• 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 penicillanic acid derivatives of the formula 1 R 0 HOCI 2 about R - B-2-amino-2-fensh1-acetamido or B-2-amino-2-
    公开号:SU1122230A3
    申请号:SU823408648
    申请日:1982-03-22
    公开日:1984-10-30
    发明作者:Стефен Келлог Майкл
    申请人:Пфайзер Инк.(Фирма)；
    IPC主号:
    专利说明:

    where y is a hydrogen atom or hydroxy group;
    B - azido or protected amino-;
    M is tetrabutipammonium, followed by hydrogenolysis of the resulting compound and the separation of the target product l.
     . ,
    The reaction is usually carried out in a suitable solvent, such as dimethylformamide, ethyl acetate, dichloromethane, ajseTOH or phosphoric acid hexamethyltriamide at temperatures from 0 to. Hydrogenolysis is usually carried out over palladium on fS angle.
    The purpose of the invention is to obtain new compounds expanding the arsenal of penicillin antibiotics.
    This goal is achieved based on the well-known reaction of the reaction of iodomethyl esters of penic-Sharic acid 1,1-dioxides with the tetrabutylammonium salts of pen-55-cillanic acids by the method of obtaining penicillanic acid derivatives of the formula I
    O 0
     , d.
    xSs /
    c: s f: sns
    o-CH23
    .one
    About S S. aureus, P.aeruginosa and .cloac, beta-lactamase synthesis was induced by a log-phase culture in the presence of a sublethal concentration of penicillin Q at 100, -1000 and 300 μg / ml, respectively, for 2.5 hours. Beta-lactamase inhibitors The activity of compound 6 and sodium 1,1-dioxide penicillanic acid are presented in Table 1. Compound 6 against beta-lactam-producing strains of Pseudomonas aeruginosa and Enterobacter cloacae is particularly active, because of the previously known beta-lactamase inhibitor i-1,1-penicillanic acid showed a lower level of activity. In vitro activity of compounds was invented by measuring the minimum inhibitory end of the walkie-talkie (MIC) in µg / ml of compound 6 together with penicillin against a large number of microorganisms. In these studies, the method was followed, which was commanded by the Community between the community to test the sensitivity of antibiotics, using heart brain extractal agar (HV) and a device for reproducing graft material. In the medium intended for growing the medium overnight, i00-fold dilution was performed in order to use the obtained material as a standard graft substance (20,000-10000 cells approximately. 0.002 ml of medium was placed on the surface of arapai 20 ml BH1 agar / bowl) Twelve 2-fold dilutions of the test compound were used in this experiment with an initial concentration of the test drug of 200 µg / ml. When examining the contents of the tubes after 18 hours with single colonies, they were neglected. The susceptibility (M1C) of the test organism was evaluated as the lowest concentration of the compound, which is able to give complete growth inhibition, as observed by the unarmed gas. The MlC of this antibiotic and compound 6 were measured separately. These M1C values are then compared with the M1C values obtained using a combination of this antibiotic and compound 6. When the antibacterial is. The power of the combination is significantly higher than the power of the individual compounds, and this is considered as the main component of the activity-hardening gain. The values of "MIC combinations were measured using the method of Barry and Sabat. Experimental results illustrate the fact that compound 6 increases the effectiveness of ampicillin (Table 2). For purposes of comparison, data obtained using a known beta-lactamase inhibitor and penicillanic acid 1,1-dioxide are included. An extended spectrum of action and increased power (synergism or enhanced synergism) of compound 6 are noted. When using the antibacterial compound of the invention in Mammal, especially in humans, such compound can be used by itself or it can be mixed with other antibiotic substances and / or pharmaceutically applicable carriers of diluents. Said carrier or diluent is selected based on the intended use. For example, when a preferred oral application is chosen, the antibacterial proposed compound can be used in the form of tablets, capsules, lozenges, powders, syrups, elixirs, aqueous solutions and suspensions in accordance with standard pharmaceutical practice. The ratio of active ingredient and carrier usually depends on the chemical nature, solubility and stability of the active ingredient, as well as on the intended dosage. In the case of tablets for oral use, carriers commonly used include lactose, sodium citrate, and phosphoric acid salts. Various disintegrators, such as starch, as well as lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, can also be used in these tablets. For oral administration in capsule form, the diluents used include lactose and high molecular weight polyethylene glycols, for example polyethylene glycols having molecular weights in the range of 2000-4000. When aqueous suspensions are intended for oral use, the active ingredient is combined with emulsifying and suspending agents. If necessary, flavoring and / or flavoring agents may be added. As previously stated, the antibacterial compounds of the invention can be used to treat people and daily dosages are only slightly different from those used in the clinical setting of other penicillium antibiotics. The dose varies depending on the age, weight, and response of the individual patient, as well as the nature and severity of the patient's illness. These compounds are usually used orally or parenterally in dosages in the range of 5-100 mg per kg of live weight per day, usually in several individual doses. In some cases, it may be necessary to use doses that go beyond these ranges. Example 1. 1, 1-Dioxide 6-beta. 1.CO-2-azido-2-phenylacetamido). Penicillanoyl-hydroxymethyl (hydroxymethyl) pycyllanate. A mixture of 3.5 g of sodium salt of 6- (D-2-alpha-azidophenylacetamido) penicillic acid in 20 ml of methylene chloride and 20 ml of water is treated with a sufficient amount of 6 N hydrochloric acid to create a pH of 2.0. Tetrabutylammonium hydroxide (40% solution in water) was gradually added to pH 7.0. The organic phase is separated, and the aqueous layer is further extracted (2 x 20 ml) with fresh chlorine methylene. The layers of netilen chloride are combined, dried over sodium sulfate, and concentrated in vacuo to give 4.2 g of the corresponding tetrabutylammonium salt. Salt, tetrabutylammonium (1.65 g, 2.7 mmol) and 1,1-dioxide iodomethyl ester 6 beta- (oximesh1) of penitshshanova acid (1.07 g, 2.7 mmol) are mixed in 20 ml of acetone and stirred to dissolve According to TLC analysis, the reaction took place in almost 3 minutes of dissolution. After another 10 minutes, the reaction mixture was evaporated in vacuo to form a foam, which was chromatographed on silica gel using a mixture of methylene chloride and ethyl acetate (3: 2) as the eluant. 20 ml fractions. The pure product fractions (TLC analysis) are combined and concentrated in Akuma to form the desired compound as a foam (1.7 g) Rf 0.12 (ethyl acetate: toluene, 1: 1) 0.43 (methylene chloride: ethyl acetate 3: 2) 0.3 (methylene chloride: ethyl acetate 1: 1 ). NMR (CflCt,) 8, ppm: 1.4; 1.5; 1.54; 1.61 (4S, 4x3H); 2.3-2.6 (t, 1H); 4.0 -4.5 (t, 3N), 4.4 (S, 2H), 5.0 (S, 1H), 5.4-5.8 (t, 2H) 5.8 (wide S, 2H), 7.05 (d, 1H), 7.3 (S, 5H). PRI mme R 2. 1, 1-6-beta-dioxide (B-2-amino-2-phenylacetamido) p-nicyllanoyloxymethyl-b -beta- (hydroxymethyl) penicillanate. The compound of the previous example (1.4 g) is mixed with 30 ml of methylene chloride and 30 ml of isopropyl alcohol and hydrogenated at a pressure of 50 psi for 45 minutes in the presence of 1.5 tons of 10% Pd / C. According to TLC analysis, the reaction was 75% complete. An additional portion (1.5 g) of catalyst is added and the hydrogenation is continued for 45 minutes. Since traces of the starting material still remain after this, an additional 1 g of catalyst is added and the hydrogenation is continued for another 30 minutes. The catalyst is recovered by filtration and washed with a mixture of methylene chloride: isopropyl alcohol (1: 1). The combined filtrate and washings are evaporated to dryness. The residue is treated with ether and filtered to form the desired substance (0.83 g). IR (nujol) 1735-1800 cm flMP (JlMCO-d) S, h / mpn: 1.381, 39, 1.42 and 1.5 (4S, 12H); 3.6-4.35 (m, 3N); 4.42 (S, 1H) j 4.55 (S, 1H), 4.81 (S, 1H); 5.1-5.26 (sh, 1H); 5.38-i, 62 (then, 2H) V 5.9 (wide S, 2H), 7.4 (wide S, 5H). PRI me R. 3. 6-Beta- (B-2-amino-2-phenylacetamido) penicillanoyloxymethyl 6-beta- (oxymethyl) penicillanate 1, 1-dioxide hydrochloride. Hydrochloric acid (O, IN, 12.5 ml) is cooled to 0 ° C and 0.78 g of the appropriate free axis is added from the previous example. The resulting mixture is stirred for 5 minutes with the formation of a turbid solution having a pH of 1.9. The solution is clarified by filtration through
    diatomaceous earth with washing with 30 ml of water. The filtrate and washings were combined and dried in the cold to form the desired compound (0.76 g).
    IR (Nujol) 1730-1800.
    NMR (DMSO-a) 5 ppm: 1.2-1.62 (t, 12H); 3.5-4.3 (t, 3N); 4.38 (S., 1H, 4.5 (S, 1H); 4.8-5.7 (t, 4H), 5., 88 (wide S, 2H) i 6.75 (d, 2H); 7.22 (d, 2H); 8.5-9.1 (wide S, 2H), 9.4 (d, W), 9.8-10.2 (wide S, 1H)
    Example 4. I, l-Dioxide 6-beta- (B-2-benzyloxycarbonylamino-2- (p-hydroxyphenyl) -acetamido) peniclosphenoltoximethyl 6-beta- (oximesh1) penicillanate. 6-Beta- (B2-benzyloxycarbonylamino-2- (p-hydroxyphenyl) acetamido) penicillanic acid (carbobenzoxyamoxycillin, 5.0 g) is mixed with 75 ml of methylene chloride and 25 ml of water. Gum formation is noted, the pH is maintained at 8.5 with the aid of: 40% tetrabutylammonium hydroxide solution; the gummy solids dissolve. The chloromethylene layer is separated, the aqueous layer is extracted with two additional portions (40 ml) of methylene chloride and the methylene chloride organic layer is combined and the extracts are evaporated to form the corresponding tetrabutylammonium salt (7.2 g).
    The tetrabutylammonium salt (3.33 g, 4.5 mmol) thus obtained is mixed with iodomethyl 6-beta (oxymethyl) penitsyl 1-lata (1.15 g, 3.1 mmol) in 15 ml of acetone. The progress of the reaction is monitored by means of a TLC analysis, which makes it possible to establish that the reaction takes place almost completely after 5 minutes and that only traces of the original substance remain after 30 minutes. The reaction mixture is concentrated in vacuo to form a viscous gum. The residue is taken up in 15 ml of a mixture of ethyl acetate: methylene chloride (7: 3) and chromatographed on 125 g of silica gel using the same system as eluant and following the reaction by TLC analysis. The fractions containing the reaction product are combined and evaporated to form 1.8 g of a partially purified product. it
    the substance is re-chromatographed to form the purified desired compound (1.25 g).
    Rf 0.32 (7: 3 ethyl acetate: methylene chloride);
    NMR (DMSO-ab) 8 ppm: 1.4; 1.42; 1.48 1.58 (4S, 12H), 3.55-4.3, (go, 3N); 4.4 (S, 1H), 4.59 (S, 1H), 5.06 (S, 2H), 5.05-5.3 (t, 2H); 5.32-5.68 (t, 2H), 5.95 (wider is S 2H); 6.68 (d, 2H), 7.2 (d, 2H) i 7.34 (S, 5E) 7.78 (d, W), 8.9 (d, 1H), 9.4 (S , W).
    Example5. 1,1, -Bioxy- (B-2-amino-2- (p-hydroxyphenyl) acetamido) penicillanoyloxymethyl 6 -beta- (hydroxymethyl) penicillanate 6,1-beta.
    The ester of the compound of the previous example (1.2 g) is mixed with 15 ml of isopropyl alcohol and 15 ml of methylene chloride and hydrogenated at a pressure of 50 psi over 1.5 g with 10% Pd / C for 45 minutes, according to TLC analysis establishes that the reaction is 50% complete. Another 1.5 g of catalyst is added and the hydrogenation is continued for another 45 minutes, until the reaction is completed by 80% according to those of. Another 1.5 g of catalyst is added and after 45 minutes of hydrogenation, only traces of the starting compound remain in the reaction mixture. The catalyst is filtered off. Evaporation of the filtrate in vacuo to a solid and treatment with ether gives the desired substance (0.42 g).
    NMR (DMSO-d) S HR / MLN: 1.38; 1.42, 1.5 (s, 12H); 3.5-4.25 (t, 3N), 4.38 (S, III); 4.52 (s, 1H); 4.8-5.7 (ta, 4H); 5.88 (wide S, 2H); 6.72 (d, 2H), 7.22 (d, 2H).
    EXAMPLE 6 6-Beta- (B-2-amino-2- (p-hydroxyphenyl) acetamido) penicillanoyloxymethyl b-beta (hydroxymethyl) penicillanate 1,1-dioxide hydrochloride
    The substance of the previous example (0.38 g) is converted to the hydrochloride salt (0.33 g).
    NMR (DMSO-dL) if ppm: 1.2-1.62 (ha, 12H), 3.5-4.3 (t, 3N) "4.38 (S, 1H), 4.5 ( S, 1H); 4.8-5.6 (t, 4H 5.88 (wide S, 2H), 6.75 (d, 2H), 7.22 (d, 2H), 8.5-9.1 (wide S, 2H 9.4 (d, W); 9.8-10.2 (wide S, 1H
    II112223012 The activity of compounds as inhibitors not containing
    beta-lactamase cells L. 1,1-Dioxide 6-6eta- {oxymethyl) penitsish1anoic acid
    (in the form of calcium salt).
    B. 1,1-Dioxide of penicillanic acid (in the form of sodium salt).
    Table
    Continuation of table 1
    Penicillin G (33 IUM)
    Pre-incubation
    The values of Ml C mixtures of ampicillin and beta-lactamase inhibitors in the ratio of 1: 1
    C. 1,1-Dioxide 6-beta- (oikimetsh1) penicillan
    acid (sodium salt) D. 1,1-dioxide penicillanic acid (sodium
    salt)
    E. Ampicillin: Staph. aureus 100 0.2 NT 01A005 Staph. aureus 3.12 PS 01A400 Esch, coli 3.12 N 51A266 Citrobacter diversus 12.5 PS 70C031 Esch. coI-i-R 200 100 51A129 Ps.aerugin. 200 100 52A104 Q1.rveit, 53A079
    66 16.5
    77.0 52.0 1.0 11.4 66 16.5
    ABOUT
    About 1.0
    About 26 66
    Table 2 NT 200 200 200 25 50 12.5 -200 100
    1122230
    15
    Proteus morgani
    synergism}
    sum of effect
    lack of effect
    antagonism,
    no tests were performed.
    16 Continuation of table 2
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING PENICILLANIC ACID DERIVATIVES OR THEIR ADDITIVE SALTS WITH ACIDS.
    or their addition salts with acids, characterized in that the 1,1-dioxo and penicillanic acid iodomethyl ester of the formula II ° O z CH 3 ~ CO-CH 2 'J
    II o, they are reacted with a salt of a penicillanic acid derivative of the formula Ill (57) A method for producing penicillanic acid derivatives of the formula I. a radical of the formula in D form, phenyl) acetamido group,
    CH— CONH I where Y is a hydrogen atom or an oxy group;
    Z is an azido or benzyloxycarbonylamino group;
    M - tetrabutylammonium, the irradiated compound is subjected to hydrogenolysis and the target product is isolated in the form of a free base or in the form of its addition salt with an acid.
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    同族专利:
    公开号 | 公开日
    YU61882A|1985-03-20|
    PT74624A|1982-04-01|
    DE3261898D1|1985-02-28|
    IE820656L|1982-09-23|
    HU186487B|1985-08-28|
    IE52812B1|1988-03-16|
    JPS6325593B2|1988-05-26|
    AU8176182A|1982-11-04|
    DK126982A|1982-09-24|
    KR830009110A|1983-12-17|
    GR76107B|1984-08-03|
    NZ200068A|1985-08-16|
    CS228921B2|1984-05-14|
    DD203723A5|1983-11-02|
    AT11291T|1985-02-15|
    FI74285B|1987-09-30|
    PT74624B|1984-11-26|
    EP0061313A3|1982-12-08|
    AU527895B2|1983-03-31|
    KR860000425B1|1986-04-19|
    PL130110B1|1984-07-31|
    PL235576A1|1983-03-14|
    JPS57169492A|1982-10-19|
    ES8305769A1|1983-04-16|
    PH18040A|1985-03-08|
    GT198274394A|1983-09-08|
    ZA821901B|1983-01-26|
    IL65306A|1986-02-28|
    CA1201709A|1986-03-11|
    US4342768A|1982-08-03|
    FI820992L|1982-09-24|
    FI74285C|1988-01-11|
    EP0061313B1|1985-01-16|
    NO820897L|1982-09-24|
    EP0061313A2|1982-09-29|
    IL65306D0|1982-05-31|
    ES510656A0|1983-04-16|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4207323A|1975-11-21|1980-06-10|Merck & Co., Inc.|6-Substituted methyl penicillins, derivatives and analogues thereof|
    IE49881B1|1979-02-13|1986-01-08|Leo Pharm Prod Ltd|B-lactam intermediates|
    US4244951A|1979-05-16|1981-01-13|Pfizer Inc.|Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide|AU559689B2|1981-09-22|1987-03-19|Kureha Kagaku Kogyo K.K.|Penicillin derivative|
    EP0084730A1|1982-01-22|1983-08-03|Beecham Group Plc|Esters of penicillin derivatives with beta-lactamase inhibitors, their preparation and their use|
    FR2520362B1|1982-01-26|1986-04-11|Leo Pharm Prod Ltd|NOVEL B-LACTAM TYPE COMPOUNDS, INCLUDING THEIR SALTS FORMED WITH ACIDS OR BASES ACCEPTABLE IN PHARMACY, METHODS FOR PRODUCING THE SAME, DRUGS CONTAINING THEM AND THEIR USE FOR COMBATING INFECTIOUS DISEASES|
    US4452796A|1982-06-14|1984-06-05|Pfizer Inc.|6-Aminoalkylpenicillanic acid 1,1-dioxides as beta-lactamase inhibitors|
    US4462934A|1983-03-31|1984-07-31|Pfizer Inc.|Bis-esters of dicarboxylic acids with amoxicillin and certain hydroxymethylpenicillanate 1,1-dioxides|
    US4536393A|1983-06-06|1985-08-20|Pfizer Inc.|6-penicillanic acid 1,1-dioxide esters and intermediates therefor|
    US4503040A|1984-02-27|1985-03-05|Pfizer Inc.|6-penicillanic acid 1,1-dioxides as beta-lactamase inhibitors|
    US4591459A|1984-12-03|1986-05-27|Pfizer Inc.|Intermediates for 6- penicillanic acid 1,1-dioxides|
    US4762921A|1985-04-18|1988-08-09|Pfizer Inc.|6-penicillanic acid derivatives|
    US4675186A|1985-04-18|1987-06-23|Pfizer Inc.|6-penicillanic acid derivatives|
    JPS63144296U|1987-03-12|1988-09-22|
    CN108107120B|2017-12-12|2020-12-01|山东鑫泉医药有限公司|Method for measuring intermediate product 6, 6-dibromo penicillanic acid by adopting high performance liquid chromatography|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/246,505|US4342768A|1979-10-22|1981-03-23|Bis-esters of 1,1-alkanediols with 6-beta-hydroxymethylpenicillanic acid 1,1-dioxide and beta-lactam antibiotics|
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