• 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:
    Beta-lactamase inhibiting 2-beta-substituted-2-alphamethyl-(5R)penam-3-alpha-carboxylic acid 1,1-dioxides and esters thereof, wherein the 2-beta-substituent is cyano, acetyl, alkoxycarbonyl, omegahydroxyalkoxycarbonyl, car- balkoxymethoxycarbonyl or dialkylaminocarbonyl; intermediates therefor wherein the 2-beta-substituent is carboxy, chlorocarbonyl or aminocarbonyl; methods for their preparation and use as beta-lactamase inhibitors.
    公开号:SU1272995A3
    申请号:SU823494115
    申请日:1982-09-13
    公开日:1986-11-23
    发明作者:Эрнест Барт Вайн
    申请人:Пфайзер,Инк.(Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new penicillin derivatives, namely ester 1 ,, 1-dioxide-2cy; methyl methyl-2j; a: - dicarboxylic acid, which possess. property to enhance the effectiveness of the action of penicillin and cephalosporin antibiotics. The purpose of the invention is to obtain new compounds that increase the effectiveness of antibiotics of the penicillus and cephalosporin series. The infrared absorption spectra are measured on potassium bromide disks (KBr disks), and the characteristic absorption bands are indicated in wave numbers. Nuclear Magnetic Resonance (NMR) spectra were measured at 60 MHz for solutions in chloroform / deuteriovine (CDClp or perdaterium dimethylsulfoxide (DMSO), and peak positions are expressed in parts per million descending fields from tetramethylsilane. Example 1. Benzyl ether 1, 1 -dioxide-2p-carboxy-2 {s-methyl-; (5K) Ccx, carboxylic acid foams. Potassium permanganate powder (17.96 g) is added portionwise to a solution of 2 | -oxymethyl 2o benzyl ester (, methyl- (5K) foam-3C |, carbonic acid (5.82 g) in acetone (100 ml) - water (60 ml), cooled to 0–5 ° C in an ice bath. adding each portion of permanganate, the apparent pI value of the mixture is adjusted to 3.0 by adding 25% phosphoric acid. The mixture is stirred for 30 minutes at about -5 ° C after the addition of permantanate is complete and the cooling bath is removed. keeping it at a value of 3.0. The mixture is stirred for another 50 hours and then poured into a mixture of water (800 ml) and ethyl acetate (300 ml). The mixture is cooled to 15 seconds and the sodium bisulfite solution is added at pH 2 5 until a brown manganese dioxide precipitate is dissolved. The pH is then adjusted to 1.6 with 2 H.HC1. The ethyl acetate phase is removed and the aqueous phase is extracted with additional ethyl acetate (300 ml). The ethyl acetate phases are mixed, washed with brine (2x100 ml) and dried (Na S (p. Evaporation under reduced pressure (as1Pfator) and 5 g) resinous solid, which is taken up in a mixture of ethyl acetate (50 ml) and water (25 ml) and the pH value is adjusted to 8.5 with 5% aqueous NaOH. The phases are separated and the aqueous phase is extracted once more with ethyl acetate (25 ml). The pH of the aqueous phase is adjusted to 1.6 with 2 and .HCl and then extracted with ethyl acetate (50 ppm). The ethyl acetate extract is washed with brine (2 x 20 ml), dried () and evaporated under vacuum to give 2.1 g of the title product in the form of a solid: recrystallization; 1 conversion from a mixture of ethyl acetate and ether gives an analytical sample: mp 122-124 ° C. (decomposition) Found: C 50.82; H 4.35; N 3.99. C ,,, 5 Calculated,%: C 50.98; H 28; N 3.96. H1 (CDClj + DMSO - dg), S: 1.58 (3H, S); 3.48 (2H, m); 4 , 84 (1H, dd, 2.4 Hz); 5.22 (2H, S); 5.46 (IH, S); 7.33 (5H, S). P p and M ep 2, Benzyl ester 1 , 1-dioxide-2 | 3-chlorocarbonyl-2 with-methyl- (5K) -penam-3o (, -carboxylic acid. Oxashil chloride (0.37 ml) is added with stirring to a solution of benzyl ester 1, 1-dioxide-2 / -carboxy-2o (-methyl- (5R) -penam-Zob-carboxylic acid (1.25 g) in chloroform (12 ml) at C ° C under nitrogen atmosphere. Immediately add diisopropylethylamine (0.68 ml) in one portion. The resulting brown foamy mixture is then heated to 50 ° C in a water bath and stirred for 30 minutes. thus, the crude acid chloride is used without further purification. NMR (CDC1,), 5: 1.70 (3H, S); 3.57 (2H, m); 4.78 (18 dd, I 2.4 Hz); 5.23 (2H, AB q, I 12 Hz); 5.47 (1H, S); 7.34 (5H, S). 1,1-Dioxide-2/3-carbomethoxy-2ob-methyl- (5E) -penam-Zo benzyl ester (.- carboxylic acid. Pyridine (10 drops) and methanol (8 drops) are added to O, 1 mmol benzyl 1,1-dioxide-2/3-chlorocarbonyl-2 (-methyl- (5K) -penam-3-carboxylic acid ester (product of example 2) under nitrogen atmosphere with cooling on an ice bath and the mixture is stirred for 90 minutes. It is then partitioned between ethyl acetate (20 ml) and water (20 ml) and the pH is adjusted to 3.0. The ethyl acetate layer was separated, washed with water (10 ml) at pH 3.0, then brine (20 ml), then dried (). Removal of ethyl acetate under vacuum gave 35 kg of the title product. It is purified by thin-layer chromatography on silica gel using a mixture of 2: 1 hexane and ethyl acetate as the eluant. Rf 0.25. NMR (CDCl,), 8: 1.52 (3H, S); 3.50 (2H, m); 3.86 (3H, S); 4.63 (1H, m); 5.22 (2H, S); 5.54 (1H, S); 7.37 (5H, S). P p and M e p 4. 1,1-Dioxide-2j3-carbomethoxy-2Y-metsh1- (5K) -penam-Zo-carboxylic acid. A solution of benzyl ester 1,1-dioxide-2y-carbomethoxy-2bb-methyl- (5E) -penam-Zo6-carboxylic acid (44 mg) in methanol (20 ml) and water (5 ml) is subjected to hydrogenolysis in a Paar apparatus over 10 % palladiro. coal (200 mg) at a hydrogen pressure of 3.52 kg / cm for 20 minutes at room temperature. The catalyst is removed by filtration and washed with a mixture of methanol and water. The filtrate is vacuum-washed to remove the methanol and the aqueous residue is extracted with ethyl acetate at a pH of 1.6 (2 x 20 ml). The mixed ethyl acetate extracts are dried (NajS04) and evaporated under vacuum to give a semi, cit, glassy residue. The product slowly crystallizes from deuterochloroform. NMR (CDci,), 1.75 (3H, S); 3.53 (2H, m); 3.90 (3H, S); 4.68 (1H, 5.49 (1H, S). P p and M ep 5. Benzyl ester 1,1-dioxide-2 | -carbethoxy-2o, -methyl- (5K) -penam-3 (4- carboxylic acid. Pyridine (0.091 ml) and ethanol (0.065 ml) are added to 0.283 mmol of benzyl ester 1,1-dioxyd-2-chloroparbonyl-2-i-methyl-5R) -penes-C C-carboxylic acid (obtained by Example 2, but using CHClCl2 as solvent instead of chloroform) in ethyl chloride (3 ml) under nitrogen at 0 ° C, the mixture is stirred for 30 minutes, then it is warmed to room temperature and the methylene chloride is removed under vacuum. partitioned between ethyl acetate ( 15 mp) and water (15 ml) at pH 3.0. The ethyl acetate phase is separated and washed with successive water (15 ml) at pH 3, 0 with water (10 ml) without adjusting the pH value, water (15 ml) at pH 8, 5 brine (15 ml) and dried (). Evaporation of ethyl acetate under vacuum gives 1bbmg product in the form of oil. NMR (CDC1), S: 1.26 (3H, t, I 7 Hz); 1.54 (3H, S) ; 3.49 (2fi, m); 4.31 (2H, q, 1 7 Hz); 4.58 (1H, in); 5.17 (2H, Abq); 5.48 (1H, S); 7.30 (5H, S). P p and M e p 6. 1,1-DIOXID-2 / 5-. -carbethoxy-2o -methyl- (5H) -penam-3c -carboxylic acid. A mixture of benzyl ester 1,1-diksid-2p-carbethoxy-2c-methyl- (5H) -penam-Craw carboxylic acid (160 mg)., Tetrahydrofuran (25 ml) water (Jucp) and 5% Pd / CaCOj (300 mg) is subjected to the Paar apparatus hydrogenolysis at hydrogen pressures of 3.37 kg / cm for 15 minutes at room temperature. The catalyst was then removed by filtration and washed with a mixture of tetrahydrofuran (15 ml) and water (6 ml). The filtrate is evaporated under vacuum to remove the tetrahydrofuran. Ether (20 ml) is added to a water residue (pH 7.8), the mixture is thoroughly stirred, the mixture is added and the phases are separated. The aqueous phase is acidified to pH 1.6 (2 and. HCl) and extracted with ethyl acetate (30 ml). The extract is dried () and evaporated under vacuum to a clear amorphous residue. The residue is taken up in ethyl acetate (5 ml) and evaporated under vacuum. This stage is repeated once more. To remove traces of ethyl acetate, chloroform (5 ml) is added to the residue, and then it is removed by vacuum melting. The addition and removal of chloroform is repeated once more to obtain 100 mg of the title product as a clear amorphous mass (glass). NMR (CDCl,), 1.33 (3H, t, I 7 Hz); 1.74 (3H, S); 3.50 (2H, m); 4.34 (2H, q, I 7 / Hz); 4.65 (1H, S); 5.48 (1H, S). The catalyst was removed by filtration, rinsed with tetrahydrofuran (20 ml) and water (10 ml), the mixed filtrate and washing were evaporated under vacuum to remove most of the tetrahydrofuran, leaving an aqueous solution. Ethyl acetate (20 ml) was added to the aqueous residue and the pH was adjusted to 8.0, the phases were mixed and then separated. Fresh ethyl acetate (20 ml) was added to the aqueous phase and the pH was adjusted to 1-6. After thorough mixing, the ethyl acetate phase is separated, washed with brine (10 ml) and dried (Na 2 SO 4). The ethyl acetate is evaporated under vacuum and chloroform (5 ml) is added to the residue. Charged chloroform under vacuum to obtain 15 mg of the title product in the form of glass, which crystallizes on standing. NMR (acetone-bb), 5: 1.74 (3H, S); 1.90 (3H, S); 3.58 (4H, m); 4.32 (2H, t, I 5.6 Hz); 4.68 (2H, broad); 4.97 (W, dd, I 2.4 Hz); 5.47 (1H, S). Example 7 Benzyl ester 1,1-dioxide-2p- (2-hydroxyethoxycarbonyl) -2 "-methyl - (5K) -Cy-carbonic acid foam. A solution of 1,1-dioxide-2p-chlorocabonyl-2 benzyl ester (C6-methyl- (5K) -penam-3'-carboxylic acid (0.53 mmol) in chloroform (2.5 ml) is added with good stirring to a solution of ethylene glycol (1.1 ml) and pyridine (0.3 ml) in methylene chloride (3 ml) at O ° under nitrogen atmosphere. The mixture was alternated for 1 hour at O ° and then allowed to warm to room temperature. the mixture is added with ethyl acetate (20 ml and water (10 ml), the pH is adjusted to 2.5 by the addition of 2N phosphoric acid, and the mixture is thoroughly mixed. The phases are separated and the ethyl acetate phase is washed They are washed with water (10 ml) at a pH of 2.5. Then it is separated, washed with water (4x10 ml), brine (15 ml) and dried (). Evaporation under vacuum gives 0.192 g of the title product as an oil. NMR (CDCl ,), S: 1.53 (3H, S); 2.94 (1H, broad S); 3.50 (2H, t); 3.76 (2H, t); 4.33 (2H, t) ; 4.66 (1H, t); 5.21 (2H, S); 5.52 (1H, S); 7.35 (5H, S). 5 "Grmera 8. 1, 1 -Dioxide-2 - (2-hydroxyethoxycarbon1) -2o -methyl- (5K) -penam-3 ": - carboxylic acid Benzyl ester 1.1-dioxide-2p (2-hydroxyethoxycarbonyl) -29 -methyl- (5K) - foams-3-6 carboxylic acid (192 mg) is subjected to hydrogenolysis in tetrahydrofuran (30 ml) and water (5 ml) over 10% Pd / C (300 mg) at a hydrogen pressure of 3.37 kg / cm When room temperature Paar apparatus for 20 min. The catalyst was removed by filtration, washed with a mixture of ethyl acetate (30 ml) and water (10 mp) and the mixed filtrate and washing solution were cooled in an ice bath. The pH is adjusted to 1.6, the phases are mixed and then separated. The aqueous phase is extracted with ethyl acetate (30 ml) and mixed; the ethyl acetate extracts are washed with brine (20 ml) and then dried (). Evaporation under vacuum gives the title product (120 mg). In a form of NMR glass (acetone-d JS: 1.79 (3H, S); 3.36 (1H, dd, 17 Hz); 3.77 (1H, dd , I 4.17 Hz); 3.80 (2H, t, I 5 Hz); 4.35 (2H, H, I 5 Hz); 4, 98 (1H, dd, I 2.4 Hz); 5 , 46 (1H, S); 6.93 (2H, broad). EXAMPLE 9 Benzyl ester 1 e 1-dioxide-2 | 3- (2-carbomethoxycarboyl) -24; -methyl- (5R a) -penam-3-carboxylic acid: A solution of pyridine (0.3 ml) and glycolic acid methyl ester (0.391 ml) in methylene chloride (1 ml) is added to a solution of 1,1-dioxide-2p-benzyl ether chloroparbonyl-2ol: -methyl- (5R) -penes-Zot-carboxylic acid (0.53 mmol) in deuterochloroform (product of example 2) at O C under nitrogen atmosphere. The mixture was stirred at 0 ° C for 1 Xr and then at room temperature for 1 h. The reaction mixture was worked up as in Example 9 to obtain 256 mg of the title compound as an oil. NMR ( CDC1 ,,), J: 1.63 (3N, S); 3.49 (2N.t): 3.73 (3H, S); 4.70 (3H, m); 5.21 (, S) ; 5.53 (1H, S); 7.32 (5H, S). Example 10. 1,1-Dioxide-2 - (2-carbomethoxymethoxycarbonyl) -2o, -methyl- (5K) -penam-ZY-carbol acid. Following the procedure of Example 10, but using a mixture of acetone and water (5: 1) as a solvent and 400 mg of 10%
    Pd / C, from benzyl ester 1,1-dioxide-2B- (2-carbomethoxymethoxycarbonkl) - o6-methyl- (5K) -penam-Zl-carboxylic acid, gives the title compound (130 mg).
    NMR (CDC1) 8: 1.82 (3N, S); 3.55 (2H, t); 3.80 (3N, S); 4.84 (ЗН, t); 5.50 (1H, S).
    C, oeittiHje (I) (formula (1), where RJ RJ, H) in combination with 729958.
    picicillin or cephaeolin, taken in equal mass amounts, significantly enhances the antibacterial activity of ampicillin or cephaeoli5 against some pathogenic microorganisms,
    The table shows the results of tests of mixtures in comparison with the activity of ampicillin and cefazolin against the same microorganisms.
    Note. CS - significant synergism; With effect, synergism; O - absence
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING COMPLEX
    ETHERS 1,1-DIOXIDE-2o6-METHYLPENAM-2 β, Goiter-DICAR BONIC ACID of the general formula
    JV ^ COORi υ 'COOR 2 is reacted with oxalic acid chloran hydride in an inert solvent at C C, the resulting compound of the formula where R ( is lower alkyl, 2-hydroxyethyl or carbomethoxymethyl;
    R 2 is a hydrogen atom or benzyl, characterized in that the compound of the formula '0 h. 0
    S ^ coct (ιν ' υ хосн 2 с б н 5 ✓θ, s. Снрн υ * сосн 2 СНН 5 is reacted with the corresponding alcohol in an inert solvent in the presence of pyridine at С С and the target product of the general formula (1) is isolated, where R z is benzyl, or it is transferred to the target product, where R z is a hydrogen atom, by catalytic hydrogenolysis.
    SU.U, 1272995 AZ
    1 272995
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    同族专利:
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    ES515649A0|1983-09-16|
    EP0074783A1|1983-03-23|
    AU532401B2|1983-09-29|
    DE3265082D1|1985-09-05|
    PT75548B|1985-12-09|
    ZA826687B|1983-07-27|
    YU205182A|1985-03-20|
    GR76726B|1984-08-30|
    PH19442A|1986-04-18|
    IN159366B|1987-05-09|
    JPS6153354B2|1986-11-17|
    AU8833982A|1983-03-24|
    DK407882A|1983-03-15|
    CA1212378A|1986-10-07|
    NZ201895A|1985-03-20|
    PL139272B1|1987-01-31|
    PT75548A|1982-10-01|
    FI823165A0|1982-09-13|
    KR860001361B1|1986-09-16|
    AT14585T|1985-08-15|
    PL238200A1|1985-02-13|
    EP0074783B1|1985-07-31|
    IE822232L|1983-03-14|
    NO823093L|1983-03-15|
    FI823165L|1983-03-15|
    JPS5859990A|1983-04-09|
    IL66776A|1985-07-31|
    US4356174A|1982-10-26|
    HU186575B|1985-08-28|
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    引用文献:
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    GB1541832A|1976-02-11|1979-03-07|Beecham Group Ltd|2-substituted penam derivatives methods for their preparation and compisitions containing them|
    US4234579A|1977-06-07|1980-11-18|Pfizer Inc.|Penicillanic acid 1,1-dioxides as β-lactamase inhibitors|
    US4241050A|1978-09-01|1980-12-23|Pfizer Inc.|Penam 1,1-dioxides as beta-lactamase inhibitors|
    US4244951A|1979-05-16|1981-01-13|Pfizer Inc.|Bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide|
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    IL61880A|1980-01-21|1984-11-30|Bristol Myers Co|2beta-chloromethyl-2alpha-methylpenam-3alpha-carboxylic acid sulfone derivatives,their preparation and pharmaceutical compositions containing them|US4760058A|1984-08-29|1988-07-26|Farmitalia Carlo Erba S.P.A.|Penam derivatives|
    US4861768A|1986-02-27|1989-08-29|Taiho Pharmaceutical Company, Limited|2 β-substituted thiomethylpenicillin derivatives and their preparation and use|
    TW383308B|1993-08-24|2000-03-01|Hoffmann La Roche|2-beta-alkenyl penam sulfones as beta-lactamase inhibitors|
    CA2282461C|1997-12-29|2004-04-20|John D. Buynak|2-.beta.-substituted-6-alkylidene penicillanic acid derivatives as .beta.-lactamase inhibitors|
    US6407091B1|1999-04-15|2002-06-18|Research Corporation Technologies, Inc.|β-lactamase inhibiting compounds|
    DE60214740T2|2001-07-24|2007-10-04|Southern Methodist University Foundation for Research, Dallas|3-SUBSTITUTED 7-ALKYLIDENE-3-CEPHEM-4-CARBOXYLIC ACIDS AS BETA-LACTAMASE INHIBITORS|
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    KR100796131B1|2005-04-06|2008-01-21|후지쯔 가부시끼가이샤|Portable electronic device|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US06/301,995|US4356174A|1981-09-14|1981-09-14|Beta-lactamase inhibiting 2-beta-substituted-2-alpha-methyl-penam-3-alpha-carboxylic acid 1,1-dioxides and intermediates therefor|
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