5-b3 pyridazinyl) thiomethyl 3-7 2- (2-amino-4-thiazolyl) -2-carboxymethoxyiminoacetamido 3-cephem-4-carboxylic acid is obtained ( syn isomer). Found: C, 37.21; H 3.02 N 24.98; S 15.64 - 9 7 11 Calculated: C 37.56; H 2.82; N 25.36; S 15.83 IR spectrum (KVg) (cm): 1770 (beta-lactam). NMR spectrum 100 MHz, (OMSO-dx) (cGmln.d.): 3.76 (2H, dd,.); 4.39 (2H, dd,); 4.64 (2H, S, -0-CH4. COOH); 5.21 (IH, d, 6-H); 5.84 (1H, dd, 7-H); 6.40 (IH, S, 7-H on the pyridazine ring); 6.8l (1H, S, 5-H on the thiazole ring); 6.90-7.50 (2H, broad S, -NHij on thiazole); 7.96 (2H, broad. S, -NH, j on the pyridazi new ring); 9.55 (1H, d, -CONH-). Example 4. 3-C (8-Amino-6-tetrazolor, 5-bj pyridazinyl) -thiomethyl-7-12- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3-cephem-4-carboxylic acid ( syn isomer). N, N Dicyclohexylcarbodiimide (0.9 g, 4J38 mmol) is added to a cooled to 0-5 ° C solution of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid (3.675 g, 8.28 mmol) 13 ml of anhydrous methylene chloride. After stirring for 40 minutes at room temperature for 30 minutes, the resulting suspension was diluted with anhydrous methylene chloride. The isolated solid dicyclohexyl urea (0.98 g, quantitative yield) is filtered and washed with fresh methylene chloride. The combined solutions in methylene chloride are evaporated to dryness and a symmetric anhydride of the starting acid is obtained, which is immediately dissolved in anhydrous acetone (30 ml). The resulting solution, while stirring, is added dropwise to a solution of 7-amino-Z-E (8-amino-6-tetrazolo D, 5-b) pyridazinyl) -thiomethyl3-3-cephem-4-carboxylic acid (1.65 g, 4.3b mmol), triztilamine (1.22 ml, 8.72 mmol) and Manso g (0.347 g, 4.14 mmol) in aqueous acetone (1: 1.120 ml). After stirring for 1 hour at 0-5 ° C, the ice-bath was removed and, after a further 2 hours, the mixture was dissolved in ethyl acetate (500 ml) and shaken with 1N. hydrochloric acid (too ml). The insoluble matter (a small amount of unreacted 7 amins cephem) is filtered off and the organic layer is washed with an aqueous solution of sodium chloride. Dry over sodium sulfate, filter, and evaporate; Most of the starting 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid contained in the crude reaction mixture is precipitated from dioxane pactBopa (30 ml) with slow addition of dicyclohexylamine (1.4 ml). After 20 minutes at 12 ° C, this cyclohexylamine salt was filtered off, the solution was diluted with ethyl acetate (200 ml), acidified with 1N hydrochloric acid, and the aqueous layer was discarded. The organic phase is washed with an aqueous solution of sodium chloride, dried over sodium sulfate, concentrated to a small volume, then added to diethyl ether, thus obtaining 3.1 g
    3- (8-aminsg b-tetrazolo l, 5-b pyridazinyl) thiomethyl -7 C2 {2-tritylamino-4-thiazolyl) -2-methoxyimino acetamido-3 cephem-4-carboxylic acid (sinisomer). This substance is treated with 501% formic acid, as described in example 1, to obtain the desired product, which, as shown by TLC, IR and NMR spectroscopy is identical to the product obtained in example.1.
    Using the same method, 3- (3-amino-b-tetrazoloEt, 5-b, pyridazinyl) -thiomethyl3-7-12 (2-amino-4-thiazolyl) -2-carboxymethoxyiminoacetamido-3-cephem-4-carboxylic acid is obtained. (syn-isomer); (elemental analysis is given in example 3).
    Example 5. 3 1 (8-Carboxy-6-tetrazolo, 5-L3 pyridazinyl) -thiomethyl-7-1 2- (2-amino-thiazolyl) -2-. -methoxyiminoacetamido 3-3-cephem- -carboxylic acid (syn-isomer-).
    N, N-dicyclohexylcarbohydrimide (0.9 g, o, 38 mmol) is added to a cooled to 0-5 ° C solution of 2- (2-tritylamino-thiazyl) -2-methoxyiminoacetic acid (g, 8.28 mmol) in anhydrous methylene chloride (, 13 ml). After stirring for 40 minutes at and 30 minutes at room temperature, the resulting suspension is diluted with anhydrous methylene chloride. The solid that is isolated, namely dicyclohexyl urea (o, 98 g, quantitative yield), is filtered off and washed with pure methylene chloride. The combined methylene chloride solutions are evaporated to dryness to give symmetrical starting acid anhydride, which is immediately dissolved in anhydrous acetone (30 ml). The resulting solution was added dropwise with stirring to a solution of 7 amino-3- (8-carboxy-6-tetrazlore, 5b pyridazinyl) -thiomethyl-3-cephemcarboxylic acid (1.78 g, k, 3 (mmol), 1j22 ml of triethylamine (8.72 mmol) and sodium bicarbonate (0, g, 14 mmol) in aqueous acetone (1: 1, 120 ml). After stirring for 1 hour at 0-5 ° C bath with
    the ice is removed and after 2 hours the mixture is dissolved in ethyl acetate (500 ml) and shaken with aqueous 1N. solution rum HCf (100 ml). The undissolved substance (a small amount of unreacted 7-aminocephem) was filtered, the organic layer was washed with an aqueous solution of sodium chloride, dried over sodium sulfate, filtered and evaporated. Most of the starting 2- (2-tritylamino-thiazolyl) -2-methoxyiminoacetic acid contained in the crude reaction mixture is precipitated from a dioxane solution (30 ml) with slow addition of dicyclohexylamine (1.4 ml). After 12 minutes, the dicyclohexylamine salt was filtered off, the solution was diluted with 200 ml of ethyl acetate, acidified with 1N. discard the hydrochloric acid and water layer (the organic phase is washed with an aqueous solution of sodium chloride, dried over sodium sulfate, concentrated to a small volume, then added to diethyl ether, resulting in 3.3 g of 3 08-carboxy-6- tetrazolo, 5-bp pyridazinyl) thiomethyl 3-7 2- (2-tritylamino-thiazolyl) -2-methoxy-thymino-acetamide-J-3-cephem-4-carboxylic acid (synisomer). This substance is treated with formic acid, as described in example 3, the result is the target product, which is identical to the product obtained in example 3, according to TLC, IR and NMR spectroscopy,
    Example 6. 3-E (8-Amino-tetrazolo j, 5 L pyridazinyl) -thiomethyl-7 2- (2-amino-4-thiazolyl) -2-oxyiminoacetamido 3-C-cephem-4-carboxylic acid (syn-isomer ).
    To a solution of 2- (2-tritylamino-thiazolyl) -2-trityloxyiminoacetic acid (2.25 g, 3.35 mmol) and triethylamine (0.7 ml, 3.35 mmol) in anhydrous methylene chloride, cooled to -5 C, in one step, 0, b97 g (3.35 mmol) of solid chloride forfor was added. After stirring for 20 minutes and 1 hour at room temperature, the reaction mixture is evaporated under reduced pressure without external heating until all of the POC is consumed. The residue was dissolved in anhydrous acetone (50 ml) and triethylamine hydrochloride was filtered off. The resulting acetone solution of 2- (2-tritylamino-4-thiazolyl) -2-trityloxyiminoacetyl chloride is added dropwise to a solution containing 0.76 g (2 mmol of 7 amino-3-1 (8-amio-6-tetrazolo 1, 5b 3-pyridazinyl) -thiomethyl -3-cephem-4-carboxylic acid, 0.5 ml of (k mol) triethylamine and 0.281 g (mmol) of sodium bicarbonate in 35 ml of water and 25 ml of acetone cooled to. After the addition of the solution, the suspension is stirred for 30 min and at-90 min. The reaction mixture is poured into ethyl acetate (350 ml) with vigorous stirring, 50 ml of water are added and then this amount is added 2N hydrochloric acid to bring the pH of the aqueous phase to 2.0.The organic phase is washed with an aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The resulting foam is triturated with diethyl ether to give 1.98 g of the crude product containing a significant amount of the starting acid.Most of this impurity is removed by dissolving the crude material in dioxane (10 ml) and dropping the resulting vegetable solution in 70 ml of diethyl ether. After stirring for 10 minutes, a white precipitate was separated by filtration, resulting in 1.02 g of 3- (8-amino-6-tetrazolor, 5-bz pyridazinyl thiomethyl 3-7 E2 (2-tritylamino-thiazolyl) -2-trityloxy). cephem-4-carboxylic acid (syn-isomer). The compound obtained above (1 g) is added with stirring to aqueous formic acid (40 ml), maintained at (oil on a bath). After 35 min, the mixture is cooled to and filtered with suction ; the solid is washed with fresh portion (20 ml) of 50% formic acid and then with distilled water and discharged The acidified solutions are combined and evaporated under reduced pressure. The residue is dissolved in ethanol and again evaporated, dissolved in ethanol, evaporated to a small volume (5 ml) and filtered. The resulting powder is dissolved in a 2% aqueous solution sodium bicarbonate (20 ml) and charcoal is added. The filtered solution is acidified to pH 2 with hydrochloric acid (2N) and stirred for 5 minutes. The precipitate is collected by filtration, washed thoroughly with water, then with a small amount of ethanol and dried 16 h, getting 0.25 g 3 (9 ° 6 tetraz {1, 5-S3 iridaainyl) -6-methyl-D-7 {2- (2-amino-4-thiazolyl) -2-oxyiminoacetamido D-3-cephem-carboxylic acid (syn-isomer) as a white powder, decomposing without melting at approximately 205 C. Found,%: With ST, 81; H 2.88; N 27.73; S 16.92, fN, H 2.75; Calculated, / and: C 37.15; N 28.03; S 17,20 ZAOO (-NH), IR spectrum (KBG), cm 3000 (-OH), 1760 (::: C O, beta-lactam), NMR spectrum, 100 MHz (DMCO - dg). ppm: 3.61 (1H, d., Z-CHj); 3.89 (1H, d, 2-CHa), J 17 Hz; 4.16 (1H, d, 3-CH2S), 4.60 (1H, d, 3-CH.S) E 13 Hz; 5.21 (1H, d. 8-H 7 5.86 (1H, AD. 7H), 6.42 (1I, C., 7-H in the pyridazine ring), 6.76 (1H, s., 5H in the thiazole ring), 7.20 (2H, broad s, -NHi in the thiazole ring); 8.02 (.2H, broad, s, -NH2 in the pyridazine ring); 9.5b (1H, d ., -CONH-), 11.66 (1H, broad sr, N-OH). Example 7. To a suspension of 3 - (8-amino-6-tetrazolo | 1,5-b3-pyridazinyl) -thiomethyl3 -7 G2 (2-amino-4-thiazolyl) -2-methoxyiminoacetamido D-3-cephem-4-carboxylic acid (sinisomer, 5.63 g) in stoichiometric amount of sodium bicarbonate is added to 80 ml of water, thus achieving complete dissolution of the compound. the solution is then lyophilized to obtain the sodium salt of 3- (8-am ino-6-tetrazolo 1, 5-b} pyridazinyl) -thiomethyl3-2- | 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-3-cephem-4-carboxylic acid (syn-isomer), t above (decomp.) Found: Na 3.80 Calculated,%: Na 3.90 IR spectrum (KBr), 17bO (beta-lactam) ... i. Example 8. For suspension 3. L (8-carboxy-6-tetrazolo p, 5-bJ-pyridazinyl) -tyrmethyl 3 7 2- (2-amino-4-thiazoyl) -2-methoxyiminoacetamido 3-cephem-4-carboxylic acid (syn-isomer. 5.92 g) in 80 ml of water, two equivalents of sodium bicarbonate are added to completely dissolve the compound. This
    权利要求:
    Claims (1)
    [1]
    Claim
    A method for the preparation of cephalosporin derivatives of formula 1 t in the form of a syn-isomer, where R ^ and R ^ have the meanings given *: those for R ^ and R 2 , except for the hydrogen atom, or with its reactive derivative in a solvent in the presence and, in the case of if necessary, in the presence of a condensing agent upon cooling or at room temperature and, if necessary, deprotecting groups, if any. and, if necessary, the target product obtained in the form of a free acid is converted into an alkali metal salt or the target product obtained in the form of a salt with an alkali metal is converted into free acid.
    类似技术:
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    同族专利:
    公开号 | 公开日
    AU530638B2|1983-07-21|
    DE3015389A1|1980-11-20|
    SE8003429L|1980-11-12|
    ES491379A0|1981-04-01|
    FR2456109A1|1980-12-05|
    IT8021822D0|1980-05-06|
    AT368512B|1982-10-25|
    CA1148939A|1983-06-28|
    DK191080A|1980-11-12|
    BE883209A|1980-11-10|
    GB2053896A|1981-02-11|
    PT71220A|1980-06-01|
    NL8002690A|1980-11-13|
    ATA249680A|1982-02-15|
    IL59791D0|1980-06-30|
    NZ193615A|1982-02-23|
    AU5744080A|1980-11-13|
    JPS55151594A|1980-11-26|
    IT1195268B|1988-10-12|
    ZA802393B|1981-04-29|
    CS219277B2|1983-03-25|
    FI801517A|1980-11-12|
    NO801400L|1980-11-12|
    GR67280B|1981-06-26|
    PH17085A|1984-05-24|
    LU82429A1|1980-07-31|
    GB2053896B|1983-04-07|
    US4331666A|1982-05-25|
    FR2456109B1|1983-12-16|
    ES8104307A1|1981-04-01|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR2345153B1|1976-03-25|1979-10-05|Roussel Uclaf|
    GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins|
    US4061861A|1976-06-21|1977-12-06|Eli Lilly And Company|7-[α-arylacetamido]cephalosporins|
    IT1075277B|1977-02-11|1985-04-22|Erba Carlo Spa|UNSATURATED AND EPOXY DERIVATIVES OF ACIO 7-ACYLAMIDE-3-CEFEM-4-CARBOXYL AND PROCEDURE FOR THEIR PREPARATION|
    DE2714880A1|1977-04-02|1978-10-26|Hoechst Ag|CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION|
    DE2716677C2|1977-04-15|1985-10-10|Hoechst Ag, 6230 Frankfurt|Cephem derivatives and processes for their preparation|
    FR2387235B1|1978-01-23|1981-11-06|Fujisawa Pharmaceutical Co|
    US4268509A|1978-07-10|1981-05-19|Fujisawa Pharmaceutical Co., Ltd.|New cephem compounds and processes for preparation thereof|
    JPH0123474B2|1978-07-10|1989-05-02|Fujisawa Pharmaceutical Co|
    BE878514A|1978-09-04|1980-02-29|Fujisawa Pharmaceutical Co|PROCESS FOR THE PREPARATION OF 3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS WITH DISUBSTITUTION IN POSITIONS 3 AND 7, NOVEL PRODUCTS THUS OBTAINED AND THEIR USE FOR THEIR ANTIBACTERIAL ACTIVITY|DE2945248A1|1978-11-13|1980-05-22|Fujisawa Pharmaceutical Co|CEPHEM COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL PHARMACEUTICAL AGENTS CONTAINING THE SAME|
    US4499088A|1983-01-04|1985-02-12|Fujisawa Pharmaceutical Co., Ltd.|Cephem compounds|
    DE150507T1|1983-12-29|1987-02-26|Mochida Pharmaceutical Co., Ltd., Tokio/Tokyo, Jp|CEPHALOSPORINE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL PREPARATIONS.|
    JPH0516437B2|1983-12-29|1993-03-04|Mochida Pharm Co Ltd|
    AU586229B2|1985-04-01|1989-07-06|Mochida Pharmaceutical Co., Ltd.|Cephalosporin derivatives|
    US4840945A|1985-04-01|1989-06-20|Mochida Pharmaceutical Co., Ltd.|Cephalosporin derivatives|
    EP0359291A1|1985-04-01|1990-03-21|Mochida Pharmaceutical Co., Ltd.|Cephalosporin derivatives|
    EP0225634B1|1985-12-13|1994-04-06|Takeda Chemical Industries, Ltd.|Antibacterial compounds, their production and use|
    US4880798A|1986-11-25|1989-11-14|Mochida Pharmaceutical Co., Ltd.|Cephalosporin derivatives|
    JPS63132893A|1986-11-25|1988-06-04|Mochida Pharmaceut Co Ltd|Novel cephalosporin derivative, production thereof and antibacterial agent containing said derivative as active ingredient|
    GB8805642D0|1988-03-09|1988-04-07|Fujisawa Pharmaceutical Co|New cephem compounds & processes for preparation thereof|
    EP0333082A3|1988-03-15|1991-05-02|Takeda Chemical Industries, Ltd.|Cephem compounds, their production and use|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB7916376|1979-05-11|
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